Topic: Basic Research

Abstract

Echocardiographic Features of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction.

Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
Background
The PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction) trial tested the efficacy of sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Existing data on cardiac structure and function in patients with HFpEF suggest significant heterogeneity.
Objectives
The aim of this study was to characterize cardiac structure and function, quantify their associations with clinical outcomes, and contextualize these findings with other HFpEF studies.
Methods
Echocardiography was performed in 1,097 of 4,822 PARAGON-HF patients within 6 months of enrollment. Associations with incident first heart failure hospitalization or cardiovascular death were assessed using Cox proportional hazards models adjusted for age, sex, region of enrollment, randomized treatment, N-terminal pro-brain natriuretic peptide, and clinical risk factors.
Results
Average age was 74 ± 8 years, 53% of patients were women, median N-terminal pro-brain natriuretic peptide level was 918 pg/ml (interquartile range: 485 to 1,578 pg/ml), 94% had hypertension, and 35% had atrial fibrillation. The mean left ventricular (LV) ejection fraction was 58.6 ± 9.8%, prevalence of LV hypertrophy was 21%, prevalence of left atrial enlargement was 83%, prevalence of elevated E/e\' ratio was 53%, and prevalence of pulmonary hypertension was 31%. Heart failure hospitalization or cardiovascular death occurred in 288 patients at 2.8-year median follow-up. In fully adjusted models, higher LV mass index (hazard ratio [HR]: 1.05 per 10 g/m; 95% confidence interval [CI]: 1.00 to 1.10; p = 0.03), E/e\' ratio (HR: 1.04 per unit; 95% CI: 1.02 to 1.06; p < 0.001), pulmonary artery systolic pressure (HR: 1.51 per 10 mm Hg; 95% CI: 1.29 to 1.76; p < 0.001), and right ventricular end-diastolic area (HR: 1.04 per cm; 95% CI: 1.01 to 1.07; p = 0.003) were each associated with this composite, while LV ejection fraction and left atrial size were not (p > 0.05 for all). Appreciable differences were observed in cardiac structure compared with other HFpEF clinical trials, despite similar E/e\' ratio, pulmonary artery systolic pressure, and event rates.
Conclusions
Diastolic dysfunction, left atrial enlargement, and pulmonary hypertension were common in PARAGON-HF. LV hypertrophy, elevated left- and right-sided pressures, and right ventricular enlargement were independently predictive of incident heart failure hospitalization or cardiovascular death. Echocardiographic differences among HFpEF trials despite similar clinical event rates highlight the heterogeneity of this syndrome. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873
Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873 | PMID: 31806129
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Abstract

Incident Heart Failure and Long-Term Risk for Venous Thromboembolism.

Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
Background
Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown.
Objectives
In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed.
Methods
During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE.
Results
Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE.
Conclusions
In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Jan 2020; 75:148-158
Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
J Am Coll Cardiol: 20 Jan 2020; 75:148-158 | PMID: 31948643
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Abstract

Utilization and Outcomes of Measuring Fractional Flow Reserve in Patients With Stable Ischemic Heart Disease.

Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
Background
The use and clinical outcomes of fractional flow reserve (FFR) measurement in patients with stable ischemic heart disease (SIHD) are uncertain, as prior studies have been based on selected populations.
Objectives
This study sought to evaluate contemporary, real-world patterns of FFR use and its effect on outcomes among unselected patients with SIHD and angiographically intermediate stenoses.
Methods
The authors used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) Program to analyze patients who underwent coronary angiography between January 1, 2009, and September 30, 2017, and had SIHD with angiographically intermediate disease (40% to 69% diameter stenosis on visual inspection). The authors documented trends in FFR utilization and evaluated predictors using generalized mixed models. They applied Cox proportional hazards models to determine the association between an FFR-guided revascularization strategy and all-cause mortality at 1 year.
Results
A total of 17,989 patients at 66 sites were included. The rate of FFR use gradually increased from 14.8% to 18.5% among all patients with intermediate lesions, and from 44% to 75% among patients who underwent percutaneous coronary intervention. One-year mortality was 2.8% in the FFR group and 5.9% in the angiography-only group (p < 0.0001). After adjustment for patient, site-level, and procedural factors, FFR-guided revascularization was associated with a 43% lower risk of mortality at 1 year compared with angiography-only revascularization (hazard ratio: 0.57; 95% confidence interval: 0.45 to 0.71; p < 0.0001).
Conclusions
In patients with SIHD and angiographically intermediate stenoses, use of FFR has slowly risen, and was associated with significantly lower 1-year mortality.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:409-419
Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
J Am Coll Cardiol: 03 Feb 2020; 75:409-419 | PMID: 32000953
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Abstract

The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade.

Kalla M, Hao G, Tapoulal N, Tomek J, ... Paterson DJ, Herring N
Aims
ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors.
Methods and results
In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P < 0.05) higher venous NPY levels despite the absence of classical risk factors including late presentation, larger infarct size, and beta-blocker usage. Receiver operating curve identified an NPY threshold of 27.3 pg/mL with a sensitivity of 0.83 and a specificity of 0.71. RT-qPCR demonstrated the presence of NPY mRNA in both human and rat stellate ganglia. In the isolated Langendorff perfused rat heart, prolonged (10 Hz, 2 min) stimulation of the stellate ganglia caused significant NPY release. Despite maximal beta-blockade with metoprolol (10 μmol/L), optical mapping of ventricular voltage and calcium (using RH237 and Rhod2) demonstrated an increase in magnitude and shortening in duration of the calcium transient and a significant lowering of ventricular fibrillation threshold. These effects were prevented by the Y1 receptor antagonist BIBO3304 (1 μmol/L). Neuropeptide Y (250 nmol/L) significantly increased the incidence of VT/VF (60% vs. 10%) during experimental ST-elevation ischaemia and reperfusion compared to control, and this could also be prevented by BIBO3304.
Conclusions
The co-transmitter NPY is released during sympathetic stimulation and acts as a novel arrhythmic trigger. Drugs inhibiting the Y1 receptor work synergistically with beta-blockade as a new anti-arrhythmic therapy.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 12 Dec 2019; epub ahead of print
Kalla M, Hao G, Tapoulal N, Tomek J, ... Paterson DJ, Herring N
Eur Heart J: 12 Dec 2019; epub ahead of print | PMID: 31834357
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Abstract

Risk Factors for Infections Involving Cardiac Implanted Electronic Devices.

Birnie DH, Wang J, Alings M, Philippon F, ... Longtin Y, Krahn AD
Background
Cardiac implantable electronic device infection is a major complication that usually requires device removal. PADIT (Prevention of Arrhythmia Device Infection Trial) was a large cluster crossover trial of conventional versus incremental antibiotics.
Objectives
This study sought to investigate independent predictors of device infection in PADIT and develop a novel infection risk score.
Methods
In brief, over 4 6-month periods, 28 centers used either conventional or incremental prophylactic antibiotic treatment in all patients. The primary outcome was hospitalization for device infection within 1 year (blinded endpoint adjudication). Multivariable logistic prediction modeling was used to identify the independent predictors and develop a risk score for device infection. The prediction models were internally validated with bootstrap methods.
Results
Device procedures were performed in 19,603 patients, and hospitalization for infection occurred in 177 (0.90%) within 1 year of follow-up. The final prediction model identified 5 independent predictors of device infection (prior procedures [P], age [A], depressed renal function [D], immunocompromised [I], and procedure type [T]) with an optimism-corrected C-statistic of 0.704 (95% confidence interval: 0.660 to 0.744). A PADIT risk score ranging from 0 to 15 points classified patients into low (0 to 4), intermediate (5 to 6) and high (≥7) risk groups with rates of hospitalization for infection of 0.51%, 1.42%, and 3.41%, respectively.
Conclusions
This study identified 5 independent predictors of device infection and developed a novel infection risk score in the largest cardiac implantable electronic device trial to date, warranting validation in an independent cohort. The 5 independent predictors in the PADIT score are readily adopted into clinical practice. (Prevention of Arrhythmia Device Infection Trial [PADIT Pilot]; NCT01002911).

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 09 Dec 2019; 74:2845-2854
Birnie DH, Wang J, Alings M, Philippon F, ... Longtin Y, Krahn AD
J Am Coll Cardiol: 09 Dec 2019; 74:2845-2854 | PMID: 31806127
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Abstract

Adipocytes promote interleukin-18 binding to its receptors during abdominal aortic aneurysm formation in mice.

Liu CL, Ren J, Wang Y, Zhang X, ... Zhang J, Shi GP
Aims
Obesity is a risk factor of abdominal aortic aneurysm (AAA). Inflammatory cytokine interleukin-18 (IL18) has two receptors: IL18 receptor (IL18r) and Na-Cl co-transporter (NCC). In human and mouse AAA lesions, IL18 colocalizes to its receptors at regions rich in adipocytes, suggesting a role of adipocytes in promoting IL18 actions in AAA development.
Methods and results
We localized both IL18r and NCC in human and mouse AAA lesions. Murine AAA development required both receptors. In mouse AAA lesions, IL18 binding to these receptors increased at regions enriched in adipocytes or adjacent to perivascular adipose tissue. 3T3-L1 adipocytes enhanced IL18 binding to macrophages, aortic smooth muscle cells (SMCs), and endothelial cells by inducing the expression of both IL18 receptors on these cells. Adipocytes also enhanced IL18r and IL18 expression from T cells and macrophages, AAA-pertinent protease expression from macrophages, and SMC apoptosis. Perivascular implantation of adipose tissue from either diet-induced obese mice or lean mice but not that from leptin-deficient ob/ob mice exacerbated AAA development in recipient mice. Further experiments established an essential role of adipocyte leptin and fatty acid-binding protein 4 (FABP4) in promoting IL18 binding to macrophages and possibly other inflammatory and vascular cells by inducing their expression of IL18, IL18r, and NCC.
Conclusion
Interleukin-18 uses both IL18r and NCC to promote AAA formation. Lesion adipocyte and perivascular adipose tissue contribute to AAA pathogenesis by releasing leptin and FABP4 that induce IL18, IL18r, and NCC expression and promote IL18 actions.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 09 Dec 2019; epub ahead of print
Liu CL, Ren J, Wang Y, Zhang X, ... Zhang J, Shi GP
Eur Heart J: 09 Dec 2019; epub ahead of print | PMID: 31821481
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Abstract

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
Background
Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves.
Objectives
This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves.
Methods
Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves.
Results
Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm vs. 15.1 ± 1.6 cm, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group.
Conclusions
In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:395-405
Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
J Am Coll Cardiol: 03 Feb 2020; 75:395-405 | PMID: 32000951
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Abstract

Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:525-538
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:525-538 | PMID: 32029136
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Abstract

Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction.

Haider N, Boscá L, Zandbergen HR, Kovacic JC, ... Ibañez B, Narula J
Background
Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content.
Objectives
This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis.
Methods
Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre);ROSA26(EYFP) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI.
Results
Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3Col1A1 cells in the heart after MI.
Conclusions
The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Dec 2019; 74:3124-3135
Haider N, Boscá L, Zandbergen HR, Kovacic JC, ... Ibañez B, Narula J
J Am Coll Cardiol: 23 Dec 2019; 74:3124-3135 | PMID: 31856969
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Abstract

A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.

George J, Rappaport M, Shimoni S, Goland S, ... Tshori S, Fassler M
Aims
Cardiac amyloidosis typically manifests as heart failure with preserved left ventricular function due to extracellular plaques comprising aggregated TTR. Despite recent success in halting disease progression with a TTR stabilizer and encouraging preliminary findings with TTR silencers, these agents are not targeting preexisting plaques. Herein, we report the development of a novel monoclonal antibody capable of attenuating experimental cardiac amyloidosis.
Methods and results
We generated an IgG1 monoclonal antibody against aggregated TTR that immunoprecipitated the protein in the sera of patients with wild-type ATTR (wtATTR) and robustly stained cardiac plaques from patients. The antibody was shown to facilitate aggregated-TTR uptake by various myeloid cells and to protect cardiomyocytes from TTR-inducible toxicity. In a novel in vivo model of wtATTR amyloidosis, the antibody enhanced the disappearance of the pyrophosphate signals attesting for a rapid amyloid deposit removal and degradation and also exhibited improved echocardiographic measures of cardiac performance. Importantly, a capture ELISA developed based on the antibody exhibited higher levels of aggregated TTR in the sera of wtATTR amyloidosis patients as compared to control patients with heart failure suggesting a potential applicability in diagnosis and pharmacodynamic guidance of dosing.
Conclusion
We developed a proprietary antibody targeting aggregated TTR that exhibits beneficial effects in a novel experimental wtATTR model and also possesses a potential diagnostic utility. The antibody could potentially be tested as a disease modifying agent in ATTR amyloidosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 21 Dec 2019; epub ahead of print
George J, Rappaport M, Shimoni S, Goland S, ... Tshori S, Fassler M
Eur Heart J: 21 Dec 2019; epub ahead of print | PMID: 31865366
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Abstract

Alcohol Abstinence in Drinkers with Atrial Fibrillation.

Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
Background
Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear.
Methods
We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week \"blanking period\") and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up.
Results
Of 140 patients who underwent randomization (85% men; mean [±SD] age, 62±9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8±7.7 to 2.1±3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4±6.9 to 13.2±6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P = 0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P = 0.01).
Conclusions
Abstinence from alcohol reduced arrhythmia recurrences in regular drinkers with atrial fibrillation. (Funded by the Government of Victoria Operational Infrastructure Support Program and others; Australian New Zealand Clinical Trials Registry number, ACTRN12616000256471.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:20-28
Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
N Engl J Med: 01 Jan 2020; 382:20-28 | PMID: 31893513
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Abstract

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
Background
Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia.
Objectives
This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype.
Methods
Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers).
Results
Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908).
Conclusions
Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:512-521
Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
J Am Coll Cardiol: 10 Feb 2020; 75:512-521 | PMID: 32029134
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Abstract

Coronary Artery Target Selection and Survival After Bilateral Internal Thoracic Artery Grafting.

Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
Background
The importance of a coronary artery, based on the myocardial mass it perfuses, is well documented, but little is known about the importance of a vessel that has been bypassed and its effect on survival in the context of bilateral internal thoracic artery (BITA) grafting.
Objectives
This study determined the effect of a dominant left anterior descending (LAD) artery and important non-LAD targets on outcomes after BITA grafting.
Methods
From January 1972 to January 2011, of 6,127 patients who underwent BITA grafting, 2,551 received 1 ITA grafted to the LAD and had an evaluable coronary angiogram. A dominant LAD was defined as one that was wrapped around the left ventricular apex. Non-LAD targets were graded based on their terminal reach toward the apex: important: >75% (n = 1,698); and less important: ≤75% (n = 853). Mean follow-up was 14 ± 8.7 years. Multivariable analysis was performed to identify risk factors for time-related mortality.
Results
A dominant LAD was present more frequently in patients with less important additional targets (51% vs. 35%; p < 0.0001). A total of 179 patients (7.0%) received a second ITA to multiple targets, 77 (43%) of which were to multiple important target vessels. Unadjusted late survival was similar regardless of degree of importance of the second ITA target-77% at 15 years (p = 0.70) for the important and less important targets, respectively. In the multivariable model, grafting the second ITA to multiple important targets was associated with better long-term survival (p = 0.005). In patients with a nondominant LAD, a second ITA grafted to a less important artery was associated with higher risk of operative mortality (2.4% vs. 0.51%; p = 0.007). A saphenous vein graft to an important or less important target did not influence long-term survival.
Conclusions
In BITA grafting, bypassing multiple important targets to maximize myocardium supplied by ITAs improved long-term survival. In patients with a nondominant LAD, selecting an important target for the second ITA lowered operative mortality.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:258-268
Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
J Am Coll Cardiol: 27 Jan 2020; 75:258-268 | PMID: 31976863
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Abstract

Long-Term Outcomes and Associations With Major Adverse Limb Events After Peripheral Artery Revascularization.

Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
Background
Long-term cardiovascular and limb outcomes after revascularization for peripheral artery disease and, in particular, prognosis after post-procedure major adverse limb events (MALE) are not well-studied.
Objectives
This study sought to describe outcomes after peripheral revascularization and assess relationships between post-procedure MALE hospitalization and subsequent events.
Methods
Patients undergoing peripheral artery revascularization between January 1, 2009, and September 30, 2015, in the Premier Healthcare Database were examined for the co-primary outcomes of interest, composite myocardial infarction (MI) or stroke and composite major amputation or peripheral revascularization. Multivariable adjusted Cox proportional hazards models with post-procedure MALE hospitalization included as a time-dependent covariate were developed to estimate hazard ratios for outcomes.
Results
Among 393,017 revascularized patients followed for a median of 2.7 years (interquartile range: 1.3 to 4.4 years), the cumulative incidence of MI or stroke was 9.8% and that of major amputation or peripheral revascularization was 41.9%. A total of 50,750 patients (12.9%) had at least 1 post-procedure MALE hospitalization. In time-dependent covariate adjusted models, post-procedure MALE hospitalization was associated with greater risk of subsequent MI or stroke (hazard ratio: 1.34; 95% confidence interval: 1.28 to 1.40) and major amputation or peripheral revascularization (hazard ratio: 8.13; 95% confidence interval: 7.96 to 8.29). After peripheral revascularization with or without post-procedure MALE hospitalization, risk of limb events increased rapidly post-procedure and more slowly after the first year, whereas cardiac risk increased steadily during follow-up.
Conclusions
Revascularized peripheral artery disease patients face earlier limb and later cardiovascular ischemic risk that is heightened among patients with post-procedure MALE hospitalization. Increased provider awareness of these long-term risks may guide efforts to improve post-procedural outcomes.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:498-508
Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
J Am Coll Cardiol: 10 Feb 2020; 75:498-508 | PMID: 32029132
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Abstract

Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A.

Pasi KJ, Rangarajan S, Mitchell N, Lester W, ... Pierce GF, Wong WY
Background
Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ.
Methods
We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years.
Results
Three years after infusion, two participants (one who had received 6×10 vector genomes [vg] per kilogram of body weight and one who had received 2×10 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed.
Conclusions
Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 vg per kilogram or 6×10 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:29-40
Pasi KJ, Rangarajan S, Mitchell N, Lester W, ... Pierce GF, Wong WY
N Engl J Med: 01 Jan 2020; 382:29-40 | PMID: 31893514
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Abstract

A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction.

Chen S, Zhang Y, Lighthouse JK, Mickelsen DM, ... Small EM, Yan C

Heart failure is a leading cause of death worldwide. Cyclic nucleotide phosphodiesterases (PDEs), through degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. Our preliminary screening studies have revealed PDE10A upregulation in the diseased heart. However, the role of PDE10A in cardiovascular biology and disease are largely uncharacterized. The current study is aimed to investigate the regulation and function of PDE10A in cardiac cells and in the progression of cardiac remodeling and dysfunction.We used isolated adult mouse cardiac myocytes (CMs) and fibroblasts (CFs), as well as preclinical mouse models of hypertrophy and/or heart failure. The PDE10A selective inhibitor TP-10, and global PDE10A knock out mice (PDE10A-KO) were used.We found that PDE10A expression remains relatively low in normal and exercised heart tissues. However, PDE10A is significantly upregulated in mouse and human failing hearts. , PDE10A deficiency or inhibiting PDE10A with selective inhibitor TP-10, attenuated CM pathological hypertrophy induced by Angiotensin II (Ang II), phenylephrine (PE), and isoproterenol (ISO), but did not affect CM physiological hypertrophy induced by insulin-like growth factor 1 (IGF-1). TP-10 also reduced transforming growth factor-β (TGF-β)-stimulated CF activation, proliferation, migration and ECM synthesis. TP-10 treatment elevated both cAMP and cGMP levels in CM and CF, consistent with PDE10A as a cAMP/cGMP dual-specific PDE. , global PDE10A deficiency significantly attenuated myocardial hypertrophy, cardiac fibrosis, and/or dysfunction induced by chronic pressure overload via thoracic aorta constriction (TAC) or chronic neurohormonal stimulation via Ang II infusion. Importantly, we demonstrated that the pharmacological effect of TP-10 is specifically through PDE10A inhibition. In addition, TP-10 is able to reverse pre-established cardiac hypertrophy and dysfunction. RNA-Sequencing and bioinformatics analysis further identified a PDE10A-regualted transcriptome involved in cardiac hypertrophy, fibrosis, and cardiomyopathy.Taken together, our study elucidates a novel role for PDE10A in the regulation of pathological cardiac remodeling and development of heart failure. Given that PDE10A has been proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy for preventing and treating cardiac diseases associated with cardiac remodeling.



Circulation: 04 Dec 2019; epub ahead of print
Chen S, Zhang Y, Lighthouse JK, Mickelsen DM, ... Small EM, Yan C
Circulation: 04 Dec 2019; epub ahead of print | PMID: 31801360
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Abstract

Chronic infarct size after spontaneous coronary artery dissection: implications for pathophysiology and clinical management.

Al-Hussaini A, Abdelaty AMSEK, Gulsin GS, Arnold JR, ... McCann GP, Adlam D
Aims
To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury.
Methods and results
One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case-control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P <0.01) compared to healthy controls. Infarcts were small with few large infarcts (median 4.06%; range 0-30.9%) and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass].
Conclusion
The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 02 Jan 2020; epub ahead of print
Al-Hussaini A, Abdelaty AMSEK, Gulsin GS, Arnold JR, ... McCann GP, Adlam D
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898721
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Abstract

Outcomes of Women Compared With Men After Non-ST-Segment Elevation Acute Coronary Syndromes.

Sarma AA, Braunwald E, Cannon CP, Guo J, ... Sabatine MS, O\'Donoghue ML
Background
It remains disputed whether women are at excess risk of adverse outcomes versus men after non-ST-segment elevation acute coronary syndromes (NSTEACS) or whether differences are explained by discordant risk factors.
Objectives
A sex-specific analysis of cardiovascular outcomes after NSTEACS across trials conducted by the Thrombolysis In Myocardial Infarction (TIMI) Study Group was performed to determine the impact of sex on cardiovascular outcomes in this dataset.
Methods
Ten TIMI trials were identified that enrolled >2,500 patients with NSTEACS within 30 days of hospitalization. Cox proportional hazards models were used to examine the association of sex with major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, or stroke) after adjusting for relevant risk factors in individual trials; point estimates were then combined by using random effects models. Individual components of the composite outcome and all-cause mortality were also analyzed.
Results
Among 68,730 patients with NSTEACS, 19,827 (29%) were women. Women were older and more frequently had hypertension, diabetes, prior heart failure, and renal impairment than men. Before considering relevant confounders, women were at similar risk of MACE compared with men (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 0.99 to 1.09; p = 0.16) but at higher risk of all-cause death (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.03). After adjustment for baseline differences, risks of MACE (HR: 0.93; 95% CI: 0.88 to 0.98; p < 0.01) and all-cause death (HR: 0.84; 95% CI: 0.78 to 0.90; p < 0.0001) were lower among women compared with men.
Conclusions
After accounting for cardiovascular risk factors, women enrolled in clinical trials were at lower risk of MACE than men after NSTEACS. Women, however, remain undertreated with many evidence-based therapies.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Dec 2019; 74:3013-3022
Sarma AA, Braunwald E, Cannon CP, Guo J, ... Sabatine MS, O'Donoghue ML
J Am Coll Cardiol: 16 Dec 2019; 74:3013-3022 | PMID: 31865968
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Abstract

Low and elevated B-type natriuretic peptide levels are associated with increased mortality in patients with preserved ejection fraction undergoing transcatheter aortic valve replacement: an analysis of the PARTNER II trial and registry.

Chen S, Redfors B, O\'Neill BP, Clavel MA, ... Leon MB, Lindman BR
Aims
B-type natriuretic peptide (BNP) is a cardiac neurohormone that is secreted in response to ventricular volume expansion and pressure overload. There are conflicting data regarding the association between BNP levels and outcomes after transcatheter aortic valve replacement (TAVR). We therefore sought to assess the association between baseline BNP and adverse outcomes in patients with symptomatic, severe aortic stenosis (AS), and left ventricular ejection fraction (LVEF) ≥50%, undergoing TAVR in the PARTNER 2 Trial and Registry.
Methods and results
A total of 1782 patients were included in the analysis, and BNP was evaluated both as a continuous log-transformed value and by a priori categories: low (<50 pg/mL), normal (≥50 and <100 pg/mL), moderately elevated (≥100 and <400 pg/mL), or markedly elevated (≥400 pg/mL). Clinical outcomes from discharge to 2 years were compared between patients according to their baseline BNP level, using Kaplan-Meier event rates and multivariable Cox proportional hazards regression models. After adjustment, spline curves revealed a non-linear association between log-transformed BNP and all-cause and cardiovascular mortality in which both the lowest and highest values were associated with increased mortality. Two-year all-cause mortality rates for those with low (n = 86), normal (n = 202), moderately elevated (n = 885), and markedly elevated (n = 609) baseline BNP were 20.0%, 9.8%, 17.7%, and 26.1%, respectively. In adjusted models, compared to a normal baseline BNP, low [adjusted hazard ratio (HR) 2.6, 95% confidence interval (CI) 1.3-5.0, P-value 0.005], moderately elevated (adjusted HR 1.6, 95% CI 1.0-2.6, P-value 0.06), and markedly elevated (adjusted HR 2.1, 95% CI 1.3-3.5, P-value 0.003) BNP were associated with increased all-cause mortality, driven by cardiovascular mortality.
Conclusions
In a large cohort of patients with severe symptomatic AS and preserved LVEF undergoing TAVR, all-cause and cardiovascular mortality rates at 2 years were higher in patients with low and markedly elevated BNP levels.
Clinical trial registration
https://clinicaltrials.gov/ unique identifier #NCT01314313, #NCT02184442, #NCT03222128, and #NCT03222141.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 27 Dec 2019; epub ahead of print
Chen S, Redfors B, O'Neill BP, Clavel MA, ... Leon MB, Lindman BR
Eur Heart J: 27 Dec 2019; epub ahead of print | PMID: 31883339
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Abstract

Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease.

Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
Background
Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.
Objectives
The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.
Methods
Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.
Results
EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.
Conclusions
Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Feb 2020; 75:608-617
Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
J Am Coll Cardiol: 17 Feb 2020; 75:608-617 | PMID: 32057375
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Abstract

Ischemic Stroke Risk in Patients With Nonvalvular Atrial Fibrillation: JACC Review Topic of the Week.

Alkhouli M, Friedman PA

The last decade has witnessed remarkable advances in pharmacological and nonpharmacological strategies for stroke prevention in patients with atrial fibrillation. However, the currently available clinical stroke risk prediction models do not account for key nonclinical factors (arrhythmia burden, left atrial physiology and anatomy, chemical and electrocardiographic markers) and other competing clinical risks. Hence, their ability to identify patients who will derive the most benefit from pharmacological and mechanical risk prevention strategies remain limited. In this paper, the authors review the current and evolving ischemic stroke risk prediction schemes in patients with nonvalvular atrial fibrillation, highlight the strengths and weaknesses of the models, and discuss the unmet needs in this field.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Dec 2019; 74:3050-3065
Alkhouli M, Friedman PA
J Am Coll Cardiol: 16 Dec 2019; 74:3050-3065 | PMID: 31865973
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Abstract

Ambient Air Pollution and Mortality After Cardiac Transplantation.

Al-Kindi SG, Sarode A, Zullo M, Brook J, ... Brook R, Rajagopalan S
Background
Heart transplant recipients are at high risk for mortality, with traditional risk scores performing modestly in predicting post-transplant survival, underscoring the importance of as yet unidentified factors in determining prognosis. In this analysis, the association between PM exposure levels and survival after heart transplantation were investigated.
Objectives
This study sought to study the association between PM exposure and mortality following heart transplantation.
Methods
On the basis of the zip code of residence, mortality data in patients who underwent heart transplantation (2004 to 2015) in the United Network for Organ Sharing (UNOS) database were linked with validated estimates of fine particulate matter concentrations (particles with diameter <2.5 μm [PM]; 1 × 1-km grids) for each calendar year during which a UNOS cardiac transplant recipient was at risk for death. Cox proportional hazard models were used to estimate the relationship between exposure and overall mortality adjusting for recipient, donor, and neighborhood variables.
Results
A total of 21,800 patients with 86,713 patient-years of follow-up was included. Mean age at transplantation was 52.6 ± 12.6 years, 75% were male, 69% were white, and 39% had ischemic etiology of heart failure. Mean annual exposure to PM was 10.6 ± 2.3 μg/m. At a median follow-up of 4.8 (95% confidence interval: 2.0 to 7.8) years, 5,208 patients (23.9%) had died. The estimated mortality hazard ratio, per 10 μg/m increment increase in annual PM exposure was 1.43 (95% confidence interval: 1.21 to 1.49). After adjusting for 30 recipient, donor, and neighborhood variables, the estimated mortality hazard ratio per 10 μg/m increment in annual exposure to PM was 1.26 (95% confidence interval: 1.11 to 1.43) relative increase in hazard of mortality. This association was consistent across subgroups.
Conclusions
This study provides evidence linking air pollution with mortality after heart transplantation. These results suggest an important influence of a key environmental factor in outcomes following heart transplantation, and supports the need for further studies in this population.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 16 Dec 2019; 74:3026-3035
Al-Kindi SG, Sarode A, Zullo M, Brook J, ... Brook R, Rajagopalan S
J Am Coll Cardiol: 16 Dec 2019; 74:3026-3035 | PMID: 31865970
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Abstract

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

Juul SE, Comstock BA, Wadhawan R, Mayock DE, ... Heagerty PJ,
Background
High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.
Methods
In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.
Results
A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events.
Conclusions
High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jan 2020; 382:233-243
Juul SE, Comstock BA, Wadhawan R, Mayock DE, ... Heagerty PJ,
N Engl J Med: 15 Jan 2020; 382:233-243 | PMID: 31940698
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Abstract

Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis.

Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG

Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 02 Jan 2020; epub ahead of print
Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898722
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Abstract

Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.

Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Aims
To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin.
Methods and results
We conducted a real-world nationwide retrospective cohort study using Taiwan\'s National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77-0.93; P < 0.001]. Sub-analyses revealed that each NOAC, namely dabigatran (aHR = 0.88, 95% CI = 0.78-0.99; P = 0.027), rivaroxaban (aHR = 0.81, 95% CI = 0.72-0.90; P < 0.001), and apixaban (aHR = 0.67, 95% CI = 0.52-0.87; P = 0.003), had a reduced fracture risk. Analyses including all eligible patients, without propensity score matching, generated similar results.
Conclusion
Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 31 Jan 2020; epub ahead of print
Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006423
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Abstract

Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction.

Carnevale R, Sciarretta S, Valenti V, di Nonno F, ... Tanzilli G, Violi F
Aims
Low-grade endotoxaemia is detectable in human circulation but its role in thrombosis is still unclear.
Methods and results
We measured serum lipopolysaccharide (LPS) concentration, soluble P-selectin (sP-selectin), a marker of platelet activation, and zonulin, a marker of gut permeability, in peripheral circulation, coronary thrombi, and intracoronary blood of patients with ST-elevation myocardial infarction (STEMI, n = 50) and stable angina (SA) (n = 50), respectively, and in controls (n = 50). Experimental study was carried out in mice to assess if Escherichia coli-LPS (E. coli-LPS) possess thrombotic property. Coronary thrombi from STEMI showed higher concentrations of LPS, sP-selectin vs. intracoronary blood of SA and peripheral blood of controls (P < 0.001). Zonulin was higher in STEMI compared to the other two groups [4.57 (3.34-5.22); 2.56 (0.41-4.36); 1.95 (1.22-2.65) ng/mL; P < 0.001] and correlated with LPS (Rs = 0.585; P < 0.001). Escherichia coli DNA was positive in 34% of STEMI vs. 12% of SA and 4% of controls (P < 0.001). In a subgroup of 12 STEMI, immunohistochemical analysis of coronary thrombi showed positivity for leucocyte Toll-like receptor 4 (TLR4), cathepsin G, and LPS from E. coli in 100%, 80%, and 25% of samples, respectively. E. coli-LPS injected in mice to reach LPS concentrations like those detected in coronary thrombi was associated with enhanced artery thrombosis and platelet activation, an effect blunted by TLR4 inhibitor co-administration. In vitro study demonstrated that LPS from E. coli enhanced platelet aggregation via TLR4-mediated leucocyte cathepsin G activation.
Conclusion
ST-elevation myocardial infarction patients disclose an enhanced gut permeability that results in LPS translocation in human circulation and eventually thrombus growth at site of artery lesion via leucocyte-platelet interaction.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 02 Jan 2020; epub ahead of print
Carnevale R, Sciarretta S, Valenti V, di Nonno F, ... Tanzilli G, Violi F
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898723
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Impact:
Abstract

Soluble Urokinase Receptor and Acute Kidney Injury.

Hayek SS, Leaf DE, Samman Tahhan A, Raad M, ... Quyyumi AA, Reiser J
Background
Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target.
Methods
We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.
Results
The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells.
Conclusions
High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:416-426
Hayek SS, Leaf DE, Samman Tahhan A, Raad M, ... Quyyumi AA, Reiser J
N Engl J Med: 29 Jan 2020; 382:416-426 | PMID: 31995687
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Impact:
Abstract

Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.

Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, ... Nathan C, Casanova JL
Background
Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 () are susceptible to the related murine CMV infection.
Methods
We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally.
Results
We found a homozygous frameshift mutation inencoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, allvariants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001.
Conclusions
These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:437-445
Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, ... Nathan C, Casanova JL
N Engl J Med: 29 Jan 2020; 382:437-445 | PMID: 31995689
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Abstract

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

Luo W, Wang Y, Zhang L, Ren P, ... LeMaire SA, Shen YH
Background
Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation.
Methods
The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in -deficient () mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro.
Results
In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model,mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challengedmice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development.
Conclusions
Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.



Circulation: 06 Jan 2020; 141:42-66
Luo W, Wang Y, Zhang L, Ren P, ... LeMaire SA, Shen YH
Circulation: 06 Jan 2020; 141:42-66 | PMID: 31887080
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Abstract

Variation in Bystander Cardiopulmonary Resuscitation Delivery and Subsequent Survival From Out-of-Hospital Cardiac Arrest Based on Neighborhood-Level Ethnic Characteristics.

Blewer AL, Schmicker RH, Morrison LJ, Aufderheide TP, ... Abella BS,
Background
Bystander cardiopulmonary resuscitation (B-CPR) delivery and survival after out-of-hospital cardiac arrest vary at the neighborhood level, with lower survival seen in predominantly black neighborhoods. Although the Hispanic population is the fastest-growing minority population in the United States, few studies have assessed whether the proportion of Hispanic residents in a neighborhood is associated with B-CPR delivery and survival from out-of-hospital cardiac arrest. We assessed whether B-CPR rates and survival vary by neighborhood-level ethnicity. We hypothesized that neighborhoods with a higher proportion of Hispanic residents have lower B-CPR rates and lower survival.
Methods
We conducted a retrospective cohort study using data from the Resuscitation Outcomes Consortium Epistry at US sites. Neighborhoods were classified by census tract based on percentage of Hispanic residents: <25%, 25% to 50%, 51% to 75%, or >75%. We independently modeled the likelihood of receipt of B-CPR and survival by neighborhood-level ethnicity controlling for site and patient-level confounding characteristics.
Results
From 2011 to 2015, the Resuscitation Outcomes Consortium collected 27 481 US arrest events; after excluding pediatric arrests, emergency medical services-witnessed arrests, or arrests occurring in a healthcare or institutional facility, 18 927 were included. B-CPR was administered in 37% of events. In neighborhoods with <25% Hispanic residents, B-CPR was administered in 39% of events, whereas it was administered in 27% of events in neighborhoods with >75% Hispanic residents. Compared with <25% Hispanic neighborhoods in a multivariable analysis, out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods had lower B-CPR rates (51% to 75% Hispanic: odds ratio, 0.79 [CI, 0.65-0.95], =0.014; >75% Hispanic: odds ratio, 0.72 [CI, 0.55-0.96], =0.025) and lower survival rates (globalvalue 0.029; >75% Hispanic: odds ratio, 0.56 [CI, 0.34-0.93], =0.023).
Conclusions
Individuals with out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods were less likely to receive B-CPR and had lower likelihood of survival. These findings suggest a need to understand the underlying disparities in cardiopulmonary resuscitationdelivery and an unmet cardiopulmonary resuscitationtraining need in Hispanic communities.



Circulation: 06 Jan 2020; 141:34-41
Blewer AL, Schmicker RH, Morrison LJ, Aufderheide TP, ... Abella BS,
Circulation: 06 Jan 2020; 141:34-41 | PMID: 31887076
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Abstract

Machine learning-based mortality prediction of patients undergoing cardiac resynchronization therapy: the SEMMELWEIS-CRT score.

Tokodi M, Schwertner WR, Kovács A, Tősér Z, ... Merkely B, Kosztin A
Aims
Our aim was to develop a machine learning (ML)-based risk stratification system to predict 1-, 2-, 3-, 4-, and 5-year all-cause mortality from pre-implant parameters of patients undergoing cardiac resynchronization therapy (CRT).
Methods and results
Multiple ML models were trained on a retrospective database of 1510 patients undergoing CRT implantation to predict 1- to 5-year all-cause mortality. Thirty-three pre-implant clinical features were selected to train the models. The best performing model [SEMMELWEIS-CRT score (perSonalizEd assessMent of estiMatEd risk of mortaLity With machinE learnIng in patientS undergoing CRT implantation)], along with pre-existing scores (Seattle Heart Failure Model, VALID-CRT, EAARN, ScREEN, and CRT-score), was tested on an independent cohort of 158 patients. There were 805 (53%) deaths in the training cohort and 80 (51%) deaths in the test cohort during the 5-year follow-up period. Among the trained classifiers, random forest demonstrated the best performance. For the prediction of 1-, 2-, 3-, 4-, and 5-year mortality, the areas under the receiver operating characteristic curves of the SEMMELWEIS-CRT score were 0.768 (95% CI: 0.674-0.861; P < 0.001), 0.793 (95% CI: 0.718-0.867; P < 0.001), 0.785 (95% CI: 0.711-0.859; P < 0.001), 0.776 (95% CI: 0.703-0.849; P < 0.001), and 0.803 (95% CI: 0.733-0.872; P < 0.001), respectively. The discriminative ability of our model was superior to other evaluated scores.
Conclusion
The SEMMELWEIS-CRT score (available at semmelweiscrtscore.com) exhibited good discriminative capabilities for the prediction of all-cause death in CRT patients and outperformed the already existing risk scores. By capturing the non-linear association of predictors, the utilization of ML approaches may facilitate optimal candidate selection and prognostication of patients undergoing CRT implantation.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 09 Jan 2020; epub ahead of print
Tokodi M, Schwertner WR, Kovács A, Tősér Z, ... Merkely B, Kosztin A
Eur Heart J: 09 Jan 2020; epub ahead of print | PMID: 31923316
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Abstract

S-Nitrosylation of Muscle LIM Protein Facilitates Myocardial Hypertrophy Through Toll-Like Receptor 3-Mediated Receptor-Interacting Protein Kinase 3 and NLRP3 Inflammasome Activation.

Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y

S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of S-nitrosylation of muscle LIM protein (MLP) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload.Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. S-nitrosylation sites were further identified through liquid chromatography-tandem mass spectrometry (LCMS/MS). Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase (GSNOR) was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry (MS) and confirmed by co-immunoprecipitation. Recruitment of toll-like receptor 3 (TLR3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA (siRNA)-transfected neonatal rat cardiomyocytes (NRCMs) and in TLR3 knockout mouse model.SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction (TAC). The level of SNO-MLP also increased in angiotensin II (Ang II) or phenylephrine (PE)-treated NRCMs. S-nitrosylated site of MLP at cysteine (Cys) 79 was identified by LCMS/MS and further confirmed in NRCMs. Mutation of Cys79 significantly reduced hypertrophic growth in Ang II or PE-treated NRCMs and TAC mice. Reducing MLP Snitrosylation level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, MLP S-nitrosylation stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupting this interaction by downregulating TLR3 attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and receptor-interacting protein kinase 3 (RIP3). This interaction in turn induced NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting the development of myocardial hypertrophy.Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a novel therapeutic target for myocardial hypertrophy and heart failure.



Circulation: 05 Jan 2020; epub ahead of print
Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y
Circulation: 05 Jan 2020; epub ahead of print | PMID: 31902237
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Abstract

Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca Handling After Pressure Overload.

Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J

Orai1 is a critical ion channel subunit, best recognized as a mediator of storeoperated Ca entry (SOCE) in non-excitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop JPIII, a small-molecule Orai1 channel inhibitor suitable fordelivery.Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. 5 weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and pro-hypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca signaling alterations (increased SOCE, decreased [Ca]i transients amplitude and decay rate, lower SR Ca load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from CdnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult.The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.



Circulation: 06 Jan 2020; epub ahead of print
Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J
Circulation: 06 Jan 2020; epub ahead of print | PMID: 31906693
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Abstract

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis Following Myocardial Infarction.

Sreejit G, Abdel-Latif A, Athmanathan B, Annabathula R, ... Murphy AJ, Nagareddy PR

Myocardial infarction (MI) triggers myelopoiesis resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.Using a mouse model of the permanent ligation of the left anterior descending (LAD) artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of acute inflammatory response and the underlying signaling pathways. Utilizing a combination of genetic and pharmacological strategies, we identified the sequalae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indices of neutrophilia with major adverse cardiovascular events (MACE) was studied in a cohort of acute MI patients.Induction of MI resulted in a rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll Like Receptor (TLR) 4 and prime the Nod Like Receptor (NLR) family Pyrin Domain-Containing 3 (Nlrp3) inflammasome in naïve neutrophils and promote interleukin 1 (IL-1β) secretion. The released IL-1β interact with its receptor (Interleukin 1 Receptor Type 1, IL1R1) on hematopoietic stem and progenitor cells in the bone marrow (BM), and stimulate granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and its downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome (ACS), higher neutrophil count on admission and post-revascularization correlates positively with major adverse cardiovascular disease (CVD) outcomes.Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response following myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or its downstream mediators (e.g. Nlrp3, IL-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in ACS patients.



Circulation: 15 Jan 2020; epub ahead of print
Sreejit G, Abdel-Latif A, Athmanathan B, Annabathula R, ... Murphy AJ, Nagareddy PR
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941367
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Abstract

Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy.

Tan AY, Elharrif K, Cardona-Guarache R, Mankad P, ... Minisi AJ, Huizar JF
Background
The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown.
Objectives
This study aimed to characterize cardiac sympathovagal balance and proarrhythmia in a canine model of PVC-CM.
Methods
In 12 canines, the investigators implanted epicardial pacemakers and radiotelemetry units to record cardiac rhythm and nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus (VNA), and arterial blood pressure. Bigeminal PVCs (200 ms coupling) were applied for 12 weeks to induce PVC-CM in 7 animals then disabled for 4 weeks to allow complete recovery of left ventricular ejection fraction (LVEF), versus 5 sham controls.
Results
After 12 weeks of PVCs, LVEF (p = 0.006) and dP/dT (p = 0.007) decreased. Resting SNA (p = 0.002) and VNA (p = 0.04), exercise SNA (p = 0.01), SNA response to evoked PVCs (p = 0.005), heart rate (HR) at rest (p = 0.003), and exercise (p < 0.04) increased, whereas HR variability (HRV) decreased (p = 0.009). There was increased spontaneous atrial (p = 0.02) and ventricular arrhythmias (p = 0.03) in PVC-CM. Increased SNA preceded both atrial (p = 0.0003) and ventricular (p = 0.009) arrhythmia onset. Clonidine suppressed SNA and abolished all arrhythmias. After disabling PVC for 4 weeks, LVEF (p = 0.01), dP/dT (p = 0.047), and resting VNA (p = 0.03) recovered to baseline levels. However, SNA, resting HR, HRV, and atrial (p = 0.03) and ventricular (p = 0.03) proarrhythmia persisted. There was sympathetic hyperinnervation in stellate ganglia (p = 0.02) but not ventricles (p = 0.2) of PVC-CM and recovered animals versus sham controls.
Conclusions
Neural remodeling in PVC-CM is characterized by extracardiac sympathetic hyperinnervation and sympathetic neural hyperactivity that persists despite normalization of LVEF. The altered cardiac sympathovagal balance is an important trigger and substrate for atrial and ventricular proarrhythmia.

Published by Elsevier Inc.

J Am Coll Cardiol: 06 Jan 2020; 75:1-13
Tan AY, Elharrif K, Cardona-Guarache R, Mankad P, ... Minisi AJ, Huizar JF
J Am Coll Cardiol: 06 Jan 2020; 75:1-13 | PMID: 31918815
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Abstract

Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure Overloaded Hearts.

Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K

Proinflammatory cytokines play an important role in the pathogenesis of heart failure. However, the mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of the mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in non-immune cells such as cardiomyocytes remains to be elucidated.To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Furthermore, interleukin-6 (IL-6) signaling was inhibited by the administration with its receptor antibody. Finally, overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer.Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared to the control littermates. Four weeks after TAC, themRNA level was upregulated, but not other cytokine mRNAs including tumor necrosis factor-α in Regnase-1-deficient hearts. Although themRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction ofmRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9- mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice.The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.



Circulation: 13 Jan 2020; epub ahead of print
Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931613
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Abstract

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Aims
Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.
Methods and results
One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson\'s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].
Conclusion
Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 11 Feb 2020; epub ahead of print
Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049275
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Abstract

Key role for CTCF in establishing chromatin structure in human embryos.

Chen X, Ke Y, Wu K, Zhao H, ... Liu J, Chen ZJ

In the interphase of the cell cycle, chromatin is arranged in a hierarchical structure within the nucleus, which has an important role in regulating gene expression. However, the dynamics of 3D chromatin structure during human embryogenesis remains unknown. Here we report that, unlike mouse sperm, human sperm cells do not express the chromatin regulator CTCF and their chromatin does not contain topologically associating domains (TADs). Following human fertilization, TAD structure is gradually established during embryonic development. In addition, A/B compartmentalization is lost in human embryos at the 2-cell stage and is re-established during embryogenesis. Notably, blocking zygotic genome activation (ZGA) can inhibit TAD establishment in human embryos but not in mouse or Drosophila. Of note, CTCF is expressed at very low levels before ZGA, and is then highly expressed at the ZGA stage when TADs are observed. TAD organization is significantly reduced in CTCF knockdown embryos, suggesting that TAD establishment during ZGA in human embryos requires CTCF expression. Our results indicate that CTCF has a key role in the establishment of 3D chromatin structure during human embryogenesis.



Nature: 03 Dec 2019; epub ahead of print
Chen X, Ke Y, Wu K, Zhao H, ... Liu J, Chen ZJ
Nature: 03 Dec 2019; epub ahead of print | PMID: 31801998
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Abstract

Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system.

Halpin-Healy TS, Klompe SE, Sternberg SH, Fernández IS

Bacteria use adaptive immune systems encoded by CRISPR and Cas genes to maintain genomic integrity when challenged by pathogens and mobile genetic elements. Type I CRISPR-Cas systems typically target foreign DNA for degradation via joint action of the ribonucleoprotein complex Cascade and the helicase-nuclease Cas3, but nuclease-deficient type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn7-like transposons. How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion remains unknown. Here we describe structures of a TniQ-Cascade complex encoded by the Vibrio cholerae Tn6677 transposon using cryo-electron microscopy, revealing the mechanistic basis of this functional coupling. The cryo-electron microscopy maps enabled de novo modelling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3\' end of the CRISPR RNA (crRNA). The natural Cas8-Cas5 fusion protein binds the 5\' crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer-adjacent motif recognition and R-loop formation. This work lays the foundation for a structural understanding of how DNA targeting by TniQ-Cascade leads to downstream recruitment of additional transposase proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome-engineering applications.



Nature: 17 Dec 2019; epub ahead of print
Halpin-Healy TS, Klompe SE, Sternberg SH, Fernández IS
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853065
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Impact:
Abstract

c-Jun overexpression in CAR T cells induces exhaustion resistance.

Lynn RC, Weber EW, Sotillo E, Gennert D, ... Chang HY, Mackall CL

Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.



Nature: 03 Dec 2019; epub ahead of print
Lynn RC, Weber EW, Sotillo E, Gennert D, ... Chang HY, Mackall CL
Nature: 03 Dec 2019; epub ahead of print | PMID: 31802004
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Impact:
Abstract

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

Brunner FJ, Waldeyer C, Ojeda F, Salomaa V, ... Blankenberg S,
Background
The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.
Methods
In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.
Findings
Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.
Interpretation
Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies.
Funding
EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 02 Dec 2019; epub ahead of print
Brunner FJ, Waldeyer C, Ojeda F, Salomaa V, ... Blankenberg S,
Lancet: 02 Dec 2019; epub ahead of print | PMID: 31810609
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Abstract

Alfvénic velocity spikes and rotational flows in the near-Sun solar wind.

Kasper JC, Bale SD, Belcher JW, Berthomier M, ... Raouafi NE, Schwadron NA

The prediction of a supersonic solar wind was first confirmed by spacecraft near Earth and later by spacecraft at heliocentric distances as small as 62 solar radii. These missions showed that plasma accelerates as it emerges from the corona, aided by unidentified processes that transport energy outwards from the Sun before depositing it in the wind. Alfvénic fluctuations are a promising candidate for such a process because they are seen in the corona and solar wind and contain considerable energy. Magnetic tension forces the corona to co-rotate with the Sun, but any residual rotation far from the Sun reported until now has been much smaller than the amplitude of waves and deflections from interacting wind streams. Here we report observations of solar-wind plasma at heliocentric distances of about 35 solar radii, well within the distance at which stream interactions become important. We find that Alfvén waves organize into structured velocity spikes with duration of up to minutes, which are associated with propagating S-like bends in the magnetic-field lines. We detect an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second-considerably above the amplitude of the waves. These flows exceed classical velocity predictions of a few kilometres per second, challenging models of circulation in the corona and calling into question our understanding of how stars lose angular momentum and spin down as they age.



Nature: 03 Dec 2019; epub ahead of print
Kasper JC, Bale SD, Belcher JW, Berthomier M, ... Raouafi NE, Schwadron NA
Nature: 03 Dec 2019; epub ahead of print | PMID: 31802006
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Abstract

DP1 Activation Reverses Age-Related Hypertension via NEDD4L-Mediated T-bet Degradation in T Cells.

Kong D, Wan Q, Li J, Zuo S, ... Breyer RM, Yu Y

Blood pressure (BP) often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of pro-inflammatory cytokines increases in T lymphocyte. Prostaglandin (PG) D, a pro-resolution mediator, suppresses Th1 cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of PGD/DP1 axis in T cells on age-related hypertension.To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants and CD4 T cells were sorted for gene expression, PG production and western bot assays. Mice BP was quantified by invasive telemetric monitor.PGD/DP1 axis was down-regulated in CD4 T cells from older humans and aged mice, DP1 deletion in CD4+ T cells (TDP1KO) augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling and CD4 T cells infiltration, superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. TNFα neutralization or IFNγ deletion ameliorated the age-related hypertension in TDP1KO mice. Mechanistically, DP1 inhibited Th1 activity via the Gαs/PKA/p-Sp1/NEDD4L pathway-mediated T-bet ubiquitination. T-bet deletion or forced NEDD4L expression in CD4 T cell attenuated age-related hypertension in TDP1KO mice. DP1 receptor activation by BW245C prevented age-associated BP elevation and reduced vascular/renal superoxide production in male mice.PGD/DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension in males.



Circulation: 01 Jan 2020; epub ahead of print
Kong D, Wan Q, Li J, Zuo S, ... Breyer RM, Yu Y
Circulation: 01 Jan 2020; epub ahead of print | PMID: 31893939
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Abstract

Frontal cortex neuron types categorically encode single decision variables.

Hirokawa J, Vaughan A, Masset P, Ott T, Kepecs A

Individual neurons in many cortical regions have been found to encode specific, identifiable features of the environment or body that pertain to the function of the region. However, in frontal cortex, which is involved in cognition, neural responses display baffling complexity, carrying seemingly disordered mixtures of sensory, motor and other task-related variables. This complexity has led to the suggestion that representations in individual frontal neurons are randomly mixed and can only be understood at the neural population level. Here we show that neural activity in rat orbitofrontal cortex (OFC) is instead highly structured: single neuron activity co-varies with individual variables in computational models that explain choice behaviour. To characterize neural responses across a large behavioural space, we trained rats on a behavioural task that combines perceptual and value-guided decisions. An unbiased, model-free clustering analysis identified distinct groups of OFC neurons, each with a particular response profile in task-variable space. Applying a simple model of choice behaviour to these categorical response profiles revealed that each profile quantitatively corresponds to a specific decision variable, such as decision confidence. Additionally, we demonstrate that a connectivity-defined cell type, orbitofrontal neurons projecting to the striatum, carries a selective and temporally sustained representation of a single decision variable: integrated value. We propose that neurons in frontal cortex, as in other cortical regions, form a sparse and overcomplete representation of features relevant to the region\'s function, and that they distribute this information selectively to downstream regions to support behaviour.



Nature: 03 Dec 2019; epub ahead of print
Hirokawa J, Vaughan A, Masset P, Ott T, Kepecs A
Nature: 03 Dec 2019; epub ahead of print | PMID: 31801999
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Abstract

IL-17a promotes sociability in mouse models of neurodevelopmental disorders.

Reed MD, Yim YS, Wimmer RD, Kim H, ... Huh JR, Choi GB

A subset of children with autism spectrum disorder appear to show an improvement in their behavioural symptoms during the course of a fever, a sign of systemic inflammation. Here we elucidate the molecular and neural mechanisms that underlie the beneficial effects of inflammation on social behaviour deficits in mice. We compared an environmental model of neurodevelopmental disorders in which mice were exposed to maternal immune activation (MIA) during embryogenesis with mouse models that are genetically deficient for contactin-associated protein-like 2 (Cntnap2), fragile X mental retardation-1 (Fmr1) or Sh3 and multiple ankyrin repeat domains 3 (Shank3). We establish that the social behaviour deficits in offspring exposed to MIA can be temporarily rescued by the inflammatory response elicited by the administration of lipopolysaccharide (LPS). This behavioural rescue was accompanied by a reduction in neuronal activity in the primary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity of which was previously implicated in the manifestation of behavioural phenotypes associated with offspring exposed to MIA. By contrast, we did not observe an LPS-induced rescue of social deficits in the monogenic models. We demonstrate that the differences in responsiveness to the LPS treatment between the MIA and the monogenic models emerge from differences in the levels of cytokine production. LPS treatment in monogenic mutant mice did not induce amounts of interleukin-17a (IL-17a) comparable to those induced in MIA offspring; bypassing this difference by directly delivering IL-17a into S1DZ was sufficient to promote sociability in monogenic mutant mice as well as in MIA offspring. Conversely, abrogating the expression of IL-17 receptor subunit a (IL-17Ra) in the neurons of the S1DZ eliminated the ability of LPS to reverse the sociability phenotypes in MIA offspring. Our data support a neuroimmune mechanism that underlies neurodevelopmental disorders in which the production of IL-17a during inflammation can ameliorate the expression of social behaviour deficits by directly affecting neuronal activity in the central nervous system.



Nature: 17 Dec 2019; epub ahead of print
Reed MD, Yim YS, Wimmer RD, Kim H, ... Huh JR, Choi GB
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853066
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Abstract

Dysfunctional HDLs are Associated with a Greater Incidence of Acute Coronary Syndrome in a Population at High Cardiovascular Risk: A Nested-Case Control Study.

Soria-Florido MT, Castañer O, Lassale C, Estruch R, ... Hernáez Á, Fitó M

Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that HDL atheroprotective role lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been comprehensively investigated.We conducted a case-control study nested within the PREDIMED () cohort, originally a randomized trial where participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (=167) were individually matched (1:2) to controls by sex, age, intervention group, body mass index, and follow-up time. We investigated its two individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B-depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between one standard deviation increments in HDL functional characteristics and clinical outcomes.Low values of cholesterol efflux capacity (OR: 0.58, 95% CI: 0.40-0.83), and levels of sphingosine-1-phosphate (OR: 0.70, 95% CI: 0.52-0.92), and apolipoprotein A-I (OR: 0.58, 95% CI: 0.42-0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR: 1.27, 95% CI: 0.99-1.63). Low values of cholesterol efflux capacity (OR: 0.33, 95% CI: 0.18-0.61), sphingosine-1-phosphate (OR: 0.60, 95% CI: 0.40-0.89) and apolipoprotein A-I (OR: 0.59, 95% CI: 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR: 1.53, 95% CI: 1.01-2.33) and low apolipoprotein A-I levels (OR: 0.52, 95% CI: 0.31-0.88) were associated with unstable angina.Low cholesterol efflux capacity values, pro-oxidant/pro-inflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in high cardiovascular risk subjects.URL: http://www.controlled-trials.com Unique identifier: ISRCTN35739639.



Circulation: 15 Jan 2020; epub ahead of print
Soria-Florido MT, Castañer O, Lassale C, Estruch R, ... Hernáez Á, Fitó M
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941372
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Abstract

Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

Schimmel K, Jung M, Foinquinos A, San José G, ... González A, Thum T

Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis.Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanisticandstudies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression.findings were confirmed , using an angiotensin II (Ang II)-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt sensitive rat model. To investigate the mechanism underlying the anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing.High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. Using multiple in vitro fibrosis assays and stringent selection algorithms we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (fromspecies) to be effective anti-fibrotic molecules bothandleading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds.We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.



Circulation: 16 Jan 2020; epub ahead of print
Schimmel K, Jung M, Foinquinos A, San José G, ... González A, Thum T
Circulation: 16 Jan 2020; epub ahead of print | PMID: 31948273
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Abstract

Last appearance of Homo erectus at Ngandong, Java, 117,000-108,000 years ago.

Rizal Y, Westaway KE, Zaim Y, van den Bergh GD, ... Putt S, Ciochon RL

Homo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago. Twelve H. erectus calvaria (skull caps) and two tibiae (lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 1933, and are of the youngest, most-advanced form of H. erectus. Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated. Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish-to our knowledge-the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence, argon/argon (Ar/Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series-electron-spin resonance (US-ESR) dating to non-human fossils to directly date our re-excavation of Ngandong. We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum) and 134 and 118 ka (US-ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions. These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species.



Nature: 17 Dec 2019; epub ahead of print
Rizal Y, Westaway KE, Zaim Y, van den Bergh GD, ... Putt S, Ciochon RL
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853068
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Abstract

Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Kakiuchi N, Yoshida K, Uchino M, Kihara T, ... Seno H, Ogawa S

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.



Nature: 17 Dec 2019; epub ahead of print
Kakiuchi N, Yoshida K, Uchino M, Kihara T, ... Seno H, Ogawa S
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853061
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Abstract

Time Trends in Cardiovascular Disease Mortality Across the BRICS: An Age-Period-Cohort Analysis of Key Nations with Emerging Economies Using the Global Burden of Disease Study 2017.

Zou Z, Cini K, Dong B, Ma Y, ... Burgner DP, Patton GC

Brazil, Russia, India, China and South Africa (BRICS) are emerging economies making up almost half the global population. We analyzed trends in cardiovascular disease (CVD) mortality across the BRICS, and associations with age, period and birth cohort.Mortality estimates were derived from the Global Burden of Disease Study 2017. We used age-period-cohort modeling to estimate cohort and period effects in CVD between 1992- 2016. Period was defined as survey year, and period effects reflect population wide exposure at a circumscribed point in time. Cohort effects are defined as differences in risks across birth cohort. Net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks were calculated.In 2016, there were 8.4 million CVD deaths across the BRICS. Between 1992 and 2016, the reduction in CVD age-standardized mortality rate (ASMR) in BRICS (-17%) was less than in North America (-39%). 88% of the increased number of all- cause deaths resulted from the increase in CVD deaths. ASMR from stroke and HHD declined by approximately one third across the BRICS, whereas IHD increased slightly (2%). Brazil had the largest ASMR reductions across all CVD categories, with both improvement over time and in recent birth cohorts. South Africa was the only country where CVD ASMR increased. Different age-related CVD mortality was seen in those aged ≥ 50 years in China, ≤ 40 years in Russia, 35-60 years in India, and ≥ 55 years in South Africa. Improving period and cohort risks for CVD mortality were generally found across countries, with the exception of worsening period effects in India and greater risks for IHD in Chinese cohorts born in the 1950s and 1960s.With the exception of Brazil, reductions of CVD mortality across the BRICS have been less than in North America, such that China, India and South Africa contribute an increasing proportion of global CVD deaths. Brazil\'s example suggests that prevention policies can both reduce the risks for younger birth cohorts and shift the risks for all age groups over time.



Circulation: 15 Jan 2020; epub ahead of print
Zou Z, Cini K, Dong B, Ma Y, ... Burgner DP, Patton GC
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941371
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Abstract

Impaired cell fate through gain-of-function mutations in a chromatin reader.

Wan L, Chong S, Xuan F, Liang A, ... Wen H, Allis CD

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by \'reader\' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.



Nature: 17 Dec 2019; epub ahead of print
Wan L, Chong S, Xuan F, Liang A, ... Wen H, Allis CD
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853060
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Abstract

Orphan G-Protein-Coupled Receptor GPRC5B Controls Smooth Muscle Contractility and Differentiation by Inhibiting Prostacyclin Receptor Signaling.

Carvalho J, Chennupati R, Li R, Günther S, ... Offermanns S, Wettschureck N

G-protein-coupled receptors (GPCRs) are important regulators of contractility and differentiation in vascular smooth muscle cells (SMC), but the specific function of SMC-expressed orphan GPCR GPRC5B is unclear.We studied the role of GPRC5B in the regulation of contractility and dedifferentiation in human and murine SMC in vitro as well as in tamoxifen-inducible, SMC-specific knockout mice (iSM-Gprc5b-KO) under conditions of arterial hypertension and atherosclerosis in vivo.Mesenteric arteries from SMC-specific Gprc5b-KOs showed ex vivo significantly enhanced prostacyclin receptor (IP)-dependent relaxation, whereas responses to other relaxant or contractile factors were normal. In vitro, knockdown of GPRC5B in human aortic SMC resulted in increased IP-dependent cAMP production and consecutive facilitation of SMC relaxation. In line with this facilitation of IP-mediated relaxation, iSM-Gprc5b-KO mice were protected from arterial hypertension, and this protective effect was abrogated by IP antagonists. Mechanistically, we show that knockdown of GPRC5B increased the membrane localization of IP both in vitro and in vivo, and that GPRC5B, but not other GPCRs, physically interact with IP. Finally, we show that enhanced IP signaling in GPRC5B-deficient smooth muscle cells does not only facilitate relaxation, but also prevents dedifferentiation during atherosclerosis development, resulting in reduced plaque load and increased differentiation of SMC in the fibrous cap.Taken together, our data show that GPRC5B regulates vascular SMC tone and differentiation by negatively regulating IP signaling.



Circulation: 15 Jan 2020; epub ahead of print
Carvalho J, Chennupati R, Li R, Günther S, ... Offermanns S, Wettschureck N
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941358
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Abstract

A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1.

Tao P, Sun J, Wu Z, Wang S, ... Yuan J, Zhou Q

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients\' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.



Nature: 10 Dec 2019; epub ahead of print
Tao P, Sun J, Wu Z, Wang S, ... Yuan J, Zhou Q
Nature: 10 Dec 2019; epub ahead of print | PMID: 31827280
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Abstract

Metabolic heterogeneity confers differences in melanoma metastatic potential.

Tasdogan A, Faubert B, Ramesh V, Ubellacker JM, ... DeBerardinis RJ, Morrison SJ

Metastasis requires cancer cells to undergo metabolic changes that are poorly understood. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1 and MCT1 cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1 cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress.



Nature: 17 Dec 2019; epub ahead of print
Tasdogan A, Faubert B, Ramesh V, Ubellacker JM, ... DeBerardinis RJ, Morrison SJ
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853067
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Abstract

Somatic inflammatory gene mutations in human ulcerative colitis epithelium.

Nanki K, Fujii M, Shimokawa M, Matano M, ... Kanai T, Sato T

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.



Nature: 17 Dec 2019; epub ahead of print
Nanki K, Fujii M, Shimokawa M, Matano M, ... Kanai T, Sato T
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853059
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Abstract

Deficiency of Circulating Monocytes Ameliorates the Progression of Myxomatous Valve Degeneration in Marfan Syndrome.

Kim AJ, Xu N, Umeyama K, Hulin A, ... Nagashima H, Yutzey KE
Background
Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known.
Methods
We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (), gene-edited MFS pigs (), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)-tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages () were generated to determine the requirements of recruited macrophages to MVD progression.
Results
MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2-), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity.
Conclusions
All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.



Circulation: 13 Jan 2020; 141:132-146
Kim AJ, Xu N, Umeyama K, Hulin A, ... Nagashima H, Yutzey KE
Circulation: 13 Jan 2020; 141:132-146 | PMID: 31928435
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Impact:
Abstract

Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

Lalaoui N, Boyden SE, Oda H, Wood GM, ... Kastner DL, Silke J

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term \'cleavage-resistant RIPK1-induced autoinflammatory syndrome\'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1 mutant mouse strain. Whereas Ripk1 mice died postnatally from systemic inflammation, Ripk1 mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1 embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1 and Ripk1 cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1 mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.



Nature: 10 Dec 2019; epub ahead of print
Lalaoui N, Boyden SE, Oda H, Wood GM, ... Kastner DL, Silke J
Nature: 10 Dec 2019; epub ahead of print | PMID: 31827281
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Impact:
Abstract

Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy.

Wei J, Long L, Zheng W, Dhungana Y, ... Geiger TL, Chi H

Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells. Here we use an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8 T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8 T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8 T cells. By contrast, the targeting of additional signalling factors-including PTPN2 and SOCS1-improves the therapeutic efficacy of REGNASE-1-deficient CD8 T cells. Our findings suggest that T cell persistence and effector function can be coordinated in tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.



Nature: 10 Dec 2019; epub ahead of print
Wei J, Long L, Zheng W, Dhungana Y, ... Geiger TL, Chi H
Nature: 10 Dec 2019; epub ahead of print | PMID: 31827283
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Abstract

The water lily genome and the early evolution of flowering plants.

Zhang L, Chen F, Zhang X, Li Z, ... Van de Peer Y, Tang H

Water lilies belong to the angiosperm order Nymphaeales. Amborellales, Nymphaeales and Austrobaileyales together form the so-called ANA-grade of angiosperms, which are extant representatives of lineages that diverged the earliest from the lineage leading to the extant mesangiosperms. Here we report the 409-megabase genome sequence of the blue-petal water lily (Nymphaea colorata). Our phylogenomic analyses support Amborellales and Nymphaeales as successive sister lineages to all other extant angiosperms. The N. colorata genome and 19 other water lily transcriptomes reveal a Nymphaealean whole-genome duplication event, which is shared by Nymphaeaceae and possibly Cabombaceae. Among the genes retained from this whole-genome duplication are homologues of genes that regulate flowering transition and flower development. The broad expression of homologues of floral ABCE genes in N. colorata might support a similarly broadly active ancestral ABCE model of floral organ determination in early angiosperms. Water lilies have evolved attractive floral scents and colours, which are features shared with mesangiosperms, and we identified their putative biosynthetic genes in N. colorata. The chemical compounds and biosynthetic genes behind floral scents suggest that they have evolved in parallel to those in mesangiosperms. Because of its unique phylogenetic position, the N. colorata genome sheds light on the early evolution of angiosperms.



Nature: 17 Dec 2019; epub ahead of print
Zhang L, Chen F, Zhang X, Li Z, ... Van de Peer Y, Tang H
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853069
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Impact:
Abstract

Multi-omics profiling of mouse gastrulation at single-cell resolution.

Argelaguet R, Clark SJ, Mohammed H, Stapel LC, ... Marioni JC, Reik W

Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan and is associated with major transcriptional changes. Global epigenetic reprogramming accompanies these changes, but the role of the epigenome in regulating early cell-fate choice remains unresolved, and the coordination between different molecular layers is unclear. Here we describe a single-cell multi-omics map of chromatin accessibility, DNA methylation and RNA expression during the onset of gastrulation in mouse embryos. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements at enhancer marks, driven by ten-eleven translocation (TET)-mediated demethylation and a concomitant increase of accessibility. By contrast, the methylation and accessibility landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or remodelled before cell-fate decisions, providing the molecular framework for a hierarchical emergence of the primary germ layers.



Nature: 10 Dec 2019; epub ahead of print
Argelaguet R, Clark SJ, Mohammed H, Stapel LC, ... Marioni JC, Reik W
Nature: 10 Dec 2019; epub ahead of print | PMID: 31827285
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Impact:
Abstract

Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus: Insights from the DECLARE-TIMI 58 Trial.

Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD

Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes and its related comorbidities including hypertension, obesity, and heart failure (HF). SGLT2i have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2DM). We therefore investigated whether SGLT2i may also reduce the risk of AF/AFL.DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin versus placebo in 17160 patients with T2DM and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1,116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using the MedDRA Preferred Terms (\"atrial fibrillation\", \"atrial flutter\").Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events, 7.8 versus 9.6 events per 1000 patient-years, hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, No AF/AFL: HR 0.81, 95% CI 0.67-0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.83, 95% CI 0.66-1.04) versus MRF (HR 0.78, 95% CI 0.62-0.99; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55-1.11, No HF: HR 0.81, 95% CI 0.68-0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, HbA1c, body mass index, blood pressure, or eGFR (all P-INT>0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, P=0.005).Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with T2DM. This effect was consistent regardless of the patients\' prior history of AF, ASCVD, or HF.URL: https://clinicaltrials.gov Unique Identifier: NCT01730534.



Circulation: 26 Jan 2020; epub ahead of print
Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983236
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Impact:
Abstract

HBO1 is required for the maintenance of leukaemia stem cells.

MacPherson L, Anokye J, Yeung MM, Lam EYN, ... Thomas T, Dawson MA

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.



Nature: 10 Dec 2019; epub ahead of print
MacPherson L, Anokye J, Yeung MM, Lam EYN, ... Thomas T, Dawson MA
Nature: 10 Dec 2019; epub ahead of print | PMID: 31827282
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Abstract

Inverse transition of labyrinthine domain patterns in ferroelectric thin films.

Nahas Y, Prokhorenko S, Fischer J, Xu B, ... Garcia V, Bellaiche L

Phase separation is a cooperative process, the kinetics of which underpin the orderly morphogenesis of domain patterns on mesoscopic scales. Systems of highly degenerate frozen states may exhibit the rare and counterintuitive inverse-symmetry-breaking phenomenon. Proposed a century ago, inverse transitions have been found experimentally in disparate materials, ranging from polymeric and colloidal compounds to high-transition-temperature superconductors, proteins, ultrathin magnetic films, liquid crystals and metallic alloys, with the notable exception of ferroelectric oxides, despite extensive theoretical and experimental work on the latter. Here we show that following a subcritical quench, the non-equilibrium self-assembly of ferroelectric domains in ultrathin films of Pb(ZrTi)O results in a maze, or labyrinthine pattern, featuring meandering stripe domains. Furthermore, upon increasing the temperature, this highly degenerate labyrinthine phase undergoes an inverse transition whereby it transforms into the less-symmetric parallel-stripe domain structure, before the onset of paraelectricity at higher temperatures. We find that this phase sequence can be ascribed to an enhanced entropic contribution of domain walls, and that domain straightening and coarsening is predominantly driven by the relaxation and diffusion of topological defects. Computational modelling and experimental observation of the inverse dipolar transition in BiFeO suggest the universality of the phenomenon in ferroelectric oxides. The multitude of self-patterned states and the various topological defects that they embody may be used beyond current domain and domain-wall-based technologies by enabling fundamentally new design principles and topologically enhanced functionalities within ferroelectric films.



Nature: 30 Dec 2019; 577:47-51
Nahas Y, Prokhorenko S, Fischer J, Xu B, ... Garcia V, Bellaiche L
Nature: 30 Dec 2019; 577:47-51 | PMID: 31894148
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Impact:
Abstract

Long-term cyclic persistence in an experimental predator-prey system.

Blasius B, Rudolf L, Weithoff G, Gaedke U, Fussmann GF

Predator-prey cycles rank among the most fundamental concepts in ecology, are predicted by the simplest ecological models and enable, theoretically, the indefinite persistence of predator and prey. However, it remains an open question for how long cyclic dynamics can be self-sustained in real communities. Field observations have been restricted to a few cycle periods and experimental studies indicate that oscillations may be short-lived without external stabilizing factors. Here we performed microcosm experiments with a planktonic predator-prey system and repeatedly observed oscillatory time series of unprecedented length that persisted for up to around 50 cycles or approximately 300 predator generations. The dominant type of dynamics was characterized by regular, coherent oscillations with a nearly constant predator-prey phase difference. Despite constant experimental conditions, we also observed shorter episodes of irregular, non-coherent oscillations without any significant phase relationship. However, the predator-prey system showed a strong tendency to return to the dominant dynamical regime with a defined phase relationship. A mathematical model suggests that stochasticity is probably responsible for the reversible shift from coherent to non-coherent oscillations, a notion that was supported by experiments with external forcing by pulsed nutrient supply. Our findings empirically demonstrate the potential for infinite persistence of predator and prey populations in a cyclic dynamic regime that shows resilience in the presence of stochastic events.



Nature: 17 Dec 2019; epub ahead of print
Blasius B, Rudolf L, Weithoff G, Gaedke U, Fussmann GF
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853064
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Impact:
Abstract

Mass balance of the Greenland Ice Sheet from 1992 to 2018.



In recent decades, the Greenland Ice Sheet has been a major contributor to global sea-level rise, and it is expected to be so in the future. Although increases in glacier flow and surface melting have been driven by oceanic and atmospheric warming, the degree and trajectory of today\'s imbalance remain uncertain. Here we compare and combine 26 individual satellite measurements of changes in the ice sheet\'s volume, flow and gravitational potential to produce a reconciled estimate of its mass balance. Although the ice sheet was close to a state of balance in the 1990s, annual losses have risen since then, peaking at 335 ± 62 billion tonnes per year in 2011. In all, Greenland lost 3,800 ± 339 billion tonnes of ice between 1992 and 2018, causing the mean sea level to rise by 10.6 ± 0.9 millimetres. Using three regional climate models, we show that reduced surface mass balance has driven 1,971 ± 555 billion tonnes (52%) of the ice loss owing to increased meltwater runoff. The remaining 1,827 ± 538 billion tonnes (48%) of ice loss was due to increased glacier discharge, which rose from 41 ± 37 billion tonnes per year in the 1990s to 87 ± 25 billion tonnes per year since then. Between 2013 and 2017, the total rate of ice loss slowed to 217 ± 32 billion tonnes per year, on average, as atmospheric circulation favoured cooler conditions and as ocean temperatures fell at the terminus of Jakobshavn Isbræ. Cumulative ice losses from Greenland as a whole have been close to the IPCC\'s predicted rates for their high-end climate warming scenario, which forecast an additional 50 to 120 millimetres of global sea-level rise by 2100 when compared to their central estimate.



Nature: 09 Dec 2019; epub ahead of print
Nature: 09 Dec 2019; epub ahead of print | PMID: 31822019
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Impact:
Abstract

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE

Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.We assayed myosin ATP binding to define the proportions of myosin in SRX or DRX conformations in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants with unknown clinical significance (VUS) that were identified in HCM patients, predicted functional consequences and associations with heart failure and arrhythmias.Myosins undergo physiologic shifts between SRX conformations that maximized energy-conservation and active states (DRX) that enable cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacologic modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased SRX conformations while pathogenic variants destabilized these and increased the proportion of DRX myosins, which enhanced cardiomyocyte contractility but impaired relaxation, and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify VUS, we showed that variants that unbalanced myosin conformations were associated with higher rates of heart failure and arrhythmias in HCM patients.Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy conserving states promotes contractile abnormalities, morphological and metabolic remodeling and adverse clinical outcomes in HCM patients. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in HCM patients.



Circulation: 26 Jan 2020; epub ahead of print
Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983222
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Abstract

The past and future of global river ice.

Yang X, Pavelsky TM, Allen GH

More than one-third of Earth\'s landmass is drained by rivers that seasonally freeze over. Ice transforms the hydrologic, ecologic, climatic and socio-economic functions of river corridors. Although river ice extent has been shown to be declining in many regions of the world, the seasonality, historical change and predicted future changes in river ice extent and duration have not yet been quantified globally. Previous studies of river ice, which suggested that declines in extent and duration could be attributed to warming temperatures, were based on data from sparse locations. Furthermore, existing projections of future ice extent are based solely on the location of the 0-°C isotherm. Here, using satellite observations, we show that the global extent of river ice is declining, and we project a mean decrease in seasonal ice duration of 6.10 ± 0.08 days per 1-°C increase in global mean surface air temperature. We tracked the extent of river ice using over 400,000 clear-sky Landsat images spanning 1984-2018 and observed a mean decline of 2.5 percentage points globally in the past three decades. To project future changes in river ice extent, we developed an observationally calibrated and validated model, based on temperature and season, which reduced the mean bias by 87 per cent compared with the 0-degree-Celsius isotherm approach. We applied this model to future climate projections for 2080-2100: compared with 2009-2029, the average river ice duration declines by 16.7 days under Representative Concentration Pathway (RCP) 8.5, whereas under RCP 4.5 it declines on average by 7.3 days. Our results show that, globally, river ice is measurably declining and will continue to decline linearly with projected increases in surface air temperature towards the end of this century.



Nature: 30 Dec 2019; 577:69-73
Yang X, Pavelsky TM, Allen GH
Nature: 30 Dec 2019; 577:69-73 | PMID: 31894147
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Abstract

Economic effects of the double burden of malnutrition.

Nugent R, Levin C, Hale J, Hutchinson B

Observations from many countries indicate that multiple forms of malnutrition might coexist in a country, a household, and an individual. In this Series, the double burden of malnutrition (DBM) encompasses undernutrition in the form of stunting, and overweight and obesity. Health effects of the DBM include those associated with both undernutrition, such as impaired childhood development and greater susceptibility to infectious diseases, and overweight, especially in terms of increased risk of added visceral fat and increased risk of non-communicable diseases. These health effects have not been translated into economic costs for individuals and economies in the form of lost wages and productivity, as well as higher medical expenses. We summarise the existing approaches to modelling the economic effects of malnutrition and point out the weaknesses of these approaches for measuring economic losses from the DBM. Where population needs suggest that nutrition interventions take into account the DBM, economic evaluation can guide the choice of so-called double-duty interventions as an alternative to separate programming for stunting and overweight. We address the evidence gap with an economic analysis of the costs and benefits of an illustrative double-duty intervention that addresses both stunting and overweight in children aged 4 years and older by providing school meals with improved quality of diet. We assess the plausibility of our method and discuss how improved data and models can generate better estimates. Double-duty interventions could save money and be more efficient than single-duty interventions.

Copyright © 2019 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.

Lancet: 12 Dec 2019; epub ahead of print
Nugent R, Levin C, Hale J, Hutchinson B
Lancet: 12 Dec 2019; epub ahead of print | PMID: 31852601
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Impact:
Abstract

Nearest neighbours reveal fast and slow components of motor learning.

Kollmorgen S, Hahnloser RHR, Mante V

Changes in behaviour resulting from environmental influences, development and learning are commonly quantified on the basis of a few hand-picked features (for example, the average pitch of acoustic vocalizations), assuming discrete classes of behaviours (such as distinct vocal syllables). However, such methods generalize poorly across different behaviours and model systems and may miss important components of change. Here we present a more-general account of behavioural change that is based on nearest-neighbour statistics, and apply it to song development in a songbird, the zebra finch. First, we introduce the concept of \'repertoire dating\', whereby each rendition of a behaviour (for example, each vocalization) is assigned a repertoire time, reflecting when similar renditions were typical in the behavioural repertoire. Repertoire time isolates the components of vocal variability that are congruent with long-term changes due to vocal learning and development, and stratifies the behavioural repertoire into \'regressions\', \'anticipations\' and \'typical renditions\'. Second, we obtain a holistic, yet low-dimensional, description of vocal change in terms of a stratified \'behavioural trajectory\', revealing numerous previously unrecognized components of behavioural change on fast and slow timescales, as well as distinct patterns of overnight consolidation across the behavioral repertoire. We find that diurnal changes in regressions undergo only weak consolidation, whereas anticipations and typical renditions consolidate fully. Because of its generality, our nonparametric description of how behaviour evolves relative to itself-rather than to a potentially arbitrary, experimenter-defined goal-appears well suited for comparing learning and change across behaviours and species, as well as biological and artificial systems.



Nature: 07 Jan 2020; epub ahead of print
Kollmorgen S, Hahnloser RHR, Mante V
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915383
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Impact:
Abstract

TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1.

Su J, Morgani SM, David CJ, Wang Q, ... Hadjantonakis AK, Massagué J

Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer. EMTs are driven by SNAIL, ZEB and TWIST transcription factors together with microRNAs that balance this regulatory network. Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs. Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer. TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector, as a key partner of TGF-β-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-β-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-β-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal-SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-β pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.



Nature: 07 Jan 2020; epub ahead of print
Su J, Morgani SM, David CJ, Wang Q, ... Hadjantonakis AK, Massagué J
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915377
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Impact:
Abstract

Prevention of tuberculosis in macaques after intravenous BCG immunization.

Darrah PA, Zeppa JJ, Maiello P, Hackney JA, ... Flynn JL, Seder RA

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis.



Nature: 30 Dec 2019; 577:95-102
Darrah PA, Zeppa JJ, Maiello P, Hackney JA, ... Flynn JL, Seder RA
Nature: 30 Dec 2019; 577:95-102 | PMID: 31894150
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Impact:
Abstract

GDF15 mediates the effects of metformin on body weight and energy balance.

Coll AP, Chen M, Taskar P, Rimmington D, ... Allan BB, O\'Rahilly S

Metformin, the world\'s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk. Over 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner. The molecular mechanisms by which metformin lowers body weight are unknown. In two, independent randomised controlled clinical trials, circulating levels of GDF15, recently described to reduce food intake and lower body weight through a brain stem-restricted receptor, were increased by metformin. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high-fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. Metformin retained its ability to lower circulating glucose levels in the absence of GDF15 action. In summary, metformin elevates circulating levels of GDF15, which are necessary for its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.



Nature: 24 Dec 2019; epub ahead of print
Coll AP, Chen M, Taskar P, Rimmington D, ... Allan BB, O'Rahilly S
Nature: 24 Dec 2019; epub ahead of print | PMID: 31875646
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Abstract

The emergence of transcriptional identity in somatosensory neurons.

Sharma N, Flaherty K, Lezgiyeva K, Wagner DE, Klein AM, Ginty DD

More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.



Nature: 07 Jan 2020; epub ahead of print
Sharma N, Flaherty K, Lezgiyeva K, Wagner DE, Klein AM, Ginty DD
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915380
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Abstract

In vitro characterization of the human segmentation clock.

Diaz-Cuadros M, Wagner DE, Budjan C, Hubaud A, ... Touboul J, Pourquié O

The segmental organization of the vertebral column is established early in embryogenesis, when pairs of somites are rhythmically produced by the presomitic mesoderm (PSM). The tempo of somite formation is controlled by a molecular oscillator known as the segmentation clock. Although this oscillator has been well-characterized in model organisms, whether a similar oscillator exists in humans remains unknown. Genetic analyses of patients with severe spine segmentation defects have implicated several human orthologues of cyclic genes that are associated with the mouse segmentation clock, suggesting that this oscillator might be conserved in humans. Here we show that human PSM cells derived in vitro-as well as those of the mouse-recapitulate the oscillations of the segmentation clock. Human PSM cells oscillate with a period two times longer than that of mouse cells (5 h versus 2.5 h), but are similarly regulated by FGF, WNT, Notch and YAP signalling. Single-cell RNA sequencing reveals that mouse and human PSM cells in vitro follow a developmental trajectory similar to that of mouse PSM in vivo. Furthermore, we demonstrate that FGF signalling controls the phase and period of oscillations, expanding the role of this pathway beyond its classical interpretation in \'clock and wavefront\' models. Our work identifying the human segmentation clock represents an important milestone in understanding human developmental biology.



Nature: 07 Jan 2020; epub ahead of print
Diaz-Cuadros M, Wagner DE, Budjan C, Hubaud A, ... Touboul J, Pourquié O
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915384
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Abstract

Microbiota-targeted maternal antibodies protect neonates from enteric infection.

Zheng W, Zhao W, Wu M, Song X, ... Mekalanos JJ, Kasper DL

Although maternal antibodies protect newborn babies from infection, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against the maternal microbiota when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates.



Nature: 07 Jan 2020; epub ahead of print
Zheng W, Zhao W, Wu M, Song X, ... Mekalanos JJ, Kasper DL
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915378
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Abstract

Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.

Rudd KE, Johnson SC, Agesa KM, Shackelford KA, ... Murray CJL, Naghavi M
Background
Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.
Methods
We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates.
Findings
In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported, representing 19·7% (18·2-21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8-54·5) and mortality decreased by 52·8% (47·7-57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia.
Interpretation
Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa.
Funding
The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children\'s Hospital Foundation, the Wellcome Trust, and the Fleming Fund.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access Article under the CC BY 4.0 licence. Published by Elsevier Ltd.. All rights reserved.

Lancet: 17 Jan 2020; 395:200-211
Rudd KE, Johnson SC, Agesa KM, Shackelford KA, ... Murray CJL, Naghavi M
Lancet: 17 Jan 2020; 395:200-211 | PMID: 31954465
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Abstract

Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response after Myocardial Infarction.

Hadas Y, Vincek AS, Youssef E, Żak MM, ... Eliyahu E, Zangi L

Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle (LV) and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze pro-apoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase (Sphk) to produce the pro-survival molecule sphingosine-1-phosphate (S1P). We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI.We performed transcriptomic, sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling post MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA (modRNA)) of AC function post hypoxia or MI.We found that several genes involved inceramide synthesis were upregulated and that ceramide (C16, C20, C20:1 and C24) levels had significantly increased 24 hours after MI. AC inhibition post hypoxia or MI resulted in reduced AC activity and increased cell death; by contrast, enhancing AC activity via AC modRNA treatment increased cell survival post hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival and smaller scar size than control mice 28 days post MI. We attributed the improvement in heart function post MI following AC modRNA delivery to decreased ceramide levels, lower cell death rates and changes in the composition of the immune cell population in the LV manifested by lowered abundance of pro-inflammatory detrimental neutrophils.Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.



Circulation: 28 Jan 2020; epub ahead of print
Hadas Y, Vincek AS, Youssef E, Żak MM, ... Eliyahu E, Zangi L
Circulation: 28 Jan 2020; epub ahead of print | PMID: 31992066
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Abstract

A Galactic-scale gas wave in the solar neighborhood.

Alves J, Zucker C, Goodman AA, Speagle JS, ... Schlafly EF, Green GM

For the past 150 years, the prevailing view of the local interstellar medium was based on a peculiarity known as Gould\'s Belt, an expanding ring of young stars, gas and dust, tilted about 20 degrees to the Galactic plane. Still, the physical relation between local gas clouds has remained practically unknown because the distance accuracy to clouds is of the same order as, or larger than, their sizes. With the advent of large photometric surveys and astrometric survey this situation has changed. Here we report the three-dimensional structure of all local cloud complexes. We find a narrow and coherent 2.7-kiloparsec arrangement of dense gas in the solar neighbourhood that contains many of the clouds thought to be associated with the Gould Belt. This finding is inconsistent with the notion that these clouds are part of a ring, disputing the Gould Belt model. The new structure comprises the majority of nearby star-forming regions, has an aspect ratio of about 1:20, and contains about three million solar masses of gas. Remarkably, the new structure appears to be undulating and its three-dimensional structure is well described by a damped sinusoidal wave on the plane of the Milky Way, with an average period of about 2 kiloparsecs and a maximum amplitude of about 160 parsecs.



Nature: 06 Jan 2020; epub ahead of print
Alves J, Zucker C, Goodman AA, Speagle JS, ... Schlafly EF, Green GM
Nature: 06 Jan 2020; epub ahead of print | PMID: 31910431
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Abstract

Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.

Zhang B, Ma S, Rachmin I, He M, ... Fisher DE, Hsu YC

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.



Nature: 21 Jan 2020; epub ahead of print
Zhang B, Ma S, Rachmin I, He M, ... Fisher DE, Hsu YC
Nature: 21 Jan 2020; epub ahead of print | PMID: 31969699
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Abstract

Coupling delay controls synchronized oscillation in the segmentation clock.

Yoshioka-Kobayashi K, Matsumiya M, Niino Y, Isomura A, ... Miyawaki A, Kageyama R

Individual cellular activities fluctuate but are constantly coordinated at the population level via cell-cell coupling. A notable example is the somite segmentation clock, in which the expression of clock genes (such as Hes7) oscillates in synchrony between the cells that comprise the presomitic mesoderm (PSM). This synchronization depends on the Notch signalling pathway; inhibiting this pathway desynchronizes oscillations, leading to somite fusion. However, how Notch signalling regulates the synchronicity of HES7 oscillations is unknown. Here we establish a live-imaging system using a new fluorescent reporter (Achilles), which we fuse with HES7 to monitor synchronous oscillations in HES7 expression in the mouse PSM at a single-cell resolution. Wild-type cells can rapidly correct for phase fluctuations in HES7 oscillations, whereas the absence of the Notch modulator gene lunatic fringe (Lfng) leads to a loss of synchrony between PSM cells. Furthermore, HES7 oscillations are severely dampened in individual cells of Lfng-null PSM. However, when Lfng-null PSM cells were completely dissociated, the amplitude and periodicity of HES7 oscillations were almost normal, which suggests that LFNG is involved mostly in cell-cell coupling. Mixed cultures of control and Lfng-null PSM cells, and an optogenetic Notch signalling reporter assay, revealed that LFNG delays the signal-sending process of intercellular Notch signalling transmission. These results-together with mathematical modelling-raised the possibility that Lfng-null PSM cells shorten the coupling delay, thereby approaching a condition known as the oscillation or amplitude death of coupled oscillators. Indeed, a small compound that lengthens the coupling delay partially rescues the amplitude and synchrony of HES7 oscillations in Lfng-null PSM cells. Our study reveals a delay control mechanism of the oscillatory networks involved in somite segmentation, and indicates that intercellular coupling with the correct delay is essential for synchronized oscillation.



Nature: 07 Jan 2020; epub ahead of print
Yoshioka-Kobayashi K, Matsumiya M, Niino Y, Isomura A, ... Miyawaki A, Kageyama R
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915376
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Abstract

A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity.

Zhao R, Chen X, Ma W, Zhang J, ... Wang J, Qi H

Humoral immune responses to immunization and infection and susceptibilities to antibody-mediated autoimmunity are generally lower in males. However, the mechanisms underlying such sexual dimorphism are not well understood. Here we show that there are intrinsic differences between the B cells that produce germinal centres in male and female mice. We find that antigen-activated male B cells do not position themselves as efficiently as female B cells in the centre of follicles in secondary lymphoid organs, in which germinal centres normally develop. Moreover, GPR174-an X-chromosome-encoded G-protein-coupled receptor-suppresses the formation of germinal centres in male, but not female, mice. This effect is intrinsic to B cells, and correlates with the GPR174-enhanced positioning of B cells towards the T-cell-B-cell border of follicles, and the distraction of male, but not female, B cells from S1PR2-driven follicle-centre localization. Biochemical fractionation of conditioned media that induce B-cell migration in a GPR174-dependent manner identifies CCL21 as a GPR174 ligand. In response to CCL21, GPR174 triggers a calcium flux and preferentially induces the migration of male B cells; GPR174 also becomes associated with more Gαi protein in male than in female B cells. Male B cells from orchidectomized mice exhibit impaired GPR174-mediated migration to CCL21, and testosterone treatment rescues this defect. Female B cells from testosterone-treated mice exhibit male-like GPR174-Gαi association and GPR174-mediated migration. Deleting GPR174 from male B cells causes more efficient positioning towards the follicular centre, the formation of more germinal centres and an increased susceptibility to B-cell-dependent experimental autoimmune encephalomyelitis. By identifying GPR174 as a receptor for CCL21 and demonstrating its sex-dependent control of B-cell positioning and participation in germinal centres, we have revealed a mechanism by which B-cell physiology is fine-tuned to impart sexual dimorphism to humoral immunity.



Nature: 24 Dec 2019; epub ahead of print
Zhao R, Chen X, Ma W, Zhang J, ... Wang J, Qi H
Nature: 24 Dec 2019; epub ahead of print | PMID: 31875850
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Abstract

Femtosecond laser-assisted versus phacoemulsification cataract surgery (FEMCAT): a multicentre participant-masked randomised superiority and cost-effectiveness trial.

Schweitzer C, Brezin A, Cochener B, Monnet D, ... Benard A,
Background
Cataract surgery is one of the most common operations in health care. Femtosecond laser-assisted cataract surgery (FLACS) enables more precise ocular incisions and lens fragmentation than does phacoemulsification cataract surgery (PCS). We hypothesised that FLACS might improve outcomes in cataract surgery compared with PCS despite having higher costs.
Methods
We did a participant-masked randomised superiority clinical trial comparing FLACS and PCS in two parallel groups (permuted block randomisation stratified on centres via a centralised web-based application, allocation ratio 1:1, block size of 2 or 4 for unilateral cases and 2 or 6 for bilateral cases). Five French University Hospitals enrolled consecutive patients aged 22 years or older who were eligible for unilateral or bilateral cataract surgery. Participants, outcome assessors, and technicians carrying out examinations were masked to the surgical treatment allocation until the last follow-up visit and a sham laser procedure was set up for participants randomly assigned to the PCS arm. The primary clinical endpoint was the success rate of surgery, defined as a composite of four outcomes at a 3-month postoperative visit: absence of severe perioperative complication, a best-corrected visual acuity (BCVA) of 0·0 LogMAR (logarithm of the minimum angle of resolution) or better, an absolute refractive error of 0·75 dioptres or less, and unchanged postoperative corneal astigmatism power (≤0·5 dioptres) and axis (≤20°). The primary economic endpoint was the incremental cost per additional patient who had treatment success at 3 months. Primary outcomes were assessed in all randomly assigned patients who met all eligibility criteria (missing data considered as failure). We used mixed logistic regression models or mixed linear regression models for statistical comparisons, adjusted on centres and whether cataract surgery was bilateral or unilateral. The study is registered with ClinicalTrials.gov, NCT01982006.
Findings
Of the 907 patients (1476 eyes) randomly assigned between Oct 9, 2013, and Oct 30, 2015, 870 (704 eyes in FLACS group and 685 eyes in the PCS group) were analysed. We identified no significant difference in the success rate of surgery between the FLACS and PCS groups (FLACS: 41·1% [289 eyes]; PCS: 43·6% [299 eyes]); adjusted odds ratio 0·85, 95% CI 0·64-1·12, p=0·250). The incremental cost-effectiveness ratio was €10 703 saved per additional patient who had treatment success with PCS compared with FLACS. We observed no severe adverse events during the femtosecond laser procedure, and most of the complications in the FLACS group related to the primary outcome measures occurred during the phacoemulsification phase or postoperatively.
Interpretation
Despite its advanced technology, femtosecond laser was not superior to phacoemulsification in cataract surgery and, with higher costs, did not provide an additional benefit over phacoemulsification for patients or health-care systems.
Funding
French Ministry of Social Affairs and Health.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 17 Jan 2020; 395:212-224
Schweitzer C, Brezin A, Cochener B, Monnet D, ... Benard A,
Lancet: 17 Jan 2020; 395:212-224 | PMID: 31954466
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Abstract

Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial.

Butler CC, van der Velden AW, Bongard E, Saville BR, ... Goossens H, Verheij TJ
Background
Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.
Methods
We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.
Findings
Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group.
Interpretation
Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner.
Funding
European Commission\'s Seventh Framework Programme.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 11 Dec 2019; epub ahead of print
Butler CC, van der Velden AW, Bongard E, Saville BR, ... Goossens H, Verheij TJ
Lancet: 11 Dec 2019; epub ahead of print | PMID: 31839279
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Abstract

Cortical pattern generation during dexterous movement is input-driven.

Sauerbrei BA, Guo JZ, Cohen JD, Mischiati M, ... Branson K, Hantman AW

The motor cortex controls skilled arm movement by sending temporal patterns of activity to lower motor centres. Local cortical dynamics are thought to shape these patterns throughout movement execution. External inputs have been implicated in setting the initial state of the motor cortex, but they may also have a pattern-generating role. Here we dissect the contribution of local dynamics and inputs to cortical pattern generation during a prehension task in mice. Perturbing cortex to an aberrant state prevented movement initiation, but after the perturbation was released, cortex either bypassed the normal initial state and immediately generated the pattern that controls reaching or failed to generate this pattern. The difference in these two outcomes was probably a result of external inputs. We directly investigated the role of inputs by inactivating the thalamus; this perturbed cortical activity and disrupted limb kinematics at any stage of the movement. Activation of thalamocortical axon terminals at different frequencies disrupted cortical activity and arm movement in a graded manner. Simultaneous recordings revealed that both thalamic activity and the current state of cortex predicted changes in cortical activity. Thus, the pattern generator for dexterous arm movement is distributed across multiple, strongly interacting brain regions.



Nature: 24 Dec 2019; epub ahead of print
Sauerbrei BA, Guo JZ, Cohen JD, Mischiati M, ... Branson K, Hantman AW
Nature: 24 Dec 2019; epub ahead of print | PMID: 31875851
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Abstract

Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial.

Vicini FA, Cecchini RS, White JR, Arthur DW, ... Bryant JL, Wolmark N
Background
Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation.
Methods
We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181.
Findings
Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5-11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94-1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7-5·7) in the APBI group versus 3·9% (3·1-5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group.
Interpretation
APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women.
Funding
National Cancer Institute, US Department of Health and Human Services.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 04 Dec 2019; epub ahead of print
Vicini FA, Cecchini RS, White JR, Arthur DW, ... Bryant JL, Wolmark N
Lancet: 04 Dec 2019; epub ahead of print | PMID: 31813636
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Abstract

Small Extracellular Microvesicles Mediated Pathological Communications between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanisms Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice.

Gan L, Xie D, Liu J, Lau WB, ... Ma XL, Wang Y

Diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Adipocyte dysfunction contributes to remote organ injury. However, the molecular mechanisms linking dysfunctional adipocytes to increased MI/R injury remain unidentified. The current study attempted to clarify whether and how small extracellular vesicles (sEV) may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating MI/R injury.Adult male mice were fed a normal or a high fat diet for 12 weeks. sEV (from diabetic serum, diabetic adipocytes, or high glucose/high lipid (HG/HL)-challenged non-diabetic adipocytes) were injected intramyocardially distal of coronary ligation. Animals were subjected to MI/R 48 hours after injection.Intramyocardial injection of diabetic serum sEV in the non-diabetic heart significantly exacerbated MI/R injury, as evidenced by poorer cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. Similarly, intramyocardial or systemic administration of diabetic adipocyte sEV or HG/HL-challenged non-diabetic adipocyte sEV significantly exacerbated MI/R injury. Diabetic epididymal fat transplantation significantly increased MI/R injury in non-diabetic mice, whereas administration of a sEV biogenesis inhibitor significantly mitigated MI/R injury in diabetic mice. Mechanistic investigation identified that miR-130b-3p is a common molecule significantly increased in diabetic serum sEV, diabetic adipocyte sEV, and HG/HL-challenged non-diabetic adipocyte sEV. Mature (but not primary) miR-130b-3p was significantly increased in the diabetic and non-diabetic heart subjected to diabetic sEV injection. Whereas intramyocardial injection of a miR-130b-3p mimic significantly exacerbated MI/R injury in non-diabetic mice, miR-130b-3p inhibitors significantly attenuated MI/R injury in diabetic mice. Molecular studies identified AMPKα1/α2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPKα2) reversed miR-130b-3p induced pro-apoptotic/cardiac harmful effect. Finally, miR-130b-3p levels were significantly increased in plasma sEV from type 2 diabetic patients. Incubation of cardiomyocytes with diabetic patient sEV significantly exacerbated ischemic injury, an effect blocked by miR-130b-3p inhibitor.We demonstrate for the first time that miR-130b-3p enrichment in dysfunctional adipocyte-derived sEV, and its suppression of multiple anti-apoptotic/cardioprotective molecules in cardiomyocytes, is a novel mechanism exacerbating MI/R injury in the diabetic heart. Targeting miR-130b-3p mediated pathological communication between dysfunctional adipocytes and cardiomyocytes may be a novel strategy attenuating diabetic exacerbation of MI/R injury.



Circulation: 09 Jan 2020; epub ahead of print
Gan L, Xie D, Liu J, Lau WB, ... Ma XL, Wang Y
Circulation: 09 Jan 2020; epub ahead of print | PMID: 31918577
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Abstract

A repeating fast radio burst source localized to a nearby spiral galaxy.

Marcote B, Nimmo K, Hessels JWT, Tendulkar SP, ... Vanderlinde K, Zwaniga AV

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes. Their physical origin remains unknown, but dozens of possible models have been postulated. Some FRB sources exhibit repeat bursts. Although over a hundred FRB sources have been discovered, only four have been localized and associated with a host galaxy, and just one of these four is known to emit repeating FRBs. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.



Nature: 05 Jan 2020; epub ahead of print
Marcote B, Nimmo K, Hessels JWT, Tendulkar SP, ... Vanderlinde K, Zwaniga AV
Nature: 05 Jan 2020; epub ahead of print | PMID: 31907402
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Abstract

Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.

Hoffman MK, Goudar SS, Kodkany BS, Metgud M, ... Derman RJ,
Background
Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation.
Methods
ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks\' gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970.
Findings
From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks\' gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (<34 weeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups.
Interpretation
In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality.
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 24 Jan 2020; 395:285-293
Hoffman MK, Goudar SS, Kodkany BS, Metgud M, ... Derman RJ,
Lancet: 24 Jan 2020; 395:285-293 | PMID: 31982074
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Abstract

Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8 cells.

McBrien JB, Mavigner M, Franchitti L, Smith SA, ... Chahroudi A, Silvestri G

Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus. Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8 lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8 lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14; 100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8 T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4 T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection.



Nature: 21 Jan 2020; epub ahead of print
McBrien JB, Mavigner M, Franchitti L, Smith SA, ... Chahroudi A, Silvestri G
Nature: 21 Jan 2020; epub ahead of print | PMID: 31969705
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Abstract

Signatures of self-organized criticality in an ultracold atomic gas.

Helmrich S, Arias A, Lochead G, Wintermantel TM, ... Diehl S, Whitlock S

Self-organized criticality is an elegant explanation of how complex structures emerge and persist throughout nature, and why such structures often exhibit similar scale-invariant properties. Although self-organized criticality is sometimes captured by simple models that feature a critical point as an attractor for the dynamics, the connection to real-world systems is exceptionally hard to test quantitatively. Here we observe three key signatures of self-organized criticality in the dynamics of a driven-dissipative gas of ultracold potassium atoms: self-organization to a stationary state that is largely independent of the initial conditions; scale-invariance of the final density characterized by a unique scaling function; and large fluctuations of the number of excited atoms (avalanches) obeying a characteristic power-law distribution. This work establishes a well-controlled platform for investigating self-organization phenomena and non-equilibrium criticality, with experimental access to the underlying microscopic details of the system.



Nature: 14 Jan 2020; epub ahead of print
Helmrich S, Arias A, Lochead G, Wintermantel TM, ... Diehl S, Whitlock S
Nature: 14 Jan 2020; epub ahead of print | PMID: 31942078
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