bluuebunny/crossref_metadata_2025_split huggingface dataset:
Free fatty-acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice
Authors: Croze Marine L. , Flisher Marcus F. , Guillaume Arthur , Tremblay Caroline , Noguchi Glyn M. , Granziera Sabrina , Vivot Kevin , Castillo Vincent C. , Campbell Scott A. , Ghislain Julien , Huising Mark O. , Poitout Vincent 
Published: July 2020

ABSTRACTObjectiveMaintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty-acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. Asgpr120mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release.MethodsGlucose tolerance tests were performed in mice after administration of the selective GPR120 agonist Compound A. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knockout ofgpr120.Gpr120expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively.ResultsAcute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Endogenous and/or pharmacological and GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion.Gpr120was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion ofgpr120and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin.ConclusionsInhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part via mitigating somatostatin release.
Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids
Authors: McCray Tara , Pacheco Julian , Baumann Bethany , Schlicht Michael J , Valyi-Nagy Klara , Nonn Larisa 
Published: July 2020

SUMMARYVitamin D is an essential steroid hormone that regulates systemic calcium homeostasis and cell fate decisions, including differentiation in many cell types. The prostate gland is hormonally regulated, requiring steroids for proliferation and terminal differentiation of secretory luminal cells. Vitamin D deficiency is associated with higher risk of lethal prostate cancer with an aggressive dedifferentiated pathology, linking vitamin D sufficiency to epithelial differentiation homeostasis. To determine regulation of prostate epithelial differentiation by vitamin D status, patient-derived benign prostate epithelial organoids were maintained in vitamin D deficient (vehicle) or sufficient (10 nM 1,25-dihydroxyvitamin D) conditions and assessed by phenotype and single cell RNA sequencing. Mechanistic validation demonstrated that vitamin D sufficiency promoted organoid growth and accelerated differentiation of lineage-committed cells by inhibiting canonical Wnt activity and Wnt family member DKK3. Wnt dysregulation is a known contributor to aggressive prostate cancer, thus these findings further link vitamin D deficiency to lethal disease.
Large-scale study validates that regional fungicide applications are major determinants of resistance evolution in the wheat pathogenZymoseptoria triticiin France
Authors: Garnault Maxime , Duplaix Clémentine , Leroux Pierre , Couleaud Gilles , David Olivier , Walker Anne-Sophie , Carpentier Florence 
Published: July 2020

SummaryResearch rationale: In modern cropping systems, the near-universal use of plant protection products selects for resistance in pest populations. The emergence and evolution of this adaptive trait threaten treatment efficacy. We identified determinants of fungicide resistance evolution and quantified their effects at a large spatiotemporal scale.Methods: We focused onZymoseptoria tritici, which causes leaf blotch in wheat. Phenotypes of qualitative or quantitative resistance to various fungicides were monitored annually, from 2004 to 2017, at about 70 sites throughout 22 regions of France (territorial units of 25 000km2on average). We modelled changes in resistance frequency with regional anti-Septoriafungicide use, yield losses due to the disease and the regional area under organic wheat.Key results: The major driver of resistance dynamics was fungicide use at the regional scale. We estimated its effect on the increase in resistance and relative apparent fitness of each resistance phenotype. The predictions of the model replicated the spatiotemporal patterns of resistance observed in field populations (R2from 0.56 to 0.82).Main conclusion: The evolution of fungicide resistance is mainly determined at the regional scale. This study therefore showed that collective management at the regional scale could effectively complete local actions.
Making data-driven hypotheses for gene functions by integrating dependency, expression, and literature data
Authors: Hirschey Matthew D. 
Published: July 2020

AbstractIdentifying the key functions of human genes is a major biomedical research goal. While some genes are well-studied, most human genes we know little about. New tools in data science -- a combination of computer programming, math & statistics, and topical expertise -- combined with the rapid adoption of open science and data sharing allow scientists to access publicly available datasets and interrogate these databeforeperforming any experiments. We present here a new research tool called data-driven hypothesis (DDH) for predicting pathways and functions for thousands of genes across the human genome. Importantly, this method integrates gene essentiality, gene expression, and literature mining to identify candidate molecular functions or pathways of known and unknown genes. Beyond single gene queries, DDH can uniquely handle queries of defined gene ontology pathways or custom gene lists containing multiple genes. The DDH project holds tremendous promise to generate hypotheses, data, and knowledge in order to provide a deep understanding of the dynamic properties of mammalian genes. We present this tool via an intuitive online interface, which will provide the scientific community a platform to query and prioritize experimental hypotheses to test in the lab.
Sex-biased gene expression in rhesus macaque and human brains
Authors: DeCasien Alex R. , Sherwood Chet C. , Higham James P. 
Published: July 2020

AbstractSexually dimorphic traits (i.e. phenotypic differences between males and females) are largely produced by sex-biased gene expression (i.e. differential expression of genes present in both sexes). These expression differences may be the result of sexual selection, although other factors (e.g., relaxed purifying selection, pleiotropy, dosage compensation) also contribute. Given that humans and other primates exhibit sex differences in cognition and neuroanatomy, this implicates sex differences in brain gene expression. Here, we compare sex-biased gene expression in humans and rhesus macaques across 16 brain regions using published RNA-Seq datasets. Our results demonstrate that most sex-biased genes are differentially expressed between species, and that overlap across species is limited. Human brains are relatively more sexually dimorphic and exhibit more male-than female-biased genes. Across species, gene expression is biased in opposite directions in some regions and in the same direction in others, suggesting that the latter may be more relevant in nonhuman primate models of neurological disorders. Finally, the brains of both species exhibit positive correlations between sex effects across regions, higher tissue specificity among sex-biased genes, enrichment of extracellular matrix among male-biased genes, and regulation of sex-biased genes by sex hormones. Taken together, our results demonstrate some conserved mechanisms underlying sex-biased brain gene expression, while also suggesting that increased neurodevelopmental plasticity and/or strong sexual selection on cognitive abilities may have played a role in shaping sex-biased brain gene expression in the human lineage.
Evaluating brain structure traits as endophenotypes using polygenicity and discoverability
Authors: Matoba Nana , Love Michael I. , Stein Jason L. 
Published: July 2020

AbstractHuman brain structure traits have been hypothesized to be broad endophenotypes for neuropsychiatric disorders, implying that brain structure traits are comparatively ‘closer to the underlying biology’. Genome-wide association studies from large sample sizes allow for the comparison of common variant genetic architectures between traits to test the evidence supporting this claim. Endophenotypes, compared to neuropsychiatric disorders, are hypothesized to have less polygenicity, with greater effect size of each susceptible SNP, requiring smaller sample sizes to discover them. Here, we compare polygenicity and discoverability of brain structure traits, neuropsychiatric disorders, and other traits (89 in total) to directly test this hypothesis. We found reduced polygenicity (FDR = 0.01) and increased discoverability of cortical brain structure traits, as compared to neuropsychiatric disorders (FDR = 3.68×10−9). We predict that ~8M samples will be required to explain the full heritability of cortical surface area by genome-wide significant SNPs, whereas sample sizes over 20M will be required to explain the full heritability of major depressive disorder. In conclusion, we find reduced polygenicity and increased discoverability of cortical structure compared to neuropsychiatric disorders, which is consistent with brain structure satisfying the higher power criterion of endophenotypes.
An immersive first-person navigation task for abstract knowledge acquisition
Authors: Kuhrt Doerte , St. John Natalie R. , Bellmund Jacob L. S. , Kaplan Raphael , Doeller Christian F. 
Published: July 2020

ABSTRACTAdvances in virtual reality (VR) technology have greatly benefited spatial navigation research. By presenting space in a controlled manner, changing aspects of the environment one at a time or manipulating the gain from different sensory inputs, the mechanisms underlying spatial behaviour can be investigated. In parallel, a growing body of evidence suggests that the processes involved in spatial navigation extend to non-spatial domains. Here, we leverage VR technology advances to test whether participants can navigate abstract knowledge. We designed a two-dimensional quantity space - presented using a head-mounted display - to test if participants can navigate abstract knowledge using a first-person perspective navigation paradigm. To investigate the effect of physical movement, we divided participants into two groups: one walking and rotating on a motion platform, the other group using a gamepad to move through the abstract space. We found that both groups learned to navigate using a first-person perspective and formed accurate representations of the abstract space. Interestingly, navigation in the quantity space resembled behavioural patterns observed in navigation studies using environments with natural visuospatial cues. Notably, both groups demonstrated similar patterns of learning. Taken together, these results imply that both self-movement and remote exploration can be used to learn the relational mapping between abstract stimuli.
Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease
Authors: Yang Stephanie Y. , Castellani Christina A. , Longchamps Ryan J. , Pillalamarri Vamsee K. , O’Rourke Brian , Guallar Eliseo , Arking Dan E. 
Published: July 2020

ABSTRACTBackgroundMitochondrial DNA copy number (mtDNA-CN) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues.ResultsWe evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35).In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90).ConclusionsThe observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.
Dynamical Ising model of spatially-coupled ecological oscillators
Authors: Nareddy Vahini Reddy , Machta Jonathan , Abbott Karen C. , Esmaeili Shadisadat , Hastings Alan 
Published: July 2020

AbstractLong-range synchrony from short-range interactions is a familiar pattern in biological and physical systems, many of which share a common set of “universal” properties at the point of synchronization. Common biological systems of coupled oscillators have been shown to be members of the Ising universality class, meaning that the very simple Ising model replicates certain spatial statistics of these systems at stationarity. This observation is useful because it reveals which aspects of spatial pattern arise independently of the details governing local dynamics, resulting in both deeper understanding of and a simpler baseline model for biological synchrony. However, in many situations a system’s dynamics are of greater interest than their static spatial properties. Here, we ask whether a dynamical Ising model can replicate universal and non-universal features of ecological systems, using noisy coupled metapopulation models with two-cycle dynamics as a case study. The standard Ising model makes unrealistic dynamical predictions, but the Ising model with memory corrects this by using an additional parameter to reflect the tendency for local dynamics to maintain their phase of oscillation. By fitting the two parameters of the Ising model with memory to simulated ecological dynamics, we assess the correspondence between the Ising and ecological models in several of their features (location of the critical boundary in parameter space between synchronous and asynchronous dynamics, probability of local phase changes, and ability to predict future dynamics). We find that the Ising model with memory is reasonably good at representing these properties of ecological metapopulations. The correspondence between these models creates the potential for the simple and well-known Ising class of models to become a valuable tool for understanding complex biological systems.
Wnt-mediated interactions of tumor-initiating cells with a macrophage niche drive skin tumor formation
Authors: Fontenete Silvia , Christensen Johan , Martinez-Silgado Adriana , Zarzuela Eduardo , Muñoz Javier , Megias Diego , Castellana Donatello , Loewe Robert , Perez-Moreno Mirna 
Published: July 2020

AbstractSkin tumor-initiating stem cells (tSCs) fuel skin squamous cell carcinoma (SCC) formation and development in a complex tumor microenvironment, but a role for immune cells in the tSC niche governing the process of tumor formation has remained elusive. Here, we define the existence of a tSC-macrophage niche, expressing high levels of Wnt ligands. Using conditional mouse genetic models to abrogate the secretion of Wnts, we show that both hair follicle SC- and macrophage-derived Wnts are essential for driving skin tumorigenesis, tSCs maintenance, and counteracting tumor regression. Loss of Wnts in either population uncouples the tSC-macrophage association. The proteomic signature of SCC cells reveals CD99 as a Wnt-dependent receptor for the macrophagecancer cell interaction. These results establish a role for a macrophage-tSC niche in governing SCC initiation and maintenance, uncovering potential candidates for immunoprevention against SCC.One Sentence SummaryA macrophage-skin tumor-initiating cells bonding Wnt loop drives tumorigenesis.
SEED-MEDIATED RNA INTERFERENCE OF ANDROGEN SIGNALING AND SURVIVAL NETWORKS INDUCES CELL DEATH IN PROSTATE CANCER CELLS
Authors: Corbin Joshua M. , Georgescu Constantin , Wren Jonathan D. , Xu Chao , Asch Adam S. , Ruiz-Echevarría Maria J. 
Published: July 2020

ABSTRACTResistance to anti-androgen therapy in prostate cancer (PCa) is often driven by genetic and epigenetic aberrations in the androgen receptor (AR) and coregulators that maintain androgen signaling activity. We show that specific small RNAs downregulate expression of multiple essential and AR-coregulatory genes, leading to potent androgen signaling inhibition and PCa cell death. Expression of different sh-/siRNAs designed to target TMEFF2, preferentially reduce viability of PCa, but not benign, cells and growth of murine xenografts. Surprisingly this effect is independent of TMEFF2 expression. Transcriptomic and sh/siRNA seed sequence studies indicate that expression of these toxic shRNAs lead to downregulation of AR-coregulatory and essential genes thru mRNA 3’-UTR sequence complementarity to the seed sequence of the toxic shRNAs. These findings reveal a specialized form of the Death Induced by Survival gene Elimination (DISE) mechanism in PCa cells, that we have termed Androgen Network (AN)-DISE, and suggest a novel therapeutic strategy for PCa.
Does the phase of ongoing EEG oscillations predict auditory perception?
Authors: Tal I. , Leszczynski M. , Mesgarani N. , Schroeder C.E. 
Published: July 2020

SummaryEffective processing of information from the environment requires the brain to selectively sample relevant inputs. The visual perceptual system has been shown to sample information rhythmically, oscillating rapidly between more and less input-favorable states. Evidence of parallel effects in auditory perception is inconclusive. Here, we combined a bilateral pitch-identification task with electroencephalography (EEG) to investigate whether the phase of ongoing EEG predicts auditory discrimination accuracy. We compared prestimulus phase distributions between correct and incorrect trials. Shortly before stimulus onset, each of these distributions showed significant phase concentration, but centered at different phase angles. The effects were strongest in theta and beta frequency bands. The divergence between phase distributions showed a linear relation with accuracy, accounting for at least 10% of inter-individual variance. Discrimination performance oscillated rhythmically at a rate predicted by the neural data. These findings indicate that auditory discrimination threshold oscillates over time along with the phase of ongoing EEG activity. Thus, it appears that auditory perception is discrete rather than continuous, with the phase of ongoing EEG oscillations shaping auditory perception by providing a temporal reference frame for information processing.
How many sirtuin genes are out there? evolution of sirtuin genes in vertebrates with a description of a new family member*
Authors: Opazo Juan C. , Vandewege Michael W. , Hoffmann Federico G. , Zavala Kattina , Meléndez Catalina , Luchsinger Charlotte , Cavieres Viviana A. , Vargas-Chacoff Luis , Morera Francisco J. , Burgos Patricia V. , Tapia-Rojas Cheril , Mardones Gonzalo A. 
Published: July 2020

AbstractStudying the evolutionary history of gene families is a challenging and exciting task with a wide range of implications. In addition to exploring fundamental questions about the origin and evolution of genes, disentangling their evolution is also critical to those who do functional/structural studies to allow a deeper and more precise interpretation of their results in an evolutionary context. The sirtuin gene family is a group of genes that are involved in a variety of biological functions mostly related to aging. Their duplicative history is an open question, as well as the definition of the repertoire of sirtuin genes among vertebrates. Our results show a well-resolved phylogeny that represents an improvement in our understanding of the duplicative history of the sirtuin gene family. We identified a new sirtuin gene family member (SIRT3.2) that was apparently lost in the last common ancestor of amniotes but retained in all other groups of jawed vertebrates. According to our experimental analyses, elephant shark SIRT3.2 protein is located in mitochondria, the overexpression of which leads to an increase in cellular levels of ATP. Moreover,in vitroanalysis demonstrated it has deacetylase activity being modulated in a similar way to mammalian SIRT3. Our results indicate that there are at least eight sirtuin paralogs among vertebrates and that all of them can be traced back to the last common ancestor of the group that existed between 676 and 615 millions of years ago.