bluuebunny/crossref_metadata_2025_split huggingface dataset:
A sleep epidemic or enlightenment? A Bayesian approach to test the sleep epidemic hypothesis shows foragers have short and fragmented sleep compared to large scale societies
Authors: Samson David R. 
Published: September 2020

AbstractHuman sleep is linked with nearly every aspect of our health and wellbeing. The question whether and to what extent human sleep is in a state of evolutionary mismatch has gained recent attention from both clinical and biological science researchers. Here, I use a comparative Bayesian approach aimed at testing the sleep epidemic hypothesis – the idea that, due to labor demands and technological disruption, sleep-wake activity is negatively impacted in post-industrial, economically developed societies. In contrast to the expectations of the sleep epidemic hypothesis, when compared to both large and small-scale subsistence societies that rely on agriculture for subsistence, foragers were the shortest, least efficient sleeping group. Coupled with previous work demonstrating that foragers have stronger circadian rhythms compared to those sleeping in buffered environments, I present the sleep-rhythm trade-off hypothesis – that sleep duration, quality, and synchrony is driven by trade-offs between sleep security and comfort versus sleep site environmental exposure. One strategy to improve wellbeing of modern sleepers would be to focus on behavioral interventions that reduce desynchronizations of circadian rhythms, while holding the positive ground of safe, secure, and regulated sleep environments typical of economically developed societies.
MiMSI - a deep multiple instance learning framework improves microsatellite instability detection from tumor next-generation sequencing
Authors: Ziegler John , Hechtman Jaclyn F. , Ptashkin Ryan , Jayakumaran Gowtham , Middha Sumit , Chavan Shweta S. , Vanderbilt Chad , DeLair Deborah , Casanova Jacklyn , Shia Jinru , DeGroat Nicole , Benayed Ryma , Ladanyi Marc , Berger Michael F. , Fuchs Thomas J. , Zehir Ahmet 
Published: September 2020

AbstractMicrosatellite instability (MSI) is a critical phenotype of cancer genomes and an FDA-recognized biomarker that can guide treatment with immune checkpoint inhibitors. Recent work has demonstrated that next-generation sequencing data can be used to identify samples with MSI-high phenotype. However, low tumor purity, as frequently observed in routine clinical samples, poses a challenge to the sensitivity of existing algorithms. To overcome this critical issue, we developed MiMSI, an MSI classifier based on deep neural networks and trained using a dataset that included low tumor purity MSI cases in a multiple instance learning framework. On a challenging yet representative set of cases, MiMSI showed higher sensitivity (0.940) and auROC (0.988) than MSISensor(sensitivity: 0.57; auROC: 0.911), an open-source software previously validated for clinical use at our institution using MSK-IMPACT large panel targeted NGS data.
Evidences for a nutritional role of iodine in plants
Authors: Kiferle Claudia , Martinelli Marco , Salzano Anna Maria , Gonzali Silvia , Beltrami Sara , Salvadori Piero Antonio , Hora Katja , Holwerda Harmen Tjalling , Scaloni Andrea , Perata Pierdomenico 
Published: September 2020

ABSTRACTLittle is known about the role of iodine in plant physiology. We evaluated the impact of low concentrations of iodine on the phenotype, transcriptome and proteome ofArabidopsis thaliana. Our experiments showed that removal of iodine from the nutrition solution compromises plant growth, and restoring it in micromolar concentrations is beneficial for biomass accumulation and leads to early flowering. In addition, iodine treatments specifically regulate the expression of several genes, mostly involved in the plant defence response, suggesting that iodine may protect against both biotic and abiotic stress. Finally, we demonstrated iodine organification in proteins. Our bioinformatic analysis of proteomic data revealed that iodinated proteins identified in the shoots are mainly associated with the chloroplast and are functionally involved in photosynthetic processes, whereas those in the roots mostly belong and/or are related to the action of various peroxidases. These results suggest that iodine should be considered as a plant nutrient.
A soluble ACE2 microbody protein fused to a single immunoglobulin Fc domain is a potent inhibitor of SARS-CoV-2 infection in cell culture
Authors: Tada Takuya , Fan Chen , Kaur Ramanjit , Stapleford Kenneth A. , Gristick Harry , Nimigean Crina , Landau Nathaniel R. 
Published: September 2020

SummarySoluble forms of ACE2 have recently been shown to inhibit SARS-CoV-2 infection. We report on an improved soluble ACE2, termed a “microbody” in which the ACE2 ectodomain is fused to Fc domain 3 of the immunoglobulin heavy chain. The protein is smaller than previously described ACE2-Ig Fc fusion proteins and contains an H345A mutation in the ACE2 catalytic active site that inactivates the enzyme without reducing its affinity for the SARS-CoV-2 spike. The disulfide-bonded ACE2 microbody protein inhibited entry of lentiviral SARS-CoV-2 spike protein pseudotyped virus and live SARS-CoV-2 with a potency 10-fold higher than unmodified soluble ACE2 and was active after initial virus binding to the cell. The ACE2 microbody inhibited the entry of ACE2-specific β coronaviruses and viruses with the high infectivity variant D614G spike. The ACE2 microbody may be a valuable therapeutic for COVID-19 that is active against SARS-CoV-2 variants and future coronaviruses that may arise.
Actin-binding compounds that affect the kinetics of the interaction of cardiac myosin with actin
Authors: Roopnarine Osha , Thomas David D. 
Published: September 2020

AbstractWe measured the effects of ten actin-binding compounds on the interaction of cardiac myosin subfragment 1 (S1) with pyrene labeled F-actin (PFA). These compounds, previously identified from a small-molecule high-throughput screen (HTS), perturb the microsecond structural dynamics of actin and the steady-state activity of actin-activated myosin ATPase. In the present study, we have further characterized their mechanisms of action by measuring their effects on PFA fluorescence, which is decreased specifically by the strong binding of myosin to actin, and is restored upon release of S1 by MgATP. We measured the effects of compounds under equilibrium and steady-state conditions, as affected by S1 and ATP, and also under transient conditions, in stopped-flow experiments following rapid addition of ATP to S1-bound PFA. We observe that these compounds affect the early steps of the myosin ATPase cycle to different extents (mild, moderate, and severe). The compounds decrease the equilibrium constant for the formation of the collision complex and the rate constant for subsequent isomerization to the ternary complex, indicating increased ATP affinity and trapping of ATP in the myosin active site. These compound effects on actin structure inhibit the kinetics of the actin-myosin interaction in ways that may be desirable for possible treatment of hypercontractile forms of hypertrophic cardiomyopathy (HCM). This work helps to elucidate the mechanisms of action of these compounds, several of which are currently used therapeutically, and it sets the stage for future HTS campaigns on a larger scale, to discover new drugs for treatment of heart failure.
VAPYRIN attenuates defence by repressing PR gene induction and localized lignin accumulation during arbuscular mycorrhizal symbiosis ofPetunia hybrida
Authors: Chen Min , Bruisson Sébastien , Bapaume Laure , Darbon Geoffrey , Glauser Gaëtan , Schorderet Martine , Reinhardt Didier 
Published: September 2020

SummaryThe intimate association of host and fungus in arbuscular mycorrhizal (AM) symbiosis can potentially trigger induction of host defence mechanisms against the fungus, implying that successful symbiosis requires suppression of defence.We addressed this phenomenon by using AM-defectivevapyrin(vpy) mutants inPetunia hybrida, including a new allele (vpy-3) with a transposon insertion close to the ATG start codon. We explore whether abortion of fungal infection invpymutants is associated with the induction of defence markers such as cell wall alterations, accumulation of reactive oxygen species (ROS), defence hormones, and induction of pathogenesis-related (PR) genes.We show thatvpymutants exhibit a strong resistance against intracellular colonization, which is associated with the generation of thick cell wall appositions (papillae) with lignin impregnation at fungal entry sites, while no accumulation of defence hormones, ROS, or callose was observed. Systematic analysis of PR gene expression revealed that several PR genes are induced in mycorrhizal roots of the wild type, and even more invpyplants. Some PR genes are induced exclusively invpymutants.Taken together, these results suggest thatVPYis involved in avoiding or suppressing the induction of a cellular defence syndrome that involves localized lignin deposition and PR gene induction.
Fixation and effective size in a haploid-diploid population with asexual reproduction
Authors: Bessho Kazuhiro , Otto Sarah P. 
Published: September 2020

AbstractThe majority of population genetic theory assumes fully haploid or diploid organisms with obligate sexuality, despite complex life cycles with alternating generations being commonly observed. To reveal how natural selection and genetic drift shape the evolution of haploid-diploid populations, we analyze a stochastic genetic model for populations that consist of a mixture of haploid and diploid individuals, allowing for asexual reproduction and niche separation between haploid and diploid stages. Applying a diffusion approximation, we derive the fixation probability and describe its dependence on the reproductive values of haploid and diploid stages, which depend strongly on the extent of asexual reproduction in each phase and on the ecological differences between them.Highlight-Classical models consider fully haploid or diploid populations-We model haploid-diploid life cycles allowing for asexual reproduction-We obtain the fixation probability of alleles subject to selection and drift-Reproductive values of haploid and diploid stages shape their evolution
Contrasting tempos of sex chromosome degeneration in sticklebacks
Authors: Sardell Jason M. , Josephson Matthew P. , Dalziel Anne C. , Peichel Catherine L. , Kirkpatrick Mark 
Published: September 2020

AbstractThe steps of sex chromosome evolution are often thought to follow a predictable pattern and tempo, but few studies have examined how the outcomes of this process differ between closely related species with homologous sex chromosomes. The sex chromosomes of the threespine stickleback (Gasterosteus aculeatus) and Japan Sea stickleback (G. nipponicus) have been well characterized. Little is known, however, about the sex chromosomes in their distantly related congener, the blackspotted stickleback (G. wheatlandi). We used pedigrees of interspecific crosses to obtain the first phased X and Y genomic sequences from blackspotted sticklebacks. Using novel statistical methods, we demonstrate that the oldest stratum of theGasterosteussex chromosomes evolved on Chromosome 19 in the ancestor of all three species. Despite this shared ancestry, the sex chromosomes of the blackspotted stickleback have experienced much more extensive recombination suppression, XY differentiation, and Y degeneration than those of the other two species. The ancestral blackspotted stickleback Y chromosome fused with Chromosome 12 less than 1.4 million years ago, which may have been favored by the very small size of the recombining region on the ancestral sex chromosome. Recombination is also suppressed between the X and Y over the bulk of Chromosome 12, although it has experienced little degeneration. These results demonstrate that sex chromosome evolution does not always follow a predictable tempo.
Histone acetylation at the sulfotransferase 1a1 gene is associated with its hepatic expression in normal aging
Authors: Kronfol Mohamad M. , Dozmorov Mikhail G. , Jahr Fay M. , Halquist Matthew S. , McRae MaryPeace , Wijesinghe Dayanjan S. , Price Elvin T. , Slattum Patricia W. , McClay Joseph L. 
Published: September 2020

AbstractPhase II drug metabolism is poorly studied in advanced age and older adults may exhibit significant variability in their expression of phase II enzymes. We hypothesized that age-related changes to epigenetic regulation of genes involved in phase II drug metabolism may contribute to these effects. We examined published epigenome-wide studies of human blood and identified theSULT1A1andUGT1A6genes as the top loci showing epigenetic changes with age. To assess possible functional alterations with age in the liver, we assayed DNA methylation (5mC) and histone acetylation changes around the mouse homologsSult1a1andUgt1a6in liver tissue from mice aged 4-32 months obtained from the National Institute on Aging rodent tissue bank. Our sample shows significant loss of 5mC atSult1a1, mirroring the loss of 5mC with age observed in human blood DNA at the same locus. We also detected increased histone 3 lysine 9 acetylation (H3K9ac) with age atSult1a1, but no change to histone 3 lysine 27 acetylation (H3K27ac).Sult1a1gene expression is significantly positively associated with H3K9ac levels, accounting for 23% of the variation in expression. We did not detect any significant changes atUgt1a6. We conclude thatSult1a1expression is under epigenetic influence in normal aging and that this influence is more pronounced for H3K9ac than DNA methylation or H3K27ac in this study. More generally, our findings support the relevance of epigenetics in regulating key drug metabolizing pathways. In future, epigenetic biomarkers could prove useful to inform dosing in older adults.
Microbiome-related aspects of locust density-dependent phase transition
Authors: Lavy Omer , Lewin-Epstein Ohad , Bendett Yonatan , Gophna Uri , Gefen Eran , Hadany Lilach , Ayali Amir 
Published: September 2020

AbstractLocust plagues are an ancient phenomenon, with references going back to the Old Testament. These swarming pests are notorious for their tendency to aggregate and perform long migrations, consuming vast amounts of vegetation and decimating the cultivated fields on their path. However, when population density is low, locusts will express a solitary, cryptic, non-aggregating phenotype that is not considered as an agricultural pest. Although transition of locusts from the solitary to the gregarious phase has been well studied, the shifts in the locust microbiome composition associated with this phase-transition have yet to be addressed. Here, using 16S rRNA amplicon sequencing, we compared the bacterial composition of solitary desert locusts before and after a crowding-induced phase-transition. Our findings reveal that the microbiome is altered during the phase transition. We also show that this significant change in bacterial composition includes the acquisition of a specific bacterial species -Weissella cibaria(Firmicutes), which has been previously shown to induce aggregation in cockroaches. Our findings led us to hypothesize that the locust microbiome may play a role in inducing aggregation behavior, contributing to the formation and maintenance of a swarm. Employing a mathematical model, we demonstrate the potential evolutionary advantage of inducing aggregation under various environmental conditions; and specifically, when the aggregation-inducing microbe exhibits a relatively high horizontal transmission rate. This is a first description of a previously unknown and important aspect of locust phase transition, demonstrating that the phase shift includes a shift in the gut and integument bacterial composition.
Struct2Graph: A graph attention network for structure based predictions of protein-protein interactions
Authors: Baranwal Mayank , Magner Abram , Saldinger Jacob , Turali-Emre Emine S. , Elvati Paolo , Kozarekar Shivani , VanEpps J. Scott , Kotov Nicholas A. , Violi Angela , Hero Alfred O. 
Published: September 2020

AbstractBackgroundDevelopment of new methods for analysis of protein-protein interactions (PPIs) at molecular and nanometer scales gives insights into intracellular signaling pathways and will improve understanding of protein functions, as well as other nanoscale structures of biological and abiological origins. Recent advances in computational tools, particularly the ones involving modern deep learning algorithms, have been shown to complement experimental approaches for describing and rationalizing PPIs. However, most of the existing works on PPI predictions use protein-sequence information, and thus have difficulties in accounting for the three-dimensional organization of the protein chains.ResultsIn this study, we address this problem and describe a PPI analysis based on a graph attention network, namedStruct2Graph, for identifying PPIs directly from the structural data of folded protein globules. Our method is capable of predicting the PPI with an accuracy of 98.89% on the balanced set consisting of an equal number of positive and negative pairs. On the unbalanced set with the ratio of 1:10 between positive and negative pairs, Struct2Graph achieves a five-fold cross validation average accuracy of 99.42%. Moreover, Struct2Graph can potentially identify residues that likely contribute to the formation of the protein-protein complex. The identification of important residues is tested for two different interaction types: (a) Proteins with multiple ligands competing for the same binding area, (b) Dynamic protein-protein adhesion interaction. Struct2Graph identifies interacting residues with 30% sensitivity, 89% specificity, and 87% accuracy.ConclusionsIn this manuscript, we address the problem of prediction of PPIs using a first of its kind, 3D-structure-based graph attention network (code available athttps://github.com/baranwa2/Struct2Graph). Furthermore, the novel mutual attention mechanism provides insights into likely interaction sites through its unsupervised knowledge selection process. This study demonstrates that a relatively low-dimensional feature embedding learned from graph structures of individual proteins outperforms other modern machine learning classifiers based on global protein features. In addition, through the analysis of single amino acid variations, the attention mechanism shows preference for disease-causing residue variations over benign polymorphisms, demonstrating that it is not limited to interface residues.
Role of Mcpip1 in obesity-induced hepatic steatosis as determined by myeloid and liver-specific conditional knockouts
Authors: Pydyn Natalia , Żurawek Dariusz , Kozieł Joanna , Kuś Edyta , Wojnar-Lason Kamila , Jasztal Agnieszka , Fu Mingui , Jura Jolanta , Kotlinowski Jerzy 
Published: September 2020

AbstractMonocyte chemoattractant protein-induced protein 1 (MCPIP1,aliasRegnase1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NFκB activity. Moreover, it was demonstrated, that MCPIP1 regulates lipid metabolism both in adipose tissue and hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of non-alcoholic fatty liver disease (NAFLD).We used knock-in control Mcpip1fl/flmice and animals with deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) and in hepatocytes (Mcpip1fl/flAlbCre), which were fed chow or a high-fat diet (HFD) for 12 weeks. Mcpip1fl/flLysMCremice were fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which subsequently resulted in hypoglycemia and dyslipidemia. These animals also displayed systemic inflammation, demonstrated by increased concentrations of cytokines in the plasma. On the other hand, there were no significant changes in phenotype in Mcpip1fl/flAlbCremice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and β-oxidation in these mice, they remained asymptomatic. Upon feeding them a HFD, Mcpip1fl/flLysMCremice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by hypoglycemia and dyslipidemia, along with proinflammatory phenotype with symptoms of cachexia. Mcpip1fl/flAlbCreanimals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1fl/flmice, and no changes in the level of soluble factors tested in the plasma were detected.In conclusion, we have demonstrated that Mcpip1 protein plays an important role in the liver homeostasis. Depletion of Mcpip1 in myeloid leukocytes, followed by systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.
Discovery of human ACE2 variants with altered recognition by the SARS-CoV-2 spike protein
Authors: Heinzelman Pete , Romero Philip A. 
Published: September 2020

AbstractUnderstanding how human ACE2 genetic variants differ in their recognition by SARS-CoV-2 can have a major impact in leveraging ACE2 as an axis for treating and preventing COVID-19. In this work, we experimentally interrogate thousands of ACE2 mutants to identify over one hundred human single-nucleotide variants (SNVs) that are likely to have altered recognition by the virus, and make the complementary discovery that ACE2 residues distant from the spike interface can have a strong influence upon the ACE2-spike interaction. These findings illuminate new links between ACE2 sequence and spike recognition, and will find wide-ranging utility in SARS-CoV-2 fundamental research, epidemiological analyses, and clinical trial design.