bluuebunny/crossref_metadata_2025_split huggingface dataset:
RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci
Authors: Fazal Sarah , Danzi Matt C. , Xu Isaac , Kobren Shilpa Nadimpalli , Sunyaev Shamil , Reuter Chloe , Marwaha Shruti , Wheeler Matthew , Dolzhenko Egor , Lucas Francesca , Wuchty Stefan , Tekin Mustafa , Züchner Stephan , Aguiar-Pulido Vanessa 
Published: March 2023

AbstractTandem repeats (TRs) are polymorphic sequences of DNA that are composed of repeating units of motifs, whose lengths can vary depending on the type of TR. Expansions of TRs are responsible for approximately 50 monogenic diseases, compared to over 4,300 disease causing genes disrupted by single nucleotide variants and small indels. It appears thus reasonable to expect the discovery of additional pathogenic repeat expansions, which has the potential of significantly narrowing the current diagnostic gap in many diseases. Recently, short and long-read whole genome sequencing with the use of advanced bioinformatics tools, have identified a growing number of TR expansions in the human population. The majority of these loci are expanded in <1% of genomes. Categorizing and prioritizing such TR loci is a growing challenge to human genomic studies. We present a first-in-class machine learning tool, RExPRT (Repeat EXpansion Pathogenicity pRediction Tool), which is designed to distinguish pathogenic from benign TR expansions. Leave-one-out cross validation results demonstrated that an ensemble approach comprised of support vector machines (SVM) and extreme gradient boosted decision tree (XGB) classify TRs with a precision of 92% and a recall of 90%. Further validation of RExPRT on unseen test data demonstrate a similar precision of 86%, and a recall of 60%. RExPRT’s high precision in particular, will be of significant value to large-scale discovery studies, which require the prioritization of promising candidate loci for time-consuming and costly functional follow-up studies. Application of RExPRT to ~800,000 TRs in the reference genome identified ~30,000 TRs that would be likely pathogenic upon expansion. Thus, RExPRT establishes a foundation for the application of machine learning approaches to categorize the pathogenicity of tandem repeat loci.
A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway
Authors:   The Proteostasis Consortium,   Overall coordination, Elsasser Suzanne , Elia Lisa P. , Morimoto Richard I. , Powers Evan T. ,   Harvard Medical School group, Elsasser Suzanne , Finley Daniel ,   University of California, San Francisco and Gladstone Institutes group I, Costa Beatrice , Budron Maher , Tokuno Zachary , Wang Shijie , Iyer Rajshri G. , Barth Bianca , Mockler Eric , Elia Lisa P. , Finkbeiner Steve ,   University of California, San Francisco group II, Gestwicki Jason E. ,   Northwestern University group, Richardson Reese A. K. , Stoeger Thomas , Morimoto Richard I. ,   The Scripps Research Institute group, Tan Ee Phie , Xiao Qiang , Cole Christian M. , Massey Lynée A. , Garza Dan , Powers Evan T. , Kelly Jeffery W. ,   Stanford University group, Rainbolt T. Kelly , Chou Ching-Chieh , Masto Vincent B. , Frydman Judith ,   New York University group, Nixon Ralph A. 
Published: March 2023

AbstractThe condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,700 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. We provided in a previous manuscript a list of chaperones and folding enzymes as well as the components that make up the machineries for protein synthesis, protein trafficking into and out of organelles, and organelle-specific degradation pathways. Here, we provide a curated list of 838 unique high-confidence components of the autophagy-lysosome pathway, one of the two major protein degradation systems in human cells.
The ER membrane protein complex governs lysosomal turnover of a mitochondrial tail-anchored protein, BNIP3, to restrict mitophagy
Authors: Delgado Jose M , Shepard Logan Wallace , Lamson Sarah W , Liu Samantha L , Shoemaker Christopher J 
Published: March 2023

ABSTRACTLysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, violate this assumption. Rather, BNIP3 and NIX are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all of its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. By this approach, we revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system regulates BNIP3 alongside, but independent of, the ubiquitin-proteosome system (UPS). Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. In short, while BNIP3 can be cleared by parallel and partially compensatory quality control pathways, non-autophagic lysosomal degradation of BNIP3 is a strong post-translational modifier of BNIP3 function. More broadly, these data reveal an unanticipated connection between mitophagy and TA protein quality control, wherein the endolysosomal system provides a critical axis for regulating cellular metabolism. Moreover, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that ensure tight regulation of endogenous TA protein localization.
Time-dependent neural arbitration between cue associative and episodic fear memories
Authors: Cortese Aurelio , Ohata Ryu , Alemany Maria , Kitagawa Norimichi , Imamizu Hiroshi , Koizumi Ai 
Published: March 2023

AbstractAfter traumatic events, simple cue-threat associative memories strengthen while episodic memories become fragmented. However, how the brain prioritizes cue associations over episodic coding of traumatic events remains unclear. Here, we developed a new episodic threat conditioning paradigm in which participants concurrently form two memory representations: cue associations and episodic cue sequence. We discovered that these two distinct memories compete for physiological fear expression, reorganizing overnight from an overgeneralized cue-based to a precise sequence-based expression. With multivariate fMRI, we track inter-area communication of the memory representations and demonstrate that a shift from hippocampal-dominant to prefrontal-dominant control of the fear regulatory circuit governs this memory maturation. Critically, this overnight reorganization is altered in individuals with heightened trait anxiety. Together, these findings suggest the brain prioritizes generalizable associative memories under recent traumatic stress, but resorts to selective episodic memories 24 hrs later. Time-dependent memory competition provides a unifying account for memory dysfunctions in posttraumatic stress disorders.
Duckweed evolution: from land back to water
Authors: Fang Yang , Tian Xueping , Jin Yanling , Du Anping , Ding Yanqiang , Liao Zhihua , He Kaize , Zhao Yonggui , Guo Ling , Xiao Yao , Xu Yaliang , Chen Shuang , Che Yuqing , Tan Li , Wang Songhu , Li Jiatang , Yi Zhuolin , Chen Lanchai , Zhao Leyi , Zhang Fangyuan , Li Guoyou , Li Jinmeng , Xiong Qinli , Zhang Yongmei , Zhang Qing , Cao Xuan Hieu , Zhao Hai 
Published: March 2023

AbstractTerrestialization is supposedly an important evolutionary process plant experience. However, directions of land back to water acquired little attention. Here we integrate multiproxy evidence to elucidate the evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in roots structure and stomatal function and decrease in lignocellulose content, accompanied by gradual contraction in relevant gene numbers and/or decline in transcription. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also related to the adaptation of duckweed to floating growth. This study reconstructs the evolution history of duckweeds from land back to water, reverse to that of early land plants.SummaryWith terrestrialization being the popularly acknowledged plant evolutionary process, little is known about the evolution of higher plant from land back to water. Here we integrate multiproxy evidence to elucidate the gradual reverse evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in the structure of roots, the function of stomata, and decrease in lignocellulose content, accompanied by gradient contraction in relevant gene numbers and/or decline in transcript expression. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also highly related to the adaptation of duckweed to floating growth. Our study combined with the fossil evidence reconstruct the evolution history of duckweeds from land back to water, reverse to that of early land plants. This study reconstructed the process of how a land plant returns to water, a reverse evolutionary approach which is different from what we studied in textbook about plant terrestrialization. This finding could be helpful for us to deeply and widely understand the adaptation of plant to the environment, and to expand and deepen the knowledge of evolution theory.
Is adaptive foraging adaptive? A resource-consumer eco-evolutionary model
Authors: Ledru Leo , Garnier Jimmy , Guillot Océane , Faou Erwan , Noûs Camille , Ibanez Sébastien 
Published: March 2023

AbstractPhenotypic plasticity has important ecological and evolutionary consequences. In particular, behavioural phenotypic plasticity such as adaptive foraging (AF) by consumers, may enhance community stability. Yet little is known about the ecological conditions that favor the evolution of AF, and how the evolutionary dynamics of AF may modulate its effects on community stability. In order to address these questions, we constructed an eco-evolutionary model in which resource and consumer niche traits underwent evolutionary diversification. Consumers could either forage randomly, only as a function of resources abundance, or adaptatively, as a function of resource abundance, suitability and consumption by competitors. AF evolved when the niche breadth of consumers with respect to resource use was large enough and when the ecological conditions allowed substantial functional diversification. In turn, AF promoted further diversification of the niche traits in both guilds. This suggests that phenotypic plasticity can influence the evolutionary dynamics at the community-level. Faced with a sudden environmental change, AF promoted community stability directly and also indirectly through its effects on functional diversity. However, other disturbances such as persistent environmental change and increases in mortality, caused the evolutionary regression of the AF behaviour, due to its costs. The causal relationships between AF, community stability and diversity are therefore intricate, and their outcome depends on the nature of the environmental disturbance, in contrast to simpler models claiming a direct positive relationship between AF and stability.
Modeling the role of immune cell conversion in the tumor-immune microenviroment
Authors: Moffett Alexander S. , Deng Youyuan , Levine Herbert 
Published: March 2023

AbstractTumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell-cell interactions in the TIME has led researchers to apply concepts from ecology to describe the dynamics. However, while tumor cells are known to induce immune cells to switch from anti-tumor to pro-tumor phenotypes, this type of ecological interaction has been largely overlooked. To address this gap in cancer modeling, we develop a minimal, ecological model of the TIME with immune cell conversion, to highlight this important interaction and explore its consequences. A key finding is that immune conversion increases the range of parameters supporting a co-existence phase in which the immune system and the tumor reach a stalemate. Our results suggest that further investigation of the consequences of immune cell conversion, using detailed, data-driven models, will be critical for greater understanding of TIME dynamics.
Estimation of Interaction and Growth Parameters to Develop a Computational Model for Gut Bacteria
Authors: Joshi Himanshu , Prakash Meher K. 
Published: March 2023

AbstractThe relevance of gut bacterial balance to human health can not be overemphasized. The gut bacterial balance delicately relies on several factors inherent to the person as well as to the environment. As the volume of evidences for the gut bacterial influence on health and the clinical data on the variance of the bacterial population across cohorts continue to grow exponentially, it is important to develop a theoretical model for gut bacteria. In this work, we suggest a new computational method for estimating the interaction parameters from the cross-sectional data of bacterial abundances in a cohort, without requiring a longitudinal followup. We introduce a nutrient type based bacterial growth model and use the Monte Carlo approach to estimate the matrix of interaction parameters for the 14 major bacterial species. These parameters were used in a comprehensive first-level computational model we developed for the large intestine to understand the patterns of re-establishing balance with different nutrient types.
Lepidopteran Synteny Units (LSUs) reveal deep conservation of macrosynteny in butterflies and moths
Authors: Traut Walther , Sahara Ken , ffrench-Constant Richard H. 
Published: March 2023

AbstractAdvances in DNA sequencing technologies have, for the first time, provided us with enough whole chromosome-level genomes to understand in detail how chromosome number and composition change over time. Here, we use the genomes of butterflies and moths to look at the levels and age of macrosynteny in the Lepidoptera and Trichoptera. We used comparative BUSCO analsysis to define reproducible units of macrosynteny which we term ‘Lepidopteran Synteny Units’ or LSUs. The 31 chromosomes of the model butterflyMelitaea cinxiaserved as a reference point. The results show that chromosome-wide macrosynteny extends from the most basal branches of the Lepidopteran phylogeny to the most distal. This synteny also extends to the order Trichoptera, a sister group of the Lepidoptera. Thus, chromosome-wide macrosynteny has been conserved for a period of >200 My in this group of insects. We found no major interchromosomal translocations, reciprocal or non-reciprocal, in the genomes studied. Intrachromosomal rearrangements, in contrast, were abundant. Beyond its use in defining LSUs, this type of homology-based analysis will be useful in determining the relationships between chromosomal elements in different animals and plants. Further, by more precisely defining the breakpoints of chromosomal rearrangements we can begin to look at their potential roles in chromosomal evolution.StatementThe authors declare no conflicting interestsContributionsConceptualisation: W.T., R.H.f.; data analysis: W.T.; writing & editing: W.T., K.S., R.H.f All authors read and approved the final manuscript.
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Long-Term Risk of Immune-Related diseases
Authors: Israel Ariel , Schäffer Alejandro A , Berkovitch Matitiahu , Ozeri David J. , Merzon Eugene , Green Ilan , Golan-Cohen Avivit , Ruppin Eytan , Vinker Shlomo , Magen Eli 
Published: March 2023

AbstractBACKGROUNDGlucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specific medications. Despite some evidence that G6PD deficiency affects the immune system, the long- term health risks associated with G6PD deficiency had not been studied in a large population.METHODSIn this retrospective cohort study, health records from G6PD deficient individuals were compared to matched controls in a national healthcare provider in Israel (Leumit Health Services). Rates of infectious diseases, allergic conditions and autoimmune disorders were compared between groups.RESULTSThe cohort included 7,473 G6PD deficient subjects (68.7% men) matched with 29,892 control subjects (4:1 ratio) of the same age, gender, socioeconomic status and ethnic group, followed during 14.3±6.2 years.Significantly increased rates for autoimmune disorders, infectious diseases and allergic conditions were observed throughout this period. Notable increases were observed for rheumatoid arthritis (OR 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR=18.70, P<0.001), fibromyalgia (OR 1.98, p<0.001), Graves’ disease (OR 1.46, P=0.001), and Hashimoto’s thyroiditis (OR 1.26, P=0.001). These findings were corroborated with elevated rates of positive autoimmune serology and higher rates of treatment with medications commonly used to treat autoimmune conditions in the G6PD deficient group.CONCLUSIONG6PD deficient individuals suffer from higher rates of autoimmune disorders, infectious diseases, and allergic conditions.
Altered sleep architecture in diabetes and prediabetes: findings from the Baependi Heart Study
Authors: Chen Daniel M. , Taporoski Tâmara P. , Alexandria Shaina J. , Aaby David A. , Beijamini Felipe , Krieger Jose E. , Schantz Malcolm von , Pereira Alexandre , Knutson Kristen L. 
Published: March 2023

AbstractObjectivePeople with diabetes are more likely to have obstructive sleep apnea, but there are few studies examining sleep architecture in people with diabetes, especially in the absence of moderate-severe sleep apnea. Therefore, we compared sleep architecture among people with diabetes, prediabetes or neither condition, whilst excluding people with moderate-severe sleep apnea.Research design and methodsThis sample is from the Baependi Heart Study, a prospective, family-based cohort of adults in Brazil. 1,074 participants underwent at-home polysomnography (PSG). Diabetes was defined as 1) FBG>125 OR 2) HbA1c>6.4 OR 3) taking diabetic medication, and prediabetes was defined as 1) [(5.7≤HbA1c≤6.4) OR (100≤FBG≤125)] AND 2) not taking diabetic medication. We excluded participants that had an apnea-hypopnea index (AHI)>30 from these analyses to reduce confounding due to severe sleep apnea. We compared sleep stages among the 3 groups.ResultsCompared to those without diabetes, we found shorter REM duration for participants with diabetes (−6.7min, 95%CI -13.2, -0.1) or prediabetes (−5.9min, 95%CI -10.5, -1.3), even after adjusting for age, gender, BMI, and AHI. Diabetes was also associated with lower total sleep time (−13.7min, 95%CI -26.8, -0.6), longer slow-wave sleep (N3) duration (+7.6min, 95%CI 0.6, 14.6) and higher N3 percentage (+2.4%, 95%CI 0.6, 4.2), compared to those without diabetes.ConclusionsPeople with diabetes and prediabetes had less REM sleep after taking into account potential confounders, including AHI. People with diabetes also had more N3 sleep. These results suggest that diabetes is associated with different sleep architecture, even in the absence of moderate-severe sleep apnea.
Autistic kinematics diverge from the power laws that typically govern movement
Authors: Cook Jennifer L. , Fraser Dagmar S. , Hickman Lydia J. , Brewer Rebecca , Huh Dongsung 
Published: March 2023

AbstractExtant work reliably demonstrates that autistic individuals move with increased jerk (where jerk concerns change in acceleration). Although it follows that autistic movement may therefore diverge from fundamental power laws that govern movement, this hypothesis has not been directly tested to date. This lack of insight holds back progress in understanding the mechanisms underpinning differences in autism in motor control particularly with respect to movement jerkiness. Here we investigated whether movements executed by autistic adults diverged from the typical power law relationship that links movement speed and curvature. x and y position of the stylus tip was recorded at 133 Hz while 21 autistic and 19 non-autistic age-, intelligence quotient- and sex-matched adults traced, on a tablet device, a range of shapes that varied in angular frequency from 2/33 (spiral-like shapes) to 4 (square-like shapes). The gradient of the relationship between speed and curvature for each angular frequency-defined shape is reliably predicted by a set of mathematical equations often referred to as fundamental power laws thus, to assess deviations from power laws, we compared autistic and non-autistic participants in terms of speed-curvature gradients. To gain insight into potential mechanisms underpinning any differences we also used fast Fourier transform to explore amplitude spectral density across all angular frequencies. Compared to non-autistic adults, autistic adults exhibited significantly steeper speed-curvature gradients. Fast Fourier transform further revealed that non-autistic participants exhibited highly precise modulation of speed oscillations around the target frequency. For example, when drawing an ellipse their speed profile was dominated by speed changes in a band centred around the angular frequency 2 with minimal changes in other bands. Autistic adults, in contrast, exhibited less precise modulation of speed oscillations around the target frequency, a result that is reminiscent of a literature reporting broader auditory filters in autistic individuals. These results evidence, in autistic adults, a deviation from the power laws that typically govern movement and suggest differences in motor cortical control policies and/or biomechanical constraints.