bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delayed Center of Mass Feedback in Elderly Humans Leads to Greater Muscle Co-Contraction and Altered Balance Strategy under Perturbed Balance: a Predictive Musculoskeletal Simulation Study
Authors: Jones Rachel , Ratnakumar Neethan , Akbaş Kübra , Zhou Xianlian 
Published: December 2023

AbstractFalls are one of the leading causes of non-disease death and injury in the elderly, often due to delayed sensory neural feedback essential for balance. This delay, challenging to measure or manipulate in human studies, necessitates exploration through neuromusculoskeletal modeling to reveal its intricate effects on balance. In this study, we developed a novel three-way muscle feedback control approach, including muscle length feedback, muscle force feedback, and enter of mass feedback, for balancing and investigated specifically the effects of center of mass feedback delay on elderly people’s balance strategies. We conducted simulations of cyclic perturbed balance at different magnitudes ranging from 0 to 80 mm and with three center of mass feedback delays (100, 150 & 200 ms). The results reveal two key points: 1) Longer center of mass feedback delays resulted in increased muscle activations and co-contraction, 2) Prolonged center of mass feedback delays led to noticeable shifts in balance strategies during perturbed standing. Under low-amplitude perturbations, the ankle strategy was predominantly used, while higher amplitude disturbances saw more frequent employment of hip and knee strategies. Additionally, prolonged center of mass delays altered balance strategies across different phases of perturbation, with a noticeable increase in overall ankle strategy usage. These findings underline the adverse effects of prolonged feedback delays on an individual’s stability, necessitating greater muscle co-contraction and balance strategy adjustment to maintain balance under perturbation. Our findings advocate for the development of training programs tailored to enhance balance reactions and mitigate muscle feedback delays within clinical or rehabilitation settings for fall prevention in elderly people.
A long-context language model for deciphering and generating bacteriophage genomes
Authors: Shao Bin 
Published: December 2023

AbstractInspired by the success of large language models, we develop a long-context generative model for genomes. Our multiscale transformer model was pre-trained on unannotated bacteriophage genomes with byte-level tokenization. We demonstrate the foundational capabilities of our model including the prediction of essential genes, genetic variant effects, regulatory element activity and taxonomy of unannotated sequences. Furthermore, it generatesde novosequences up to 96K base pairs, which contain functional regulatory elements and novel proteins with phage-related functions.
Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner
Authors: Otero Ashley M. , Connolly Meghan G. , Gonzalez-Ricon Rafael J. , Wang Selena S. , Allen Jacob M. , Antonson Adrienne M. 
Published: December 2023

AbstractEpidemiological studies link neurodevelopmental disorders (NDDs) with exposure to maternal viral infection in utero. It is hypothesized that the mechanism governing this link involves the activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17. While IL-17 is implicated as a major driver of fetal brain abnormalities, this inflammation-induced TH17 pathway has not been thoroughly examined in models of live viral infection during pregnancy. Influenza A virus (IAV) infection is consistently linked to offspring NDDs and can result in host intestinal dysregulation. Therefore, it is possible that intestinal TH17 cells and subsequent production of IL-17 could drive fetal brain abnormalities during gestational IAV infection. To test this, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-dose IAV group, despite a lack of IL-17 signaling. Profiling fetal microglia and border-associated macrophages (BAMs) –potential cellular mediators of IAV-induced cortical abnormalities –revealed dose-dependent differences in the numbers of BAMs but not microglia. Overall, our data support the idea of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, confirming the use of live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.
High order expression dependencies finely resolve cryptic states and subtypes in single cell data
Authors: Jansma Abel , Yao Yuelin , Wolfe Jareth , Del Debbio Luigi , Beentjes Sjoerd , Ponting Chris P. , Khamseh Ava 
Published: December 2023

AbstractSingle cells are typically typed by clustering in reduced dimensional transcriptome space. Here we introduce Stator, a novel method, workflow and app that reveals cell types, subtypes and states without relying on local proximity of cells in gene expression space. Rather, Stator derives higher-order gene expression dependencies from a sparse gene-by-cell expression matrix. From these dependencies the method multiply labels the same single cell according to type, sub-type and state (activation, differentiation or cell cycle sub-phase). By applying the method to data from mouse embryonic brain, and human healthy or diseased liver, we show how Stator first recapitulates other methods’ cell type labels, and then reveals combinatorial gene expression markers of cell type, state, and disease at higher resolution. By allowing multiple state labels for single cells we reveal cell type fates of embryonic progenitor cells and liver cancer states associated with patient survival.
Development of a sensor for disulfide bond formation in diverse bacteria
Authors: Mendoza Jocelyne , Dyotima  , Abulaila Sally , Landeta Cristina 
Published: December 2023

SummaryIn bacteria, disulfide bonds contribute to the folding and stability of proteins important for processes in the cellular envelope. InE. coli, disulfide bond formation is catalyzed by DsbA and DsbB enzymes. DsbA is a periplasmic protein that catalyzes disulfide bond formation in substrate proteins while DsbB is an inner membrane protein that transfers electrons from DsbA to quinones, thereby regenerating the DsbA active state. Actinobacteria including mycobacteria use an alternative enzyme named VKOR which performs the same function as DsbB. Disulfide bond formation enzymes, DsbA and DsbB/ VKOR represent novel drug targets because their inhibition could simultaneously affect the folding of several cell envelope proteins including virulence factors, proteins involved in outer membrane biogenesis, cell division, and antibiotic resistance. We have previously developed a cell-based and target-based assay to identify molecules that inhibit the DsbB and VKOR in pathogenic bacteria, usingEscherichia colicells expressing a periplasmic β-Galactosidase sensor (β-Galdbs) which is only active when disulfide bond formation is inhibited. Here we report the construction of plasmids that allow fine-tuning of the expression of the β-Galdbssensor and can be mobilized into other gram-negative organisms. As an example, when harbored inP. aeruginosaUCBPP-PA14, β-Galdbsbehaves similarly as inE. coliand the biosensor responds to the inhibition of the two DsbB proteins. Thus, these β-Galdbsreporter plasmids provide a basis for identifying novel inhibitors of DsbA and DsbB/VKOR against multi-drug resistant, gram-negative pathogens and to further study oxidative protein folding in diverse gram-negative bacteria.ImportanceDisulfide bonds contribute to the folding and stability of proteins in the bacterial cell envelope. Disulfide bond-forming enzymes represent new drug targets against multidrug-resistant bacteria since inactivation of this process would simultaneously affect several proteins in the cell envelope, including virulence factors, toxins, proteins involved in outer membrane biogenesis, cell division, and antibiotic resistance. Identifying the enzymes involved in disulfide bond formation in gram-negative pathogens as well as their inhibitors can contribute to the much-needed antibacterial innovation. In this work, we developed sensors of disulfide bond formation for gram-negative bacteria. These tools will enable the study of disulfide bond formation and the identification of inhibitors for this crucial process in diverse gram-negative pathogens.
Between group heritability and the status of hereditarianism as an evolutionary science
Authors: Roseman Charles C , Bird Kevin A 
Published: December 2023

AbstractHereditarianism is a school of thought that contends there are substantial evolved cognitive and behavioral differences among groups of humans which are both resistant to environmental intervention and are a root cause of differential social outcomes across groups. The relationship of betweengroup heritabilityto within-group heritabilityis one of the key theoretical components of hereditarianism and forms one of the bases for its claim to be an evolutionary science. Here, we examine the relationship betweenandand its application to problems in the hereditarian literature from an evolutionary genetic perspective. We demonstrate that the formulation of the relationship betweenandused in the hereditarian literature has no evolutionary content. By re-writing the relationship betweenandin a novel evolutionary framework, we demonstrate that there is no way to predictusingwithout considerable additional theory that is absent from the hereditarian literature. Furthermore, we demonstrate that the hereditarian technique that usesandas a means of judging whether a given difference between groups may be plausibly ameliorated through environmental intervention is mathematically flawed. Lastly, we fill a gap in the hereditarian literature by writing out a means of usingto predict the absolute difference between groups under a neutral evolutionary model and find that it is much smaller than claimed by hereditarians. In conclusion, we propose a path forward for the study of human variation that moves us past the ill-conceived nature vs. nurture question and allows us to focus on more productive issues.
Wolbachiainfection negatively impactsDrosophila simulansheat tolerance in a strain- and trait-specific manner
Authors: Ferguson Liam , Ross Perran A. , van Heerwaarden Belinda 
Published: December 2023

AbstractThe susceptibility of insects to rising temperatures has largely been measured by their ability to survive thermal extremes. However, until recently, the capacity for maternally inherited endosymbionts to influence insect heat tolerance has been overlooked. Further, the impact of heat on traits like fertility, which can decline at temperatures below the lethal thermal limit has largely been ignored. Here, we assess the impact of threeWolbachiastrains (wRi,wAu, andwNo) on the survival and fertility ofDrosophila simulansexposed to heat stress during development or as adults. The impact ofWolbachiainfection on heat tolerance was generally small and trait/strain specific. Only thewNo infection significantly reduced survival and fertility of adult males after a heat shock. When exposed to a fluctuating heat stress during development, thewRi andwAu strains reduced egg-to-adult survival but only thewNo infection reduced male fertility.Wolbachiadensities of all three strains decreased under developmental heat stress, but reductions occurred at temperatures above those that reduced fertility of the host. These findings reveal the complexity of endosymbiont-host-environment interactions and emphasise the necessity to account for endosymbionts and their effect on both survival and fertility when investigating the vulnerability of insects to climate change.
Vagal interoception of microbial metabolites from the small intestinal lumen
Authors: Jameson Kelly G. , Kazmi Sabeen A. , Son Celine , Mazdeyasnan Donya , Leshan Emma , Vuong Helen E. , Paramo Jorge , Lopez-Romero Arlene , Yang Long , Schweizer Felix E. , Hsiao Elaine Y. 
Published: December 2023

SUMMARYThe vagus nerve is proposed to enable communication between the gut microbiome and brain, but activity-based evidence is lacking. Herein, we assess the extent of gut microbial influences on afferent vagal activity and metabolite signaling mechanisms involved. We find that mice reared without microbiota (germ-free, GF) exhibit decreased vagal afferent tone relative to conventionally colonized mice (specific pathogen-free, SPF), which is reversed by colonization with SPF microbiota. Perfusing non-absorbable antibiotics (ABX) into the small intestine of SPF mice, but not GF mice, acutely decreases vagal activity, which is restored upon re-perfusion with bulk lumenal contents or sterile filtrates from the small intestine and cecum of SPF, but not GF, mice. Of several candidates identified by metabolomic profiling, microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate stimulate vagal activity with varied response kinetics, which is blocked by co-perfusion of pharmacological antagonists of FFAR2, TGR5, and TRPA1, respectively, into the small intestine. At the single-unit level, serial perfusion of each metabolite class elicits more singly responsive neurons than dually responsive neurons, suggesting distinct neuronal detection of different microbiome- and macronutrient-dependent metabolites. Finally, microbial metabolite-induced increases in vagal activity correspond with activation of neurons in the nucleus of the solitary tract, which is also blocked by co-administration of their respective receptor antagonists. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate chemosensory vagal afferent neurons, thereby enabling microbial modulation of interoceptive signals for gut-brain communication.HIGHLIGHTSMicrobiota colonization status modulates afferent vagal nerve activityGut microbes differentially regulate metabolites in the small intestine and cecumSelect microbial metabolites stimulate vagal afferents with varied response kineticsSelect microbial metabolites activate vagal afferent neurons and brainstem neurons via receptor-dependent signaling
Spatial transcriptomics analysis identifies a unique tumor-promoting function of the meningeal stroma in melanoma leptomeningeal disease
Authors: Alhaddad Hasan , Ospina Oscar E. , Khaled Mariam Lotfy , Ren Yuan , Forsyth Peter , Pina Yolanda , Macaulay Robert , Law Vincent , Tsai Kenneth Y. , Cress W Douglas , Fridley Brooke , Smalley Inna 
Published: December 2023

ABSTRACTLeptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. The inaccessible nature of the disease site and lack of understanding of the biology of this unique metastatic site are major barriers to developing efficacious therapies for patients with melanoma LMD. Here, we characterize the tumor microenvironment of the leptomeningeal tissues and patient-matched extra-cranial metastatic sites using spatial transcriptomic analyses within vitroandin vivovalidation. We show the spatial landscape of melanoma LMD to be characterized by a lack of immune infiltration and instead exhibit a higher level of stromal involvement. We show that the tumor-stroma interactions at the leptomeninges activate pathways implicated in tumor-promoting signaling, mediated through upregulation of SERPINA3 at the tumor-stroma interface. Our functional experiments establish that the meningeal stroma is required for melanoma cells to survive in the CSF environment and that these interactions lead to a lack of MAPK inhibitor sensitivity in the tumor. We show that knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in re-sensitization of the tumor to MAPK-targeting therapy and tumor cell death in the leptomeningeal environment. Our data provides a spatial atlas of melanoma LMD, identifies the tumor-promoting role of meningeal stroma, and demonstrates a mechanism for overcoming microenvironment-mediated drug resistance unique to this metastatic site.
Seasonal tissue-specific gene expression reveals reproductive and stress-related transcriptional systems in wild crown-of-thorns starfish
Authors: Morin Marie , Jönsson Mathias , Wang Conan K. , Craik David J. , Degnan Sandie M. , Degnan Bernard M. 
Published: December 2023

SummaryAnimals are influenced by the season, yet we know little about the changes that occur in most species throughout the year. This is particularly true in tropical marine animals that experience relatively small annual temperature and daylight changes. Like many coral reef inhabitants, the crown-of-thorns starfish (COTS), well known as a notorious consumer of corals and destroyer of coral reefs, reproduces exclusively in the summer. By comparing gene expression in seven somatic tissues procured from wild COTS sampled on the Great Barrier Reef, we identified more than 2,000 protein-coding genes that change significantly between summer and winter. COTS genes that appear to mediate conspecific communication – including both signalling factors released into the surrounding sea water and cell surface receptors – are upregulated in external secretory and sensory tissues in the summer, often in a sex-specific manner. The sexually dimorphic gene expression appears to be underpinned by sex- and season-specific transcription factors (TFs) and gene regulatory programs. There are over 100 TFs that are seasonally expressed, 86% of which are significantly upregulated in the summer. Six nuclear receptors are upregulated in all tissues in the summer, suggesting that systemic seasonal changes are hormonally controlled, as occurs in vertebrates. Unexpectedly, there is a suite of stress-related chaperone proteins and TFs, including HIFα, ATF3, C/EBP, CREB and NF-κB, that are uniquely co-expressed in gravid females. The upregulation of these stress proteins in the summer suggests the demands of oogenesis in this highly fecund starfish affects protein stability and turnover in somatic cells. Together, these circannual changes in COTS gene expression provide novel insights into seasonal changes in this coral reef pest and have the potential to identify vulnerabilities for targeted biocontrol.
Single-cell transcriptomics reveals heterogenous thymic dendritic cell subsets with distinct functions and requirements for thymocyte-regulated crosstalk
Authors: Srinivasan Jayashree , Helm Bryan R. , Yang Yilin , Moore Colin , Moore John F. , Calindi Aparna , Selden Hilary J , Heiser Cody N. , Liu Qi , Lau Ken S. , Ehrlich Lauren I. R. 
Published: December 2023

SUMMARYDendritic cells (DCs) are essential for establishing central tolerance in the thymus; however, mechanisms supporting their homeostasis and activation remain unresolved. Through single-cell transcriptomics and functional assays, we identify seven thymic conventional DC (cDC) subsets and discriminate their abilities to present self-antigens and induce regulatory T cells (Tregs). Mice blocked at different stages of T-cell development reveal that CD4+single-positive (SP) and CD8SP thymocytes differentially support homeostasis and activation of cDC1s versus cDC2s/ plasmacytoid DCs (pDCs), respectively. CD8SP regulate cDCs via interferon signaling, while CD4SP promote NF-kB activation. CD40, which activates non-canonical NF-kB signaling, is required for both activation and homeostasis of cDC1s, although only activation is driven by cognate interactions with CD4SPs. Surprisingly, some DCs display an activated signature in the absence of mature thymocytes. Altogether, this study comprehensively identifies functionally distinct thymic DC subsets and elucidates requirements for crosstalk with thymocyte subsets that support their homeostasis and activation.
Structural and practical identifiability of contrast transport models for DCE-MRI
Authors: Conte Martina , Woodall Ryan T. , Gutova Margarita , Chen Bihong T. , Shiroishi Mark S. , Brown Christine E. , Munson Jennifer M. , Rockne Russell C. 
Published: December 2023

AbstractCompartment models are widely used to quantify blood flow and transport in dynamic contrast-enhanced magnetic resonance imaging. These models analyze the time course of the contrast agent concentration, providing diagnostic and prognostic value for many biological systems. Thus, ensuring accuracy and repeatability of the model parameter estimation is a fundamental concern. In this work, we analyze the structural and practical identifiability of a class of nested compartment models pervasively used in analysis of MRI data. We combine artificial and real data to study the role of noise in model parameter estimation. We observe that although all the models are structurally identifiable, practical identifiability strongly depends on the data characteristics. We analyze the impact of increasing data noise on parameter identifiability and show how the latter can be recovered with increased data quality. To complete the analysis, we show that the results do not depend on specific tissue characteristics or the type of enhancement patterns of contrast agent signal.
FURNA: a database for function annotations of RNA structures
Authors: Zhang Chengxin , Freddolino P. Lydia 
Published: December 2023

AbstractDespite the increasing number of 3D RNA structures in the Protein Data Bank, the majority of experimental RNA structures lack thorough functional annotations. As the significance of the functional roles played by non-coding RNAs becomes increasingly apparent, comprehensive annotation of RNA function is becoming a pressing concern. In response to this need, we have developed FURNA (Functions ofRNAs), the first database for experimental RNA structures that aims to provide a comprehensive repository of high-quality functional annotations. These include Gene Ontology terms, Enzyme Commission numbers, ligand binding sites, RNA families, protein binding motifs, and cross-references to related databases. FURNA is available athttps://seq2fun.dcmb.med.umich.edu/furna/to enable quick discovery of RNA functions from their structures and sequences.