bluuebunny/crossref_metadata_2025_split huggingface dataset:
FGF21 Response Varies by Sugar Type and is Associated with Body Weight, Dietary Added Sugar, and Neural Signaling in Humans
Authors: Yunker Alexandra G. , Alves Jasmin M. , Luo Shan , Angelo Brendan , DeFendis Alexis , Pickering Trevor A. , Jann Kay , Monterosso John R. , Page Kathleen A. 
Published: May 2021

AbstractFibroblast growth factor 21 (FGF21) is a liver-derived hormone that regulates energy homeostasis. In humans, few studies have investigated whether FGF21 may act to suppress sugar intake and influence eating behavior, and the effects of adiposity on post-ingestive FGF21 regulation of appetite are unknown. Here, we demonstrate among two cohorts of healthy, young adults that acute oral fructose and sucrose compared to glucose lead to greater circulating FGF21. Moreover, high compared to low dietary added sugar intake is associated with greater sucrose-stimulated FGF21 among participants with healthy weight but attenuated in people with overweight and obesity. In addition, our study is the first to demonstrate associations between circulating FGF21 and neural signaling following an acute sucrose load among humans with healthy weight. Collectively, our results suggest that these potential compensatory relationships between sucrose-stimulated circulating FGF21, habitual sugar intake, and post-ingestive brain responses may be altered among adults with overweight and obesity.Significance StatementAnimal models have established FGF21 as an autoregulator of sweet consumption, but few studies have examined post-ingestive FGF21 effects in humans. In this report, we demonstrate a compensatory relationship between sucrose-stimulated FGF21 and high dietary added sugar intake through a potential liver-to-brain negative-feedback cycle among healthy, young adults. Notably, our findings also suggest that humans with overweight and obesity may have altered FGF21 neuroendocrine signaling.
Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells
Authors: Mouri Kousuke , Guo Michael H. , de Boer Carl G. , Newby Gregory A. , Gentili Matteo , Liu David R. , Hacohen Nir , Tewhey Ryan , Ray John P. 
Published: May 2021

ABSTRACTGenome-wide association studies have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variant(s) within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naïve CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.
Distinct Brain Mechanisms for Conflict Adaptation Within and Across Conflict Types
Authors: Yang Guochun , Wang Kai , Nan Weizhi , Li Qi , Zheng Ya , Wu Haiyan , Liu Xun 
Published: May 2021

AbstractCognitive conflict, like other cognitive processes, shows the characteristic of adaptation, i.e., conflict effects are attenuated when immediately following a conflicting event, a phenomenon known as the conflict adaptation effect (CAE). One important aspect of CAE is its sensitivity to the intertrial coherence of conflict type, i.e., behavioral CAE occurs only if consecutive trials are of the same conflict type. Although reliably observed behaviorally, the neural mechanisms underlying such a phenomenon remains elusive. With a paradigm combining the classic Simon task and Stroop task, this fMRI study examined neural correlates of conflict adaptation both within and across conflict types. The results revealed that when the conflict type repeated (but not when it alternated), the CAE-like neural activations were observed in dorsal anterior cingulate cortex, inferior frontal gyrus, superior parietal lobe, etc. (i.e., regions within typical task-positive networks). In contrast, when the conflict type alternated (but not when it repeated), we found CAE-like neural deactivations in a range of regions including bilateral superior and medial frontal gyri, bilateral angular cortex, bilateral temporal cortices, etc. (i.e., regions within the typical task-negative network). Moreover, this CAE-like neural deactivation predicts behavior performance. Network analyses suggested that these regions (for CAE-like neural activities within and across conflict type[s] respectively) can be clustered into two antagonistic networks. This evidence suggests that our adaptation to cognitive conflicts within a conflict type and across different types may rely on these two distinct neural mechanisms.
The inner nuclear membrane protein Lem2 coordinates RNA degradation at the nuclear periphery
Authors: Caballero Lucía Martín , Capella Matías , Barrales Ramón Ramos , Dobrev Nikolay , van Emden Thomas , Fischer-Burkart Sabine , Kinugasa Yasuha , Hirano Yasuhiro , Sinning Irmgard , Fischer Tamás , Hiraoka Yasushi , Braun Sigurd 
Published: May 2021

AbstractTranscriptionally silent chromatin often localizes to the nuclear periphery. However, whether the nuclear envelope (NE) is a site for post-transcriptional gene repression is unknown. Here we demonstrate that S. pombe Lem2, an NE protein, regulates nuclear exosome-mediated RNA degradation. Lem2 deletion causes accumulation of non-coding RNAs and meiotic transcripts. Indeed, an engineered exosome substrate RNA shows Lem2-dependent localization to the nuclear periphery. Lem2 does not directly bind RNA, but instead physically interacts with the exosome-targeting MTREC complex and promotes RNA recruitment. The Lem2-assisted pathway acts independently of nuclear bodies where exosome factors assemble, revealing that multiple spatially distinct degradation pathways exist. The Lem2 pathway is environmentally responsive: nutrient availability modulates Lem2 regulation of meiotic transcripts. Our data indicate that Lem2 recruits exosome co-factors to the nuclear periphery to coordinate RNA surveillance and regulates transcripts during the mitosis-to-meiosis switch.
Sex differences and estradiol effects in MAPK and Akt cell signalling across subregions of the hippocampus
Authors: Sheppard Paul A. S. , Puri Tanvi A. , Galea Liisa A. M. 
Published: May 2021

AbstractIntroductionRapid effects of estrogens within the hippocampus of rodents are dependent upon cell signaling cascades, and activation of these cascades by estrogens varies by sex. Whether these pathways are rapidly activated within the dentate gyrus (DG) and CA1 by estrogens and across the anatomical longitudinal axis has been overlooked.MethodsGonadally-intact female and male rats were given either vehicle or physiological systemic low (1.1µg/kg) or high (37.3µg/kg) doses of 17β-estradiol thirty minutes prior to tissue collection. To control for the effects of circulating estrogens, an additional group of female rats was ovariectomized (OVX) and administered 17β-estradiol. Brains were extracted and tissue punches of the CA1 and DG were taken along the longitudinal hippocampal axis (dorsal and ventral) and analyzed for key MAPK and Akt cascade phosphoproteins.ResultsIntact females had higher Akt pathway phosphoproteins (pAkt, pGSK-3β, pp70S6K) than males in the DG (dorsal, ventral) and lower pERK1/2 in the dorsal DG. Most effects of 17β-estradiol on cell signalling occurred in OVX animals. In OVX animals, 17β-estradiol increased cell signalling of MAPK and Akt phosphoproteins (pERK1/2, pJNK, pAkt, pGSK-3β) in the CA1 and pERK1/2 and pJNK DG.Discussion/ConclusionsSystemic 17β-estradiol treatment rapidly alters phosphoprotein levels in the hippocampus dependent on reproductive status and intact females have greater expression of Akt phosphoproteins than intact males across the hippocampus. These findings shed light on underlying mechanisms of sex differences in hippocampal function and response to interventions that affect MAPK or Akt signaling.
metapredict: a fast, accurate, and easy-to-use predictor of consensus disorder and structure
Authors: Emenecker Ryan J. , Griffith Daniel , Holehouse Alex S. 
Published: May 2021

AbstractIntrinsically disordered proteins and protein regions make up a substantial fraction of many proteomes where they play a wide variety of essential roles. A critical first step in understanding the role of disordered protein regions in biological function is to identify those disordered regions correctly. Computational methods for disorder prediction have emerged as a core set of tools to guide experiments, interpret results, and develop hypotheses. Given the multiple different predictors available, consensus scores have emerged as a popular approach to mitigate biases or limitations of any single method. Consensus scores integrate the outcome of multiple independent disorder predictors and provide a per-residue value that reflects the number of tools that predict a residue to be disordered. Although consensus scores help mitigate the inherent problems of using any single disorder predictor, they are computationally expensive to generate. They also necessitate the installation of multiple different software tools, which can be prohibitively difficult. To address this challenge, we developed a deep-learning-based predictor of consensus disorder scores. Our predictor, metapredict, utilizes a bidirectional recurrent neural network trained on the consensus disorder scores from 12 proteomes. By benchmarking metapredict using two orthogonal approaches, we found that metapredict is among the most accurate disorder predictors currently available. Metapredict is also remarkably fast, enabling proteome-scale disorder prediction in minutes. Importantly, metapredict is fully open source and is distributed as a Python package, a collection of command-line tools, and a web server, maximizing the potential practical utility of the predictor. We believe metapredict offers a convenient, accessible, accurate, and high-performance predictor for single-proteins and proteomes alike.Statement of SignificanceIntrinsically disordered regions are found across all kingdoms of life where they play a variety of essential roles. Being able to accurately and quickly identify disordered regions in proteins using just the amino acid sequence is critical for the appropriate design and interpretation of experiments. Despite this, performing large-scale disorder prediction on thousands of sequences is challenging using extant disorder predictors due to various difficulties including general installation and computational requirements. We have developed an accurate, high-performance and easy-to-use predictor of protein disorder and structure. Our predictor, metapredict, was designed for both proteome-scale analysis and individual sequence predictions alike. Metapredict is implemented as a collection of local tools and an online web server, and is appropriate for both seasoned computational biologists and novices alike.
Mendelian randomization analyses show that higher acetyl-carnitine and carnitine levels in blood protect against severe Covid19
Authors: Kazmi Nabila , Smith George Davey , Lewis Sarah J 
Published: May 2021

AbstractBackgroundSevere Covid19 is characterised by a hyperactive immune response. Carnitine, an essential nutrient, and it’s derivative acetyl-carnitine can downregulate proinflammatory cytokines and has been suggested as a potential treatment for the disease.MethodsWe carried out Mendelian randomization analyses using publicly available data from a large genome wide association study (GWAS) of metabolites and a collaborative genome wide study of Covid19 to investigate the nature of the relationship between carnitine and acetyl-carnitine and Covid19 infection, hospitalisation with Covid19 and very severe Covid19. We used the same methodology to determine whether carnitine was associated with co-morbidities commonly found among those with severe Covid19.ResultsWe found evidence of a protective effect against very severe Covid19 for both carnitine and acetyl-carnitine, with around a 40% reduction in risk associated with a doubling of carnitine or acetyl-carnitine (carnitine odds ratio (OR) = 0.56, 95% confidence intervals (CI) 0.33 to 0.95, p=0.03 and acetyl-carnitine OR=0.60, 95% CI 0.35 to 1.02, p=0.06), and evidence of protective effects on hopitalisation with Covid19. For acetyl-carnitine the largest protective effect was seen in the comparison between those hospitalised with Covid19 and those infected but not hospitalised (OR=0.34, 95%CI 0.18 to 0.62, p=0.0005).ConclusionCarnitine and acetyl-carnitine merit further investigation in respect to the prevention of severe Covid19.
The neurogenic fate of the hindbrain boundaries relies on Notch-dependent asymmetric cell divisions
Authors: Hevia Covadonga F , Engel-Pizcueta Carolyn , Udina Frederic , Pujades Cristina 
Published: May 2021

ABSTRACTThe generation of cell diversity in the central nervous system occurs during embryogenesis and requires a precise balance between cell proliferation, commitment to specific fates, and further neuronal differentiation. The cellular and molecular mechanisms regulating this balance in the embryonic brain are still poorly understood. Here we study how the neurogenic capacity in the embryonic hindbrain is spatiotemporally allocated, and how the fate and the growth of the hindbrain boundary cells are regulated. By generating a CRISPR-based knock-in zebrafish transgenic line to specifically label the hindbrain boundaries, we unveiled that boundary cells undergo a functional transition to become neurogenic during hindbrain segmentation concurrently as they maintain the progenitor cell pool. Boundary cells engaged in neurogenesis coinciding with the onset of Notch signaling, which triggered their asymmetrical cell division. Our findings reveal that distinct neurogenic phases take place during hindbrain growth and suggest that boundary cells contribute to refine the final number, identity, and proportion of neurons in the brain.SUMMARYHindbrain boundary cells undergo a functional transition to become neurogenic concurrently as they are maintained as a progenitor cell pool. This involves a behavioral switch from symmetrically dividing progenitor cells to asymmetrically dividing progenitors, which depends on Notch-activity.
Deep learning models for poorly differentiated colorectal adenocarcinoma classification in whole slide images using transfer learning
Authors: Tsuneki Masayuki , Kanavati Fahdi 
Published: May 2021

ABSTRACTColorectal poorly differentiated adenocarcinoma (ADC) is known to have a poor prognosis as compared with well to moderately differentiated ADC. The frequency of poorly differentiated ADC is relatively low (usually less than 5% among colorectal carcinomas). Histopathological diagnosis based on endoscopic biopsy specimens is currently the most cost effective method to perform as part of colonoscopic screening in average risk patients, and it is an area that could benefit from AI-based tools to aid pathologists in their clinical workflows. In this study, we trained deep learning models to classify poorly differentiated colorectal ADC from Whole Slide Images (WSIs) using a simply transfer learning method. We evaluated the models on a combination of test sets obtained from five distinct sources, achieving receiver operator curve (ROC) area under the curves (AUCs) in the range of 0.94-0.98.
Mechanistic insights into the Japanese Encephalitis Virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica
Authors: Dwivedi Vivek Dhar , Singh Ankita , El-Kafraway Sherif Aly , Alandijany Thamir A. , Bajrai Leena Hussein , Kamal Mohammad Amjad , Azhar Esam Ibraheem 
Published: May 2021

AbstractJapanese encephalitis (JE) virus, belongs to the genus flavivirus, is a major cause of viral encephalitis, which results in neurological damage. RNA-dependent RNA polymerase (RdRp) protein is the sole enzyme responsible for viral genome replication in RNA viruses and serves as an excellent target for anti-viral therapeutic development, as its homolog is not present in humans. In this study, the crystal structure of JE RNA-dependent RNA polymerase (jRdRp) protein was obtained from protein data bank while 43 by bioflavonoids reported in Azadirachta indica were retrieved from the PubChem database. Following, structure based virtual screening was employed using MTiOpenScreen server and top four compounds, viz. Gedunin, Nimbolide, Ohchinin acetate, and Kulactone, with the most negative docking scores (> -10 kcal/mol) conformations were redocked using AutoDock Vina; these complexes showed mechanistic interactions with Arg474, Gly605, Asp668, and Trp800 residues in the active site of jRdRp protein against reference ligand, i.e., Guanosine-5’-Triphosphate. Furthermore, 100 ns classical molecular dynamics simulation and binding free energy calculation showed considerable stability (via hydrogen bonding and hydrophobic interactions) of docked bioflavonoids in the active pocket of jRdRp and significant contribution of van der Waals interactions for docked complex stability during simulation, respectively. Therefore, the outcome of this study predicted the substantial anti-viral activity of Gedunin, Nimbolide, Ohchinin acetate, and Kulactone against jRdRp protein and can be considered for further antiviral drug development.
Structural and biochemical analysis of ATPase activity and EsxAB substrate binding of M. tuberculosis EccCb1 enzyme
Authors: Bandyopadyay Arkita , Saxena Ajay K. 
Published: May 2021

AbstractThe EccC enzyme of M. tuberculosis ESX-1 system is a promising target for antivirulence drug development. The EccC enzyme comprises two polypeptides (i) EccCa1, a membrane bound enzyme having two ATPase domains D2 & D3 (ii) cytosolic EccCb, which contains two ATPase domains. In current study, we have analyzed the low-resolution structure of EccCb1, performed ATPase activity and EsxAB substrate binding analysis. The EccCb1 enzyme eluted as oligomer from size exclusion column and small angle X-ray scattering analysis revealed the double hexameric structure in solution. The EccCb1 enzyme showed catalytic efficiency (kcat/KM)∼ 0.020±0.005 μM-1 min-1, however ∼ 3.7 fold lower than its D2 and ∼1.7 fold lower than D3 domains respectively. The D2 and D3 domains exhibited the ATPase activity and mutation of residues involved in ATP+Mg2+ binding have yielded 56-94% reduction in catalytic efficiency for both D2 and D3 domains. The EccCb1 binds the EsxAB substrate with KD ∼ 11.4±3.4 nM via specific groove located at C-terminal region of D3 domain. ATP binding to EccCb1 enhanced the EsxAB substrate binding by ∼ 3 fold, indicating ATPase energy involvement in EsxAB substrate translocation. We modeled the dodecameric EccCb1+EsxAB+ ATP+Mg2+ complex, which showed the binding pockets involved in ATP+Mg2+ and EsxAB substrate binding. The enzyme dynamics involved in ATP+Mg2+ and EsxAB substrate recognition were identified and showed the enhanced stability of EccCb1 enzyme as a result of ligand binding. Overall, our structural and biochemical analysis showed the low-resolution structure and mechanism involved in ATPase activity and EsxAB substrate binding and dynamics involved in EsxAB substrate and ATP+Mg2+ recognition. Overall, our structural and biochemical data on EccCb1 will contribute significantly in development of antivirulence inhibitors, which will prevent virulence factor secretion by M. tuberculosis ESX-1 system.
Longevity interventions temporally scale healthspan inCaenorhabditis elegans
Authors: Statzer Cyril , Reichert Peter , Dual Jürg , Ewald Collin Y. 
Published: May 2021

SummaryHuman centenarians and longevity mutants of model organisms show lower incidence rates of late-life morbidities than the average population. However, whether longevity is caused by a compression of the portion of life spent in a state of morbidity,i.e., “sickspan,” is highly debated even in isogenicC. elegans. Here, we developed a microfluidic device that employs acoustophoretic force fields to quantify the maximum muscle strength and dynamic power in agingC. elegans. Together with different biomarkers for healthspan, we found a stochastic onset of morbidity, starting with a decline in dynamic muscle power and structural integrity, culminating in frailty. Surprisingly, we did not observe a compression of sickspan in longevity mutants but instead observed a temporal scaling of healthspan. Given the conservation of these longevity interventions, this raises the question of whether the healthspan of mammalian longevity interventions is also temporally scaled.
Single seed microbiota: assembly and transmission from parent plant to seedling
Authors: Chesneau Guillaume , Laroche Béatrice , Préveaux Anne , Marais Coralie , Briand Martial , Marolleau Brice , Simonin Marie , Barret Matthieu 
Published: May 2021

AbstractGaining basic understanding of processes involved in seed microbiota assembly is a prerequisite for improving crop establishment. Investigation of microbiota structure during seed development revealed that individual seeds of bean and radish were associated with a dominant bacterial taxon representing more than 75% of all reads. The identity of this taxon was highly variable between plants and within seeds of the same plant. Succession of dominant taxa occurred during seed filling and maturation through Selection. In a second step, we evaluated seed to seedling transmission of these dominant seed-borne taxa. We showed that initial bacterial abundance on seeds was not a good predictor of seedling transmission and that the identity of seed-borne taxa can impact seedling phenotype. Altogether this work unveiled that seeds are colonized by few bacterial taxa of highly variable identity, which appears to be important for the early stages of plant development.
Food tracking and blockchain-induced knowledge: a corporate social responsibility tool for sustainable decision-making
Authors: Rainero Christian , Modarelli Giuseppe 
Published: May 2021

PurposeIn the disruptive technologies era, the lack of convincing business cases on blockchain (BC) adoption about food supply chain, the existence of uncertainties and barriers to adoption due to knowledge scarcity on characteristics as well as the potentialities and risks involved in it, have triggered the need to investigate the first multinational BC adoption for food supply chain in Europe, to consider how it can guarantee knowledge for the consumption/purchase decision-making and the creation-mechanism of consciousness for sustainable behavioral choice.Design/methodology/approachThe authors provide a field exploratory analysis based on customers' perceptions and real knowledge about BC (as a knowledge-constructive tool) in the food and beverage sector. This connected with the need for an informed context, favoring sustainable conscious decision-making related to both the food chain and innovation acceptance. This analysis included the use of innovation acceptance as a corporate social responsibility (CSR) strategic orientation through a survey- and interview-based field analysis (80 respondents).FindingsThe findings of this study can be considered as antecedents of innovation acceptance in the sector. The analysis assesses consumers' scarce knowledge and perceptions on the BC system, the scarce usage level and the higher acquiring propensity for traceable foodstuffs generating bi-directional/dimensional value, considering that consumption habits could change through security and certainty antecedents and induced knowledge provided by external technological intervention.Originality/valueBy trying to match innovation and the knowledge-construction need as a vehicle for acceptance, the theoretical contribution would empower the literature on food traceability from the perspective of strategic BC application through a from-knowledge-to-knowledge strategy.