bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differentiation of SARS-CoV-2 naturally infected and vaccinated individuals in an inner-city emergency department
Authors: Beck Evan J , Hsieh Yu-Hsiang , Fernandez Reinaldo E , Dashler Gaby , Egbert Emily R , Truelove Shawn A , Garliss Caroline , Wang Richard , Bloch Evan M. , Shrestha Ruchee , Blankson Joel , Cox Andrea L. , Manabe Yukari C , Kickler Thomas , Rothman Richard E , Redd Andrew D , Tobian Aaron AR , Milstone Aaron M , Quinn Thomas C , Laeyendecker Oliver 
Published: October 2021

AbstractBackgroundEmergency Departments (EDs) can serve as surveillance sites for infectious diseases. Our purpose was to determine the burden of SARS-CoV-2 infection and prevalence of vaccination against COVID-19 among patients attending an urban ED in Baltimore City.MethodsUsing 1914 samples of known exposure status, we developed an algorithm to differentiate previously infected, vaccinated, and unexposed individuals using a combination of antibody assays. We applied this testing algorithm to 4360 samples ED patients obtained in the springs of 2020 and 2021. Using multinomial logistic regression, we determined factors associated with infection and vaccination.ResultsFor the algorithm, sensitivity and specificity for identifying vaccinated individuals was 100% and 99%, respectively, and 84% and 100% for naturally infected individuals. Among the ED subjects, seroprevalence to SARS-CoV-2 increased from 2% to 24% between April 2020 and March 2021. Vaccination prevalence rose to 11% by mid-March 2021. Marked differences in burden of disease and vaccination coverage were seen by sex, race, and ethnicity. Hispanic patients, though 7% of the study population, had the highest relative burden of disease (17% of total infections) but similar vaccination rates. Women and White individuals were more likely to be vaccinated than men or Black individuals (adjusted odds ratios [aOR] 1.35 [95% CI: 1.02, 1.80] and aOR 2.26 [95% CI: 1.67, 3.07], respectively).ConclusionsIndividuals previously infected with SARS-CoV-2 can be differentiated from vaccinated individuals using a serologic testing algorithm. SARS-CoV-2 exposure and vaccination uptake frequencies reflect gender, race and ethnic health disparities in this urban context.SummaryUsing an antibody testing algorithm, we distinguished between immune responses from SARS-CoV-2-infected and vaccinated individuals. When applied to blood samples from an emergency department in Baltimore, disparities in disease burden and vaccine uptake by sex, race, and ethnicity were identified.
Severe Prenatal Shocks and Adolescent Health: Evidence from the Dutch Hunger Winter
Authors: Conti Gabriella , Poupakis Stavros , Ekamper Peter , Bijwaard Govert E. , Lumey L.H. 
Published: October 2021

AbstractThis paper investigates impacts, mechanisms and selection effects of prenatal exposure to multiple shocks, by exploiting the unique natural experiment of the Dutch Hunger Winter. At the end of World War II, a famine occurred abruptly in the Western Netherlands (November 1944 - May 1945), pushing the previously and subsequently well-nourished Dutch population to the brink of starvation. We link high-quality military recruits data with objective health measurements for the cohorts born in the years surrounding WWII with newly digitised historical records on calories and nutrient composition of the war rations, daily temperature, and warfare deaths. Using difference-in-differences and triple differences research designs, we show that the cohorts exposed to the Dutch Hunger Winter since early gestation have a higher Body Mass Index and an increased probability of being overweight at age 18, and that this effect is partly accounted for by warfare exposure and a reduction in energy-adjusted protein intake. Moreover, we account for selective mortality using a copula-based approach and newly-digitised data on survival rates, and find evidence of both selection and scarring effects. These results emphasise the complexity of the mechanisms at play in studying the consequences of early conditions.
Reorganization of postmitotic neuronal chromatin accessibility for maturation of serotonergic identity
Authors: Zhang Xinrui L. , Spencer W. Clay , Tabuchi Nobuko , Kitt Meagan M. , Deneris Evan S. 
Published: October 2021

SUMMARYMaturation of transcriptomes encoding unique neuronal identities requires selective accessibility of transcription factors to cis-regulatory sequences in nucleosome- embedded postmitotic chromatin. Yet the mechanisms controlling postmitotic neuronal chromatin accessibility are poorly understood. We used ATAC-seq, ChIPmentation, and single-cell analyses to show that heterogeneous chromatin landscapes are established early and reveal the regulatory programs driving subtype identities of Pet1-lineage neurons that generate serotonin (5-HT) neurons. Distal enhancer accessibility is highly dynamic as Pet1 neurons mature, suggesting the existence of regulatory factors that reorganize postmitotic neuronal chromatin. We find that Pet1 and Lmx1b control chromatin accessibility to select Pet1-lineage specific enhancers for 5-HT neurotransmission and synaptogenesis. Additionally, these factors are required to maintain chromatin accessibility during early maturation suggesting that postmitotic neuronal open chromatin is unstable and requires continuous regulatory input. Together our findings reveal postmitotic transcription factors that reorganize accessible chromatin for neuron specialization.
Organizing memories for generalization in complementary learning systems
Authors: Sun Weinan , Advani Madhu , Spruston Nelson , Saxe Andrew , Fitzgerald James E. 
Published: October 2021

ABSTRACTMemorization and generalization are complementary cognitive processes that jointly promote adaptive behavior. For example, animals should memorize a safe route to a water source and generalize to features that allow them to find new water sources, without expecting new paths to exactly resemble previous ones. Memory aids generalization by allowing the brain to extract general patterns from specific instances that were spread across time, such as when humans progressively build semantic knowledge from episodic memories. This cognitive process depends on the neural mechanisms of systems consolidation, whereby hippocampal-neocortical interactions gradually construct neocortical memory traces by consolidating hippocampal precursors. However, recent data suggest that systems consolidation only applies to a subset of hippocampal memories; why certain memories consolidate more than others remains unclear. Here we introduce a novel neural network formalization of systems consolidation that highlights an overlooked tension between neocortical memory transfer and generalization, and we resolve this tension by postulating that memories only consolidate when it aids generalization. We specifically show that unregulated memory transfer can be detrimental to generalization in unpredictable environments, whereas optimizing systems consolidation for generalization generates a high-fidelity, dual-system network supporting both memory and generalization. This theory of generalization-optimized systems consolidation produces a neural network that transfers some memory components to the neocortex and leaves others dependent on the hippocampus. It thus provides a normative principle for reconceptualizing numerous puzzling observations in the field and provides new insight into how adaptive behavior benefits from complementary learning systems specialized for memorization and generalization.
YeastMate: Neural network-assisted segmentation of mating and budding events in S. cerevisiae
Authors: Bunk David , Moriasy Julian , Thoma Felix , Jakubke Christopher , Osman Christof , Hörl David 
Published: October 2021

Here, we introduce YeastMate, a user-friendly deep learning-based application for automated detection and segmentation of Saccharomyces cerevisiae cells and their mating and budding events in microscopy images. We build upon Mask R-CNN with a custom segmentation head for the subclassification of mother and daughter cells during lifecycle transitions. YeastMate can be used directly as a Python library or through a stand-alone GUI application and a Fiji plugin as easy to use frontends.The source code for YeastMate is freely available at https://github.com/hoerlteam/YeastMate under the MIT license. We offer packaged installers for our whole software stack for Windows, macOS and Linux. A detailed user guide is available at https://yeastmate.readthedocs.io.
A quantitative model of sporadic axonal degeneration in theDrosophilavisual system
Authors: Richard Mélisande , Doubková Karolína , Nitta Yohei , Kawai Hiroki , Sugie Atsushi , Tavosanis Gaia 
Published: October 2021

AbstractIn human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modelling early degenerative events inDrosophilaadult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered that neurotransmission to postsynaptic partners of R7 and their response are required to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structure. This model can be used to dissect cellular circuit mechanisms involved in the early events of axonal degeneration, allowing for a better understanding of how neurons cope with stress and lose their resilience capacities.
PSEA: A phenotypic similarity ensemble approach for prioritizes candidate genes to aid mendelian disease diagnosis
Authors: Wang Zhonghua , Liu Lipei , Chen Chao , Liu Xi , Tang Fei , Zhang Yixiang , Chen Yunmei , Wang Yaoshen , Sun Jun , Peng Zhiyu 
Published: October 2021

AbstractMotivationNext-generation sequencing (NGS) is increasingly applied to the molecular diagnosis of genetic disorders. However, challenges for the interpretation of NGS data remain given the massive number of variants produced by NGS. Careful assessment is required to identify the most likely disease-causing variants that best match the patients’ clinical phenotypes, which is highly experience-dependent and of low cost-effectiveness.ResultsThe human phenotype ontology (HPO) together with the information content (IC) are widely used for phenotypic similarity evaluation. Here, we introduce PSEA, a new phenotypic similarity evaluation tool capable of quantifying groups of HPO terms unbiasedly. By comparing with other methods, PSEA show optimal performance and show a higher tolerance to phenotypic noise or incompleteness. We also developed a web server for disease-causing gene prioritization and HPO-gene weighted linkage visualization.AvailabilitySource code and Web service are free available at https://github.com/zhonghua-wang/psea and https://phoenix.bgi.com/psea, respectively.Contactwangzhonghua@genomics.cnSupplementary informationSupplementary data are available at Bioinformatics online.
ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP
Authors: Xiong Chao , Jia Li-Na , Shen Ming-He , Xiong Wei-Xi , Xiong Liu-Lin , Wang Ting-Hua , Zhou Dong , Liu Zheng , Tang Lin 
Published: October 2021

AbstractThe malfunction of ABCD1 causes X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disease that affect all tissues in human. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long chain fatty acids (VLCFA) for their damage by β-oxidation. Here, we present five Cryo-Electron microscopy structures of ABCD1 in four conformational states. Combined with functional analysis, we found that substrate and ATP trigger the closing of two nucleotide binding domains (NBDs) over a distance of 40 Å and the rearrangement of the transmembrane domains. Each of the three inward-facing structure of ABCD1 has a vestibule opens to cytosol with variable size. Furthermore, the structure of ABCD1 in the outward-facing state supports that ATP molecules pull the two NBDs together and open the transmembrane domain to the peroxisomal lumen for substrate release. The five structures provide a snapshot of substrate transporting cycle and mechanistic implications for disease-causing mutations.
Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids
Authors: Vanslambrouck Jessica M. , Wilson Sean B. , Tan Ker Sin , Groenewegen Ella , Rudraraju Rajeev , Neil Jessica , Lawlor Kynan T. , Mah Sophia , Scurr Michelle , Howden Sara E. , Subbarao Kanta , Little Melissa H. 
Published: October 2021

AbstractWhile pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of the nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification to metanephric nephron progenitors results in elongated and radially aligned proximalised nephrons with distinct S1 - S3 proximal tubule cell types. Such PT-enhanced organoids possess improved albumin and organic cation uptake, appropriate KIM-1 upregulation in response to cisplatin, and improved expression of SARS-CoV-2 entry factors resulting in increased viral replication. The striking proximo-distal orientation of nephrons resulted from localized WNT antagonism originating from the organoid stromal core. PT-enhanced organoids represent an improved model to study inherited and acquired proximal tubular disease as well as drug and viral responses.
A Novel Mice Model of Catecholaminergic Polymorphic Ventricular Tachycardia Generated by CRISPR/Cas9
Authors: Hou Cuilan , Jiang Xunwei , Qiu Qingzhu , Zheng Junmin , Lin Shujia , Chen Shun , Xu Meng , Zhang Yongwei , Xie Lijian , Xiao Tingting 
Published: October 2021

AbstractCatecholaminergic polymorphic ventricular tachycardia (CPVT) has been considered as one of the most important causes of children’s sudden cardiac death. Mutations in the genes for RyR2 and CASQ2, two mainly subtypes of CPVT, have been identified. However, the mutation in the gene of TECRL was rarely reported, which could be another genetic cause of CPVT. We evaluated myocardial contractility, electrophysiology, calcium handling in Tecrl knockout (Tecrl KO) mice and human induced pluripotent stem cell-derived cardiomyocytes. Immediately after epinephrine plus caffeine injection, Tecrl KO mice showed much more multiple premature ventricular beats and ventricular tachycardia. The Tecrl KO mice demonstrate CPVT phenotypes. Mechanistically, intracellular calcium amplitude was reduced, while time to baseline of 50 was increased in acute isolated cardiomyocytes. RyR2 protein levels decreased significantly upon cycloheximide treatment in TECRL deficiency cardiomyocytes. Overexpression of TECRL and KN93 can partially reverse cardiomyocytes calcium dysfunction, and this is p-CaMKII/CaMKII dependent. Therefore, a new CPVT mouse model was constructed. We propose a previously unrecognized mechanism of TECRL and provide support for the therapeutic targeting of TECRL in treating CPVT.
Direct induction of human neurons from fibroblasts carrying the neuropsychiatric 22q11.2 microdeletion reveals transcriptome- and epigenome-wide alterations
Authors: Purmann Carolin , Ang Cheen Euong , Tanabe Koji , Zhang Yue , Kundu Soumya , Danko Tamas , Ma Shining , Mitelpunkt Alexis , Wong Wing Hung , Bernstein Jonathan , Hallmayer Joachim , Aronow Bruce , Südhof Thomas C , Kundaje Anshul , Wernig Marius , Urban Alexander E. 
Published: October 2021

AbstractStandard methods for the creation of neuronal cells via direct induction from primary tissue use perinatal fibroblasts, which hinders the important study of patient specific genetic lesions such as those underlying neuropsychiatric disorders. To address this we developed a novel method for the direct induction of neuronal cells (induced neuronal cells, iN cells) from adult human fibroblast cells. Reprogramming fibroblasts into iN cells via recombinant virus resulted in cells that stain for markers such as MAP2 and PSA-NCAM and exhibit electrophysiological properties such as action potentials and voltage dependent sodium- and potassium currents that reveal a neuronal phenotype. Transcriptome and chromatin analysis using RNA-Seq, microRNA-Seq and ATAC-Seq, respectively, further confirm neuronal character. 22q11.2 Deletion-Syndrome (22q11DS) is caused by a large 3 million base-pair heterozygous deletion on human chromosome 22 and is strongly associated with neurodevelopmental, neuropsychiatric phenotypes such as schizophrenia and autism. We leverage the direct-iN cell model for the study of genetic neurodevelopmental conditions by presenting gene-by-gene as well as networkwide effects of the 22q11DS deletion on gene expression in human neuronal cells, on several levels of functional genomics analysis. Some of the genes within the 22q11DS deletion boundary exhibit unexpected cell-type-specific changes in transcript levels, and genome-wide we can detect dysregulation of calcium channel subunit genes and other genes known to be involved in autism or schizophrenia, such as NRXN1, as well synaptic pathways. This genome-wide effect on gene expression can also be observed at the microRNA and chromatin levels, showing that the iN cells have indeed converted to a neuronal phenotype at several regulatory levels: chromatin, protein-coding RNAs and microRNAs, revealing relevant disease pathways and genes. We present this model of inducing neurons from fibroblasts as a useful general resource to study the genetic and molecular basis of normal and abnormal brain development and brain function.
Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload
Authors: Shahzadi Syeda Kiran , Marzook Hezlin , Qaisar Rizwan , Ahmad Firdos 
Published: October 2021

AbstractNicotinamide riboside kinase-2 (NRK-2) has recently emerged as a critical regulator of cardiac remodeling however, underlying molecular mechanisms is largely unknown. To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric parameters as well as increased fetal genes ANP and BNP expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II-induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a regulator of JNK MAP kinase and mitochondrial function where NRK-2 overexpression in human cardiomyocytes markedly suppressed the angiotensin II-induced JNK activation and mitochondrial depolarization. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload-induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy, interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation and mitochondrial dysfunction.
OAC-39 is an O-acyltransferase required for the synthesis of maradolipids in the dauer larva of C. elegans
Authors: Penkov Sider 
Published: October 2021

AbstractUpon overcrowding or low food availability, the nematode C. elegans enters a specialized diapause stage for survival, called the dauer larva. The growth-arrested, non-feeding dauer larva undergoes a profound metabolic and physiologic switch underlying its extraordinary stress resistance and longevity. One of the metabolic signatures of dauer larvae is the accumulation of the disaccharide trehalose, which lowers the sensitivity of worms to desiccation and hyperosmotic shock. Previously, we have found that trehalose is incorporated as a headgroup into dauer-specific 6,6’-di-O-acyltrehalose lipids, named maradolipids. Despite comprising a bulk fraction of the polar lipids in dauer larvae, little is known about the physiological function of maradolipds because the enzyme(s) involved in their synthesis has not yet been identified. Here, we report that the dauer-upregulated O-acyltransferase homolog OAC-39 is essential for the synthesis of maradolipids. This enzyme is enriched at the apical region of the intestinal cells of dauer larvae, where it might participate in the structuring of the gut lumen. As OAC-39 is most probably responsible for the last step of maradolipid synthesis, its identification will pave the way for the elucidation of the function of this obscure class of lipids.