bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new theoretical framework jointly explains behavioral and neural variability across subjects performing flexible decision-making
Authors: Pagan Marino , Tang Vincent D , Aoi Mikio C. , Pillow Jonathan W. , Mante Valerio , Sussillo David , Brody Carlos D. 
Published: November 2022

AbstractThe ability to flexibly switch our response to external stimuli according to contextual information is critical for successful interactions with a complex world. Context-dependent computations are necessary across many domains1–3, yet their neural implementations remain poorly understood. Here we developed a novel behavioral task in rats to study context-dependent selection and accumulation of evidence for decision-making4–6. Under assumptions supported by both monkey and rat data, we first show mathematically that a network can solve this problem through a combination of three defined components. These components can be identified and tested directly with experimental data. We further show that existing electrophysiological and modeling data are compatible with the full variety of possible combinations of these components, suggesting that different individuals could use different component combinations. To study variability across individual subjects, we developed automated, high-throughput methods to train rats on our task, and we trained many subjects on it. Consistent with theoretical predictions, neural and behavioral analyses revealed substantial heterogeneity across rats, despite uniformly good task performance. Our theory further predicts a specific link between behavioral and neural signatures, which was robustly supported in the data. In summary, our results provide a new experimentally-supported theoretical framework to analyze individual variability in biological and artificial systems performing flexible decision-making tasks, they open the door to cellular-resolution studies of individual variability in higher cognition, and they provide insights into neural mechanisms of context-dependent computation more generally.
Imputation of low-coverage sequencing data from 150,119 UK Biobank genomes
Authors: Rubinacci Simone , Hofmeister Robin , da Mota Bárbara Sousa , Delaneau Olivier 
Published: November 2022

AbstractRecent work highlights the advantages of low-coverage whole genome sequencing (lcWGS), followed by genotype imputation, as a cost-effective genotyping technology for statistical and population genetics. The release of whole genome sequencing data for 150,119 UK Biobank (UKB) samples represents an unprecedented opportunity to impute lcWGS with high accuracy. However, despite recent progress1,2, current methods struggle to cope with the growing numbers of samples and markers in modern reference panels, resulting in unsustainable computational costs. For instance, the imputation cost for a single genome is 1.11£ using GLIMPSE v1.1.1 (GLIMPSE1) on the UKB research analysis platform (RAP) and rises to 242.8£ using QUILT v1.0.4. To overcome this computational burden, we introduce GLIMPSE v2.0.0 (GLIMPSE2), a major improvement of GLIMPSE, that scales sublinearly in both the number of samples and markers. GLIMPSE2 imputes a low-coverage genome from the UKB reference panel for only 0.08£ in compute cost while retaining high accuracy for both ancient and modern genomes, particularly at rare variants (MAF < 0.1%) and for very low-coverage samples (0.1x-0.5x).
TheStreptococcus mutansRhamnose-glucose Polysaccharide Plays an Important Role in Oxidative Stress Resistance and Iron Homeostasis
Authors: Bischer Andrew P. , Faustoferri Roberta C. , Kovacs Christopher J. , Gill Steven R. , Quivey Robert G. 
Published: November 2022

AbstractThe rhamnose-glucose polysaccharide (RGP) ofStreptococcus mutansis known to play an essential role in cell division and biofilm formation. It has become increasingly apparent that the structure plays a role in protection against external stress, including an undefined role in oxidative stress. In this study, we demonstrate that the loss of RGP impairs the uptake of glucose and the susceptibility ofS. mutansto lethal concentrations of iron, while at the same time, generates elevated content of intracellular iron, a prominent producer of reactive oxygen species. Intracellular iron levels were significantly higher in a strain lacking rhamnose production (ΔrmlD), compared to a strain deficient in components of the RGP production pathway (ΔrgpG). The seemingly paradoxical discrepancy between iron uptake and iron susceptibility may be partially explained by increased expression ofdprandsod, genes that protect against oxidative stress and primeS. mutansagainst oxidative stressors such as H2O2and superoxide. Analysis of the promoter of the rhamnose biosynthesis genermlDindicated the presence of regulatory motifs, including Rex and PerR, which we have shown control expression for the genes responsible for rhamnose biosynthesis and RGP production. These results provide initial insights into the role that RGP plays in toleration of oxidative stress and suggest a complexity in regulation of the genes responsible for production of the RGP.ImportanceDental caries, a disease caused byStreptococcus mutans, imposes significant healthcare burdens and productivity losses in the US. The outer structure ofS. mutans, which is primarily composed of the rhamnose-glucose polysaccharide (RGP), is understudied, though it plays a crucial role in survival of the organism in response to environmental stress. Elucidating the protective role of RGP and the regulatory mechanisms that control the synthesis of RGP inS. mutanswill lead to insights into the structure and function of cell wall polysaccharides in other streptococci. This study reveals a role for L-rhamnose, the building block of RGP, in mediating homeostasis of iron uptake, while the loss of rhamnose biosynthesis causes alterations in transcription ofsodanddpr.
Generative network modeling reveals quantitative definitions of bilateral symmetry exhibited by a whole insect brain connectome
Authors: Pedigo Benjamin D. , Powell Mike , Bridgeford Eric W. , Winding Michael , Priebe Carey E. , Vogelstein Joshua T. 
Published: November 2022

AbstractComparing connectomes can help explain how neural connectivity is related to genetics, disease, development, learning, and behavior. However, making statistical inferences about the significance and nature of differences between two networks is an open problem, and such analysis has not been extensively applied to nanoscale connectomes. Here, we investigate this problem via a case study on the bilateral symmetry of a larvalDrosophilabrain connectome. We translate notions of “bilateral symmetry” to generative models of the network structure of the left and right hemispheres, allowing us to test and refine our understanding of symmetry. We find significant differences in connection probabilities both across the entire left and right networks and between specific cell types. By rescaling connection probabilities or removing certain edges based on weight, we also present adjusted definitions of bilateral symmetry exhibited by this connectome. This work shows how statistical inferences from networks can inform the study of connectomes, facilitating future comparisons of neural structures.
Increasing Ciliary ARL13B Expression Drives Active and Inhibitor-Resistant SMO and GLI into Glioma Primary Cilia
Authors: Shi Ping , Tian Jia , Mallinger Julianne C. , Deleyrolle Loic P. , McIntyre Jeremy C. , Caspary Tamara , Breunig Joshua J , Sarkisian Matthew R. 
Published: November 2022

AbstractADP-ribosylation factor-like protein 13B (ARL13B), a regulatory GTPase and guanine exchange factor (GEF) enriches in primary cilia and promotes tumorigenesis in part by regulating Smoothened (SMO), GLI, and Sonic hedgehog (SHH) signaling. Gliomas with increasedARL13B, SMOandGLI2expression are more aggressive but the relationship to cilia is unclear. Previous studies showed increasing ARL13B in glioblastoma cells promoted ciliary SMO accumulation, independent of exogenous SHH addition. Here we show SMO accumulation is due to increased ciliary, but not extraciliary ARL13B. Increasing ARL13B expression promotes the accumulation of both activated SMO and GLI2 in glioma cilia, but not in NIH3T3 fibroblast cilia. ARL13B-driven increases in ciliary SMO and GLI2 are resistant to SMO inhibitors, GDC-0449 and cyclopamine. Finally, temozolomide chemotherapy which increases ARL13B expression in glioma, stimulates SMO and GLI2 into glioma cilia, but not fibroblast cilia. Collectively, our data suggest factors that elevate ARL13B may drive drug-resistant SMO and GLI into cilia. This suggests the ARL13B-associated mechanism that leads to ciliary SMO/GLI recruitment may promote treatment resistance in glioma.
Age-related differences in prefrontal glutamate are associated with increased working memory decay that gives the appearance of learning deficits
Authors: Rmus Milena , He Mingjian , Baribault Beth , Walsh Edward G. , Festa Elena K. , Collins Anne G.E. , Nassar Matthew R. 
Published: November 2022

AbstractThe ability to use past experience to effectively guide decision making declines in older adulthood. Such declines have been theorized to emerge from either impairments of striatal reinforcement learning systems (RL) or impairments of recurrent networks in prefrontal and parietal cortex that support working memory (WM). Distinguishing between these hypotheses has been challenging because either RL or WM could be used to facilitate successful decision making in typical laboratory tasks. Here we investigated the neurocomputational correlates of age-related decision making deficits using an RL-WM task to disentangle these mechanisms, a computational model to quantify them, and magnetic resonance spectroscopy to link them to their molecular bases. Our results reveal that task performance is worse in older age, in a manner best explained by working memory deficits, as might be expected if cortical recurrent networks were unable to sustain persistent activity across multiple trials. Consistent with this, we show that older adults had lower levels of prefrontal glutamate, the excitatory neurotransmitter thought to support persistent activity, compared to younger adults. Individuals with the lowest prefrontal glutamate levels displayed the greatest impairments in working memory after controlling for other anatomical and metabolic factors. Together, our results suggest that lower levels of prefrontal glutamate may contribute to failures of working memory systems and impaired decision making in older adulthood.
Learning from the unknown: exploring the range of bacterial functionality
Authors: Mahlich Yannick , Zhu Chengsheng , Chung Henri , Velaga Pavan K. , De Paolis Kaluza M. Clara , Radivojac Predrag , Friedberg Iddo , Bromberg Yana 
Published: November 2022

ABSTRACTDetermining the repertoire of a microbe’s molecular functions is a central question in microbial biology. Modern techniques achieve this goal by comparing microbial genetic material against reference databases of functionally annotated genes/proteins or known taxonomic markers such as 16S rRNA. Here we describe a novel approach to exploring bacterial functional repertoires without reference databases. OurFusionscheme establishes functional relationships between bacteria and assigns organisms to Fusion-taxa that differ from otherwise defined taxonomic clades. Three key findings of our work stand out. First, bacterial functional comparisons outperform marker genes in assigning taxonomic clades. Fusion profiles are also better for this task than other functional annotation schemes. Second, Fusion-taxa are robust to addition of novel organisms and are, arguably, able to capture the environment-driven bacterial diversity. Finally, our alignment-free nucleic acid-based Siamese Neural Network model, created using Fusion functions, enables finding shared functionality of very distant, possibly structurally different, microbial homologs. Our work can thus help annotate functional repertoires of bacterial organisms and further guide our understanding of microbial communities.
IL-17C is a driver of damaging inflammation duringNeisseria gonorrhoeaeinfection of human Fallopian tube
Authors: Garcia Erin M. , Lenz Jonathan D. , Hackett Kathleen T. , Salgado-Pabón Wilmara , Dillard Joseph P. 
Published: November 2022

AbstractThe human-restricted pathogenNeisseria gonorrhoeaeascends into the upper female reproductive tract to cause damaging inflammation within the Fallopian tubes (salpingitis) and pelvic inflammatory disease (PID), increasing the risk of infertility and life-threatening ectopic pregnancy. The loss of ciliated cells from the epithelium is thought to be both a consequence of inflammation and a cause of the associated adverse sequelae. However, the links between infection, inflammation, and ciliated cell extrusion remain unresolved. With the use ofex vivocultures of human Fallopian tube paired with RNA sequencing we defined the tissue response to gonococcal challenge, identifying cytokine, chemokine, cell adhesion, and apoptosis related transcripts not previously recognized as potentiators of gonococcal PID. Unexpectedly, the cytokine IL-17C was one of the most highly induced genes. Yet, this cytokine has no previous association with gonococcal disease nor any sexually transmitted infection and thus it was selected for further characterization in our model. We show that human Fallopian tubes express the IL-17C receptor (IL-17RE) on the epithelial surface and that treatment with purified IL-17C induces pro-inflammatory cytokine secretion in addition to sloughing of the epithelium and generalized tissue damage. These results demonstrate a previously unrecognized but critical role of IL-17C in the damaging inflammation induced by gonococci in a human explant model of PID.SignificanceWe performed untargeted transcriptional analysis of the human Fallopian tube response toNeisseria gonorrhoeae. Focusing on one upregulated transcript not previously identified in any context of gonococcal infection, we show that the human Fallopian tube secretes the inflammation amplifying cytokine IL-17C in response toN. gonorrhoeaechallenge. IL-17C treatment of human Fallopian tubes stimulated pro-inflammatory cytokine secretion and was sufficient to elicit epithelial cell pathologies characteristic of pelvic inflammatory disease (sloughing, exfoliation). Thus, we identify IL-17C as a previously unrecognized component of the host response to gonococci that promotes inflammation and tissue damage within the human Fallopian tube.
Bioavailability of Schisandrin B and its effect on 5-Fluorouracil metabolism in a xenograft mouse model of colorectal cancer
Authors: Lee Pui-Kei , Co Vanessa Anna , Yang Yang , Wan Murphy Lam Yim , El-Nezami Hani , Zhao Danyue 
Published: November 2022

AbstractSchisandrin B (Sch-B) is a predominant bioactive lignan in the fruit of a traditional Chinese medicinal plantSchisandra Chinensiswith widely reported anti-cancer properties. Using a xenograft mouse model of colorectal cancer (CRC), we showed potent anti-tumor effects of Sch-B and synergistic effects when co-treated with the chemotherapy drug, fluorouracil (5-FU). To explore the underlying anti-tumor mechanism of Sch-B, we first compared the bioavailability, metabolism and tissue distribution of Sch-B and its metabolites among healthy and tumor-bearing mice. To understand the drug-phytochemical interactions associated with the synergy between Sch-B and 5-FU, we examined their reciprocal influence on drug metabolism, tissue distribution, and multidrug resistance (MDR) gene expression in tumor-bearing mice. Using a targeted metabolomics approach, three Sch-B metabolites and two bioactive 5-FU metabolites were quantified and found to reach tumor tissue. Generally, Sch-B metabolites were present at higher levels in tumor-bearing than healthy mice, whereas 5-FU metabolite accumulation was remarkably higher in the co-treatment than 5-FU alone group. Moreover, MDR genes were significantly downregulated upon co-treatment, demonstrating the capacity of Sch-B to reverse MDR in chemotherapy. This study showed that Sch-B may serve as a promising adjuvant to chemotherapy drugs via favorably modulating drug metabolism and bioavailability, and attenuating MDR.
1Arche: An Advanced Flexible Tool for High-throuput Annotation of Functions on Microbial Contigs
Authors: Alonso-Reyes Daniel Gonzalo , Albarracin Virginia Helena 
Published: November 2022

AbstractThe growing amount of genomic data has prompted a need for less demanding and user friendly functional annotators. At the present, it’s hard to find a pipeline for the annotation of multiple functional data, such as both enzyme commission numbers (E.C.) and orthologous identifiers (KEGG and eggNOG), protein names, gene names, alternative names, and descriptions. In this work, we provide a new solution which combines different algorithms (BLAST, DIAMOND, HMMER3) and databases (UniprotKB, KOfam, NCBIFAMs, TIGRFAMs, and PFAM), and also overcome data download challenges. The software framework, Arche, herein demonstrated competitive results overEscherichia coliK-12 genome, the metagenome-assembled genome ofFerrovum myxofaciensS2.4, and a freshwater metagenome when compared to other annotators. Finally, Arche provides an analysis pipeline that can accommodate advanced tools in a unique order, creating several advantages regarding to other commonly used annotators.
Structural Elucidation of a Protective B cell Epitope on Outer Surface Protein C (OspC) of the Lyme disease spirochete,Borreliella burgdorferi
Authors: Rudolph Michael J. , Davis Simon A. , Haque H M Emranul , Weis David D. , Vance David J , Piazza Carol Lyn , Ejemel Monir , Cavacini Lisa , Wang Yang , Mbow M. Lamine , Gilmore Robert D. , Mantis Nicholas J 
Published: November 2022

ABSTRACTOutersurfaceprotein C (OspC) plays a pivotal role in mediating tick-to-host transmission and infectivity of the Lyme disease spirochete,Borreliella burgdorferi. OspC is a helical-rich homodimer that interacts with tick salivary proteins, as well as components of the mammalian immune system. Several decades ago, it was shown that the OspC-specific monoclonal antibody, B5, was able to passively protect mice from experimental tick-transmitted infection byB. burgdorferistrain B31. However, B5’s epitope has never been elucidated, despite widespread interest in OspC as a possible Lyme disease vaccine antigen. Here we report the crystal structure of B5 antigen-binding fragments (Fabs) in complex with recombinant OspC type A (OspCA). Each OspC monomer within the homodimer was bound by a single B5 Fab in a side-on orientation, with contact points along OspC’s α-helix 1 and α-helix 6, as well as interactions with the loop between a-helices 5 and 6. In addition, B5’s complementarity-determining region (CDR) H3 bridged the OspC-OspC’ homodimer interface, revealing the quaternary nature of the protective epitope. To provide insight into the molecular basis of B5 serotype specificity, we solved the crystal structures of recombinant OspC types B and K and compared them to OspCA. This study represents the first structure of a protective B cell epitope on OspC and will aid in the rational design of OspC-based vaccines and therapeutics for Lyme disease.IMPORTANCEThe spirochete,Borreliella burgdorferi, is the causative agent of Lyme borreliosis, the most common tickborne disease in the United States. The spirochete is transmitted to humans during the course of a tick taking a bloodmeal. AfterB. burgdorferiis deposited into the skin of a human host, it replicates locally and spreads systemically, often resulting in clinical manifestations involving the central nervous system, joints, and/or heart. Antibodies directed againstB. burgdorferi’s outer surface protein C (OspC) are known to block tick-to-host transmission, as well as dissemination of the spirochete within a mammalian host. In this report, we reveal the first atomic structure of one such antibody in complex with OspC. Our results have implications for the design of a Lyme disease vaccine capable to interfering with multiple stages inB. burgdorferiinfection.
Long-range inhibitory axons from medial entorhinal cortex target lateral entorhinal neurons projecting to the hippocampus
Authors: Nilssen Eirik S. , Jacobsen Bente , Doan Thanh P. , Girão Paulo J. B. , Witter Menno P. 
Published: November 2022

ABSTRACTFunctionally distinct information encoded by the two main divisions of the entorhinal cortex (EC), the lateral EC (LEC) and the medial EC (MEC), is thought to be first integrated at the level of the hippocampus. Here we examine a circuit connecting MEC to LEC that supports functional interplay at the level of the two entorhinal domains. Using a combination of anatomical,in vitroelectrophysiological and behavioral experiments in the mouse, we report that axons from MEC somatostatin-expressing GABAergic neurons densely distribute in layer I of LEC, where they drive strong and near selective inhibition of principal neurons in layer IIa. This inhibitory pathway is accompanied by MEC glutamatergic axons that innervate multiple layers of LEC and preferentially synapse onto principal neurons in layers IIb and III. Our findings indicate that excitatory and inhibitory projections from MEC may separately regulate the activity of different populations of hippocampal-projecting principal neurons in LEC.
Human Gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signaling in budding yeast
Authors: Valenti Marta , Molina María , Cid Víctor J 
Published: November 2022

SummaryGasdermin D (GSDMD) and mixed lineage kinase domain-like protein (MLKL) are the pore-forming effectors of pyroptosis and necroptosis, respectively, with the capacity to disturb plasma membrane selective permeability and induce programmed cell death. The budding yeastSaccharomyces cerevisiaehas long been used as a simple eukaryotic model for the study of proteins associated with human diseases by heterologous expression. In this work, we expressed in yeast both GSDMD and its N-terminal domain [GSDMD(NT)] to characterize their cellular effects, and compare them to those of MLKL. GSDMD(NT) and MLKL inhibited yeast growth, formed cytoplasmic aggregates, and fragmented mitochondria. Loss-of-function point mutants of GSDMD(NT) showed affinity for this organelle. Besides, GSDMD(NT) and MLKL caused an irreversible cell cycle arrest through TORC1 inhibition, and disrupted endosomal and autophagic vesicular traffic. Our results provide a basis for a humanized yeast platform to study GSDMD and MLKL, a useful tool for structure-function assays and drug discovery.