bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional specialization, polyploidy, and seminal fluid transcripts in the Drosophila female reproductive tract
Authors: Thayer Rachel C. , Polston Elizabeth S. , Xu Jixiang , Begun David J. 
Published: October 2023

ABSTRACTInternal fertilization requires the choreographed interaction of female cells and molecules with seminal fluid and sperm. In many animals, including insects, the female reproductive tract is physically subdivided into sections that carry out specialized functions. For example, females of many species have specialized organs for sperm storage.Drosophila melanogasteris a premier model system for investigating many aspects of animal reproduction. Nevertheless, in contrast to males, much of the basic biology of theD. melanogasterfemale reproductive tract remains poorly understood or completely unknown. Here we use single-cell RNA-seq data and in situ hybridization to reveal a rich and previously unknown female reproductive tract cell diversity, including widespread variation in ploidy levels. We find that many so-called seminal fluid protein genes appear to be transcribed in specialized cells of the female reproductive tract, motivating a re-evaluation of the functional and evolutionary biology of this major class of proteins.
Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants
Authors: McDonald Eli Fritz , Oliver Kathryn E. , Schlebach Jonathan P. , Meiler Jens , Plate Lars 
Published: October 2023

AbstractVariants in the cystic fibrosis transmembrane conductance regulator gene (CFTR) result in cystic fibrosis – a lethal autosomal recessive disorder. Missense variants that alter a single amino acid in the CFTR protein are among the most common cystic fibrosis variants, yet tools for accurately predicting molecular consequences of missense variants have been limited to date. AlphaMissense (AM) is a new technology that predicts the pathogenicity of missense variants based on dual learned protein structure and evolutionary features. Here, we evaluated the ability of AM to predict the pathogenicity of CFTR missense variants. AM predicted a high pathogenicity for CFTR residues overall, resulting in a high false positive rate and fair classification performance on CF variants from theCFTR2.orgdatabase. AM pathogenicity score correlated modestly with pathogenicity metrics from persons with CF including sweat chloride level, pancreatic insufficiency rate, andPseudomonas aeruginosainfection rate. Correlation was also modest with CFTR trafficking and folding competencyin vitro. By contrast, the AM score correlated well with CFTR channel functionin vitro– demonstrating the dual structure and evolutionary training approach learns important functional information despite lacking such data during training. Different performance across metrics indicated AM may determine if polymorphisms in CFTR are recessive CF variants yet cannot differentiate mechanistic effects or the nature of pathophysiology. Finally, AM predictions offered limited utility to inform on the pharmacological response of CF variants i.e.,theratype. Development of new approaches to differentiate the biochemical and pharmacological properties of CFTR variants is therefore still needed to refine the targeting of emerging precision CF therapeutics.
Generating complex explanations from machine learning models using class-contrastive reasoning
Authors: Yang Yujia , Banerjee Soumya 
Published: October 2023

AbstractObjectiveOne of the major limitations of most black-box machine learning models is the lack of explainability. In healthcare, explainability is important. Furthermore, most healthcare professionals do not have technical knowledge of machine learning. Consequently, it is necessary to translate the predictions of the machine learning model into an explainable narrative.Our research focuses on the healthcare domain. The goal of this study is to generate complex explanations from a black-box machine learning model applied to heaalthcare.ResultsClass-contrastive techniques can be used to generate explanations. In this method, class-contrastive counterfactual reasoning is applied to a machine learning model on tabular data (in health-care). The model predictions are explained by observing the changes in prediction by altering the inputs. This is visualized using heatmaps (class-contrastive heatmaps). This approach displays prediction results as visualizations (heatmaps).Our contribution is to extend class-contrastive analysis of black-box machine learning models to numeric features. Our work also allows machine learning scientists to visually inspect class-contrastive heatmaps and generate complex explanations for models. The resulting explanations (visual and text) are easier for non-technical people to follow.We show how machine learning scientists can extract complex explanations from machine learning models which can be interpreted by nontechnical audiences. Our work may be broadly applicable in domains where explainability is important.
Assessing health equity in wastewater monitoring programs: Differences in the demographics and social vulnerability of sewered and unsewered populations across North Carolina
Authors: Hu Xindi C. , Reckling Stacie K. , Keshaviah Aparna 
Published: October 2023

AbstractBackgroundWastewater monitoring is a valuable tool to track community-level disease trends. However, the extent to which vulnerable populations have been included in statewide wastewater monitoring programs remains unstudied.ObjectivesWe conducted a geospatial analysis to examine (1) the representativeness of wastewater data collected through the North Carolina Wastewater Monitoring Network as of June 2022, and (2) the potential of wastewater data to generalize to unsewered populations in the county.MethodsAfter intersecting wastewater treatment plant (WWTP) service areas (sewersheds) with census block and tract boundaries for 38 WWTPs across 18 counties, we compared the demographics and social vulnerability of (1) people residing in sewersheds of monitored WWTPs with countywide and statewide populations, and (2) people connected to any sewer system—regardless of inclusion in wastewater monitoring—with unsewered populations. We flagged differences greater than +/-5 percentage points or percent (for categorical and continuous variables, respectively) and noted which were statistically significant (i.e., greater than twice the margin of error).ResultsAs a whole, populations in monitored sewersheds resembled the statewide population on most demographics analyzed, with a few exceptions. When multiple WWTPs were monitored within a county, their combined service populations resembled the countywide population, although populations in individually monitored sewersheds sometimes differed from the countywide population. In nine counties for which we had comprehensive sewershed maps, we found that sewered residents had higher social vulnerability, a greater share of Hispanics and African Americans, lower income, and lower educational attainment than unsewered residents.DiscussionOur results suggest that wastewater monitoring in North Carolina well represents the larger community. Ongoing analyses will be needed as sites are added or removed. The approach we present here can be used to ensure that wastewater surveillance programs nationwide are implemented in a manner that informs equitable public health decision-making.
Risk Factors for Sudden Cardiac Arrest and Ventricular Arrhythmias in Arrhythmogenic Mitral Valve Prolapse Syndrome
Authors: Chakrabarti Apurba , Giudicessi John R. , Ezzeddine Fatima M. , Delling Francesca N. , Dixit Shalini , Lee Yoo Jin , Muser Daniele , Magnani Silvia , Van Wijngaarden Aniek , Ajmone Marsan Nina , Miller Marc A. , Gandhi Jonathan , Trivieri Maria G. , Font Jonaz , Martins Raphael , McCaffrey James A. , Santangeli Pasquale , Marchlinski Francis E. , Chapagain Himal , Mathew Don , Kancharla Krishna , Syed Faisal F. , Abid Ahad , Cerbin Lukasz , Tzou Wendy S. , Garg Lohit , Della Rocca Domenico G. , Natale Andrea , Mohanty Sanghamitra , Sheldon Seth H. , Kuo Ling , Haugaa Kristina H. , Aabel Eivind W. , Enriquez Andres , Maeda Shingo , Deshmukh Amrish , Ghannam Michael , Bogun Frank M. , Ackerman Michael J. , Liang Jackson J. 
Published: October 2023

ABSTRACTBackgroundPatients with the arrhythmogenic mitral valve prolapse syndrome (AMVPS) are at increased risk for life-threatening ventricular arrhythmias (VAs), but studies have been limited by small sample sizes. We sought to assemble an international AMVPS registry to delineate clinical, imaging, treatment characteristics, and risk factors for sudden cardiac arrest (SCA).MethodsWe retrospectively identified two groups of subjects with AMVPS: 1) the MVP-SCA group with SCA, sustained ventricular tachycardia (VT), and ventricular fibrillation (VF); and 2) the MVP-PVC group with significant premature ventricular complexes (PVCs) only. Deidentified data was abstracted locally and combined centrally.ResultsWe included 217 subjects with AMVPS: 148 (68%) had SCA or VT/VF (MVP-SCA group) and 69 (32%) had PVCs only (MVP-PVC group). Phenotypically, both groups were similar [mean age 44.2±16.7 years, 66% female, 76% with bileaflet prolapse, 55% with mitral annular disjunction (MAD)]. Syncope was more common in the MVP-SCA group than the MVP-PVC group (47% vs 22%, p=0.001) as were anterolateral T-wave inversions (TWIs, 22% vs 7%, p=0.011). Prior mitral valve surgery was less common in the MVP-SCA group (6% vs 20%, p=0.002). These differences remained significant after multivariable adjustment. An electrophysiology (EP) study was negative in 15/45 (33%) of the MVP-SCA subjects.ConclusionsIn this international registry, AMVPS subjects were young, female, and had bileaflet prolapse with MAD. A history of syncope and anterolateral TWIs were associated with SCA. Prior mitral valve surgery was less common in SCA subjects. A negative EP study had limited negative predictive value in high-risk patients.
Quantifying Adaptive Evolution of the Human Immune Cell Landscape
Authors: Salvador-Martínez Irepan , Murga-Moreno Jesus , Nieto Juan C. , Alsinet Clara , Enard David , Heyn Holger 
Published: October 2023

AbstractThe human immune system is under constant evolutionary pressure, primarily through its role as first line of defence against pathogens. Accordingly, population genomics studies have shown that immune-related genes have a high rate of adaptive evolution. These studies, however, are mainly based on protein-coding genes without cellular context, leaving the adaptive role of cell types and states uncharted. Inferring the rate of protein-coding genes adaptation in developing and adult immune cells at cellular resolution, we found cell types from both the lymphoid and myeloid compartments to harbour significantly increased adaptation rates. Specific cell states, such as foetal Pre-Pro B cells and adult T resident memory CD8+ cells show highly elevated rates of adaptation. We further analysed activated cell states, specifically, iPSC-derived macrophages responding to various challenges, including pro- and anti-inflammatory cytokines or bacterial and viral infections, the latter simulating the evolutionary arms race between humans and pathogens. Here, we found positive selection to be concentrated in early immune responses, suggesting benefits for the host to adapt to early stages of infection to control pathogen numbers and spread. Together, our study reveals spatio-temporal and functional biases in human immune populations with evidence of rapid adaptive evolution and provides a retrospect of forces that shaped the complexity, architecture, and function of the human body.
Reply to: Commentary on Pang et al. (2023) Nature
Authors: Pang James C. , Aquino Kevin M. , Oldehinkel Marianne , Robinson Peter A. , Fulcher Ben D. , Breakspear Michael , Fornito Alex 
Published: October 2023

AbstractIn Pang et al. (2023)1, we identified a close link between the geometry and function of the human brain by showing that: (1) eigenmodes derived from cortical geometry parsimoniously reconstruct activity patterns recorded with functional magnetic resonance imaging (fMRI); (2) task-evoked cortical activity results from excitations of brain-wide modes with long wavelengths; (3) wave dynamics, constrained by geometry and distance-dependent connectivity, can account for diverse aspects of spontaneous and evoked brain activity; and (4) geometry and function are strongly coupled in the subcortex. Faskowitz et al. (2023)2raise concerns about the framing of our paper and the specificity of the eigenmode reconstructions in result (1). Here, we address these concerns and show how specificity is established by using appropriate benchmarks.
Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling
Authors: Chang Yen-Ching , Gao Yuan , Lee Joo Yeun , Langen Jennifer , Chang Karen T. 
Published: October 2023

AbstractThe ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood. Here, using an RNAi screen inDrosophilaagainst genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity from synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We further demonstrate that neuronal activity stimulates autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a novel trans-synaptic signaling mechanism modulating structural plasticity.
Hybrid hydrogel-extracellular matrix scaffolds identify distinct ligand and mechanical signatures in cardiac aging
Authors: Sun Avery Rui , Ramli Md. Faris H. , Shen Xingyu , Chen Dixiao , Foo Roger S. , Zhu Jin , Ackers-Johnson Matthew , Young Jennifer L. 
Published: October 2023

AbstractExtracellular matrix (ECM) remodeling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Aberrant secretion, structural perturbations, and degradation of specific ECM components lead to significant alterations in ECM properties that disrupt healthy cell and tissue homeostasis. These changes in ECM are multifaceted, as alterations in ligand presentation, including both biochemical and architectural aspects, are often accompanied by stiffness changes, clouding our understanding of how and which ECM properties contribute to a dysfunctional state. To identify the specific roles of these interconnected ECM cues and elucidate their mechanistic regulation in cellular function, we developed a material system that can independently present these two distinct matrix properties, i.e., ligand presentation and stiffness, to cultured cellsin vitro. We describe a decellularized ECM-synthetic hydrogel hybrid scaffold that maintains native matrix composition and organization of young or aged murine cardiac tissue with independently tunable scaffold mechanics that mimic young or aged tissue stiffness. Seeding these scaffolds with primary cardiac fibroblasts (CFs) from young or aged mice, we identify distinct age- and ECM-dependent mechanisms of CF activation. Importantly, we show that ligand presentation of young ECM can outweigh profibrotic stiffness cues typically present in aged ECM in maintaining or driving CF quiescence, thereby highlighting the unique roles of ECM in aging. Ultimately, these tunable scaffolds can enable the discovery of specific ECM targets to prevent aging dysfunction and promote rejuvenation.DECIPHER:DECellularizedIn SituPolyacrylamideHydrogel-ECM hybRid
Modular RNA motifs for orthogonal phase separated compartments
Authors: Stewart Jaimie Marie , Li Shiyi , Tang Anli , Klocke Melissa Ann , Gobry Martin Vincent , Fabrini Giacomo , Di Michele Lorenzo , Rothemund Paul W.K. , Franco Elisa 
Published: October 2023

AbstractRecent discoveries in biology have highlighted the importance of protein and RNA-based condensates as an alternative to classical membrane-bound organelles for the task of compartmentalizing molecules and biochemical reactions. Here, we demonstrate the rational design of pure RNA condensates from star-shaped RNA motifs. We generate condensates using two different RNA nanostar architectures: multi-stranded nanostars whose binding interactions are programmed via single-stranded overhangs, and single-stranded nanostars whose interactions are programmed via kissing loops. Through rational design of the nanostar interaction sequences, we demonstrate that both architectures can produce orthogonal (distinct and immiscible) condensates, which can be individually tracked via fluorogenic aptamers. We also show that aptamers make it possible to recruit peptides and proteins to the condensates with high specificity. Successful cotranscriptional formation of condensates from single-stranded nanostars suggests that they may be genetically encoded and produced in living cells. We provide a library of orthogonal RNA condensates that can be modularly customized and offer a route toward creating systems of functional artificial organelles.
Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice
Authors: Muralidharan Charanya , Huang Fei , Enriquez Jacob R. , Wang Jiayi E. , Nelson Jennifer B. , Nargis Titli , May Sarah C. , Chakraborty Advaita , Figatner Kayla T. , Navitskaya Svetlana , Anderson Cara M. , Calvo Veronica , Surguladze David , Mulvihill Mark J. , Yi Xiaoyan , Sarkar Soumyadeep , Oakes Scott A. , Webb-Robertson Bobbie-Jo M. , Sims Emily K. , Staschke Kirk A , Eizirik Decio L. , Nakayasu Ernesto S. , Stokes Michael E. , Tersey Sarah A. , Mirmira Raghavendra G. 
Published: October 2023

ABSTRACTPreventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2α. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We show that inhibition of the eIF2α kinase PERK, a common component of the UPR and ISR, reverses the mRNA translation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the UPR and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics of islets from these mice shows an increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following PERK inhibition in human islets and EndoC-βH1 human β cells, interacts with and stabilizes PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.
Gapped-kmer sequence modeling robustly identifies regulatory vocabularies and distal enhancers conserved between evolutionarily distant mammals
Authors: Oh Jin Woo , Beer Michael A. 
Published: October 2023

AbstractGene regulatory elements drive many complex biological phenomena such as fetal development, and their mutations are linked to a multitude of common human diseases. The phenotypic impacts of regulatory variants are often tested using their conserved orthologous counterparts in model organisms such as mice. However, mapping human enhancers to conserved elements in mice remains a challenge, due to both rapid evolution of enhancers and limitations of current computational methods to detect conserved regulatory sequences. To improve upon existing computational methods and to better understand the sources of this apparent regulatory divergence, we comprehensively measured the evolutionary dynamics of distal enhancers across 45 matched human/mouse cell/tissue pairs from more than 1,000 DNase-seq experiments. Using this expansive dataset, we show that while cell-specific regulatory vocabulary is conserved, enhancers evolve more rapidly than other genomic elements such as promoters and CTCF binding sites. We observed surprisingly high levels of cell-specific variability in enhancer conservation rates, in part explainable by tissue specific transposable element activity. To improve orthologous enhancer mapping, we developed an improved genome alignment algorithm using gapped-kmer sequence features, and using the matched cell/tissue pairs, we show that this novel computational method,gkm-align, discovers 23,660 novel human/mouse conserved enhancers missed by standard alignment algorithms.
Pulsation waves along theCionaheart tube reverse by bimodal rhythms expressed by a remote pair of pacemakers
Authors: Fujikake Yuma , Fukuda Keita , Matsushita Katsuyoshi , Iwatani Yasushi , Fujimoto Koichi , Nishino Atsuo S. 
Published: October 2023

ABSTRACTThe heart of ascidians, marine invertebrate chordates, exhibits a tubular structure, and heartbeats propagate from one end to the other. The direction of pulsation waves intermittently reverses in the heart of ascidians and their relatives; however, the underlying mechanisms remain unclear. We herein performed a series of experiments to characterize the pacemaker systems in isolated hearts and their fragments and applied a mathematical model to examine the conditions leading to heart reversals. The isolated heart ofCionasufficiently performed heart reversals, and experimental bisections of isolated hearts revealed that independent pacemakers resided on each side and also that their beating frequencies periodically changed as they expressed bimodal rhythms. Only fragments including 5% or shorter terminal regions of the heart tube maintained autonomous pulsation rhythms, whereas other regions did not. Our mathematical model, based on FitzHugh-Nagumo equations applied to a one-dimensional alignment of cells, demonstrated that the difference between frequencies expressed by the two independent terminal pacemakers determined the direction of propagated waves. Changes in the statuses of the terminal pacemakers between the excitatory and oscillatory modes as well as in their endogenous oscillation frequencies were sufficient to lead to heart reversals. These results suggest that the directions of pulsation waves in theCionaheart reverse according to the changing rhythms independently expressed by remotely coupled terminal pacemakers.Summary statementPulsation waves traveling along the heart tube of the ascidianCionaintermittently reverse because of autonomous and periodical changes in beating frequencies at a pair of terminal pacemakers.