bluuebunny/crossref_metadata_2025_split huggingface dataset:
Males are more sensitive to their audience than females when scent-marking in the redfronted lemur
Authors: Peckre Louise R. , Michiels Alexandra , Socias-Martínez Lluís , Kappeler Peter M. , Fichtel Claudia 
Published: September 2021

AbstractAudience effects, i.e. changes in behaviour caused by the presence of conspecifics, have rarely been studied in the context of olfactory communication, even though they may provide important insights into the functions of olfactory signals. Functional sex differences in scent-marking behaviours are common and influenced by the social system. To date, patterns of functional sex differences in scent-marking behaviours remain unknown in species without overt dominance relationships. We investigated sex differences in intra-group audience effects on anogenital scent-marking in a wild population of redfronted lemurs (Eulemur rufifrons) by performing focal scent-marking observations. With a combination of generalised linear mixed models and exponential random graph models, we found different audience effects in both sexes. Males were overall more sensitive than females to their audience. Only males seemed to be sensitive to the presence of both members of the opposite sex and same-sex conspecifics in the audience. Females were only moderately sensitive to the presence of other females in the audience. This study offers a potential behavioural pattern associated with anogenital scent-marking that seem to differ from those described for species exhibiting female dominance, supporting the notion that the social systems co-varies with scent-marking behaviours and scent-complexity in strepsirrhines.
The AmiC/NlpD pathway dominates peptidoglycan breakdown in Neisseria meningitidis and affects cell separation, NOD1 agonist production, and infection
Authors: Chan Jia Mun , Hackett Kathleen T. , Woodhams Katelynn L. , Schaub Ryan E. , Dillard Joseph P. 
Published: September 2021

ABSTRACTThe human-restricted pathogen Neisseria meningitidis, which is best known for causing invasive meningococcal disease, has a nonpathogenic lifestyle as an asymptomatic colonizer of the human naso- and oropharyngeal space. N. meningitidis releases small peptidoglycan (PG) fragments during growth. It was demonstrated previously that N. meningitidis releases low levels of tripeptide PG monomer, which is an inflammatory molecule recognized by the human intracellular innate immune receptor NOD1. In this present study, we demonstrated that N. meningitidis released more PG-derived peptides compared to PG monomers. Using a reporter cell line overexpressing human NOD1, we showed that N. meningitidis activates NOD1 using PG-derived peptides. Generation of such peptides required the presence of the periplasmic N-acetylmuramyl-L-alanine amidase AmiC, and the outer membrane lipoprotein, NlpD. AmiC and NlpD were found to function in cell separation, and mutation of either amiC or nlpD resulted in large clumps of unseparated N. meningitidis cells instead of the characteristic diplococci. Using stochastic optical reconstruction microscopy, we demonstrated that FLAG epitope-tagged NlpD localized to the septum, while similarly-tagged AmiC was found at the septum in some diplococci but distributed around the cell in most cases. In a human whole blood infection assay, an nlpD mutant was severely attenuated and showed particular sensitivity to complement. Thus, in N. meningitidis the cell separation proteins AmiC and NlpD are necessary for NOD1 stimulation and for survival during infection of human blood.
Long COVID: Assessment of Neuropsychiatric Symptoms in Children and Adolescents - A Clinical Data Analysis
Authors: Frölich Jan , Banaschewski Tobias , Ulmer Annabelle 
Published: September 2021

AbstractCOVID-19 infections in adults often result in medical, neuropsychiatric, and unspecific symptoms, called Long COVID, and the premorbid functional status cannot be achieved. Regarding the course in children and adolescents, however, reliable data are not yet available.Objective380 children and adolescents/young adults aged between 6 and 21 years, being treated for various psychiatric diseases in an outpatient clinical service, were examined for COVID-19 infections and Long COVID symptoms following a structured protocol.ResultsThree patients had COVID-19; one patient had symptoms of Long COVID in his medical history, but they could not be objectivized in an in-depth neuropsychiatric and neuropsychological assessment.ConclusionsLong COVID seems to occur rarely in children and adolescents. Objectivizing the symptoms is a difficult task that requires various diagnostic considerations.
Two new compartmental epidemiological models and their equilibria
Authors: Balisacan Jonas , Chyba Monique , Shanbrom Corey 
Published: September 2021

AbstractCompartmental models have long served as important tools in mathematical epidemiology, with their usefulness highlighted by the recent COVID-19 pandemic. However, most of the classical models fail to account for certain features of this disease and others like it, such as the ability of exposed individuals to recover without becoming infectious, or the possibility that asymptomatic individuals can indeed transmit the disease but at a lesser rate than the symptomatic. Furthermore, the rise of new disease variants and the imperfection of vaccines suggest that concept of endemic equilibrium is perhaps more pertinent than that of herd immunity.Here we propose a new compartmental epidemiological model and study its equilibria, characterizing the stability of both the endemic and disease-free equilibria in terms of the basic reproductive number. Moreover, we introduce a second compartmental model, generalizing our first, which accounts for vaccinated individuals, and begin an analysis of its equilibria.
CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer
Authors: O’Reilly Debbie , Downing Tim , Kouba Sana , Potier-Cartereau Marie , McKenna Declan J , Vandier Christophe , Buchanan Paul 
Published: September 2021

AbstractAndrogen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that expression of voltage gated calcium channels (VGCC) is increased in cancer, particularly the CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology.Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients regardless of TMPRSS2:ERG status. Corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. The expression was found to be a shortened 170kDA CaV1.3 isoform associated which failed to mediate calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This in turn drove both proliferation and survival of long-term ADT CRPC cells.Overall, this study demonstrates for the first time in PCa that increased SOCE through a novel CaV1.3 mechanism which represents a novel oncogenic switch that contributes to ADT resistance and promotes CRPC biology. Highlighting aberrant intracellular calcium in CRPC as a potential area for therapeutic development to improve patient outcomes.
Evolution and functional dynamics of dehydrins in model Brachypodium grasses
Authors: Decena M.A. , Galvez-Rojas S. , Agostini F. , Sancho R. , Contreras-Moreira B. , Des Marais D. L. , Hernández P. , Catalán P. 
Published: September 2021

AbstractDehydration proteins (dehydrins, DHNs) confer tolerance to water-stress deficit to plants, thus playing a fundamental role in plant response and adaptation to water-deprivation stressful environments. We have performed a comparative genomics and evolutionary study of DHN genes in four model Brachypodium grass species, and a drought-induced functional analysis in 32 ecotypes of the flagship species B. distachyon, to gain insight into the origins and dynamics of these proteins and the correlated drought-mediated phenotypic responses in ecotypes showing different hydric requirements. Genomic sequence analysis detected 10 types of dehydrin genes (Bdhn) across the Brachypodium species, totalling 47 genes. Domain and conserved motif contents of peptides encoded by Bdhn genes revealed eight protein architectures, YSɸK2 being the most common architecture. Bdhn genes were spread across several chromosomes and more frequent in syntenic chromosomes 3 and 4 of B. distachyon, 4 and 5 of B. stacei and 4 of B. sylvaticum. Tandem and segmental duplication events were detected for four Bdhn genes. Selection analysis indicated that all the Bdhn genes were constrained by purifying selection. Three upstream cis-regulatory motifs (BES1, MYB124, ZAT) were consistently detected in several Bdhn genes. Functional analysis in 32 natural accessions of B. distachyon demonstrated that only four Bdhn genes (Bdhn1, Bdhn2, Bdhn3, Bdhn7) were expressed in mature leaves and that all of them were significantly more highly expressed in plants under drought conditions. These genes corresponded to wheat orthologs that were also significantly more expressed under drought stress. Brachypodium dehydrin expression was significantly correlated with drought-response phenotypic traits (plant biomass, leaf carbon and proline contents and WUE increases, leaf water and nitrogen content changes) being more pronounced in drought-tolerant ecotypes. Bdhn expression, associated phenotypic trait changes and climate niche variation did not show significant phylogenetic signal when tested in the B. distachyon genealogical-species tree. By contrast, some of them showed low or marginal significant phylogenetic signal when tested in the B. distachyon Bdhn tree, suggesting that Bdhn gene evolution is partially related to adaptation to drought in this species. Our results demonstrate that dehydrin composition and regulation is a key factor determining the acquisition of water-stress tolerance in grasses.
Tbet expression by Tregs is needed to protect against Th1-mediated immunopathology duringToxoplasmainfection in mice
Authors: Warunek Jordan , Jin Richard M. , Blair Sarah J. , Garis Matthew , Marzullo Brandon , Wohlfert Elizabeth A. 
Published: September 2021

AbstractT. gondiiinfection has proven to be an ideal model to understand the delicate balance between protective immunity and immune-mediated pathology during infection. Lethal infection causes a collapse of Tregs mediated by loss of IL-2, and conversion of Tregs to IFNγ producing cells. Importantly, these Tregs highly express the Th1 transcription factor Tbet. To determine the role of Tbet in Tregs, we infectedTbx21f/f-Foxp3YFPCreand control Foxp3YFPCremice with the type II strain ofT. gondii, ME49. The majority ofTbx21f/f-Foxp3YFPCremice succumb to a non-lethal acute infection. Notably, parasite burden is comparable betweenTbx21f/f-Foxp3YFPCreand Foxp3YFPCrecontrol mice. We found thatTbx21f/f-Foxp3YFPCremice have significantly higher serum levels of proinflammatory cytokines IFNγ and TNFα, suggestive of a heightened immune response. To test if CD4+T cells were driving immunopathology, we treatedTbx21f/f-Foxp3YFPCremice with anti-CD4 depleting antibody and partially rescued these mice. Broad spectrum antibiotic treatment also improved survival, demonstrating a role for commensal flora in immunopathology inTbx21f/f-Foxp3YFPCremice. RNA-seq analysis reinforced that Tbet regulates several key cellular pathways, including chromosome segregation, cytokine receptor activity and cell cycle progression, that help to maintain fitness in Tregs during Th1 responses. Taken together, our data shows an important role for Tbet in Tregs in preventing lethal immunopathology duringToxoplasma gondiiinfection, further highlighting the protective role of Treg plasticity to self and microbiota.
Tissue scale properties of the extracellular matrix regulates nuclear shape, organisation and fate in the embryonic midline sutures
Authors: Alves-Afonso Diana , Ryan Allyson Quinn , Lahola-Chomiak Adrian , Prakash Mangal , Jug Florian , Modes Carl D. , Tabler Jacqueline M. 
Published: September 2021

AbstractBalancing self-renewal and differentiation is a key feature of every stem cell niche and one that is tuned by mechanical interactions of cells with their neighbors and surrounding extracellular matrix. The fibrous stem cell niches that develop as sutures between skull bones must balance the complex extracellular environment that emerges to define them with self-renewal and bone production. Here, we address the role for physical stimuli in suture development by probing the relationship between nuclear shape, organization and gene expression in response to a developing collagen network in embryonic midline sutures. This work complements genetic approaches used to study sutures and provides the first quantitative analyses of physical structure in these sutures. By combining multiple imaging modalities with novel shape description, in addition to network analysis methods, we find the early emergence of a complex extracellular collagen network to have an important role in regulating morphogenesis and cell fate. We show that disrupted collagen crosslinking can alter ECM organization of midline sutures as well as stimulate expression of bone differentiation markers. Further, our findings suggest that in vivo, skeletal tissues can uncouple the response of the nuclear lamina from collagen mediated tissue stiffening seen in vitro. Our findings highlight a crucial relationship between the cellular microenvironment, tissue stiffness and geometry with gene expression in normal development and maintenance of progenitor fate in embryonic sutures.
Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
Authors: Conde-Dusman María J. , Dey Partha N. , Elía-Zudaire Oscar , Rabaneda Luis G. , García-Lira Carmen , Grand Teddy , Briz Victor , Velasco Eric R. , Andero Raúl , Niñerola Sergio , Barco Angel , Paoletti Pierre , Wesseling John F. , Gardoni Fabrizio , Tavalin Steven J. , Pérez-Otaño Isabel 
Published: September 2021

ABSTRACTDe novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mTOR kinase and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.
Structural anatomy of C1 domain interactions with DAG and other agonists
Authors: Katti Sachin S. , Krieger Inna V. , Ann Jihyae , Lee Jeewoo , Sacchettini James C. , Igumenova Tatyana I. 
Published: September 2021

AbstractDiacylglycerol (DAG) is a versatile lipid whose 1,2-sn-stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and as metabolic precursor for downstream signaling lipids such as phosphatidic acid1,2. DAG effector proteins compete for available lipid using conserved homology 1 (C1) domains as DAG-sensing modules. Yet, how C1 domains recognize and capture DAG in the complex environment of a biological membrane has remained unresolved for the 40 years since the discovery of Protein Kinase C (PKC)3 as the first member of the DAG effector cohort. Herein, we report the first high-resolution crystal structures of a C1 domain (C1B from PKCδ) complexed to DAG and to each of four potent PKC agonists that produce different biological readouts and that command intense therapeutic interest. This structural information details the mechanisms of stereospecific recognition of DAG by the C1 domains, the functional properties of the lipid-binding site, and the identities of the key residues required for the recognition and capture of DAG and exogenous agonists. Moreover, the structures of the five C1 domain complexes provide the high-resolution guides for the design of agents that modulate the activities of DAG effector proteins.
In lupus nephritis, specificin situinflammatory states are associated with refractory disease and progression to renal failure
Authors: Abraham Rebecca , Durkee Madeleine , Ai Junting , Veselits Margaret , Casella Gabriel , Asano Yuta , Chang Anthony , Ko Kichul , Oshinsky Charles , Peninger Emily , Giger Maryellen , Clark Marcus R. 
Published: September 2021

AbstractIn human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end stage renal disease (ESRD). However, while approximately half of patients with moderate or severe TII develop ESRD, half do not. Therefore, we hypothesized that TII is heterogeneous, with distinct inflammatory states associated with different renal outcomes. We interrogated renal biopsies from LN longitudinal and cross-sectional cohorts using both conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed unique computational pipelines by training and implementing several deep learning models and other computer vision techniques. Surprisingly, across biopsies, high B cell densities were strongly associated with protection from ESRD. In contrast, elevated CD4-T cell population densities, which included CD8, γδ and double negative (CD4-CD8-δ-, DN) T cells, were associated with both acute refractory renal failure and gradual progression to ESRD. Interestingly, lymphocytes and dendritic cells were organized into discrete clusters or neighborhoods that could be characterized by the enrichment for specific cell populations. B cells were often organized into large neighborhoods with CD4+ T cells including T follicular helper-like cells. In contrast, the CD4-T cell populations formed small cellular neighborhoods whose frequency predicted subsequent progression to ESRD. These data reveal that in LN, specificin situinflammatory states are associated with refractory disease and progression to ESRD.One sentence summaryUsing deep machine learning to analyze confocal microscopy data, we demonstrate that in lupus nephritis, CD4-T cell populations, including CD8+ and γδ T cells, organize into specific spatial neighborhoods that predict progression to renal failure.
AbmR is a mycobacterial dual-function transcription factor and ribonucleoprotein with distinct DNA and RNA-binding determinants
Authors: Girardin Roxie C. , Pata Janice , Qin Xiaohong , Sui Haixin , McDonough Kathleen A. 
Published: September 2021

ABSTRACTThe bacteriumMycobacterium tuberculosis(Mtb) must adapt to myriad host-associated stressors. A recently identified transcription factor, AbmR (ATP-bindingmcr11-regulator), regulates expression of an essential stress-responsive small RNA (Mcr11) and inhibits the growth of Mtb. Previously, AbmR was found to make 39S complexes of unknown function. Here we report that AbmR 39S complexes are comprised of AbmR and co-purifying RNAs and that RNA-binding inhibits AbmR’s DNA-binding function. While AbmR binds DNA and regulates gene expression in a sequence specific manner, RNA-binding is not sequence specific. Amino acid R146 is important for DNA-binding but completely dispensable for RNA-binding and 39S complex formation, establishing that the RNA- and DNA-binding functions of AbmR are distinct. RNA bound by AbmR was protected from RNase digestion, supporting an RNA modulatory function for the 39S complex. We also found thatabmRis required for optimal survival during treatment with the ATP-depleting antibiotic bedaquiline, which is associated with extended RNA stability. These data establish a paradigm wherein a transcription factor assembles into large complexes to transition between mutually exclusive DNA-binding gene regulatory and RNA-binding RNA modulatory functions. Our findings indicate that AbmR is a dual-function protein that may have novel RNA regulatory roles in stress adapted Mtb.
Machine learning enables accurate and rapid prediction of active molecules against breast cancer cells
Authors: He Shuyun , Zhao Duancheng , Ling Yanle , Cai Hanxuan , Cai Yike , Zhang Jiquan , Wang Ling 
Published: September 2021

AbstractSummaryBreast cancer (BC) has surpassed lung cancer as the most frequently occurring cancer, and it is the leading cause of cancer-related death in women. Therefore, there is an urgent need to discover or design new drug candidates for BC treatment. In this study, we first collected a series of structurally diverse datasets consisting of 33,757 active and 21,152 inactive compounds for 13 breast cancer cell lines and one normal breast cell line commonly used in in vitro antiproliferative assays. Predictive models were then developed using five conventional machine learning algorithms, including naïve Bayesian, support vector machine, k-Nearest Neighbors, random forest, and extreme gradient boosting, as well as five deep learning algorithms, including deep neural networks, graph convolutional networks, graph attention network, message passing neural networks, and Attentive FP. A total of 476 single models and 112 fusion models were constructed based on three types of molecular representations including molecular descriptors, fingerprints, and graphs. The evaluation results demonstrate that the best model for each BC cell subtype can achieve high predictive accuracy for the test sets with AUC values of 0.689–0.993. Moreover, important structural fragments related to BC cell inhibition were identified and interpreted. To facilitate the use of the model, an online webserver called ChemBC and its local version software were developed to predict potential anti-BC agents.AvailabilityChemBC webserver is available at http://chembc.idruglab.cn/ and its local version Python software is maintained at a GitHub repository (https://github.com/idruglab/ChemBC).Contactzjqgmc@163.com or lingwang@scut.edu.cnSupplementary informationSupplementary data are available at Bioinformatics online.