bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying the effects of recent glacial history and future climate change on a unique population of mountain goats
Authors: Young Kiana B. , Lewis Tania M. , White Kevin S. , Shafer Aaron B.A. 
Published: January 2022

AbstractHuman disturbance and climate change can impact populations by disrupting movement corridors and reducing important habitat. Characterizing how animals respond to such environmental changes is valuable for conservation as many species, especially habitat specialists, can experience reduced genetic diversity when deleterious habitat change occurs, leading to an increased likelihood of extirpation. Mountain goats (Oreamnos americanus) exemplify this conservation challenge; their geographically isolated habitat can inhibit gene flow, making them susceptible to population declines in the face of anthropogenic-induced landscape change. To facilitate biologically informed population management of mountain goats in Glacier Bay National Park, Alaska, we characterized the fine-scale genetic population structure and examined how future climate change could impact the population density of these mountain goats. We used DNA samples to estimate diversity and depict the genealogical history. Climate response models allowed us to simulate changes to suitable habitat and predict how this might influence future population structure. Our results indicated that three genetically distinct subpopulations exist in Glacier Bay and that the population structure is reflective of the historic landscape patterns. Climate modeling predicted that demographic productivity was likely to be reduced for all subpopulations; additionally, we found that climate change likely degrades the suitability of movement corridors that facilitate gene flow between subpopulations, ultimately increasing the cost of travel. Understanding such fine-scale patterns are key to managing subpopulations, particularly with impending changes to the landscape.
Sex differences in predictors and regional patterns of brain-age-gap estimates
Authors: Sanford N , Ge R , Antoniades M , Modabbernia A , Haas SS , Whalley HC , Galea L , Popescu SG , Cole JH , Frangou S 
Published: January 2022

AbstractBackgroundThe brain-age-gap estimate (brainAGE) quantifies the difference between chronological age and age predicted by applying machine-learning models to neuroimaging data, and is considered a biomarker of brain health. Understanding sex-differences in brainAGE is a significant step toward precision medicine.MethodsGlobal and local brainAGE (G-brainAGE and L-brainAGE, respectively) were computed by applying machine learning algorithms to brain structural magnetic resonance imaging data from 1113 healthy young adults (54.45% females; age range: 22-37 years) participating in the Human Connectome Project. Sex-differences were determined in G-brainAGE and L-brainAGE. Random forest regression was used to determine sex-specific associations between G-brainAGE and non-imaging measures pertaining to sociodemographic characteristics and mental, physical, and cognitive functions.ResultsL-brainAGE showed sex-specific differences in brain ageing. In females, compared to males, L-brainAGE was higher in the cerebellum and brainstem and lower in the prefrontal cortex and insula. Although sex-differences in G-brainAGE were minimal, associations between G-brainAGE and non-imaging measures differed between sexes with the exception for poor sleep quality, which was common to both. The most important predictor of higher G-brainAGE was non-white race in males and systolic blood pressure in females.ConclusionsThe results demonstrate the value of applying sex-specific analyses and machine learning methods to advance our understanding of sex-related differences in factors that influence the rate of brain ageing and provide a foundation for targeted interventions.
RET activation controlled by MAB21L4-CacyBP interaction drives squamous cell carcinoma
Authors: Srivastava Ankit , Tommasi Cristina , Sessions Dane , Mah Angela , Bencomo Tomas , Garcia Jasmine M. , Jiang Tiffany , Lee Michael , Shen Joseph Y. , Seow Lek Wei , Nguyen Audrey , Rajapakshe Kimal , Coarfa Cristian , Tsai Kenneth Y. , Lopez-Pajares Vanessa , Lee Carolyn S. 
Published: January 2022

AbstractEpithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared to cutaneous SCC (cSCC) and identified MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids enabled malignant transformation through increased expression of the receptor tyrosine kinase rearranged during transfection (RET). In addition to transcriptional upregulation of RET, MAB21L4 deletion preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. Both genetic disruption of RET or selective RET inhibition with BLU-667 (pralsetinib) suppressed tumorigenesis in SCC organoids and in vivo tumors while inducing concomitant differentiation. Our results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC.Statement of SignificanceFew targeted therapies are available to individuals with cSCC who seek or require non-surgical management. Our study demonstrates that downregulation of RET is required for epithelial differentiation and opposes carcinogenesis in cSCC as well as SCC arising from other epithelial tissues.
Environment constrains fitness advantages of division of labor in microbial consortia engineered for metabolite push or pull interactions
Authors: Beck Ashley E. , Pintar Kathryn , Schepens Diana , Schrammeck Ashley , Johnson Timothy , Bleem Alissa , Du Martina , Harcombe William R. , Bernstein Hans C. , Heys Jeffrey J. , Gedeon Tomas , Carlson Ross P. 
Published: January 2022

ABSTRACTFitness benefits from division of labor in microbial consortia are well documented, but the dependency of the benefits on environmental context is poorly understood. Two synthetic Escherichia coli consortia were built to test the relationships between exchanged organic acid, local environment, and opportunity costs of different metabolic strategies. Opportunity costs quantify benefits not realized due to selecting one phenotype over another. The consortia catabolized glucose and exchanged either acetic or lactic acid to create producer-consumer food webs. The organic acids had different inhibitory properties and different opportunity costs associated with their positions in central metabolism. The exchanged metabolites modulated different consortial dynamics. The acetic acid-exchanging (AAE) consortium had a ‘push’ interaction motif where acetic acid was secreted faster by the producer than the consumer imported it, while the lactic acid-exchanging (LAE) consortium had a ‘pull’ interaction motif where the consumer imported lactic acid at a comparable rate to its production. The LAE consortium outperformed wild type (WT) batch cultures under the environmental context of weakly buffered conditions, achieving a 55% increase in biomass titer, a 51% increase in biomass per proton yield, an 86% increase in substrate conversion, and the complete elimination of byproduct accumulation all relative to the WT. However, the LAE consortium had the tradeoff of a 42% lower specific growth rate. The AAE consortium did not outperform the WT in any considered fitness metric. Fitness advantages of the LAE consortium were sensitive to environment; increasing the medium buffering capacity negated the fitness advantages compared to WT.IMPORTANCEMost naturally occurring microorganisms persist in consortia where metabolic interactions are common and often essential to ecosystem function. This study uses synthetic ecology to test how different cellular interaction motifs influence fitness properties of consortia. Environmental context ultimately controlled the division of labor fitness as shifts from weakly buffered to highly buffered conditions negated the benefits of the strategy. Understanding the limits of division of labor advances our understanding of natural community functioning which is central to nutrient cycling and provides design rules for assembling consortia used in applied bioprocessing.
Antigenic determinants of SARS-CoV-2-specific CD4+ T cell lines reveals M protein-driven dysregulation of interferon signaling
Authors: Gazzinelli-Guimaraes Pedro Henrique , Sanku Gayatri , Sette Alessandro , Weiskopf Daniela , Schaughency Paul , Lack Justin , Nutman Thomas B. 
Published: January 2022

AbstractWe generated CD4+ T cell lines (TCLs) reactive to either SARSCoV-2 spike (S) or membrane (M) proteins from unexposed naïve T cells from six healthy donor volunteers to understand in fine detail whether the S and M structural proteins have intrinsic differences in driving antigen-specific CD4+ T cell responses. Having shown that each of the TCLs were antigen-specific and antigen-reactive, single cell mRNA analyses demonstrated that SARS-CoV-2 S and M proteins drive strikingly distinct molecular signatures. Whereas the S-specific responses are virtually indistinguishable from those responses induced by other viral antigens (e.g. CMV), the M protein-specific CD4+ TCLs have a transcriptomic signature that indicate a marked suppression of interferon signaling, characterized by a downregulation of the genes encoding ISG15, IFITM1, IFI6, MX1, STAT1, OAS1, IFI35, IFIT3 and IRF7 (a molecular signature which is not dissimilar to that found in severe COVID-19). Our study suggests a potential link between the antigen specificity of the SARS-CoV-2-reactive CD4+ T cells and the development of specific sets of adaptive immune responses. Moreover, the balance between T cells of significantly different specificities may be the key to understand how CD4+ T cell dysregulation can determine the clinical outcomes of COVID-19.
Transmission dynamics and vaccination strategies for Crimean-Congo haemorrhagic fever virus in Afghanistan: a modelling study
Authors: Vesga Juan F , Clark Madeleine H A , Ayazi Edris , Apolloni Andrea , Leslie Toby , Edmunds W John , Métras Raphaëlle 
Published: January 2022

AbstractBackgroundCrimean-Congo haemorrhagic fever virus (CCHFV) is a highly pathogenic virus for which a safe and effective vaccine is not yet available, despite being considered a priority emerging pathogen. Understanding transmission patterns and the use of potential effective vaccines are central elements of the future plan against this infection.MethodsWe developed a series of models of transmission amongst livestock, and spillover infection into humans. We use real-world human and animal data from a CCHFV endemic area in Afghanistan (Herat) to calibrate our models. We assess the value of environmental drivers as proxy indicators of vector activity, and select the best model using deviance information criteria. Finally we assess the impact of vaccination by simulating campaigns targeted to humans or livestock, and to high-risk subpopulations (i.e, farmers).FindingsSaturation deficit is the indicator that better explains tick activity trends in Herat. Recent increments in reported CCHFV cases in this area are more likely explained by increased surveillance capacity instead of changes in the background transmission dynamics. Modelling suggests that clinical cases only represent 31% (95% CrI 28%-33%) of total infections in this area. Vaccination campaigns targeting humans would result in a much larger impact than livestock vaccination (266 vs 31 clinical cases averted respectively) and a more efficient option when assessed in courses per case averted (35 vs 431 respectively). Targeted vaccination to farmers is impactful and more efficient, resulting in 19 courses per case averted (95% CrI 7-62) compared to targeting the general population (35 95% CrI 16-107)InterpretationCCHFV is endemic in Herat, and transmission cycles are well predicted by environmental drivers like saturation deficit. Vaccinating humans is likely to be more efficient and impactful than animals, and importantly targeted interventions to high risk groups like farmers can offer a more efficient approach to vaccine roll-out.FundingW.J.E., JFV and MHAC were funded by the Department of Health and Social Care using UK Aid funding managed by the National Institute for Health Research (Vaccine Efficacy Evaluation for Priority Emerging Diseases: PR-OD-1017-20002). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health and Social Care.
Causal associations between body fat accumulation and COVID-19 severity: A Mendelian randomization study
Authors: Yoshiji Satoshi , Tanaka Daisuke , Minamino Hiroto , Murakami Takaaki , Fujita Yoshihito , Richards J. Brent , Inagaki Nobuya 
Published: January 2022

AbstractPurposeThe causal effects of body fat mass and body fat-free mass on coronavirus disease 2019 (COVID-19) severity remain unclear. Here, we used Mendelian randomization (MR) to evaluate the causal relationships between body fat-related traits and COVID-19 severity.Material and MethodsWe identified single nucleotide polymorphisms associated with body mass index (BMI) and direct measures of body fat (i.e., body fat percentage, body fat mass, and body fat-free mass) in 461,460, 454,633, 454,137, and 454,850 individuals of European ancestry from the UK Biobank, respectively. We then performed two-sample MR to ascertain their effects on severe COVID-19 (cases: 4,792; controls: 1,054,664) from the COVID-19 Host Genetics Initiative.ResultsWe found that an increase in BMI, body fat percentage, and body fat mass by one standard deviation were each associated with severe COVID-19 (odds ratio (OR)BMI = 1.49, 95%CI: 1.19–1.87, P = 5.57×10−4; ORbody fat percentage = 1.94, 95%CI: 1.41–2.67, P = 5.07×10−5; and ORbody fat mass = 1.61, 95%CI: 1.28–2.04, P = 5.51×10−5). Further, we evaluated independent causal effects of body fat mass and body fat-free mass using multivariable MR and revealed that only body fat mass was independently associated with severe COVID-19 (ORbody fat mass = 2.91, 95%CI: 1.71–4.96, P = 8.85×10−5 and ORbody fat-free mass = 1.02, 95%CI: 0.61–1.67, P = 0.945).ConclusionsThis study demonstrates the causal effects of body fat accumulation on COVID-19 severity and indicates that the biological pathways influencing the relationship between COVID-19 and obesity are likely mediated through body fat mass.
Coupling a Live Cell Directed Evolution Assay with Coevolutionary Landscapes to Engineer an Improved Fluorescent Rhodopsin Chloride Sensor
Authors: Chi Hsichuan , Zhou Qin , Tutol Jasmine N. , Phelps Shelby M. , Lee Jessica , Kapadia Paarth , Morcos Faruck , Dodani Sheel C. 
Published: January 2022

AbstractOur understanding of chloride in biology can be accelerated through the application of fluorescent protein-based sensors in living cells. Laboratory-guided evolution can be used to diversify and identify sensors with specific properties. Recently, we established that the fluorescent proton-pumping rhodopsinwtGR fromGloeobacter violaceuscan be converted into a fluorescent sensor for chloride. To unlock this non-natural function, a single point mutation at the Schiff counterion position from D121V was introduced intowtGR fused with cyan fluorescent protein (CFP) resulting in GR1-CFP. Here, we have integrated coevolutionary analysis with directed evolution to understand how the rhodopsin sequence space can be explored and engineered to improve this starting point. We first show how evolutionary couplings are predictive of functional sites in the rhodopsin family and how a fitness metric based on sequence can be used to quantify known proton-pumping activities of GR-CFP variants. Then, we couple this ability to predict potential functional outcomes with a screening and selection assay in liveEscherichia colito reduce the mutational search space of five residues along the proton-pumping pathway in GR1-CFP. This iterative selection process results in GR2-CFP with four additional mutations, E132K, A84K, T125C, and V245I. Finally, bulk, and single fluorescence measurements in liveE. colireveal that GR2-CFP is a reversible, ratiometric fluorescent sensor for extracellular chloride with an improved dynamic range. We anticipate that our framework will be applicable to other systems, providing a more efficient methodology to engineer fluorescent-protein based sensors with desired properties.Abstract Figure
Poison frog dietary preference depends on prey type and alkaloid load
Authors: Moskowitz Nora A. , D’Agui Rachel , Alvarez-Buylla Aurora , Fiocca Katherine , O’Connell Lauren A. 
Published: January 2022

AbstractThe ability to acquire chemical defenses through the diet has evolved across several major taxa. Chemically defended organisms may need to balance chemical defense acquisition and nutritional quality of prey items. However, these dietary preferences and potential trade-offs are rarely considered in the framework of diet-derived defenses. Poison frogs (Family Dendrobatidae) acquire defensive alkaloids from their arthropod diet of ants and mites, although their dietary preferences have never been investigated. We conducted prey preference assays with the Dyeing Poison frog (Dendrobates tinctorius) to test the hypothesis that alkaloid load and prey traits influence frog dietary preferences. We tested size preferences (big versus small) within each of four prey groups (ants, beetles, flies, and fly larvae) and found that frogs preferred interacting with smaller prey items of the fly and beetle groups. Frog taxonomic prey preferences were also tested as we experimentally increased their chemical defense load by feeding frogs decahydroquinoline, an alkaloid compound similar to those naturally found in their diet. Contrary to our expectations, overall preferences did not change during alkaloid consumption, as frogs across groups preferred fly larvae over other prey. Finally, we assessed the protein and lipid content of prey items and found that small ants have the highest lipid content while large fly larvae have the highest protein content. Our results suggest that consideration of toxicity and prey nutritional value are important factors in understanding the evolution of acquired chemical defenses and niche partitioning as a whole.
Dopamine and ALK4 signaling synergize to induce PCBP1-mediated alternative splicing of FosB and sustained behavioral sensitization to cocaine
Authors: Krapacher Favio A. , Fernández-Suárez Diana , Andersson Annika , Carrier-Ruiz Alvaro , Ibáñez Carlos F. 
Published: January 2022

AbstractΔFosB, an alternative spliced product of FosB, is an essential component of dopamine-induced reward pathways and a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus-accumbens (NAc) through activation of the RNA binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Importantly, ALK4 was required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.
Genetic variation of human myokine signaling is dominated by biologic sex and sex hormones
Authors: Velez Leandro M. , Van Cassandra , Moore Timothy M. , Zhou Zhenqi , Johnson Casey , Hevener Andrea L. , Seldin Marcus M. 
Published: January 2022

Abstract/IntroductionProteins secreted from skeletal muscle, termed myokines, allow muscle to impact systemic physiology and disease. Myokines play critical roles in a variety of processes, including metabolic homeostasis, exercise improvements, inflammation, cancer and cognitive functions1–6. Despite the clear relevance of these factors in mediating a multitude of physiological outcomes, the genetic architecture, regulation and functions of myokines, as well as degree of conservation of these communication circuits remains inadequately understood. Given that biologic sex controls critical aspects of nearly every physiologic outcome, it is essential to consider when relating specific mechanisms to complex genetic and metabolic interactions. Specifically, many metabolic traits impacted by myokines show striking sex differences arising from hormonal7–10, genetic7,11 or gene-by-sex interactions12,13. In this study, we performed a genetic survey of myokine gene regulation and cross-tissue signaling in humans where sex as a biological variable was emphasized. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estrogens. These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral and subcutaneous adipose tissue. Skeletal muscle estrogen receptor enrichments across metabolic tissues appeared stronger than androgen receptor and, surprisingly, ~3-fold higher in males compared to females. To define the causal roles of estrogen signaling on myokine gene expression and functions, we generated male and female mice which lack estrogen receptor α (Esr1) specifically in skeletal muscle and integrated global RNA-Sequencing with human data. These analyses highlighted mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes. Several other sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived TNFα exerting stronger inflammatory signaling in females compared to males and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide the first genetic survey of human myokines and highlight sex and estrogen receptor signaling as critical variables when assaying myokine functions and how changes in cell composition impact other metabolic organs.