bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India
Authors: Andrews Shan V , Kukkle Prashanth L , Menon Ramesh , Geetha Thenral S , Goyal Vinay , Kandadai Rukmini Mridula , Kumar Hrishikesh , Borgohain Rupam , Mukherjee Adreesh , Wadia Pettarusp M , Yadav Ravi , Desai Soaham , Kumar Niraj , Joshi Deepika , Murugan Sakthivel , Biswas Atanu , Pal Pramod K , Oliver Merina , Nair Sandhya , Kayalvizhi Anbu , Samson Praveena L , Deshmukh Manjari , Bassi Akshi , Sandeep Charugulla , Mandloi Nitin , Davis Oliver B , Roberts Melissa A , Leto Dara E , Henry Anastasia G , Di Paolo Gilbert , Muthane Uday , Das Shymal K , Peterson Andrew S , Sandmann Thomas , Gupta Ravi , Ramprasad Vedam L ,   Parkinson Research Alliance of India (PRAI)
Published: June 2023

AbstractBackgroundRecent studies have advanced our understanding of the genetic drivers of Parkinson’s Disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD GWAS study identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused.ObjectivesTo identify genetic risk factors for PD in a South Asian population.Methods674 PD subjects predominantly with age of onset ≤ 50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period. 1,376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and age of onset.ResultsA genome-wide significant signal for PD diagnosis was identified in theSNCAregion, strongly colocalizing withSNCAregion signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identifiedBSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease.ConclusionsThis study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group.
An explainable machine learning-based phenomapping strategy for adaptive predictive enrichment in randomized controlled trials
Authors: Oikonomou Evangelos K , Thangaraj Phyllis M. , Bhatt Deepak L , Ross Joseph S , Young Lawrence H , Krumholz Harlan M , Suchard Marc A , Khera Rohan 
Published: June 2023

ABSTRACTRandomized controlled trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate’s probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: – 14.8% ± 3.1%,pone-sample t-test=0.001; SPRINT: –17.6% ± 3.6%,pone-sample t-test<0.001), while preserving the original average treatment effect (IRIS: hazard ratio of 0.73 ± 0.01 for pioglitazone vs placebo, vs 0.76 in the original trial; SPRINT: hazard ratio of 0.72 ± 0.01 for intensive vs standard systolic blood pressure, vs 0.75 in the original trial; all withpone-sample t-test<0.01). This adaptive framework has the potential to maximize RCT enrollment efficiency.
A Novel Autosomal Dominant Childhood-Onset Disorder Associated with Pathogenic Variants inVCP
Authors: Mah-Som Annelise Y. , Daw Jil , Huynh Diana , Wu Mengcheng , Creekmore Benjamin C. , Burns William , Skinner Steven A. , Holla Øystein L. , Smeland Marie F. , Planes Marc , Uguen Kevin , Redon Sylvia , Bierhals Tatjana , Scholz Tasja , Denecke Jonas , Mensah Martin A. , Sczakiel Henrike L. , Tichy Heidelis , Verheyen Sarah , Blatterer Jasmin , Schreiner Elisabeth , Thies Jenny , Lam Christina , Spaeth Christine , Pena Loren , Ramsey Keri , Narayanan Vinodh , Seaver Laurie H. , Rodriguez Diana , Afenjar Alexandra , Burglen Lydie , Lee Edward B. , Chou Tsui-Fen , Weihl Conrad C. , Shinawi Marwan S. 
Published: June 2023

ABSTRACTValosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants inVCPare associated with adult-onset multisystem proteinopathy (MSP) that presents with myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who carry novel heterozygousVCPvariants (12de novo, 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performedin vitrofunctional studies andin silicomodelling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This is the first description ofVCP-related neurodevelopmental disease presenting in childhood.
Different indicators of stress-induced hyperglycemia and poor outcomes after spontaneous intracerebral hemorrhage
Authors: Song Xintong , Zhang Jia , Wang Wenjuan , Wang Anxin , Zhang Xiaoli , Li Sijia , Wang Chuanying , Zhao Xingquan , Zhang Qian 
Published: June 2023

AbstractBackgroundThis study aimed to compare the predictive value of metrics unique to stress-induced hyperglycemia (SIH) with fasting blood on poor functional outcomes of spontaneous intracerebral hemorrhage (sICH).MethodsThis investigation included 528 patients from a multicenter, observational, prospective cohort study. Poor functional outcomes were defined as modified Rankin Scale(mRS) ≥ 3. Logistic regression analyses were used to assess the relationship between indicators of SIH, including fasting blood glucose (FBG), two definitions of the stress hyperglycemia ratio [SHR, the fast blood glucose concentration/estimated average glucose (SHR1) and the ratio of glucose to HbA1c(SHR2)], and glycemic gap (GG), and poor functional outcomes at 30-day, 90-day, and 1-year.ResultsHigher values of all these indicators for SIH (e.g., FBG, GG, SHR1, and SHR2) were independently related to poor outcomes at 30-day, 90-day, and 1-year in patients with sICH (p < 0.05 for all models). Compared with the area under the curve (AUC), all these indicators performed greater AUC in predicting poor prognosis at 1-year (FBG: AUC=0.710; GG: AUC=0.741; SHR1: AUC=0.743) than 30-day and 90-day. And SHR2 has the highest predictive value among these indicators (AUC=0.748). Finally, diabetes had no statistical effect on the correlation between these indicators and poor functional outcomes at 30-day, 90-day, and 1-year in subgroup analysis (p for interaction >0.05).ConclusionsPatients with higher FBG, GG, SHR1, and SHR2 values were more likely to have a poor functional outcome. SHR2 has the highest predictive value for poor outcomes at 30-day, 90-day and 1-year.
Portable Arbitrary Pulse Generator for Driving μCoils for Micromagnetic Neurostimulation
Authors: Bloom Robert P. , Saha Renata , Sanger Zachary , Benally Onri J. , Wu Kai , Girolamo Arturo di , Low Walter C. , Netoff Theoden I. , Wang Jian-Ping 
Published: June 2023

AbstractMicromagnetic stimulation (μMS) is a promising branch of neurostimulation technologies. Microcoil (μcoil) based magnetic stimulation uses micrometer sized coils that generate a time-varying magnetic field which as per Faraday’s Laws of Electromagnetic Induction induces an electric field on a conductive surface. This method of stimulation has the advantage of not requiring electrical contact with tissue, however these μcoils are not easy to operate. Large currents are required to generate the required magnetic field. These currents are too large for standard test equipment to provide, and additional power amplifiers are needed. To aid in the development and application of micromagnetic stimulation devices, we have created a compact single unit test setup for driving these devices called the μCoil Driver. This unit is designed to drive small inductive loads up to ±8 V at 5 A and 10 kHz.
Dual proteomic signature of immune cells andYersinia pestisupon blood infection
Authors: Lê-Bury Pierre , Douché Thibaut , Gianetto Quentin Giai , Matondo Mariette , Pizarro-Cerdá Javier , Dussurget Olivier 
Published: June 2023

AbstractEmerging and reemerging infectious diseases represent major public health concerns. The urgent need for infection control measures requires deep understanding of molecular pathogenesis. Global approaches to study biological systems such as mass-spectrometry based proteomics benefited from groundbreaking physical and bioinformatical technological developments over recent years. However, dual proteomic study of highly pathogenic microorganisms and their hosts in complex matrices encountered during infection remains challenging due to high protein dynamic range of samples and requirements imposed in biosafety level 3 or 4 laboratories. Here, we constructed a dual proteomic pipeline ofYersinia pestisin human blood and plasma, mirroring bacteremic phase of plague. We provide the most completeY. pestisproteome revealing a major reshaping of important bacterial path-ways such as methionine biosynthesis and iron acquisition in human plasma. Remarkably, proteomic profiling in human blood highlights a greaterYersiniaouter proteins intoxication of monocytes than neutrophils. Our study unravels global expression changes and points to a specific pathogenic signature during infection, paving the way for future exploration of proteomes in the complex context of host-pathogen interactions.Subject CategoriesMicrobiology, Virology and Host Pathogen Interaction, Proteomics
CellStitch: 3D Cellular Anisotropic Image Segmentation via Optimal Transport
Authors: Liu Yining , Jin Yinuo , Azizi Elham , Blumberg Andrew J. 
Published: June 2023

AbstractBackgroundSpatial mapping of transcriptional states provides valuable biological insights into cellular functions and interactions in the context of the tissue. Accurate 3D cell segmentation is a critical step in the analysis of this data towards understanding diseases and normal developmentin situ. Current approaches designed to automate 3D segmentation include stitching masks along one dimension, training a 3D neural network architecture from scratch, and reconstructing a 3D volume from 2D segmentations on all dimensions. However, the applicability of existing methods is hampered by inaccurate segmentations along the non-stitching dimensions, the lack of high-quality diverse 3D training data, and inhomogeneity among different dimensions; as a result, they have not been widely used in practice.MethodsTo address these challenges, we formulate the problem of finding cell correspondence across layers with a novel optimal transport (OT) approach. We propose CellStitch, a flexible pipeline that segments cells from 3D images without requiring large amounts of 3D training data. We further extend our method to interpolate internal slices from highly anisotropic cell images to recover isotropic cell morphology.ResultsWe evaluated the performance of CellStitch through eight 3D plant microscopic datasets with diverse anisotropic levels and cell shapes. CellStitch substantially outperforms the state-of-the art methods on anisotropic images, and achieves comparable segmentation quality against competing methods in isotropic setting. We benchmarked and reported 3D segmentation results of all the methods with instance-level precision, recall and average precision (AP) metrics.ConclusionThe proposed OT-based 3D segmentation pipeline outperformed the existing state-of-the-art methods on different datasets with nonzero anisotropy, providing high fidelity recovery of 3D cell morphology from microscopic images.
Constructing neural networks with pre-specified dynamics
Authors: Mininni Camilo J. , Zanutto B. Silvano 
Published: June 2023

AbstractA main goal in neuroscience is to understand the computations carried out by neural populations that give animals their cognitive skills. Neural network models allow to formulate explicit hypothesis regarding the algorithms instantiated in the dynamic of a neural population, its firing statistics, and the underlying connectivity. Neural networks can be defined by a small set of parameters, carefully chosen to procure specific capabilities, or by a large set of free parameters, fitted with optimization algorithms that minimize a given loss function. In this work we alternatively propose a method to make a detailed adjustment of the network dynamic and firing statistic to better answer questions that link dynamic, structure and function. Our algorithm – termed generalized Firing-to-Parameter (gFTP) – provides a way to construct binary recurrent neural networks whose dynamic strictly follows a user pre-specified transition graph that details the transitions between population firing states triggered by stimulus presentations. Our main contribution is a procedure that detects when a transition graph is not realizable in terms of a neural network, and makes the necessary modifications in order to obtain a new transition graph that is realizable and preserves all the information encoded in the transitions of the original graph. With a realizable transition graph, gFTP assigns values to the network firing states associated with each node in the graph, and finds the synaptic weight matrices by solving a set of linear separation problems. We test gFTP performance by constructing networks with random dynamics, continuous attractor-like dynamics that encode position in 2-dimensional space, and discrete attractor dynamics. We then show how gFTP can be employed as a tool to explore the broad dependencies between structure and function, and the specific dependencies subserving the algorithms instantiated in the network activity.
Genomic and ecological factors shaping specialism and generalism across an entire subphylum
Authors: Opulente Dana A. , LaBella Abigail Leavitt , Harrison Marie-Claire , Wolters John F. , Liu Chao , Li Yonglin , Kominek Jacek , Steenwyk Jacob L. , Stoneman Hayley R. , VanDenAvond Jenna , Miller Caroline R. , Langdon Quinn K. , Silva Margarida , Gonçalves Carla , Ubbelohde Emily J. , Li Yuanning , Buh Kelly V. , Jarzyna Martin , Haase Max A. B. , Rosa Carlos A. , Čadež Neža , Libkind Diego , DeVirgilio Jeremy H. , Hulfachor Amanda Beth , Kurtzman Cletus P. , Sampaio José Paulo , Gonçalves Paula , Zhou Xiaofan , Shen Xing-Xing , Groenewald Marizeth , Rokas Antonis , Hittinger Chris Todd 
Published: June 2023

AbstractOrganisms exhibit extensive variation in ecological niche breadth, from very narrow (specialists) to very broad (generalists). Paradigms proposed to explain this variation either invoke trade-offs between performance efficiency and breadth or underlying intrinsic or extrinsic factors. We assembled genomic (1,154 yeast strains from 1,049 species), metabolic (quantitative measures of growth of 843 species in 24 conditions), and ecological (environmental ontology of 1,088 species) data from nearly all known species of the ancient fungal subphylum Saccharomycotina to examine niche breadth evolution. We found large interspecific differences in carbon breadth stem from intrinsic differences in genes encoding specific metabolic pathways but no evidence of trade-offs and a limited role of extrinsic ecological factors. These comprehensive data argue that intrinsic factors driving microbial niche breadth variation.One-Sentence SummaryA nearly complete genomic catalog of the yeast subphylum illuminates the evolution of their diverse ecologies and metabolisms.
Testing relationships between multiple regional features and biogeographic processes of speciation, extinction, and dispersal
Authors: Swiston Sarah K. , Landis Michael J. 
Published: June 2023

AbstractThe spatial and environmental features of regions where clades are evolving are expected to impact biogeographic processes such as speciation, extinction, and dispersal. Any number of regional features (such as altitude, distance, area, etc.) may be directly or indirectly related to these processes. For example, it may be that distances or differences in altitude or both may limit dispersal rates. However, it is difficult to disentangle which features are most strongly related to rates of different processes. Here, we present an extensible Multi-feature Feature-Informed GeoSSE (MultiFIG) model that allows for the simultaneous investigation of any number of regional features. MultiFIG provides a conceptual framework for incorporating large numbers of features of different types, including categorical, quantitative, within-region, and between-region features, along with a mathematical framework for translating those features into biogeographic rates for statistical hypothesis testing. Using traditional Bayesian parameter estimation and reversible-jump Markov chain Monte Carlo, MultiFIG allows for the exploration of models with different numbers and combinations of feature-effect parameters, and generates estimates for the strengths of relationships between each regional feature and core process. We validate this model with a simulation study covering a range of scenarios with different numbers of regions, tree sizes, and feature values. We also demonstrate the application of MultiFIG with an empirical case study of the South American lizard genus Liolaemus, investigating sixteen regional features related to area, distance, and altitude. Our results show two important feature-process relationships: a negative distance/dispersal relationship, and a negative area/extinction relationship. Interestingly, although speciation rates were found to be higher in Andean versus non-Andean regions, the model did not assign significance to Andean- or altitude-related parameters. These results highlight the need to consider multiple regional features in biogeographic hypothesis testing.
GATA-regulated transcriptional program dictate cell fate equilibrium to establish the maternal-fetal exchange interface and fetal development
Authors: Ghosh Ananya , Kumar Rajnish , Kumar Ram , Ray Soma , Saha Abhik , Roy Namrata , Dasgupta Purbasa , Marsh Courtney , Paul Soumen 
Published: June 2023

AbstractThe placenta establishes a maternal–fetal exchange interface to transport nutrients and gases between the mother and the fetus. Establishment of this exchange interface relies on the development of multinucleated syncytiotrophoblasts (SynT) from trophoblast progenitors and defect in SynT development often leads to pregnancy failure and impaired embryonic development. Here, we show that mouse embryos with conditional deletion of GATA2 and GATA3 in labyrinth trophoblast progenitors have underdeveloped placenta and die ∼ embryonic day 9.5 (E9.5). Single cell RNA Seq (scRNA-Seq) analysis revealed excessive accumulation of multipotent labyrinth trophoblast progenitors upon conditional deletion of GATA factors. The GATA factor-deleted multipotent progenitors were unable to differentiate to matured SynTs. We also show that the GATA factor-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. Loss of either GATA2 or GATA3 in cytotrophoblast (CTB)-derived human trophoblast stem cells (human TSCs) drastically inhibits SynT differentiation potential. Identification of GATA2 and GATA3 target genes along with comparative bioinformatics analyses revealed that GATA factors directly regulate hundreds of common genes in human TSCs, including genes that are essential for SynT development and implicated in preeclampsia and fetal growth retardation. Thus, our study uncovers a conserved molecular mechanism, in which coordinated function of GATA2 and GATA3 promote trophoblast progenitor-to-SynT commitment ensuring establishment of the maternal–fetal exchange interface.
TRAF6 initiates inflammatory signaling via organizing membraneless cytoplasmic condensates
Authors: Wang Jia , Zhong Xincheng , Yin Hang 
Published: June 2023

AbstractThe tumor necrosis factor receptor-associated factor 6 (TRAF6) is a central molecule in multiple signaling pathways, i.e. the TNF receptor, the Toll-like receptors (TLRs), and interleukin-1 receptor (IL-1R) pathways. Upon pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs) stimulations, TRAF6 activates downstream of NF-κB signaling. However, the precise mechanism of how TRAF6 activates downstream molecules remains unclear.Here, we demonstrate that TRAF6 acts as a sensor for upstream signals to initiate liquid-liquid phase separation (LLPS) of itself and downstream proteins, forming membraneless condensates. Subsequent recruitment, enrichment and activation of downstream effectors in the condensates lead to robust inflammatory signal transduction. The multivalent interactions mediated by its RING domain, zinc finger domain 1, and coiled-coil domain mediates the LLPS process. Forced phase separation of TRAF6 induced NF-κB activation. Disruption of TRAF6 phase separation abrogates activation of NF-κB signaling. Overall, we uncover the spatial organization of molecules by TRAF6 through phase separation as a subcellular platform to activate inflammatory signaling. Targeting TRAF6 phase separation hold promises for therapeutics aiming autoimmune diseases, inflammation and cancers.