bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravenous streptokinase for myocardial infarction: a reanalysis of the historical cumulative evidence using Trial Sequential Analysis
Authors: Boesen Kim , Gluud Christian 
Published: September 2024

AbstractIntroductionCumulative meta-analysis of intravenous streptokinase for myocardial infarction has been used as a text-book example to show how the megatrials GISSI and ISIS-II were redundant and wasteful. We decided to reanalyse the dataset with Trial Sequential Analysis to account for statistical heterogeneity and the risk of bias of the historical trials to reassess whether GISSI and ISIS-II were justified or redundant.MethodsWe extracted data from overviews published in 1982 and 1985 and trial reports on mortality outcomes. For the five largest trials conducted before GISSI and ISIS-II, we also extracted information on the used comparator, randomisation, blinding, dropout proportions, and the use of intention-to-treat analyses. We did random-effects cumulative meta-analyses with Trial Sequential Analysis considering diversity.ResultsThe largest trials conducted before GISSI and ISIS-II had serious methodological differences and high risks of bias making a cumulative meta-analysis invalid by today’s standards of evidence synthesis. The Trial Sequential Analysis showed that the monitoring boundary for a mortality benefit of streptokinase was reached during the ISAM trial. However, both GISSI and ISIS-II were launched before the ISAM trial was published. Focusing only on the cumulative assessment, the megatrials were potentially futile. Sensitivity analyses corroborated these results.ConclusionOur Trial Sequential Analysis of the historical dataset of streptokinase for myocardial infarction found that conclusive evidence favouring streptokinase was established after the megatrials were launched. However, considering the methodological differences and risks of bias, such cumulative meta-analysis seems invalid. Accordingly, the megatrials were not wasteful.
Subcortical imaging-derived phenotypes are associated with the risk of Parkinson’s disease: A Mendelian Randomization Study
Authors: Chen Zhichun , Liu Jun , You Yong 
Published: September 2024

ABSTRACTBackgroundThe abnormalities of subcortical structures, such as putamen and caudate, play a key role in the occurrence of Parkinson’s disease (PD); however, whether and how imaging-derived phenotypes (IDPs) in subcortical structures are causally associated with the risk of PD remain poorly understood.MethodsThe causal associations between subcortical IDPs from UK biobank and risk of PD were evaluated with bidirectional two-sample Mendelian randomization (MR) studies.ResultsTotally five subcortical IDPs were found to be causally associated with the risk of PD. Among these IDPs, IDP 168 (Global volume of subcortical gray matter, OR = 1.38 [1.16, 1.63],P= 1.82 x 10−4), IDP 214 (Right putamen volume, OR = 1.31 [1.15, 1.50],P= 7.71 x 10−5) and IDP 1441 (T2* signal in right caudate, OR = 1.21 [1.09, 1.35],P= 5.23 x 10−4) were found to be associated with increased risk of PD. In contrast, IDP 1358 (Mean intensity in right caudate, OR = 0.72 [0.62, 0.85),P= 6.77 x 10−5) and IDP 1344 (Mean intensity in left caudate, OR = 0.76 [0.65, 0.88],P= 3.23 x 10−4) were associated with reduced risk of PD.ConclusionsThe specific imaging features of the caudate and putamen are causally associated with altered risk of developing PD, thereby providing new insights into the development of novel predictive imaging biomarkers and therapies for PD patients.
Neanderthal-derived variants shape craniofacial enhancer activity at a human disease locus
Authors: Uttley Kirsty , Jüllig Hannah J , De Angelis Carlo , Auer Julia MT , Ozga Ewa , Bengani Hemant , Long Hannah K 
Published: September 2024

AbstractFacial appearance is one of the most variable morphological traits in humans, influenced by both rare and common genetic variants that can impact facial form between individuals and in disease. Deletion of an enhancer cluster 1.45 megabases upstream of theSOX9gene (EC1.45) results in Pierre Robin sequence, a human craniofacial disorder characterised by underdevelopment of the lower jaw and frequently associated with cleft palate. We reasoned that single nucleotide variants in EC1.45 may cause more subtle alterations to facial morphology. Here, we took advantage of recent human evolution, and the distinct morphology of the Neanderthal lower jaw, to investigate the impact of three Neanderthal-derived single nucleotide variants on EC1.45 function and jaw development. Utilising a dual enhancer-reporter system in zebrafish, we observed enhanced Neanderthal regulatory activity relative to the human orthologue during a specific developmental window. At this same stage, we show that EC1.45 appears to be selectively active in neural crest- derived progenitor cells which lie in close apposition with and are transcriptionally related to precartilaginous condensations that contribute to craniofacial skeletal development. To examine the potential consequences of increasedSOX9expression in this specific cellular population during jaw development, we overexpressed human SOX9 specifically in EC1.45-active cells and observed an increase in the volume of developing cartilaginous precursors. Taken together, our work implicates Neanderthal-derived variants in increased regulatory activity for a disease- associated enhancer with the potential to impact craniofacial skeletal development and jaw morphology across recent hominin evolution.
Nucleosome placement and polymer mechanics explain genomic contacts on 100kbp scales
Authors: Corrette John , Li Jiachun , Shao Hanjuan , Veerasubramanian Praveen Krishna , Spakowitz Andrew , Downing Timothy L. , Allard Jun 
Published: September 2024

AbstractThe 3d organization of the genome — in particular, which two regions of DNA are in contact with each other — plays a role in regulating gene expression. Several factors influence genome 3d organization. Nucleosomes (where∼100 basepairs of DNA wrap around histone proteins) also bend, twist and compactify chromosomal DNA, altering its polymer mechanics. How much does the positioning of nucleosomes between gene loci influence contacts between those gene loci? And, to what extent is polymer mechanics responsible for this? To address this question, we combine a stochastic polymer mechanics model of chromosomal DNA including twists and wrapping induced by nucleosomes with two data-driven pipelines. The first estimates nucleosome positioning from ATACseq data in regions of high accessibility. Most of the genome is low-accessibility, so we combine this with a novel image analysis method that estimates the distribution of nucleosome spacing from electron microscopy data. There are no free parameters in the biophysical model. We apply this method to IL6, IL15, CXCL9, and CXCL10, inflammatory marker genes in macrophages, before and after immune stimulation, and compare the predictions with contacts measured by conformation capture experiments (4C-seq). We find that within a 500 kilo-basepairs genomic region, polymer mechanics with nucleosomes can explain 71% of close contacts. These results suggest that, while genome contacts on 100kbp-scales are multifactorial, they may be amenable to mechanistic, physical explanation. Our work also highlights the role of nucleosomes, not just at the loci of interest, but between them, and not just the total number of nucleosomes, but their specific placement. The method generalizes to other genes, and can be used to address whether a contact is under active regulation by the cell (e.g., a macrophage during inflammatory stimulation). Importantly, our findings suggest that gene function may have evolved through selective pressures that co-opted contact-mediated regulatory mechanisms reliant largely on polymer mechanics.
Context-Dependent Modulations in Acoustic Features of Zebra Finch Distance Calls: Insights from a Novel Goal-Directed Vocalization Paradigm
Authors: Safarcharati Zohreh , Bahramani Amirreza , Mokari Amjad Pouya , Ravanbakhsh Mahsa , Raoufy Mohammad Reza , Khademian Mahdi 
Published: September 2024

AbstractSongbirds are renowned for their complex vocal communication abilities; among them, zebra finches (Taeniopygia guttata) are a key species for studying vocal learning and communication. Zebra finches use various calls with different meanings, including the distance call, which is used for long-distance contact. Whether these calls are static with fixed meanings or flexible remains an open question. In this study we aimed to answer this question by designing a novel behavioral paradigm, in which we trained food-restricted zebra finches to use distance calls for food request. Nine out of ten birds learned this association and used their distance calls to obtain food when they were hungry. We then introduced a visually-separated audience and compared the distance calls used for food requests with those used for communication between birds. Results revealed significant acoustic differences in power, pitch, and other spectral characteristics between the distance calls uttered in these two contexts. Our findings suggest that zebra finches can use their distance call for different goals and also acoustically modulate it based on the context. Therefore, it demonstrates a level of vocal control thought to be exclusive to songs. This study enhances our understanding of vocal flexibility and its role in vocal communication.
Molecular Mechanisms Underlying the Spectral Shift in Zebrafish Cone Opsins
Authors: Chi L. América , Pandey Shubham Kumar , Kolodziejczyk Wojciech , Lund-Andersen Peik , Barnes Jonathan E. , Kapusta Karina , Patel Jagdish Suresh 
Published: September 2024

AbstractVisual pigments are essential for converting light into electrical signals during vision. Composed of an opsin protein and a retinal-based chromophore, pigments in vertebrate rods (Rh1) and cones (Rh2) have different spectral sensitivities, with distinct peak absorption wavelengths determined by the shape and composition of the chromophore binding pocket. Despite advances in understanding Rh1 pigments such as bovine rhodopsin, the molecular basis of spectral shifts in Rh2 cone opsins has been less studied, particularly the E122Q mutation, which accounts for about half of the observed spectral shift in these pigments. In this study, we employed molecular modeling and quantum mechanical techniques to investigate the molecular mechanisms behind the spectral difference in blue-shifted Rh2-1 (absorption peak = 467 nm, 122Q) and green-shifted Rh2-4 (absorption peak = 505 nm, 122E) zebrafish cone opsins. We modeled the pigments 3D structures based on their sequences and conducted all-atom molecular dynamics simulations totaling 2 microseconds. Distance analysis of the trajectories identified three key sites: E113, E181, and E122. The E122Q mutation, previously known, validates our findings, while E181 and E113 are newly identified contributors. Structural analysis revealed key features with differing values that explain the divergent spectral sensitivities of Rh2-1 and Rh2-4: 1) chromophore atom fluctuations and C5-C6 torsion angle, 2) binding pocket volume, 3) hydration patterns, and 4) E113-chromophore interaction stability. Quantum mechanics further confirms the critical role of residue E181 in Rh2-1 and E122 in Rh2-4 for their spectral behavior. Our study provides new insights into the molecular determinants of spectral shifts in cone opsins, and we anticipate that it will serve as a starting point for a broader understanding of the functional diversity of visual pigments.
Dynamic transcriptional and epigenetic changes define postnatal tendon growth
Authors: Dingwall Heather L. , Grinstein Mor , Capellini Terence D. , Galloway Jenna L. 
Published: September 2024

AbstractTendons are dynamic structures that efficiently transmit forces and enable movement. From birth, tendons undergo dramatic changes from a principally cellular tissue to a hypocellular one characterized by a dense and highly ordered extracellular matrix. During this time, tendon cells change morphology from rounded to stellate in appearance and their proliferative rates decline. There is also significant expansion and maturation of the extracellular matrix (ECM) as tendons grow in length and diameter and alter their biomechanical properties to sustain increased physical activities. Surprisingly, for such an important stage of tendon maturation, we understand very little about the transcriptional and epigenetic regulators that direct these processes. Here, we present a roadmap of genes that are differentially regulated during the early neonatal and postnatal time period. We find differentially expressed genes fall into specific transcriptional modules, representing expression increases, decreases, or gene sets undergoing dynamic changes over postnatal time. By pairing our transcriptomic data with epigenetic data, we were able to perform an integrative analysis of the datasets and further define modules with highly correlated changes in gene expression and chromatin accessibility. From this analysis, several new pathways emerge. Among them, we focus on Yap1, a transcriptional co-activator of the Hippo signaling pathway. We observe accessible regions near to differentially expressed genes, containing motifs for TEAD, the transcription factor that binds Yap to regulate transcription. Conditional loss ofYap1at postnatal stages results in altered expression ofCol1a1and disrupted matrix organization and density, suggesting that Yap is important for refining tendon ECM maturation. Together, our analyses identify a regulator of matrix maturation and provides a rich dataset with which to interrogate transcriptional networks and pathways during this poorly understood time in tendon growth.
Absorbing discretization effects with a massive renormalization scheme: The charm-quark mass
Authors: Del Debbio L. , Erben F. , Flynn J. M. , Mukherjee R. , Tsang J. T. ,   RBC and UKQCD Collaborations
Published: September 2024

We present the first numerical implementation of the massive symmetric-momentum-subtraction (mSMOM) renormalization scheme and use it to calculate the charm-quark mass. Based on ensembles with three flavors of dynamical domain-wall fermions with lattice spacings in the range 0.11–0.08 fm, we demonstrate that the mass scale which defines the mSMOM scheme can be chosen such that the extrapolation has significantly smaller discretization effects than the SMOM scheme. Converting our results to the MS¯ scheme we obtain m¯c(3  GeV)=1.008(13)  GeV and m¯c(m¯c)=1.292(12)  GeV.

Published by the American Physical Society
2024
(Re)Emergence of the factor zoo debate: a bibliometric review
Authors: Guimarães Paulo Roberto , Kimura Herbert 
Published: September 2024

PurposeAsset pricing literature is facing a credibility crisis, given debates associated with publication biases, data mining, replicability, crowding and lack of theoretic foundations. This study proposes that emerging markets (EMs), with their specific socioeconomic characteristics and lesser financial integration with developed markets (DMs), might provide useful arguments to the debate and improve our understanding of asset pricing. Beyond out-of-sample evidence for DM findings, EM research can unveil regional-specific factors overlooked by mainstream literature and investigating reasons behind differences can reveal epistemological elements for proposing and testing theories, and clarifying causal mechanisms.Design/methodology/approachThe present work conducts an EM-focused systematic review, by applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, a transparent and replicable procedure, to gather a representative collection of papers and using bibliometric methods to analyze bibliographic data.FindingsBesides summarizing and contextualizing scientific production, revealing most important themes and actors, we confirm a clear bias toward DM and identify low scientific collaboration among EM. Additionally, we assess to which extent current studies fulfills EM research potential.Originality/valueThere is a home bias in literature, with most studies focusing on DM. This systematic review is exclusive to EM literature and suggests how EM research can improve literature credibility.
Alcohol and brain structure across the lifespan: A systematic review of large‐scale neuroimaging studies
Authors: Karoly Hollis C. , Kirk‐Provencher Katelyn T. , Schacht Joseph P. , Gowin Joshua L. 
Published: September 2024

AbstractAlcohol exposure affects brain structure, but the extent to which its effects differ across development remains unclear. Several countries are considering changes to recommended guidelines for alcohol consumption, so high‐quality evidence is needed. Many studies have been conducted among small samples, but recent efforts have been made to acquire large samples to characterize alcohol's effects on the brain on a population level. Several large‐scale consortia have acquired such samples, but this evidence has not been synthesized across the lifespan. We conducted a systematic review of large‐scale neuroimaging studies examining effects of alcohol exposure on brain structure at multiple developmental stages. We included studies with an alcohol‐exposed sample of at least N = 100 from the following consortia: ABCD, ENIGMA, NCANDA, IMAGEN, Framingham Offspring Study, HCP and UK BioBank. Twenty‐seven studies were included, examining prenatal (N = 1), adolescent (N = 9), low‐to‐moderate‐level adult (N = 11) and heavy adult (N = 7) exposure. Prenatal exposure was associated with greater brain volume at ages 9–10, but contemporaneous alcohol consumption during adolescence and adulthood was associated with smaller volume/thickness. Both low‐to‐moderate consumption and heavy consumption were characterized by smaller volume and thickness in frontal, temporal and parietal regions, and reductions in insula, cingulate and subcortical structures. Adolescent consumption had similar effects, with less consistent evidence for smaller cingulate, insula and subcortical volume. In sum, prenatal exposure was associated with larger volume, while adolescent and adult alcohol exposure was associated with smaller volume and thickness, suggesting that regional patterns of effects of alcohol are similar in adolescence and adulthood.
Traces of Bronze Age globalization in East Asia: Insights from a revised phylogeography of the Y‐chromosome haplogroup Q1a1a‐M120
Authors: Mai La‐Su , Zhang Xian‐Peng , Liu Kai‐Jun , Ma Peng‐Cheng , Li Hui , Sun Jin , Wei Lan‐Hai 
Published: September 2024

AbstractObjectiveIn this study, we aim to explore the genetic imprint of Bronze Age globalization in East Asia from a phylogeographic perspective by examining the Y‐chromosome haplogroup Q1a1a‐M120, and to identify key demographic processes involved in the formation of early China and the ancient Huaxia people.MethodsOver the past few decades, we have collected the sequences of 347 Y chromosomes from the haplogroup Q1a1a‐M120. These sequences were utilized to analyze and reconstruct a highly revised phylogenetic tree with age estimates. And we analyzed the geographical distribution and spatial autocorrelation of nine major sub‐branches of Q1a1a‐M120. Finally, we observed the expansion of Q1a1a‐M120 from the beginning of the Bronze Age in East Asia, along with the continuous dissemination of its sub‐lineages among East Asian populations.ResultsWe suggest that certain sub‐lineages played a significant role in the formation of states and early civilizations in China, as well as in the development of the ancient Huaxia people, who are the direct ancestors of the Han population. Overall, we propose that haplogroup Q‐M120 played a role in the introduction of Bronze Age culture to the central region of East Asia. Therefore, it is haplogroup Q‐M120, rather than the Western Eurasian paternal lineage, that expanded and contributed to the gene pool of the East Asian population.ConclusionIn summary, the globalization of the Bronze Age led to large‐scale population replacement and admixture across various regions of Eurasia; our findings highlight the unique demographic processes that occurred in East Asia during this period.
HIV‐Associated Genital Immune Biomarkers in the Female Sex Worker Population: A Pilot Study
Authors: Capozzi Eleanor , Daniels Jason , Mohamed Hani , Mejia Fernando Cabezas , Sternberg David , Bouey Jennifer , Ghosh Mimi 
Published: September 2024

ABSTRACTProblemFemale sex workers (FSW) experience a disproportionately high burden of HIV infection, yet characterization of the vaginal immune microenvironment that may impact biological risk is not well studied among FSW in the United States. Additionally, feasible methodology for collecting biological materials has not been evaluated in this population.MethodsWe enrolled 10 FSW (5 premenopausal, 5 postmenopausal) who participated in a survey and provided vaginal swabs. Biomarkers were assessed by ELISA, and included cytokines, chemokines, and antimicrobial/wound‐healing mediators.ResultsOne hundred percent of FSW were African American, with a median age of 43.5. The median age when participants started sex work was 17.5, with 60% working 7 days per week and seeing up to 10 clients per night. Eighty percent reported recent unprotected sex and only 30% used some form of contraception. One self‐reported sexually transmitted infection at the time of visit and two reported living with HIV. Vaginal secretions showed detectable levels of all biomarkers tested, except MIP3α and MIP1α, which were undetectable in all samples. When stratified by age/menopause status, no significant changes were observed except for Serpin A1 with higher median levels in premenopausal compared to postmenopausal FSW (median 5.79 vs. 5.205 log pg/mL, p = 0.016). Comparison with samples from an existing repository of non‐FSW women showed significantly reduced chemokines IL8 (p = 0.045), MIP3α (p ≤ 0.001), and MIP1β (p = 0.015) in the FSW group.ConclusionsWe report characterization of the vaginal secretome in a cohort of FSW in the United States. Understanding of the genital immune microenvironment can inform future research in HIV prevention and therapeutic options in this population.