Topic: Basic Research

Abstract
<div><h4>CRISPR-Cas9 In Vivo Gene Editing of for Hereditary Angioedema.</h4><i>Longhurst HJ, Lindsay K, Petersen RS, Fijen LM, ... Lebwohl D, Cohn DM</i><br /><b>Background</b><br />Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (<i>KLKB1</i>), with the goal of lifelong control of angioedema attacks after a single dose.<br /><b>Methods</b><br />In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks.<br /><b>Results</b><br />Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%.<br /><b>Conclusions</b><br />In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).<br /><br />Copyright © 2024 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Feb 2024; 390:432-441</small></div>
Longhurst HJ, Lindsay K, Petersen RS, Fijen LM, ... Lebwohl D, Cohn DM
N Engl J Med: 01 Feb 2024; 390:432-441 | PMID: 38294975
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<div><h4>The Born in Guangzhou Cohort Study enables generational genetic discoveries.</h4><i>Huang S, Liu S, Huang M, He JR, ... Xia H, Qiu X</i><br /><AbstractText>Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health<sup>1</sup>. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study<sup>2</sup> (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 31 Jan 2024; epub ahead of print</small></div>
Huang S, Liu S, Huang M, He JR, ... Xia H, Qiu X
Nature: 31 Jan 2024; epub ahead of print | PMID: 38297123
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Abstract
<div><h4>7-Dehydrocholesterol dictates ferroptosis sensitivity.</h4><i>Li Y, Ran Q, Duan Q, Jin J, ... Jiang X, Wang P</i><br /><AbstractText>Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer<sup>1-3</sup>, degenerative disorders<sup>4</sup> and organ ischaemia-reperfusion injury (IRI)<sup>5,6</sup>. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 31 Jan 2024; epub ahead of print</small></div>
Li Y, Ran Q, Duan Q, Jin J, ... Jiang X, Wang P
Nature: 31 Jan 2024; epub ahead of print | PMID: 38297130
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<div><h4>7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.</h4><i>Freitas FP, Alborzinia H, Dos Santos AF, Nepachalovich P, ... Conrad M, Friedmann Angeli JP</i><br /><AbstractText>Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation<sup>1,2</sup>. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation<sup>3</sup>, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt\'s lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 31 Jan 2024; epub ahead of print</small></div>
Freitas FP, Alborzinia H, Dos Santos AF, Nepachalovich P, ... Conrad M, Friedmann Angeli JP
Nature: 31 Jan 2024; epub ahead of print | PMID: 38297129
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<div><h4>Establishing reaction networks in the 16-electron sulfur reduction reaction.</h4><i>Liu R, Wei Z, Peng L, Zhang L, ... Sautet P, Duan X</i><br /><AbstractText>The sulfur reduction reaction (SRR) plays a central role in high-capacity lithium sulfur (Li-S) batteries. The SRR involves an intricate, 16-electron conversion process featuring multiple lithium polysulfide intermediates and reaction branches<sup>1-3</sup>. Establishing the complex reaction network is essential for rational tailoring of the SRR for improved Li-S batteries, but represents a daunting challenge<sup>4-6</sup>. Herein we systematically investigate the electrocatalytic SRR to decipher its network using the nitrogen, sulfur, dual-doped holey graphene framework as a model electrode to understand the role of electrocatalysts in acceleration of conversion kinetics. Combining cyclic voltammetry, in situ Raman spectroscopy and density functional theory calculations, we identify and directly profile the key intermediates (S<sub>8</sub>, Li<sub>2</sub>S<sub>8</sub>, Li<sub>2</sub>S<sub>6</sub>, Li<sub>2</sub>S<sub>4</sub> and Li<sub>2</sub>S) at varying potentials and elucidate their conversion pathways. Li<sub>2</sub>S<sub>4</sub> and Li<sub>2</sub>S<sub>6</sub> were predominantly observed, in which Li<sub>2</sub>S<sub>4</sub> represents the key electrochemical intermediate dictating the overall SRR kinetics. Li<sub>2</sub>S<sub>6</sub>, generated (consumed) through a comproportionation (disproportionation) reaction, does not directly participate in electrochemical reactions but significantly contributes to the polysulfide shuttling process. We found that the nitrogen, sulfur dual-doped holey graphene framework catalyst could help accelerate polysulfide conversion kinetics, leading to faster depletion of soluble lithium polysulfides at higher potential and hence mitigating the polysulfide shuttling effect and boosting output potential. These results highlight the electrocatalytic approach as a promising strategy for tackling the fundamental challenges regarding Li-S batteries.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 01 Feb 2024; 626:98-104</small></div>
Liu R, Wei Z, Peng L, Zhang L, ... Sautet P, Duan X
Nature: 01 Feb 2024; 626:98-104 | PMID: 38297176
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<div><h4>Stereodivergent 1,3-difunctionalization of alkenes by charge relocation.</h4><i>Brutiu BR, Iannelli G, Riomet M, Kaiser D, Maulide N</i><br /><AbstractText>Alkenes are indispensable feedstocks in chemistry. Functionalization at both carbons of the alkene-1,2-difunctionalization-is part of chemistry curricula worldwide<sup>1</sup>. Although difunctionalization at distal positions has been reported<sup>2-4</sup>, it typically relies on designer substrates featuring directing groups and/or stabilizing features, all of which determine the ultimate site of bond formation<sup>5-7</sup>. Here we introduce a method for the direct 1,3-difunctionalization of alkenes, based on a concept termed \'charge relocation\', which enables stereodivergent access to 1,3-difunctionalized products of either syn- or anti-configuration from unactivated alkenes, without the need for directing groups or stabilizing features. The usefulness of the approach is demonstrated in the synthesis of the pulmonary toxin 4-ipomeanol and its derivatives.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 01 Feb 2024; 626:92-97</small></div>
Brutiu BR, Iannelli G, Riomet M, Kaiser D, Maulide N
Nature: 01 Feb 2024; 626:92-97 | PMID: 38297174
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<div><h4>Single-photon superradiance in individual caesium lead halide quantum dots.</h4><i>Zhu C, Boehme SC, Feld LG, Moskalenko A, ... Kovalenko MV, Rainò G</i><br /><AbstractText>The brightness of an emitter is ultimately described by Fermi\'s golden rule, with a radiative rate proportional to its oscillator strength times the local density of photonic states. As the oscillator strength is an intrinsic material property, the quest for ever brighter emission has relied on the local density of photonic states engineering, using dielectric or plasmonic resonators<sup>1,2</sup>. By contrast, a much less explored avenue is to boost the oscillator strength, and hence the emission rate, using a collective behaviour termed superradiance. Recently, it was proposed<sup>3</sup> that the latter can be realized using the giant oscillator-strength transitions of a weakly confined exciton in a quantum well when its coherent motion extends over many unit cells. Here we demonstrate single-photon superradiance in perovskite quantum dots with a sub-100 picosecond radiative decay time, almost as short as the reported exciton coherence time<sup>4</sup>. The characteristic dependence of radiative rates on the size, composition and temperature of the quantum dot suggests the formation of giant transition dipoles, as confirmed by effective-mass calculations. The results aid in the development of ultrabright, coherent quantum light sources and attest that quantum effects, for example, single-photon emission, persist in nanoparticles ten times larger than the exciton Bohr radius.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 31 Jan 2024; epub ahead of print</small></div>
Zhu C, Boehme SC, Feld LG, Moskalenko A, ... Kovalenko MV, Rainò G
Nature: 31 Jan 2024; epub ahead of print | PMID: 38297126
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<div><h4>Exosomes From IgE-Stimulated Mast Cells Aggravate Asthma-Mediated Atherosclerosis Through circRNA CDR1as-Mediated Endothelial Cell Dysfunction in Mice.</h4><i>Yang H, Chen J, Liu S, Xue Y, ... Wang J, Zhao H</i><br /><b>Background</b><br />IgE has been known for mediating endothelial cell dysfunction and mast cell (MC) activation to fuel asthma-aggravated high-fat diet-induced atherosclerosis. However, it remains unclear for the mechanism of asthma-mediated atherosclerosis, especially the potential involvement of IgE in the exacerbation of asthma-mediated atherosclerosis with a standard laboratory diet, and the cross talk between endothelial cells and MCs.<br /><b>Methods</b><br />Asthma-mediated atherosclerosis mice models under a standard laboratory diet and FcεR1 knock-out mice were used to determine the role of IgE-FcεR1 signaling in asthma-mediated atherosclerosis, which was assessed by Oil Red O staining and immunohistochemistry. Various in vitro assays including nanoparticle tracking analysis and transmission electron microscopy were used to evaluate exosome characteristics. Immunofluorescence and fluorescent in situ hybridization approaches were used to evaluate the effect and mechanism of MC-secreted exosomes encapsulated circular RNA CDR1as (cerebellar degeneration-related 1 antisense) on endothelial cells in vivo and in vitro. Finally, cohort studies examined the plasma CDR1as levels in patients with atherosclerosis with or without allergies.<br /><b>Results</b><br />Asthma mice with a standard laboratory diet showed increased atherosclerotic lesions and inflammatory infiltration depending on IgE-FcεR1 signal. FcεR1 knockout mice and blockage of IgE-FcεR1 signaling with IgE monoclonal antibody, omalizumab, all significantly alleviated asthma-mediated atherosclerosis and vascular inflammatory remodeling. Anti-inflammation with dexamethasone and stabilization of MC with cromolyn partially alleviated atherosclerotic lesions and mitigated the inflammatory infiltration in arteries. Mechanistically, IgE stimulation upregulates MC CDR1as expression in exosomes and upregulates the endothelial cell adhesive factors VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) via the CDR1as-FUS (fused in sarcoma)-phos-p65 axis. Knockdown of CDR1as in vivo significantly decreased the endothelial adhesion function and mitigated asthma-mediated atherosclerosis. Furthermore, a cohort study indicated higher plasma CDR1as levels in patients with atherosclerosis with allergies than in patients with atherosclerosis and healthy controls.<br /><b>Conclusions</b><br />Exosomes from IgE-stimulated MCs aggravated atherosclerosis through circular RNA CDR1as-mediated endothelial dysfunction, providing a novel insight into asthma-mediated atherosclerosis and potential diagnostic and therapeutic targets.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 01 Mar 2024; 44:e99-e115</small></div>
Yang H, Chen J, Liu S, Xue Y, ... Wang J, Zhao H
Arterioscler Thromb Vasc Biol: 01 Mar 2024; 44:e99-e115 | PMID: 38235556
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<div><h4>Histone content, and thus DNA content, is associated with differential in vitro lysis of acute ischemic stroke clots.</h4><i>Akkipeddi SMK, Rahmani R, Ellens NR, Kohli GS, ... Morrell CN, Bender MT</i><br /><b>Background</b><br />Fibrin, von Willebrand factor, and extracellular DNA from neutrophil extracellular traps (NETs) all contribute to acute ischemic stroke (AIS) thrombus integrity.<br /><b>Objectives</b><br />In this study, we explore how the proteomic composition of retrieved thromboemboli relates to susceptibility to lysis with distinct thrombolytics.<br /><b>Methods</b><br />26 retrieved stroke thromboemboli were portioned into four segments, with each subjected to one hour of in vitro lysis at 37ºC in one of four solutions: tissue plasminogen activator (tPA), tPA + von Willebrand factor-cleaving ADAMTS13, tPA + DNA-cleaving DNase I, and all three enzymes. Lysis, characterized by the percent change in pre- and post-lysis weight, was compared across the solutions and related to the corresponding abundance of proteins identified on mass spectrometry for each of the thromboemboli used in lysis.<br /><b>Results</b><br />Solutions containing DNase resulted in approximately threefold greater thrombolysis relative to the standard-of-care tPA solution (post-hoc Tukey, p < 0.01 for all). DNA content, was directly related to lysis in solutions containing DNase (Spearman\'s ρ > 0.39 and p < 0.05 for all significant histones) and inversely related to lysis in solutions without DNase (Spearman\'s ρ < -0.40 and p < 0.05 for all significant histones). Functional analysis suggests distinct pathways associated with susceptibility to thrombolysis with tPA (platelet-mediated) or DNase (innate immune system-mediated).<br /><b>Conclusion</b><br />This study demonstrates synergy of DNase and tPA in thrombolysis of stroke emboli, and points to DNase as a potential adjunct to our currently limited selection of thrombolytics in treating acute ischemic stroke.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 29 Jan 2024; epub ahead of print</small></div>
Akkipeddi SMK, Rahmani R, Ellens NR, Kohli GS, ... Morrell CN, Bender MT
J Thromb Haemost: 29 Jan 2024; epub ahead of print | PMID: 38296159
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<div><h4>Prothrombin conversion and thrombin decay in patients with cirrhosis - role of prothrombin and antithrombin deficiencies.</h4><i>Sinegre T, Abergel A, Lecompte T, Lebreton A</i><br /><b>Background</b><br />Thrombin generation in the presence of thrombomodulin (TG-TM) in plasma of patients with cirrhosis (PWC) is tilted toward a hypercoagulable phenotype. Low protein C and elevated factor VIII play a role, but other determinants, such as the prothrombin/antithrombin pair, must also be studied.<br /><b>Objectives</b><br />The objectives were: (i) to quantitatively assess the sub-processes (prothrombin conversion and thrombin decay); (ii) to understand the underlying mechanism by studying TG dynamics after prothrombin and antithrombin plasma levels correction in PWC.<br /><b>Patients/methods</b><br />We studied TG-TM in plasma samples of 36 healthy controls (HC) and 41 PWC with prothrombin and antithrombin levels <70% and after their correction. We initiated coagulation with an intermediate picomolar concentration of tissue factor. We determined the overall thrombin potential, prothrombin conversion and thrombin decay.<br /><b>Results</b><br />TG-TM was increased in PWC compared with HC due to impaired thrombin inhibition. Indeed, thrombin decay capacity (min<sup>-1</sup>) decreased from 0.37 (0.35-0.40) in HC to 0.33 (0.30-0.37) in the Child-Turcotte-Pugh (CTP)-A (p=0.09), 0.27 (0.26-0.30) in the CTP-B (p<0.001), and 0.20 (0.19-0.20) in the CTP-C (p<0.001) group. Concomitant correction of prothrombin and antithrombin increased endogenous thrombin potential with prothrombin conversion surpassing thrombin decay. By contrast, when we corrected only antithrombin, TG-TM was normalized and even consistent with a hypocoagulable phenotype in the CTP-C group.<br /><b>Conclusions</b><br />Our results highlight that in PWC, hypercoagulability (evidenced in the presence of TM) is due to impaired thrombin decay, whereas low prothrombin levels do not translate into decreased prothrombin conversion, likely due to altered TM-activated protein C negative feed-back.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 Feb 2024; epub ahead of print</small></div>
Sinegre T, Abergel A, Lecompte T, Lebreton A
J Thromb Haemost: 01 Feb 2024; epub ahead of print | PMID: 38309434
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<div><h4>A new look at an old body: molecular determinants of Weibel-Palade body composition and VWF exocytosis.</h4><i>Hordijk S, Carter T, Bierings R</i><br /><AbstractText>Endothelial cells, forming a monolayer along blood vessels, intricately regulate vascular hemostasis, inflammatory responses, and angiogenesis. A key determinant of these functions is the controlled secretion of Weibel-Palade bodies (WPBs) which are specialized endothelial storage organelles housing a pre-synthesized pool of the hemostatic protein von Willebrand factor (VWF) and various other hemostatic, inflammatory, angiogenic, and vasoactive mediators. This review delves into recent mechanistic insights into WPB biology, including the biogenesis that results in their unique morphology, the acquisition of intraluminal vesicles and other cargo, and the contribution of proton pumps to organelle acidification. Additionally, in light of a number of proteomic approaches to unravel the regulatory networks that control WPB formation and secretion we provide a comprehensive overview of the WPB exocytotic machinery, including their molecular and cellular mechanisms.</AbstractText><br /><br />Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 31 Jan 2024; epub ahead of print</small></div>
Hordijk S, Carter T, Bierings R
J Thromb Haemost: 31 Jan 2024; epub ahead of print | PMID: 38307391
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<div><h4>Altered whole blood thrombin generation and hyperresponsive platelets in patients with pancreatic cancer.</h4><i>Willems RAL, Konings J, Huskens D, Middelveld H, ... de Laat B, Roest M</i><br /><b>Background</b><br />Thromboembolic disease is a major complication in patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC often have altered blood cell counts, which are associated with venous thromboembolism (VTE) development. The high thrombotic risk in patients with PDAC may be partially caused by procoagulant blood cells.<br /><b>Objectives</b><br />The aim of this study was to compare blood cell-dependent coagulation between patients with PDAC (n = 18) and healthy controls matched for age and sex (n = 18).<br /><b>Methods</b><br />Thrombin generation (TG) was measured in whole blood (WB) and plasma. The capacity of platelets to release granules (PGRCs) was measured in WB. We explored the occurrence of thromboembolic events in patients with PDAC during a 6-month follow-up.<br /><b>Results</b><br />Patients showed an increased endogenous thrombin potential in WB compared with controls. This difference was not observed in plasma, indicating a procoagulant effect of blood cells. Both in WB and plasma, the lag time was prolonged in patients compared with controls. Patients had hyperresponsive platelets, with a shorter time to peak granule release. Of the 18 patients with PDAC, 4 developed a venous thromboembolism (22%) and 1 developed an arterial thrombosis (6%). A shorter lag time in WB, but not in plasma, and an increased PGRC were associated with thromboembolic events.<br /><b>Conclusion</b><br />Patients with PDAC have an increased and delayed WB TG coagulation profile compared with controls. A shorter lag time in WB TG and increased PGRC are associated with the incidence of thromboembolic events. Platelets appear to be key players in thrombosis development. Measuring hemostasis in WB could improve thrombosis risk estimation in patients with PDAC.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 Apr 2024; 22:1132-1144</small></div>
Willems RAL, Konings J, Huskens D, Middelveld H, ... de Laat B, Roest M
J Thromb Haemost: 01 Apr 2024; 22:1132-1144 | PMID: 38237861
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<div><h4>High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment.</h4><i>Chang X, You J, Yang P, He Y, ... Zhang Y, Zhu Z</i><br /><b>Background</b><br />BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke).<br /><b>Methods</b><br />We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI.<br /><b>Results</b><br />In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, <i>APOE ɛ4</i> carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; <i>P</i>=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (<i>P</i> value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, <i>P</i>=0.001; integrated discrimination index: 1.02%, <i>P</i>=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score.<br /><b>Conclusions</b><br />Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.<br /><br /><br /><br /><small>Stroke: 01 Mar 2024; 55:643-650</small></div>
Chang X, You J, Yang P, He Y, ... Zhang Y, Zhu Z
Stroke: 01 Mar 2024; 55:643-650 | PMID: 38235585
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<div><h4>Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.</h4><i>Montoya S, Bourcier J, Noviski M, Lu H, ... Abdel-Wahab O, Taylor J</i><br /><AbstractText>Increasing use of covalent and noncovalent inhibitors of Bruton\'s tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.</AbstractText><br /><br /><br /><br /><small>Science: 02 Feb 2024; 383:eadi5798</small></div>
Montoya S, Bourcier J, Noviski M, Lu H, ... Abdel-Wahab O, Taylor J
Science: 02 Feb 2024; 383:eadi5798 | PMID: 38301010
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<div><h4>Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum.</h4><i>Mätlik K, Baffuto M, Kus L, Deshmukh AL, ... Pearson CE, Heintz N</i><br /><AbstractText>Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington\'s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nat Genet: 30 Jan 2024; epub ahead of print</small></div>
Mätlik K, Baffuto M, Kus L, Deshmukh AL, ... Pearson CE, Heintz N
Nat Genet: 30 Jan 2024; epub ahead of print | PMID: 38291334
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<div><h4>Blood pressure pulsations modulate central neuronal activity via mechanosensitive ion channels.</h4><i>Jammal Salameh L, Bitzenhofer SH, Hanganu-Opatz IL, Dutschmann M, Egger V</i><br /><AbstractText>The transmission of the heartbeat through the cerebral vascular system causes intracranial pressure pulsations. We discovered that arterial pressure pulsations can directly modulate central neuronal activity. In a semi-intact rat brain preparation, vascular pressure pulsations elicited correlated local field oscillations in the olfactory bulb mitral cell layer. These oscillations did not require synaptic transmission but reflected baroreceptive transduction in mitral cells. This transduction was mediated by a fast excitatory mechanosensitive ion channel and modulated neuronal spiking activity. In awake animals, the heartbeat entrained the activity of a subset of olfactory bulb neurons within ~20 milliseconds. Thus, we propose that this fast, intrinsic interoceptive mechanism can modulate perception-for example, during arousal-within the olfactory bulb and possibly across various other brain areas.</AbstractText><br /><br /><br /><br /><small>Science: 02 Feb 2024; 383:eadk8511</small></div>
Jammal Salameh L, Bitzenhofer SH, Hanganu-Opatz IL, Dutschmann M, Egger V
Science: 02 Feb 2024; 383:eadk8511 | PMID: 38301001
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Abstract
<div><h4>Inherited polygenic effects on common hematological traits influence clonal selection on JAK2 and the development of myeloproliferative neoplasms.</h4><i>Guo J, Walter K, Quiros PM, Gu M, ... Nangalia J, Soranzo N</i><br /><AbstractText>Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2<sup>V617F</sup>, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2<sup>V617F</sup> clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2<sup>V617F</sup> positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2<sup>V617F</sup> carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nat Genet: 01 Feb 2024; 56:273-280</small></div>
Guo J, Walter K, Quiros PM, Gu M, ... Nangalia J, Soranzo N
Nat Genet: 01 Feb 2024; 56:273-280 | PMID: 38233595
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Abstract
<div><h4>The ZmWAKL-ZmWIK-ZmBLK1-ZmRBOH4 module provides quantitative resistance to gray leaf spot in maize.</h4><i>Zhong T, Zhu M, Zhang Q, Zhang Y, ... Balint-Kurti P, Xu M</i><br /><AbstractText>Gray leaf spot (GLS), caused by the fungal pathogens Cercospora zeae-maydis and Cercospora zeina, is a major foliar disease of maize worldwide (Zea mays L.). Here we demonstrate that ZmWAKL encoding cell-wall-associated receptor kinase-like protein is the causative gene at the major quantitative disease resistance locus against GLS. The ZmWAKL<sup>Y</sup> protein, encoded by the resistance allele, can self-associate and interact with a leucine-rich repeat immune-related kinase ZmWIK on the plasma membrane. The ZmWAKL<sup>Y</sup>/ZmWIK receptor complex interacts with and phosphorylates the receptor-like cytoplasmic kinase (RLCK) ZmBLK1, which in turn phosphorylates its downstream NADPH oxidase ZmRBOH4. Upon pathogen infection, ZmWAKL<sup>Y</sup> phosphorylation activity is transiently increased, initiating immune signaling from ZmWAKL<sup>Y</sup>, ZmWIK, ZmBLK1 to ZmRBOH4, ultimately triggering a reactive oxygen species burst. Our study thus uncovers the role of the maize ZmWAKL-ZmWIK-ZmBLK1-ZmRBOH4 receptor/signaling/executor module in perceiving the pathogen invasion, transducing immune signals, activating defense responses and conferring increased resistance to GLS.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nat Genet: 01 Feb 2024; 56:315-326</small></div>
Zhong T, Zhu M, Zhang Q, Zhang Y, ... Balint-Kurti P, Xu M
Nat Genet: 01 Feb 2024; 56:315-326 | PMID: 38238629
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Abstract
<div><h4>Geranylgeranyl Isoprenoids and Hepatic Rap1a Regulate Basal and Statin-Induced Expression of PCSK9.</h4><i>Wang Y, Tinsley B, Spolitu S, Zadroga JA, ... Sarecha AK, Ozcan L</i><br /><AbstractText>Low-density lipoprotein cholesterol (LDL-C) lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.</AbstractText><br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 01 Feb 2024:100515; epub ahead of print</small></div>
Wang Y, Tinsley B, Spolitu S, Zadroga JA, ... Sarecha AK, Ozcan L
J Lipid Res: 01 Feb 2024:100515; epub ahead of print | PMID: 38309417
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Abstract
<div><h4>PI(4,5)P binding sites in the Ebola virus matrix protein VP40 modulate assembly and budding.</h4><i>Johnson KA, Budicini MR, Bhattarai N, Sharma T, ... Li S, Stahelin RV</i><br /><AbstractText>Ebolavirus (EBOV) causes severe hemorrhagic fever in humans and is lethal in a large percentage of those infected. The EBOV matrix protein VP40 is a peripheral binding protein that forms a shell beneath the lipid bilayer in virions and virus-like particles (VLPs). VP40 is required for virus assembly and budding from the host cell plasma membrane. VP40 is a dimer that can rearrange into oligomers at the plasma membrane interface, but it is unclear how these structures form and how they are stabilized. We therefore investigated the ability of VP40 to form stable oligomers using in vitro and cellular assays. We characterized two lysine-rich regions in the VP40 C-terminal domain (CTD) that bind PI(4,5)P<sub>2</sub> and play distinct roles in lipid binding and the assembly of the EBOV matrix layer. The extensive analysis of VP40 with and without lipids by hydrogen deuterium exchange mass spectrometry revealed that VP40 oligomers become extremely stable when VP40 binds PI(4,5)P<sub>2</sub>. The PI(4,5)P<sub>2</sub> induced stability of VP40 dimers and oligomers is a critical factor in VP40 oligomerization and release of VLPs from the plasma membrane. The two lysine-rich regions of the VP40 CTD have different roles with respect to interactions with plasma membrane phosphatidylserine (PS) and PI(4,5)P<sub>2</sub>. CTD region 1 (Lys221, Lys224, and Lys225) interacts with PI(4,5)P<sub>2</sub> more favorably than PS and is important for VP40 extent of oligomerization. In contrast, region 2 (Lys270, Lys274, Lys275, and Lys279) mediates VP40 oligomer stability via lipid interactions and has a more prominent role in release of VLPs.</AbstractText><br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 29 Jan 2024:100512; epub ahead of print</small></div>
Johnson KA, Budicini MR, Bhattarai N, Sharma T, ... Li S, Stahelin RV
J Lipid Res: 29 Jan 2024:100512; epub ahead of print | PMID: 38295986
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Abstract
<div><h4>Exercise and hypoxia-induced hypercoagulability is counterbalanced in women in part by decreased platelet reactivity.</h4><i>Ninivaggi M, Swieringa F, Middelveld H, Schmalschläger V, ... de Laat-Kremers R, de Laat B</i><br /><AbstractText>Hypoxia plays an important role in several pathologies, e.g. chronic obstructive pulmonary disease and obstructive sleep apnea syndrome, and is linked to an increased thrombosis risk. Furthermore, oxygen deprivation is associated with hypercoagulability. In this study, we investigated the effect of gender and exercise on the coagulation potential under hypoxic conditions at high altitude by assessing thrombin generation (TG) and platelet activation. Hereto, ten healthy volunteers were included (50 % male, median age of 27.5 years). The measurements were conducted first at sea level and then twice at high altitude (3883 m), first after a passive ascent by cable car and second after an active ascent by a mountain hike. As expected, both the passive and active ascent resulted in a decreased oxygen saturation and an increased heart rate at high altitude. Acute mountain sickness symptoms were observed independently of the ascent method. After the active ascent, platelet, white blood cell and granulocyte count were increased, and lymphocytes were decreased, without a gender-related difference. FVIII and von Willebrand factor were significantly increased after the active ascent for both men and women. Platelet activation was reduced and delayed under hypobaric conditions, especially in women. TG analysis showed a prothrombotic trend at high altitude, especially after the active ascent. Women had a hypercoagulable phenotype, compared to men at all 3 timepoints, indicated by a higher peak height and endogenous thrombin potential (ETP), and shorter lag time and time-to-peak. In addition, ETP and peak inhibition by thrombomodulin was lower in women after the active ascent, compared to men. Interestingly, data normalisation for subject baseline values indicated an opposing effect of altitude-induced hypoxia on α2-macroglobulin levels and TG lag time between men and women, decreasing in men and increasing in women. We conclude that hypoxia increases TG, as well as FVIII and VWF levels in combination with exercise. In contrast, platelets lose their responsiveness at high altitude, which is most pronounced after heavy exercise. Women had a more pronounced prothrombotic phenotype compared to men, which we theorize is counterbalanced under hypobaric conditions by decreased platelet activation.</AbstractText><br /><br />Copyright © 2024 Elsevier Ltd. All rights reserved.<br /><br /><small>Thromb Res: 01 Feb 2024; 234:142-150</small></div>
Ninivaggi M, Swieringa F, Middelveld H, Schmalschläger V, ... de Laat-Kremers R, de Laat B
Thromb Res: 01 Feb 2024; 234:142-150 | PMID: 38241764
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Abstract
<div><h4>Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.</h4><i>Gamez M, Elhegni HE, Fawaz S, Ho KH, ... Satchell SC, Foster RR</i><br /><b>Background</b><br />Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined.<br /><b>Methods</b><br />In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized to investigate the impact of endothelial cell surface (i.e., endothelial glycocalyx) heparan sulphate loss on microvascular barrier function. Endothelial glycocalyx changes were measured using fluorescence microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2D, db/db) mouse model was used to determine the therapeutic potential of preventing heparan sulphate damage using treatment with a novel heparanase inhibitor, OVZ/HS-1638. Endothelial glycocalyx changes were measured as above, and microvascular barrier function assessed by albumin extravasation in the eye and a glomerular permeability assay in the kidney.<br /><b>Results</b><br />In both models of heparan sulphate depletion, endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permeability was increased. T2D mice treated with OVZ/HS-1638 had improved endothelial glycocalyx measurements compared to vehicle treated T2D mice and were simultaneously protected from microvascular permeability changes associated with DR and DKD.<br /><b>Conclusion</b><br />We demonstrate that endothelial glycocalyx heparan sulphate plays a common mechanistic role in microvascular barrier function in the eye and kidney. Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor OVZ/HS-1638, effectively prevents microvascular permeability changes associated with DR and DKD, demonstrating a novel systemic approach to address diabetic microvascular complications.<br /><br />© 2024. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 01 Feb 2024; 23:50</small></div>
Gamez M, Elhegni HE, Fawaz S, Ho KH, ... Satchell SC, Foster RR
Cardiovasc Diabetol: 01 Feb 2024; 23:50 | PMID: 38302978
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<div><h4>Higher Cholesterol Absorption Marker at Baseline Predicts Fewer Cardiovascular Events in Elderly Patients Receiving Hypercholesterolemia Treatment: The KEEP Study.</h4><i>Kuwabara M, Sasaki J, Ouchi Y, Oikawa S, ... Saikawa T, Arai H</i><br /><b>Background</b><br />Higher cholesterol absorption has been reported to be related to a higher incidence of cardiovascular events (CVEs). The KEEP (Kyushu Elderly Ezetimibe Phytosterol) study, a substudy of the EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study, investigated the relationships of cholesterol absorption and synthesis markers with CVEs in older old individuals with hypercholesterolemia, particularly in relation to ezetimibe treatment.<br /><b>Methods and results</b><br />Eligible patients were those aged ≥75 years who had low-density lipoprotein cholesterol ≥140 mg/dL, no history of coronary artery disease, and no recent use of lipid-lowering drugs. Participants were randomly assigned into a diet-only or diet-plus-ezetimibe group. Baseline and 24-week follow-up blood samples were analyzed for cholesterol absorption (eg, campesterol) and synthesis markers (eg, lathosterol). Of 1287 patients, 1061 patients with baseline measurement were analyzed. Over a median follow-up of 4.0 years, 64 CVEs occurred. Higher campesterol levels at baseline were significantly associated with a lower risk of CVEs. After adjustment for sex, age, and treatment, the hazard ratios for the lowest to highest quartile categories of baseline campesterol were 1.00 (reference), 0.59 (95% CI, 0.30-1.17), 0.44 (95% CI, 0.21-0.94), and 0.44 (95% CI, 0.21-0.93), respectively (trend <i>P</i>=0.01). This association persisted after further adjustment for hypertension, diabetes, and other cardiovascular risk factors. Neither interactions with ezetimibe treatment nor mediating effects of the changes in cholesterol absorption markers were observed.<br /><b>Conclusions</b><br />The KEEP study indicated that higher campesterol levels without lipid-lowering drugs were associated with a lower incidence of CVEs in older old individuals with hypercholesterolemia who were subsequently treated with diet or ezetimibe.<br /><b>Registration</b><br />URL: https://www.umin.ac.jp; unique identifier: UMIN000017769.<br /><br /><br /><br /><small>J Am Heart Assoc: 06 Feb 2024; 13:e031865</small></div>
Kuwabara M, Sasaki J, Ouchi Y, Oikawa S, ... Saikawa T, Arai H
J Am Heart Assoc: 06 Feb 2024; 13:e031865 | PMID: 38240241
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