bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic model of bovine brucellosis to investigate control strategies in endemic settings
Authors: Holt H. R. , Walker M. , Beauvais W. , Kaur P. , Bedi J.S. , Mangtani P. , Sharma N.S. , Gill J.PS. , Godfroid J. , McGiven J. , Guitian J. 
Published: March 2022

AbstractBrucellosis imposes substantial impacts on livestock production and public health worldwide. A stochastic, age-structured model incorporating herd demographics was developed describing within- and between-herd transmission of Brucella abortus in dairy cattle herds. The model was fitted to data from a cross-sectional study conducted in Punjab State of India and used to evaluate the effectiveness of control strategies under consideration. Based on model results, stakeholder acceptance and constraints regarding vaccine supply, vaccination of replacement calves in large farms should be prioritised. Test and removal applied at early stages of the control programme where seroprevalence is high would not constitute an effective use of resources. Critically, under current model assumptions, significant numbers of animals ‘removed’ (culled or not used for breeding) in this strategy would be removed based on false positive results. To achieve sustained reductions in brucellosis, policymakers must commit to maintaining vaccination in the long term, which may eventually reduce frequency of infection in the livestock reservoir to a low enough level for elimination to be a realistic objective. This exercise provided important insights into the control of brucellosis in India, which has the largest cattle population globally, and a general framework for evaluating control strategies in endemic settings.
Comparison and evaluation of data-driven protein stability prediction models
Authors: Csicsery-Ronay Jennifer A. , Zaitzeff Alexander , Singer Jedediah M. 
Published: March 2022

AbstractPredicting protein stability is important to protein engineering yet poses unsolved challenges. Computational costs associated with physics-based models, and the limited amount of data available to support data-driven models, have left stability prediction behind the prediction of structure. New data and advancements in modeling approaches now afford greater opportunities to solve this challenge. We evaluate a set of data-driven prediction models using a large, newly published dataset of various synthetic proteins and their experimental stability data. We test the models in two separate tasks, exercising extrapolation to new protein classes and prediction of the effects on stability of small mutations. Small convolutional neural networks trained from scratch on stability data and large protein embedding models passed through simple downstream models trained on stability data are both able to predict stability comparably well. The largest of the embedding models yields the best performance in all tasks and metrics. We also explored the marginal performance gains seen with two ensemble models.
A novel method accounting for predictor uncertainty and model transferability of invasive species distribution models
Authors: Hill Matt , Caley Peter , Camac James , Elith Jane , Barry Simon 
Published: March 2022

AbstractPredicting novel ranges of non-native species is a critical component to understanding the biosecurity threat posed by pests and diseases on economic, environmental and social assets. Species distribution models (SDMs) are often employed to predict the potential ranges of exotic pests and diseases in novel environments and geographic space. To date, researchers have focused on model complexity, data available for model fitting, the size of the geographic area to be considered and how the choice of model impacts results. These investigations are coupled with considerable examination of how model evaluation methods and test scores are influenced by these choices. An area that remains under-discussed is how to account for uncertainty in predictor selection while also selecting variables that increase a model’s ability to predict to novel environments (model transferability).Here we propose a novel method to finesse this problem by using multiple simple (bivariate) models to search for the candidate sets of predictor variables that are likely to produce transferable models. Once identified, each set is then used to construct 2-dimensional niche envelopes of pest presence/absence. This process ultimately results in a number of possible models that can be used to predict pest potential distributions, however, rather than relying on a single model, we ensemble these models in an attempt to account for predictor uncertainty. We apply this method to both virtual species and real species data, and find that it generally performs well against conventional approaches for statistically fitting numerous variables in a single model. While our methods only consider simple ecological relationships of species to environmental predictors, they allow for increased model transferability because they reduce the likelihood of over-fitting and collinearity issues. Simple models are also likely to be more conservative (over-predict potential distributions) relative to complex models containing many covariates – making them more appropriate for risk-averse applications such as biosecurity. The approach we have explored transforms a model selection problem, for which there is no true correct answer amongst the typically distal covariates on offer, to one of model uncertainty. We argue that increased model transferability at the expense of model interpretation is perhaps more important for effective rapid predictions and management of non-native species and biological invasions.
High-fat diet promotes Acute Promyelocytic Leukemia through PPARδ-enhanced self-renewal of preleukemic progenitors
Authors: Mazzarella Luca , Falvo Paolo , Adinolfi Marta , Tini Giulia , Gatti Elena , Piccioni Rossana , Bonetti Emanuele , Dorronzoro Elena Gavilan , Bodini Margherita , Gallo Barbara , Orecchioni Stefania , Duso Bruno Achutti , Ronchini Chiara , Sanarico Anna Giulia , Pallavi Rani , Roerink Sophie , Bertolini Francesco , Alcalay Myriam , Dellino Gaetano Ivan , Pelicci Pier Giuseppe 
Published: March 2022

AbstractObesity is associated with a higher risk of developing many cancer types including acute promyelocytic leukaemia (APL), a subset of acute myeloid leukemias (AML) characterized by expression of the PML-RARα oncogene. The molecular mechanisms linking obesity and APL development are not known. To model clinical observations, we established a mouse model of diet-induced obesity using transgenic mice constitutively expressing PML-RARA α in the hematopoietic system (PML-RARα KI mice) fed either standard (SD) or high-fat (HFD) diets. HFD-fed PML-RARα KI mice developed leukaemia with reduced latency and increased penetrance, as compared to SD-fed mice. HFD leads to accumulation of DNA damage in hematopoietic stem cells (HSCs), but, surprisingly, this was not associated with mutational load gain, as shown by whole genome/exome sequencing of pre-leukemic and leukemic cells. Importantly, very few of the observed mutations were predicted to act as cancer drivers, suggesting the relevance of nongenetic mechanisms. HFD led to an expansion of hematopoietic progenitor cells with a concomitant reduction in long-term hematopoietic stem cells, and in the presence of PML-RARα this was also accompanied by an enhancement of in vitro and in vivo self-renewal. Interestingly, Linoleic Acid (LA), abundant in HFD, recapitulates the effect of HFD on the self-renewal of PML-RARα HPCs by activating the peroxisome proliferator-activated receptor delta (PPARδ), a central regulator of fatty acid metabolism involved in the promotion of cancer progression. Our findings have implications for dietary or pharmacological interventions aimed at counteracting the cancer-promoting effect of obesity.Key pointshigh fat diet (HFD) promotes APL leukemogenesis in mouse models, reproducing the exquisite sensitivity to obesity observed in humansalthough HFD leads to DNA damage and mutations, the molecular mechanism is nongenetic and linked to the transcription factor PPARδ
Prediction of m6A and m5C at single-molecule resolution reveals a cooccurrence of RNA modifications across the transcriptome
Authors: Acera Mateos P. , Sethi A.J. , Ravindran A. , Srivastava A. , Woodward K. , Mahmud S. , Kanchi M. , Guarnacci M. , Xu J. , Yuen Z.W.S. , Zhou Y. , Sneddon A. , Hamilton W. , Gao J. , Starrs L.M. , Hayashi R. , Wickramasinghe V. , Zarnack K. , Preiss T. , Burgio G. , Dehorter N. , Shirokikh N. , Eyras E. 
Published: March 2022

ABSTRACTThe epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI’s capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.
Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis
Authors: Steiner Alex , Owen Benjamin M. , Bauer James P. , Seanez Leann , Kwon Sam , Biddinger Jessica E. , Huffman Ragan , Ayala Julio E. , Nobis William P. , Lewis Alan S. 
Published: March 2022

AbstractUnderstanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. What is not well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through selective expression of its receptor, GLP-1R. RNA-seq demonstrated that most Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study identifies a potential neurohormonal mechanism linking a critically important satiety signal with activity of MCs in the ventral DG that might have functional effects on learning and memory during distinct states.
Tetrasulfide Bridge (TTSB) Formation: an Extraordinary Intermediate Structure in the Architecture and Dynamics of the HIV-1’s gp120 molecule
Authors: Crevecoeur Harry F. 
Published: March 2022

AbstractGp120, one of the molecules that execute HIV viral entry in CD4+ cells has a number of allosteric disulfide bridges. In this study we explore the dynamics of these potential disulfide (disulphide) bridges in the 3-D configuration (based on crystallography) and UNSW DBA analyses of various gp120 crystals. The data reveal the existence of a tetrasulfide (tetrasulphide) bridge (TTSB) which, together with a disulfide bridge, keeps two perpendicular beta sheets (namely V3 and V4) approximated in the architecture of the gp120 while allowing safe transfer of energy between the allosteric bonds. Analyses of multiple gp120 crystals reveal the existence of the TTSB to be more as an intermediate as opposed to a constant landmark, which implies more complex functions than just structural attributes. This TTSB, which is observed in various crystals of gp120, in various strains and clades of HIV-1, is demonstrated by various rendering software and some are also detected, reported and characterized by the UNSW Disulfide Bond Analysis (DBA) engine. This tetrasulfide bridge connects the allosteric bond Cys296–Cys331 to Cys385-Cys418, sometimes as CYS331:SG – CYS385:SG, and sometimes as CYS331:SG – CYS418:SG. Moreover in crystals 3TIH, 4LSR and 4R4N, we also observed an intermediate state of the TTSB where it presents a triangular formation in which the sulfur atom CYS331:SG binds to both CYS385:SG and CYS418:SG simultaneously, which represents an important intermediate in the functional dynamics of the gp120 molecule. The presence of this extraordinary structure (TTSB) does point to some intriguing insights in the multifunctional design and mechanics as well as some complex fragilities of the gp120 molecule, exposing a new target for antiviral therapy.
AHR agonist ITE boosted PD1 antibody’s effects by inhibiting myeloid-derived cells suppressive cells in an orthotopic mouse glioma model
Authors: Zhao Lijiao , Ma Yunlong , Shu Qiuting , Sun Hui , Lu Jing , Gong Pei , Meng Fanhua , Wan Fang 
Published: March 2022

AbstractGlioblastoma is a “cold“ tumor lacking T cell infiltration and tryptophan metabolites such as kynurenine function as an immune suppressor by binding to aryl hydrocarbon receptor(AHR). Hence AHR antagonists have been developed and some shown to activate the immune response in IDO over-expressing cancer models. Paradoxically, AHR has been reported to block glioma cell invasion like a tumor suppressor, and how to target AHR in cancer remains an open question. We previously discovered that an AHR agonist ITE can effectively inhibit glioma invasion. Here we report that ITE combined with PD1 antibody significantly increased the infiltration of CD8+ T cells while reducing that of the myeloid-derived suppressive cells (MDSCs), extending mouse survival. To identify factors that possibly mediated ITE’s effects, we analyzed RNA-seq data and discovered that ITE significantly down-regulated IL11, a known MDSC regulator. In contrast, kynurenine upregulated IL11, further supporting IL11 as an AHR target. Moreover, ITE inhibited IL11’s induction of MDSC from mouse PBMC in vitro, supporting that IL11 might mediate ITE’s MDSC regulation effects. The discovery of ITE’s immune-activating effects highlighted the complexity of AHR’s signaling in cancers. The unexpected increase in STAT3, downstream of IL11 provided clues for combination therapy development.
Little skate genome exposes the gene regulatory mechanisms underlying the evolution of vertebrate locomotion
Authors: Yoo DongAhn , Lee Chul , Park JunHee , Lee Young Ho , Heguy Adriana , Dasen Jeremy S. , Kim Heebal , Baek Myungin 
Published: March 2022

AbstractThe little skateLeucoraja erinacea, a cartilaginous fish, displays pelvic fin driven walking-like behaviors using genetic programs and neuronal subtypes similar to those of land vertebrates. However, mechanistic studies on little skate motor circuit development have been limited, due to a lack of high-quality reference genome. Here, we generated an assembly of the little skate genome, containing precise gene annotation and structures, which allowed post-genome analysis of spinal motor neurons (MNs) essential for locomotion. Through interspecies comparison of mouse, skate and chicken MN transcriptomes, shared and divergent MN expression profiles were identified. Conserved MN genes were enriched for early-stage nervous system development. Comparison of accessible chromatin regions between mouse and skate MNs revealed conservation of the potential regulators with divergent transcription factor (TF) networks through which expression of MN genes is differentially regulated. TF networks in little skate MNs are much simpler than those in mouse MNs, suggesting a more fine-grained control of gene expression operates in mouse MNs. These findings suggest conserved and divergent mechanisms controlling MN development system of vertebrates during evolution and the contribution of intricate gene regulatory networks in the emergence of sophisticated motor system in tetrapods.
Direct detection of natural selection in Bronze Age Britain
Authors: Mathieson Iain , Terhorst Jonathan 
Published: March 2022

AbstractWe developed a novel method for efficiently estimating time-varying selection coefficients from genome-wide ancient DNA data. In simulations, our method accurately recovers selective trajectories, and is robust to mis-specification of population size. We applied it to a large dataset of ancient and present-day human genomes from Britain, and identified seven loci with genome-wide significant evidence of selection in the past 4500 years. Almost all of them are related to increased vitamin D or calcium levels, and we conclude that lack of vitamin D and consequent low calcium was consistently the most important selective pressure in Britain since the Bronze Age. However, the strength of selection on individual loci varied substantially over time, suggesting that cultural or environmental factors moderated the genetic response to this pressure. Of 28 complex anthropometric and metabolic traits, skin pigmentation was the only one with significant evidence of polygenic selection, further underscoring the importance of phenotypes related to vitamin D. Our approach illustrates the power of ancient DNA to characterize selection in human populations and illuminates the recent evolutionary history of Britain.
Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies
Authors: O’Neill Matthew J. , Wada Yuko , Hall Lynn D. , Mitchell Devyn W. , Glazer Andrew M. , Roden Dan M. 
Published: March 2022

AbstractBackgroundRare protein-altering variants in SCN5A, KCNQ1, and KCNH2 are major causes of Brugada Syndrome (BrS) and the congenital Long QT Syndrome (LQTS). While splice-altering variants lying outside 2-bp canonical splice sites can cause these diseases, their role remains poorly described.ObjectiveWe implemented two functional assays to assess 12 recently reported putative splice-altering variants of uncertain significance (VUS) and 1 likely pathogenic (LP) variant without functional data observed in BrS and LQTS probands.MethodsWe deployed minigene assays to assess the splicing consequences of 10 variants. Three variants incompatible with the minigene approach were introduced into control induced pluripotent stem cells (iPSCs) by CRISPR genome editing. We differentiated cells into iPSC-derived cardiomyocytes (iPSC-CMs) and studied splicing outcomes by reverse transcription-polymerase chain reaction (RT-PCR). We used the American College of Medical Genetics and Genomics functional assay criteria (PS3/BS3) to reclassify variants.ResultsWe identified aberrant splicing, with presumed disruption of protein sequence, in 8/10 variants studied using the minigene assay and 1/3 studied in iPSC-CMs. We reclassified 9 VUS to LP, 1 VUS to Likely Benign, and 1 LP variant to pathogenic.ConclusionsFunctional assays reclassified splice-altering variants outside canonical splice sites in BrS- and LQTS-associated genes.
Spontaneous myocarditis in mice predisposed to autoimmune disease: Including Vaccination-induced onset
Authors: Hayashi Takuma , Ichikawa Motoki , Konishi Ikuo 
Published: March 2022

AbstractNon-obese diabetic (NOD)/ShiLtJ mice, like biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with a moderate glycosuria and a non-fasting hyperglycemia. Previously, in non-obese diabetic (NOD)/ShiLtJ mice spontaneously developing type 1 diabetes, the possible involvement of decreased expression of LMP2/β1i, an immunoproteasome β subunit, and associated decreased expression of NF-κB1 (also called as p50) in the development of type 1 diabetes was argued between our research team and other research groups. In response to these arguments, we created NOD mice in which NF-κB1 expression is not consistently observed. Unexpectedly, most NOD Nfκb1 homozygote mice were found to die by the 8th week of age due to the development of severe myocarditis. Furthermore, in all NOD Nfκb1 heterozygote mice, the onset of Insulitis was observed from 4 months of age. In addition, in NOD Nfκb1 heterozygote mice, an increase in cTnT due to vaccination with influenza or HBV vaccine was observed without gender difference. Now, we found a direct involvement of decreased expression of NF-κB1 in the development of autoimmune diseases in NOD/ShiLtJ mice. Therefore, we would like to introduce new research results on autoimmune diseases, including findings on important risk factors for the development of myocarditis observed after vaccination with mRNA-based COVID-19 vaccine.
Conditions of Confinement in U.S. Carceral Facilities during COVID-19: Individuals Speak: Incarcerated during the COVID-19 Epidemic (INSIDE)
Authors: Cassarino Nicole , Dabbara Harika , Monteiro Carla B. , Bembury Arthur , Credle Leslie , Grandhi Uma , White Samantha , Jiménez Monik C. 
Published: March 2022

AbstractObjectivesWe aimed to describe conditions of confinement among people incarcerated in the United States during the coronavirus disease 2019 (COVID-19) pandemic and assess the feasibility of a community-science data collection approach.MethodsWe developed a web-based survey with community partners to collect information on confinement conditions (COVID-19 safety, basic needs, support). Formerly incarcerated adults released after March 1, 2020, or non-incarcerated adults in communication with an incarcerated person (proxy) were recruited through social media from July 25, 2020, through March 27, 2021. Descriptive statistics were estimated in aggregate and separately by proxy or formerly incarcerated status. Additionally, we compared responses between proxy and formerly incarcerated respondents using chi-square or Fisher’s exact tests as appropriate based on alpha=0.05.ResultsOf 378 responses, 94% were by proxy, and 76% reflected state prison conditions. Participants reported inability to physically distance (≥6ft at all times) (92%), inadequate access to soap (89%), water (46%), toilet paper (49%) and showers (68%). Among people who received mental healthcare before the pandemic, 75% reported reduced care. We found that responses were consistent between formerly incarcerated people and proxy-respondents.ConclusionsOur findings suggest that a community-science approach to data collection is feasible. Based on these findings, COVID-19 safety and basic needs were not sufficiently addressed within some carceral settings. Thus, we recommend the lived experiences of incarcerated individuals should be included to make informed and equitable policy decisions.