tbuckley/cabot-search huggingface dataset:
The shared genetic architecture and evolution of human language and musical rhythm
Authors: Gökberk Alagöz, Else Eising, Yasmina Mekki, Giacomo Bignardi, Pierre Fontanillas, Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K. Bell, Jessica Bielenberg, Jonathan Bowes, Katarzyna Bryc, Ninad S. Chaudhary, Daniella Coker, Sayantan Das, Emily DelloRusso, Sarah L. Elson, Nicholas Eriksson, Teresa Filshtein, Will Freyman, Zach Fuller, Chris German, Julie M. Granka, Karl Heilbron, Alejandro Hernandez, Barry Hicks, David A. Hinds, Ethan M. Jewett, Yunxuan Jiang, Katelyn Kukar, Alan Kwong, Yanyu Liang, Keng-Han Lin, Bianca A. Llamas, Matthew H. McIntyre, Steven J. Micheletti, Meghan E. Moreno, Priyanka Nandakumar, Dominique T. Nguyen, Jared O’Connell, Aaron A. Petrakovitz, G. David Poznik, Alexandra Reynoso, Shubham Saini, Morgan Schumacher, Leah Selcer, Anjali J. Shastri, Janie F. Shelton, Jingchunzi Shi, Suyash Shringarpure, Qiaojuan Jane Su, Susana A. Tat, Vinh Tran, Joyce Y. Tung, Xin Wang, Wei Wang, Catherine H. Weldon, Peter Wilton, Corinna D. Wong, Michel G. Nivard, Michelle Luciano, Nancy J. Cox, Simon E. Fisher, Reyna L. Gordon
Journal: Nature Human Behaviour (2024)

Abstract This study aimed to test theoretical predictions over biological underpinnings of previously documented phenotypic correlations between human language-related and musical rhythm traits. Here, after identifying significant genetic correlations between rhythm, dyslexia and various language-related traits, we adapted multivariate methods to capture genetic signals common to genome-wide association studies of rhythm ( N = 606,825) and dyslexia ( N = 1,138,870). The results revealed 16 pleiotropic loci ( P &lt; 5 × 10 −8 ) jointly associated with rhythm impairment and dyslexia, and intricate shared genetic and neurobiological architectures. The joint genetic signal was enriched for foetal and adult brain cell-specific regulatory regions, highlighting complex cellular composition in their shared underpinnings. Local genetic correlation with a key white matter tract (the left superior longitudinal fasciculus-I) substantiated hypotheses about auditory–motor connectivity as a genetically influenced, evolutionarily relevant neural endophenotype common to rhythm and language processing. Overall, we provide empirical evidence of multiple aspects of shared biology linking language and musical rhythm, contributing novel insight into the evolutionary relationships between human musicality and linguistic communication traits.
Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk
Authors: Elaine GY Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M. Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y. Ng, Louis CS Tan, Wee Ling Chng, Tiak Ju Tan, Esther KL Peh, Ying Swan Ho, Xiao Yin Chen, Erin YT Lim, Chu Hua Chang, Jonavan J. Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing-Lok Au, Kumar M. Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne YY Chan, Juei-Jueng Lin, Beom S. Jeon, Kyuyoung Song, Clement C. Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L. Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B. Makarious, Cornelis Blauwendraat, Mike A. Nalls, Laurie A. Robak, Roy N. Alcalay, Ziv Gan-Or, Richard Reynolds, Shen-Yang Lim, Yun Xia, Chiea Chuen Khor, Eng-King Tan, Zhenxun Wang, Jia Nee Foo
Journal: Nature Aging (2024)

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease. Using whole-exome sequencing followed by in vitro enzymatic assays, Chew, Liu, Li, Chung et al. identified rare protein-coding variants in GBA1 and SMPD1 that significantly associate with risk of Parkinson's disease across cohorts of Asian descent.
Solvent-mediated analgesia via the suppression of water permeation through TRPV1 ion channels
Authors: Yuxia Liu, Yuanyuan He, Jiahuan Tong, Shengyang Guo, Xinyu Zhang, Zichao Luo, Linlin Sun, Chao Chang, Bilin Zhuang, Xiaogang Liu
Journal: Nature Biomedical Engineering (2024)
PD-1 and CD73 on naive CD4+ T cells synergistically limit responses to self
Authors: Felix Sebastian Nettersheim, Simon Brunel, Robert S. Sinkovits, Sujit Silas Armstrong, Payel Roy, Monica Billitti, Kouji Kobiyama, Ahmad Alimadadi, Sergei Bombin, Lihui Lu, Martina Zoccheddu, Mohammad Oliaeimotlagh, Chris A. Benedict, Alessandro Sette, Klaus Ley
Journal: Nature Immunology (2024)
Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease
Authors: Stephanie L. Fowler, Tiana S. Behr, Emir Turkes, Darragh P. O’Brien, Paula Maglio Cauhy, Isadora Rawlinson, Marisa Edmonds, Martha S. Foiani, Ari Schaler, Gerard Crowley, Sumi Bez, Elena Ficulle, Eliona Tsefou, Roman Fischer, Beth Geary, Pallavi Gaur, Chelsea Miller, Pasquale D’Acunzo, Efrat Levy, Karen E. Duff, Benjamin Ryskeldi-Falcon
Journal: Nature Neuroscience (2024)

Abstract The abnormal assembly of tau protein in neurons is a pathological hallmark of multiple neurodegenerative diseases, including Alzheimer’s disease (AD). Assembled tau associates with extracellular vesicles (EVs) in the central nervous system of individuals with AD, which is linked to its clearance and prion-like propagation. However, the identities of the assembled tau species and EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from individuals with AD. We found tau filaments composed mainly of truncated tau that were enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.
A STAT3–STING–IFN axis controls the metastatic spread of small cell lung cancer
Authors: Aleks C. Guanizo, Quinton Luong, W. Samantha N. Jayasekara, Eveline D. de Geus, Chaitanya Inampudi, Vincent Senyang Xue, Jasmine Chen, Nicole A. de Weerd, Antony Y. Matthews, Michael P. Gantier, Jesse J. Balic, Surein Arulananda, Daniel J. Garama, Paul J. Hertzog, Vinod Ganju, D. Neil Watkins, Jason E. Cain, Daniel J. Gough
Journal: Nature Immunology (2024)
Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS
Authors: Yuekai Ji, Michael J. Zhang, Wendy Wang, Faye L. Norby, Anne A. Eaton, Riccardo M. Inciardi, Alvaro Alonso, Sanaz Sedaghat, Peter Ganz, Jeremy Van’t Hof, Scott D. Solomon, Paulo H. M. Chaves, Susan R. Heckbert, Amil M. Shah, Lin Yee Chen
Journal: Circulation (2024)

BACKGROUND: Coagulation factor XI (FXI) inhibitors are a promising and novel class of anticoagulants, but a recent animal study found that FXI inhibition exacerbated diastolic dysfunction and heart failure (HF). In the ARIC study (Atherosclerosis Risk in Communities), we investigated whether plasma FXI level was associated with cardiovascular events and cardiac function. METHODS: ARIC was our primary analytic cohort. We included 4471 participants (median age, 75 years; 57% female; 17% Black) who attended visit 5 (2011–2013) with Somalogic-quantified plasma FXI levels and echocardiographic cardiac function. Prevalent HF and atrial fibrillation (AF) cases were defined as having HF or AF diagnosed at or before each participant’s visit 5 exam date. Incident HF and AF events were ascertained through 2021. Associations were assessed using Cox, logistic, and linear regression models. Primary prospective associations were also validated in the CHS (Cardiovascular Health Study) using an orthogonal FXI assay (enzyme-linked immunosorbent assay). RESULTS: At ARIC visit 5, there were 665 and 419 participants with prevalent HF and AF, respectively. During a median follow-up of 9 years, there were 580 and 788 incident HF and AF events, respectively. Lower FXI level was associated prospectively with higher incidence of HF (hazard ratio [HR], 1.36 [for each 1-unit decrement of log 2 -transformed FXI level] [95% CI, 1.01–1.83]) but not incident AF, and cross-sectionally with increased odds of AF (odds ratio [OR], 1.96 [95% CI, 1.23–3.07]) but not HF. In age-stratified analyses, decreased FXI was associated with higher incidence of HF in participants ≥75 years of age (HR, 1.57 [95% CI, 1.08–2.28]) but not &lt;75 years of age (HR, 1.11 [95% CI, 0.68–1.79]). The inverse FXI–HF association was validated in CHS (HR, 1.18 [95% CI, 1.02–1.36]). At ARIC visit 5, lower FXI level was also associated with higher prevalence of diastolic dysfunction and worse E/A ratio, left atrial (LA) volume index, LA function, and left ventricular mass index, but not left ventricular ejection fraction or global longitudinal strain. CONCLUSIONS: Decreased FXI level is associated with greater incidence of HF, especially in older adults. It is also associated with prevalent AF, worse diastolic function, worse LA function, and greater LA size. More research is needed to assess potential unwanted effects of FXI inhibition on the risk of cardiovascular events and cardiac function.
S100A1ct: A Synthetic Peptide Derived From S100A1 Protein Improves Cardiac Performance and Survival in Preclinical Heart Failure Models
Authors: Dorothea Kehr, Julia Ritterhoff, Manuel Glaser, Lukas Jarosch, Rafael E. Salazar, Kristin Spaich, Karl Varadi, Jennifer Birkenstock, Michael Egger, Erhe Gao, Walter J. Koch, Max Sauter, Marc Freichel, Hugo A. Katus, Norbert Frey, Andreas Jungmann, Cornelius Busch, Paul J. Mather, Arjang Ruhparwar, Martin Busch, Mirko Völkers, Rebecca C. Wade, Patrick Most
Journal: Circulation (2024)

BACKGROUND: The EF-hand Ca 2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca 2+ ATPase) and RyR2 (ryanodine receptor 2) in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal α-helix (residues 75–94). We hypothesized that a synthetic peptide consisting of residues 75 through 94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance-enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts. METHODS: We applied an integrative translational research pipeline ranging from in silico computational molecular modeling and in vitro biochemical molecular assays as well as isolated rodent and human cardiomyocyte performance assessments to in vivo safety and efficacy studies in small and large animal cardiac disease models. RESULTS: We characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in preclinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca 2+ cycling and prevents β-adrenergic receptor–triggered Ca 2+ imbalances by targeting SERCA2a and RyR2 activity. In line with the S100A1ct-mediated enhancement of SERCA2a activity, modeling suggests an interaction of the peptide with the transmembrane segments of the sarcoplasmic Ca 2+ pump. Incorporation of a cardiomyocyte-targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo. CONCLUSIONS: S100A1ct is a promising lead for the development of novel peptide-based therapeutics against heart failure with reduced ejection fraction.
Long-Term Management of Right Ventricular Outflow Tract Dysfunction in Repaired Tetralogy of Fallot: A Scientific Statement From the American Heart Association
Authors: Tal Geva, Rachel M. Wald, Emily Bucholz, James F. Cnota, Doff B. McElhinney, Laura M. Mercer-Rosa, Carlos M. Mery, Andrea Leann Miles, Jeremy Moore
Journal: Circulation (2024)

Right ventricular outflow dysfunction, manifesting as stenosis, regurgitation, or both, is nearly universal in patients with repaired tetralogy of Fallot, precipitating a complex pathophysiological cascade that leads to increasing rates of morbidity and mortality with advancing age. As the number of adolescent and adult patients with repaired tetralogy of Fallot continues to grow as a result of excellent survival during infancy, the need to improve late outcomes has become an urgent priority. This American Heart Association scientific statement provides an update on the current state of knowledge of the pathophysiology, methods of surveillance, risk stratification, and latest available therapies, including transcatheter and surgical pulmonary valve replacement strategies, as well as management of life-threatening arrhythmias. It reviews emerging evidence on the roles of comorbidities and patient-reported outcomes and their impact on quality of life. In addition, this scientific statement explores contemporary evidence for clinical choices such as transcatheter or surgical pulmonary valve replacement, discusses criteria and options for intervention for failing implanted bioprosthetic pulmonary valves, and considers a new approach to determining optimal timing and indications for pulmonary valve replacement.
A Latent Cardiomyocyte Regeneration Potential in Human Heart Disease
Authors: Wouter Derks, Julian Rode, Sofia Collin, Fabian Rost, Paula Heinke, Anjana Hariharan, Lauren Pickel, Irina Simonova, Enikő Lázár, Evan Graham, Ramadan Jashari, Michaela Andrä, Anders Jeppsson, Mehran Salehpour, Kanar Alkass, Henrik Druid, Christos P. Kyriakopoulos, Iosif Taleb, Thirupura S. Shankar, Craig H. Selzman, Hesham Sadek, Stefan Jovinge, Lutz Brusch, Jonas Frisén, Stavros Drakos, Olaf Bergmann
Journal: Circulation (2024)

BACKGROUND: Cardiomyocytes in the adult human heart show a regenerative capacity, with an annual renewal rate of ≈0.5%. Whether this regenerative capacity of human cardiomyocytes is employed in heart failure has been controversial. METHODS: We determined cardiomyocyte renewal in 52 patients with advanced heart failure, 28 of whom received left ventricular assist device support. We measured the concentration of nuclear bomb test–derived 14 C in cardiomyocyte genomic DNA and performed mathematical modeling to establish cardiomyocyte renewal in heart failure with and without LVAD unloading. RESULTS: We show that cardiomyocyte generation is minimal in end-stage heart failure patients at rates 18 to 50× lower compared with the healthy heart. However, patients receiving left ventricle support device therapy, who showed significant functional and structural cardiac improvement, had a &gt;6-fold increase in cardiomyocyte renewal relative to the healthy heart. CONCLUSIONS: Our findings reveal a substantial cardiomyocyte regeneration potential in human heart disease, which could be exploited therapeutically.
Multitranscriptome analysis revealed that stromal cells in the papillary dermis promote angiogenesis in psoriasis vulgaris
Authors: Bo Zhang, Junpu Mei, Qijun Liao, Shan Zhou, He Huang, Hui Liu, Xiaoli Xu, Yafen Yu, Chao Wu, Wenjun Wang, Weining Hu, Tingting Zhu, Yin Zhang, Mengyun Chen, Caihong Zhu, Mengjun Yu, Jinping Gao, Xianfa Tang, Xiawei Liu, Ze Guo, Xiaodong Zheng, Wen Zhuang, Gang Chen, Lili Tang, Xiaoyan Ding, Hui Cheng, Yang Li, Hongyan Wang, Hui Li, Yangrui Zhang, Xing Fan, Rouxi Chen, Zherou Rong, Ping Liu, Shengxiu Liu, Zhen Yue, Peiguang Wang, Zhiming Cai, Min Gao, Zaixing Wang, Xiaodong Fang, Fusheng Zhou, Huayang Tang
Journal: British Journal of Dermatology (2024)

Abstract Background The pathogenesis of psoriasis is incompletely understood. Growing evidence suggests the involvement of stromal cells in the inflammatory process. Objectives To investigate the roles of stromal cells, including fibroblasts, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), in the psoriatic inflammatory microenvironment, and the possible underlying mechanisms involved. Methods We used a combination of single-cell, spatial transcriptome and bulk RNA sequencing of lesional and nonlesional skin samples from patients with psoriasis vulgaris (PV) and healthy skin samples from unaffected individuals. Results By analysing transcriptomes from 364 098 single cells, we uncovered WNT5A+ (Wnt-5a) fibroblasts, ITIH5+ (inter-α-trypsin inhibitor heavy chain 5) VECs and VCAN+ (versican) VSMCs, with significantly increased proportions of these cells in the papillary dermis of lesional psoriatic skin. We defined eight unique subclusters of fibroblasts in the skin and observed a shift of WIF1+ (Wnt inhibitory factor 1) fibroblasts toward WNT5A+ fibroblasts, with abnormal activation of the noncanonical Wnt signalling pathway and increased angiogenic and proinflammatory capabilities. VSMCs were able to undergo phenotypic transformation from a contractile to a synthetic phenotype during the development of psoriatic inflammation. ITIH5+ VECs and VCAN+ VSMCs were found to have an essential role in regulating angiogenesis and vascular remodelling in the pathological changes seen in PV. Ligand receptor analyses found that WNT5A+ fibroblasts are extensively implicated in interactions with various skin cell types, especially TIH5+ VECs and VCAN+ VSMCs in the papillary dermis. Conclusions Interactions of stromal cells in the papillary dermis were identified as possible pathogenic elements in PV. Improving the inflammatory microenvironment by targeting stromal cells might be a potential treatment strategy in PV.
α-Synuclein seeding amplification assays for diagnosing synucleinopathies: an innovative tool in clinical implementation
Authors: Yaoyun Kuang, Hengxu Mao, Xiaoyun Huang, Minshan Chen, Wei Dai, Tingting Gan, Jiaqi Wang, Hui Sun, Hao Lin, Qin Liu, Xinling Yang, Ping-Yi Xu
Journal: Translational Neurodegeneration (2024)

Abstract The spectrum of synucleinopathies, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), is characterized by α-synuclein (αSyn) pathology, which serves as the definitive diagnostic marker. However, current diagnostic methods primarily rely on motor symptoms that manifest years after the initial neuropathological changes, thereby delaying potential treatment. The symptomatic overlap between PD and MSA further complicates the diagnosis, highlighting the need for precise and differential diagnostic methods for these overlapping neurodegenerative diseases. αSyn misfolding and aggregation occur before clinical symptoms appear, suggesting that detection of pathological αSyn could enable early molecular diagnosis of synucleinopathies. Recent advances in seed amplification assay (SAA) offer a tool for detecting neurodegenerative diseases by identifying αSyn misfolding in fluid and tissue samples, even at preclinical stages. Extensive research has validated the effectiveness and reproducibility of SAAs for diagnosing synucleinopathies, with ongoing efforts focusing on optimizing conditions for detecting pathological αSyn in more accessible samples and identifying specific αSyn species to differentiate between various synucleinopathies. This review offers a thorough overview of SAA technology, exploring its applications for diagnosing synucleinopathies, addressing the current challenges, and outlining future directions for its clinical use.
Myofibroblast-derived extracellular vesicles facilitate cancer stemness of hepatocellular carcinoma via transferring ITGA5 to tumor cells
Authors: Yang Xiao, Ping Tao, Keke Zhang, Liuyan Chen, Jinyu Lv, Zhiwei Chen, Lu He, Hongling Jia, Jian Sun, Mingrong Cao, Jian Hong, Chen Qu
Journal: Molecular Cancer (2024)

Myofibroblasts constitute a significant component of the tumor microenvironment (TME) and play a pivotal role in the progression of hepatocellular carcinoma (HCC). Integrin α5 (ITGA5) is a crucial regulator in myofibroblasts of malignant tumors. Therefore, the potential of ITGA5 as a novel target for the therapeutic strategy of HCC should be investigated. Digital scanning and analysis of the HCC tissue microarray were performed to locate the distribution of ITGA5 and conduct the prognosis analysis. CRISPR Cas9-mediated ITGA5 knockout was performed to establish the ITGA5-KO myofibroblast cell line. Extracellular vesicles (EVs) derived from LX2 were extracted for the treatment of HCC cells. Subsequently, the sphere-forming ability and the stemness markers expression of the treated HCC cells were examined. An orthotopic HCC mouse model with fibrotic injury was constructed to test the outcomes of ITGA5-targeting therapy and its efficacy in the programmed death-ligand 1 (PD-L1) treatment. Co-immunoprecipitation/mass spectrometry and transcriptome data were integrated to delve into the mechanism. The tissue microarray results revealed that ITGA5 was highly enriched in the stromal myofibroblasts of HCC tissues and contributed to enhanced tumor progression and poor prognosis. Notably, ITGA5 transmission via extracellular vesicles (EVs) from myofibroblasts to HCC cells induced the acquisition of cancer stem cell-like properties. Mechanistically, ITGA5 directly bind to YES1, facilitating the activation of YES1 and its downstream pathways, thereby enhancing the stemness of HCC cells. Furthermore, the blockade of ITGA5 impeded tumor progression driven by ITGA5+ myofibroblasts and enhanced the efficacy of treatment with PD-L1 in a mouse model of HCC. Our findings elucidated a novel mechanism by which the EV-mediated transfer of ITGA5 from myofibroblasts to tumor cells augmented HCC stemness. ITGA5-targeting therapy helped prevent the progression of HCC and improved the efficacy of PD-L1 treatment.
Becker’s nevi are associated with neurological abnormalities
Authors: Pablo Lopez-Balboa, Nicole Knöpfel, Mitesh Ramwani, Noreen Muwanga-Nanyonjo, Claire O'Neill, Debra Lomas, Thomas Cullup, S Polubothu, Veronica A Kinsler
Journal: Journal of the American Academy of Dermatology (2024)
Corrigendum to “Persistent hesitancy for SARS-CoV-2 vaccines among healthcare workers in the United Kingdom: analysis of longitudinal data from the UK-REACH cohort study” [The Lancet Regional Health – Europe, Volume 13, February 2022, 100299]
Authors: Christopher A Martin, Katherine Woolf, Luke Bryant, Sue Carr, Laura J Gray, Amit Gupta, Anna L Guyatt, Catherine John, Carl Melbourne, I Chris McManus, Joshua Nazareth, Laura B Nellums, Martin D Tobin, Daniel Pan, Kamlesh Khunti, Manish Pareek
Journal: The Lancet Regional Health - Europe (2024)