bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence of survival bias in the association betweenAPOE-Є4and age of ischemic stroke onset
Authors: von Berg Joanna , McArdle Patrick F. , Häppölä Paavo , Haessler Jeffrey , Kooperberg Charles , Lemmens Robin , Pezzini Alessandro , Thijs Vincent , Pulit Sara L. , Kittner Steven J. , Mitchell Braxton D. , de Ridder Jeroen , van der Laan Sander W. 
Published: December 2023

AbstractLarge genome-wide association studies (GWAS) employing case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing age at onset (AAO) of ischemic stroke. Analyses were conducted in a Discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value < 1×10−5in a sex-combined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for association of AAO with rs429358, an exonic variant inAPOEthat encodes for the APOE-є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29 years earlier stroke AOO (meta p-value = 2.48×10−11).ThisAPOEvariant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decline in mortality among APOE-є4 carriers and have no association to stroke AAO per se. Using a simulation study, we found that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a two-fold increase on mortality risk would lead to an observed effect of AAO that is comparable to what we found. In conclusion, we detected a robust association of theAPOElocus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.
Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing
Authors: Humphrey Jack , Brophy Erica , Kosoy Roman , Zeng Biao , Coccia Elena , Mattei Daniele , Ravi Ashvin , Efthymiou Anastasia G. , Navarro Elisa , Muller Benjamin Z. , Snijders Gijsje JLJ , Allan Amanda , Münch Alexandra , Kitata Reta Birhanu , Kleopoulos Steven P , Argyriou Stathis , Shao Zhiping , Francoeur Nancy , Tsai Chia-Feng , Gritsenko Marina A , Monroe Matthew E , Paurus Vanessa L , Weitz Karl K , Shi Tujin , Sebra Robert , Liu Tao , de Witte Lot D. , Goate Alison M. , Bennett David A. , Haroutunian Vahram , Hoffman Gabriel E. , Fullard John F. , Roussos Panos , Raj Towfique 
Published: December 2023

AbstractMicroglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. We previously mapped the genetic regulation of gene expression and mRNA splicing in human microglia, identifying several loci where common genetic variants in microglia-specific regulatory elements explain disease risk loci identified by GWAS. However, identifying genetic effects on splicing has been challenging due to the use of short sequencing reads to identify causal isoforms. Here we present the isoform-centric microglia genomic atlas (isoMiGA) which leverages the power of long-read RNA-seq to identify 35,879 novel microglia isoforms. We show that the novel microglia isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ethnic meta-analysis of 555 human microglia short-read RNA-seq samples from 391 donors, the largest to date, and found associations with genetic risk loci in Alzheimer’s disease and Parkinson’s disease. We nominate several loci that may act through complex changes in isoform and splice site usage.
Comparative studies of genetic and phenotypic associations for 2,168 plasma proteins measured by two affinity-based platforms in 4,000 Chinese adults
Authors: Wang Baihan , Pozarickij Alfred , Mazidi Mohsen , Wright Neil , Yao Pang , Said Saredo , Iona Andri , Kartsonaki Christiana , Fry Hannah , Lin Kuang , Chen Yiping , Du Huaidong , Avery Daniel , Schmidt Dan Valle , Yu Canqing , Sun Dianjianyi , Lv Jun , Hill Michael , Li Liming , Bennett Derrick A , Collins Rory , Walters Robin G , Clarke Robert , Millwood Iona Y , Chen Zhengming 
Published: December 2023

AbstractProteomics offers unique insights into human biology and drug development, but few studies have directly compared the utility of different proteomics platforms. We measured 2,168 plasma proteins in 3,976 Chinese adults using both OLINK and SomaScan platforms and compared their genetic determinants and associations with traits and disease risk. For 1,694 proteins with one-to-one matched reagents, there was a modest between platform correlation (median rho=0.20). OLINK-proteins had fewertrans-pQTLs (766 vs 812 proteins) but morecis-pQTLs (725 vs 565) than SomaScan-proteins, including 342 with colocalisingcis-pQTLs. Moreover, 1,095 OLINK- and 963 SomaScan-proteins showed significant associations with BMI, while 279 and 165 proteins were significantly associated with IHD, respectively. Addition of these IHD-associated proteins to conventional risk factors yielded NRIs for IHD of 15.3% and 17.1% for OLINK and SomaScan respectively. The results demonstrate the complementarity of different proteomic platforms and should inform assay selection in future population and clinical studies.
The virtual multiple sclerosis patient: on the clinical-radiological paradox
Authors: Sorrentino P , Pathak A , Ziaeemehr A , Troisi Lopez E , Cipriano L , Romano A , Sparaco M , Quarantelli M , Banerjee A , Sorrentino G , Hashemi M , Jirsa V 
Published: December 2023

AbstractMultiple sclerosis (MS) is typically diagnosed based on the clinical presentation, the presence of structural MRI lesions, and a “no better explanation” criterion. The structural lesions, disseminated in time and space, are a consequence of autoimmune processes leading to the damage of the myelin sheath in the central nervous system. As such, one would expect that more lesions would relate to higher clinical disability. However, a conflicting scenario is often present, with a high lesion load related to mild clinical impairment, and vice versa, a phenomenon referred to as the “clinico-radiological paradox”. The myelin damage in MS is widespread, which is likely mirrored in a widespread slowing of conduction velocities. However, conduction velocities are typically measured on selected white-matter tracts (e.g., visual evoked potentials), which do not directly relate to clinical impairment. In this paper, we hypothesize that the overall slowing of conduction velocities (i.e., across all brain tracts) is a better predictor of clinical disability. However, estimating the whole-brain average velocities is challenging. To overcome this obstacle, we estimated patient-specific conduction velocities in MS patients by merging multimodal data (i.e., DTI and source-reconstructed magnetoencephalography) to inform large-scale brain models, fitted on each individual patient. We started from the known reduction of the power of the alpha frequency band, as well as the shift in its peak, observed in MS patients. We then reproduced these individual spectral features in silico using large-scale models based on the individual connectomes. We then used state-of-the-art deep neural networks for Bayesian model inversion to estimate the most likely average conduction velocity in each patient, given the observed spectral features (and the connectomes). Finally, we used the inferred conduction velocities to predict the individual clinical disability. We find that the conduction velocities inferred for patients are significantly lower than those inferred for controls and that they are predictive of individual clinical disability, well above the predictive power of demographic and clinical variables and lesion load. Our results suggest a biologically and physically plausible solution to the “clinico-radiological” paradox, where the inferred, individual changes in conduction velocities across the whole networks are proposed as causative to the clinical disability.
Three-dimensional Isotropic Imaging of Live Suspension Cells Enabled by Droplet Microvortices
Authors: Cardenas-Benitez Braulio , Hurtado Richard , Luo Xuhao , Lee Abraham P. 
Published: December 2023

AbstractThree-dimensional (3D) imaging of non-adherent cells in suspension media is challenging due to their propensity to drift when not fixed to a substrate, as required by optical sectioning technologies. Resolution differences in the lateral versus depth directions typically present in those systems further complicates single-cell morphometry of cellular features indicative of effector functions, such as cytosol and organelle volumetric distribution, and cell membrane topography. Here, we present a method for 3D fluorescent isotropic imaging of live, non-adherent single cells encapsulated in picoliter droplets using Optical Projection Tomography (OPT) enabled by droplet microvortices. Our microfluidic platform features a droplet trap array that leverages flow-induced droplet interfacial shear to generate intra-droplet microvortices, which in turn are modulated to rotate single-cells on their axis to enable OPT-based imaging. This strategy allows observation of cells encapsulated inside non-toxic isotonic buffer droplets and facilitates scalable OPT acquisition by the simultaneous spinning of hundreds of cells. Specifically, we demonstrate 3D imaging of live myeloid and lymphoid cells in suspension, including K562 cells, as well as naïve and activated T cells—small cells prone to movement in their suspended phenotype. In addition, morphometry of primary T cells under different immunological activation states allowed us to identify six distinct nuclear content distributions, which differ from the conventional 2D images depicting spheroid and bean-like nuclear shapes commonly associated with lymphocytes. This Arrayed-Droplet Optical Projection Tomography (ADOPT) technology is capable of isotropic, single live-cell 3D imaging and has the potential to perform large-scale morphometry of immune cell effector function states, while providing compatibility with microfluidic droplet operations.
Mechanism of homology search expansion during recombinational DNA break repair
Authors: Dumont Agnès , Mendiboure Nicolas , Savocco Jérôme , Anani Loqmen , Moreau Pierrick , Thierry Agnès , Modolo Laurent , Jost Daniel , Piazza Aurèle 
Published: December 2023

AbstractHomology search catalyzed by a RecA/Rad51 nucleoprotein filament (NPF) is a central step of DNA double-strand break (DSB) repair by homologous recombination. How it operates in cells remains elusive. Here we developed a Hi-C-based methodology to map single-stranded DNA (ssDNA) contacts genome-wide inS. cerevisiae, which revealed two main homology search phases. Initial search conducted by short NPFs is confined incisby cohesin-mediated chromatin loop folding. Progressive growth of stiff NPFs enables exploration of distant genomic sites. Long-range resection by Exo1 drives this transition from local to genome-wide search by providing ssDNA substrates for assembly of extensive NPFs. DSB end-tethering promotes coordinated homology search by NPFs formed on the two DSB ends. Finally, an autonomous genetic element on chromosome III engages the NPF and stimulates homology search in its vicinity. This work reveals the mechanism of the progressive and uneven expansion of homology search orchestrated by chromatin organizers, long-range resection, end-tethering, specialized genetic elements, and that exploits the stiff NPF structure conferred by Rad51 oligomerization.Highlights–Cohesin-mediated chromatin loops constrain homology search incisfor NPF regions close to the resection front–Stiffening of ssDNA by Rad51 enables genome-wide homology search by DSB-proximal sites–Exo1-mediated long-range resection promotes genome-wide homology search–DSB end-tethering promotes coordinated homology search by NPFs formed on both DSB ends–The recombination enhancer focuses homology search in its vicinity
A point cloud segmentation framework for image-based spatial transcriptomics
Authors: Defard Thomas , Laporte Hugo , Ayan Mallick , Juliette Soulier , Curras-Alonso Sandra , Weber Christian , Massip Florian , Londoño-Vallejo José-Arturo , Fouillade Charles , Mueller Florian , Walter Thomas 
Published: December 2023

AbstractRecent progress in image-based spatial RNA profiling enables to spatially resolve tens to hundreds of distinct RNA species with high spatial resolution. It hence presents new avenues for comprehending tissue organization. In this context, the ability to assign detected RNA transcripts to individual cells is crucial for downstream analyses, such as in-situ cell type calling. Yet, accurate cell segmentation can be challenging in tissue data, in particular in the absence of a high-quality membrane marker. To address this issue, we introduce ComSeg, a segmentation algorithm that operates directly on single RNA positions and that does not come with implicit or explicit priors on cell shape. ComSeg is thus applicable in complex tissues with arbitrary cell shapes. Through comprehensive evaluations on simulated datasets, we show that ComSeg outperforms existing state-of-the-art methods for in-situ single-cell RNA profiling and cell type calling. On experimental data, our method also demonstrates proficiency in estimating RNA profiles that align with established scRNA-seq datasets. Importantly, ComSeg exhibits a particular efficiency in handling complex tissue, positioning it as a valuable tool for the community.
First detection ofAnopheles stephensiin Ghana using molecular surveillance
Authors: Afrane Yaw A. , Abdulai Anisa , Mohammed Abdul R. , Akuamoah-Boateng Yaw , Owusu-Asenso Christopher Mfum , Sraku Isaac K. , Yanney Stephina A. , Malm Keziah , Lobo Neil F. 
Published: December 2023

AbstractThe invasiveAnopheles stephensimosquito has been rapidly expanding in range in Africa over the last decade, spreading from the Indian sub-continent to several East African countries (Djibouti, Ethiopia, Sudan, Somalia and Kenya) and now in West Africa, Nigeria. The rapid expansion of this invasive vector poses a major threat to current malaria control and elimination efforts. In line with the WHO’s strategy to stop the spread of this invasive species by enhancing surveillance and control measures in Africa, we incorporated morphological and molecular surveillance ofAn. stephensiinto routine entomological surveillance of malaria vectors in the city of Accra, Ghana. Here, we report on the first detection ofAn. stephensiin Ghana.An. stephensimosquitoes were confirmed using PCR and sequencing of the ITS2 regions. These findings highlight the urgent need for increased surveillance and response strategies to mitigate the spread ofAn. stephensiin Ghana.
Cryo-EM structures of human α1B/βI+βIVb microtubules shed light on isoform specific assembly
Authors: Zehr Elena A. , Roll-Mecak Antonina 
Published: December 2023

AbstractMicrotubules are dynamic polymers assembled from αβ-tubulin dimers. Mammals have multiple α and β-tubulin isoforms. Despite a high degree of conservation, microtubules assembled from different tubulin isoforms have unique dynamic properties. How isoform sequence variation affects polymerization interfaces and nucleotide dependent conformational changes in microtubules is still not well understood. Here we report 2.9Å resolution cryo-EM structures of human α1B/βI+βIVb microtubules in the GDP state, and a GTP-like state, bound to GMPCPP. Our structures show that, similar to microtubules assembled from other mammalian isoforms, transition from the GTP to the GDP states in α1B/βI+βIVb microtubules results in strengthening of the longitudinal interface and an overall compaction of the axial dimer repeat distance in the lattice. Interestingly, we find that α-tail residues link longitudinally adjacent tubulin dimers through interactions with two conserved arginine residues in β-tubulin that are mutated in human disease. Comparative analysis of tubulin isoforms shows minimal isoform-specific effects at the longitudinal interface or the α-tubulin lateral interface, but a high concentration of sequence variability in the second shell of residues away from the β-tubulin lateral interface which can modulate polymerization interfaces and thus impact microtubule dynamics.
Leptomeningeal Neural Organoid (LMNO) Fusions as Models to Study Meninges-Brain Signaling
Authors: Jones Hannah E , Robertson Gabriella L , Romero-Morales Alejandra , O’Rourke Rebecca , Siegenthaler Julie A , Gama Vivian 
Published: December 2023

AbstractNeural organoids derived from human induced pluripotent stem cells (iPSCs) provide a model to study the earliest stages of human brain development, including neurogenesis, neural differentiation, and synaptogenesis. However, neural organoids lack supportive tissues and some non-neural cell types that are key regulators of brain development. Neural organoids have instead been co-cultured with non-neural structures and cell types to promote their maturation and model interactions with neuronal cells. One structure that does not formde novowith neural organoids is the meninges, a tri-layered structure that surrounds the CNS and secretes key signaling molecules required for mammalian brain development. Most studies of meninges-brain signaling have been performed in mice or using two-dimensional (2D) cultures of human cells, the latter not recapitulating the architecture and cellular diversity of the tissue. To overcome this, we developed a co-culture system of neural organoids generated from human iPSCs fused with fetal leptomeninges from mice with fluorescently labeled meninges (Col1a1-GFP). These proof-of-concept studies test the stability of the different cell types in the leptomeninges (fibroblast and macrophage) and the fused brain organoid (progenitor and neuron), as well as the interface between the organoid and meningeal tissue. We test the longevity of the fusion pieces after 30 days and 60 days in culture, describe best practices for preparing the meninges sample prior to fusion, and examine the feasibility of single or multiple meninges pieces fused to a single organoid. We discuss potential uses of the current version of the LMNO fusion model and opportunities to improve the system.
PIEZO2‐dependent rapid pain system in humans and mice
Authors: Bouchatta Otmane , Brodzki Marek , Manouze Houria , Carballo Gabriela B. , Kindström Emma , de‐Faria Felipe M. , Yu Huasheng , Kao Anika R. , Thorell Oumie , Liljencrantz Jaquette , Ng Kevin K. W. , Frangos Eleni , Ragnemalm Bengt , Saade Dimah , Bharucha‐Goebel Diana , Szczot Ilona , Moore Warren , Terejko Katarzyna , Cole Jonathan , Bonnemann Carsten , Luo Wenquin , Mahns David A. , Larsson Max , Gerling Gregory J. , Marshall Andrew G. , Chesler Alexander T. , Olausson Håkan , Nagi Saad S. , Szczot Marcin 
Published: December 2023

SummaryThe PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception – a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aβ deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aβ input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.
Enhancing the auditor's mindset: a framework for nurturing professional skepticism
Authors: Kelly Martin , Larres Patricia 
Published: December 2023

PurposeFollowing recent high-profile audit failures, concern has been expressed that auditors are not demonstrating sufficient skepticism when exercising professional judgment. In particular, client assumptions and estimations relating to hypothetical valuations in financial reporting are not being challenged. This paper seeks to address the issue by advancing a decision-making framework aimed at guiding auditors beyond regulatory reductionist thinking towards an enhanced understanding of the cognitive processes which shape professional judgment in forming a reliable audit opinion.Design/methodology/approachDrawing on the normative philosophical and theological teachings of Bernard Lonergan, the authors' decision-making framework embodies reflective thinking and the data of consciousness to highlight the central role played by enquiry in the dynamics of understanding, judgment and decision-making. Such enquiry elicits challenge of the management bias inherent in hypothetical valuations.FindingsAuditing through a Lonerganian lens allows auditors to reflect on their approach to objective decision-making by offering a set of cognitive tools to enhance the enquiry essential for nurturing professional skepticism.Originality/valueThis paper contributes to the literature by developing the somewhat neglected discourse on the cognitive processes essential for professional skepticism and audit judgment. The authors demonstrate how Lonerganian self-appropriation intensifies an awareness of the recursive cognitive activities pertinent to objective judgment and decision-making. This awakened consciousness has the potential not only to change how auditors question evidence to make informed judgments and decisions, but also to normalize the practice of challenge.