bluuebunny/crossref_metadata_2025_split huggingface dataset:
Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function
Authors: Weber Lilian A. , Tomiello Sara , Schöbi Dario , Wellstein Katharina V. , Müller Daniel , Iglesias Sandra , Stephan Klaas E. 
Published: March 2021

AbstractThe auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Pathophysiological theories suggest that such dysfunction might be partially caused by aberrant interactions of different modulatory neurotransmitters with NMDARs, which could explain heterogeneity among patients with schizophrenia and their treatment response. Understanding the differential impact of different neuromodulators on readouts of NMDAR function is therefore of high clinical relevance.Here, we report results from two studies (N=81 each) which systematically tested whether the MMN is sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. Both studies used a double-blind, placebo-controlled between-subject design and monitored individual drug plasma levels. Using a novel variant of the auditory oddball paradigm, we contrasted phases with stable versus volatile probabilities of tone switches. In the first study, we found that the muscarinic acetylcholine receptor antagonist biperiden reduced and/or delayed mismatch responses, particularly during stable phases of the experiment, whereas this effect was absent for amisulpride, a dopamine D2/D3 receptor antagonist. The direct comparison between biperiden and amisulpride indicated a significant drug × mismatch interaction. In the second study, neither elevating acetylcholine nor dopamine levels via administration of galantamine and levodopa, respectively, exerted significant effects on MMN.Overall, our results indicate differential sensitivity of the MMN to changes in cholinergic (muscarinic) versus dopaminergic receptor function. This finding may prove useful for developments of future tools for predicting individual treatment responses in disorders that show abnormal MMN, such as schizophrenia.
Analysis of correlation and trail coefficients for componentperformance s in nine experimental tomato lines
Authors: Choque Gonzalo Quispe 
Published: March 2021

AbstractThe objective of the research was to analyze the main variables related to tomato yield, and guide the selection of materials for the INIAF vegetable improvement program. The experiment was carried out in the open field using nine tomato lines on the grounds of the National Vegetable Seed Production Center, during the 2017-2018 agricultural campaign. A randomized complete block experimental design was used, with three repetitions and 10 plants per experimental unit. For the analysis of the data, the variable yield was considered as dependent and the variables number of flowers per inflorescence, number of clusters per plant, number of fruits per plant, weight of fruit, equatorial and polar diameter as independent variables. Analysis of variance, phenotypic correlations and path coefficients were performed. The performance of the L015 line was 80. 79 t ha-1 higher than the L014, L019 and Rio Grande lines. The fruit yield had a significant correlation with the weight of fruit per plant followed by the polar diameter, equatorial diameter, number of fruits per plant and weight of fruit. The analysis of path coefficients showed that the number of fruits per plant had the highest direct positive effect on the fruit yield, fruit weight and equatorial diameter that have a significant correlation and a direct effect on the fruit yield, emerged as the components with coefficients of 0.96 and 0.52 respectively. These characters may be relevant within the selection criteria in the development of new varieties. number of fruits per plant and weight of fruit. The analysis of path coefficients showed that the number of fruits per plant had the highest direct positive effect on the fruit yield, fruit weight and equatorial diameter that have a significant correlation and a direct effect on the fruit yield, emerged as the components with coefficients of 0.96 and 0.52 respectively. These characters may be relevant within the selection criteria in the development of new varieties. number of fruits per plant and weight of fruit. The analysis of path coefficients showed that the number of fruits per plant had the highest direct positive effect on the fruit yield, fruit weight and equatorial diameter that have a significant correlation and a direct effect on the fruit yield, emerged as the components with coefficients of 0.96 and 0.52 respectively. These characters may be relevant within the selection criteria in the development of new varieties.
Convergent Usage of Amino Acids in Human Cancers as a Reversed Process of Tissue Development
Authors: Luo Yikai , Liang Han 
Published: March 2021

AbstractGenome and transcriptome-wide amino acid usage preference across different species is a well-studied phenomenon in molecular evolution, but its characteristics and implication in cancer evolution and therapy remain largely unexplored. Here, we analyzed large-scale transcriptome/proteome profiles such as TCGA, GTEx, and CPTAC and found that compared to normal tissues, different cancer types showed a convergent pattern towards using biosynthetically low-cost amino acids. Such a pattern can be accurately captured by a single index based on the average biosynthetic energy cost of amino acids, termed Energy Cost Per Amino Acid (ECPA). With this index, we further compared the trends of amino acid usage and the contributing genes in cancer and tissue development and revealed their reversed patterns. Finally, focusing on the liver, a tissue with a dramatic increase in ECPA during development, we found that EPCA represented a powerful biomarker that could distinguish liver tumors from normal liver samples consistently across 11 independent patient cohorts (AUROC = ~0.99) and outperformed any index based on single genes. Our study reveals an important principle underlying cancer evolution and suggests the global amino acid usage as a system-level biomarker for cancer diagnosis.
Growth of Lahontan Cutthroat Trout from multiple sources reintroduced into Sagehen Creek, CA
Authors: Stead Jonathan E. , Boucher Virginia L. , Moyle Peter B. , Rypel Andrew L. 
Published: March 2021

AbstractLahontan Cutthroat TroutOncorhynchus clarkii henshawihave experienced massive declines in their native range and are now a threatened species under the US Endangered Species Act. A key management goal for this species is re-establishing extirpated populations using translocations and conservation hatcheries. In California USA, two broodstocks (Pilot Peak and Independence Lake) are available for translocation, in addition to potential wild sources. Yet suitability of these sources for re-introduction in different ecosystem types and regions remains an open and important topic. We conducted growth experiments using Lahontan Cutthroat Trout stocked into Sagehen Creek, CA USA. Experiments evaluated both available broodstocks and a smaller sample of wild fish translocated from a nearby creek. Fish from the Independence Lake source had significantly higher growth in weight and length compared to the other sources. Further, Independence Lake fish were the only stock that gained weight on average over the duration of the experiment. Our experiments suggest fish from the Independence Lake brood stock may be useful for re-introduction efforts into small montane headwater streams in California.
Predicting activatory and inhibitory drug–target interactions based on mol2vec and genetically perturbed transcriptomes
Authors: Lee Won-Yung , Lee Choong-Yeol , Kim Chang-Eop 
Published: March 2021

ABSTRACTA computational approach to identifying drug–target interactions (DTIs) is a credible strategy for accelerating drug development and understanding the mechanisms of action of small molecules. However, current methods are limited to providing simple DTIs without mode of action (MoA), or they show unsatisfactory performance for a limited range of compounds and targets. Here, we propose AI-DTI, a novel method that predicts activatory and inhibitory DTIs by combining the mol2vec and genetically perturbed transcriptomes. We trained the model on large-scale DTIs with MoA and found that our model outperformed a previous model that predicted activatory and inhibitory DTIs. To extend the applicability, we applied the inferential method for the target vector so that our method can learn and predict a wider range of targets. Our method achieved satisfactory performance in an independent dataset where the target was unseen in the training set and a high-throughput screening dataset where positive and negative samples were explicitly defined. Finally, our method successfully rediscovered approximately half of the DTIs for drugs used in the treatment of COVID-19. These results indicate that AI-DTI is a practically useful tool for guiding drug discovery processes and generating plausible hypotheses that can reveal unknown mechanisms of drug action.
Impact of anaesthesia on static and dynamic functional connectivity in mice
Authors: Tsurugizawa Tomokazu , Yoshimaru Daisuke 
Published: March 2021

AbstractA few studies have compared the static functional connectivity between awake and anaesthetized states in rodents by resting-state fMRI. However, impact of anaesthesia on static and dynamic fluctuations in functional connectivity has not been fully understood. Here, we developed a resting-state fMRI protocol to perform awake and anaesthetized functional MRI in the same mice. Static functional connectivity showed a widespread decrease under anaesthesia, such as when under isoflurane or a mixture of isoflurane and medetomidine. Several interhemispheric connections were key connections for anaesthetized condition from awake. Dynamic functional connectivity demonstrates the shift from frequent broad connections across the cortex, the hypothalamus, and the auditory-visual cortex to frequent local connections within the cortex only. Fractional amplitude of low frequency fluctuation in the thalamic nuclei decreased under both anaesthesia. These results indicate that typical anaesthetics for functional MRI alters the spatiotemporal profile of the dynamic brain network in subcortical regions, including the thalamic nuclei and limbic system.HighlightsResting-state fMRI was compared between awake and anaesthetized in the same mice.Anaesthesia induced a widespread decrease of static functional connectivity.Anaesthesia strengthened local connections within the cortex.fALFF in the thalamus was decreased by anaesthesia.
The Human Milk Oligosaccharide 3’Sialyllactose Promotes Inflammation Resolution and Reduces Atherosclerosis Development in Mice
Authors: Pessentheiner Ariane R. , Spann Nathanael J. , Autran Chloe A. , Ramms Bastian , Chiang Austin W.T. , Grunddal Kaare V. , Wang Yiwen , Quach Anthony , Booshehri Laela M. , Hammond Alexandra , Tognaccini Chiara , Latasiewicz Joanna , Witztum Joseph L. , Hoffman Hal M. , Lewis Nathan E. , Glass Christopher K. , Bode Lars , Gordts Philip L.S.M. 
Published: March 2021

SUMMARYMacrophages contribute to the induction and resolution of inflammation and play a central role in the chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3’sialyllactose (3’SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3’SL attenuates a selected set of inflammatory gene expression and promotes activity of LXR and SREBP. These acute anti-inflammatory effects of 3’SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CTCF, IRF2, BCL6, and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3’SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3’SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.
Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis
Authors: Dai Zhiyu , Cheng Jianding , Liu Bin , Yi Dan , Feng Anlin , Wang Ting , Gao Chen , Wang Yibin , Zhu Maggie M. , Zhang Xianming , Zhao You-Yang 
Published: March 2021

AbstractBackgroundCardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive.Methods and ResultsMice withTie2-Cre-mediated deletion ofEgln1(encoding PHD2) (Egln1Tie2Cre) exhibited left ventricular (LV) hypertrophy evident by increased thickness of anterior and posterior wall and LV mass, as well as cardiac fibrosis. Tamoxifen-induced endothelialEgln1deletion in adult mice also induced LV hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation ofHif2abut notHif1ainEgln1Tie2Cremice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2α attenuated cardiac hypertrophy and fibrosis inEgln1Tie2Cremice.ConclusionsThe present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.
GABAergic signaling in human and murine NK cells upon challenge withToxoplasma gondii
Authors: Bhandage Amol K. , Friedrich Laura M. , Kanatani Sachie , Jakobsson-Björkén Simon , Escrig-Larena J. Ignacio , Wagner Arnika K. , Chambers Benedict J. , Barragan Antonio 
Published: March 2021

AbstractProtective cytotoxic and proinflammatory cytokine responses by natural killer (NK) cells impact the outcome of infections byToxoplasma gondii, a common parasite in humans and other vertebrates. However,T. gondiican also sequester within NK cells and downmodulate their effector functions. Recently, the implication of γ–aminobutyric acid (GABA) signaling in infection and inflammation-related responses of mononuclear phagocytes and T cells has become evident. Yet, the role of GABAergic signaling in NK cells has remained unknown. Here, we report that human and murine NK cells synthesize and secrete GABA in response to infection challenge. Parasitized NK cells secreted GABA while activation stimuli, such as IL-12/IL-18 or parasite lysates, failed to induce GABA secretion. GABA secretion by NK cells was associated to a transcriptional upregulation of GABA synthesis enzymes (GAD65/67) and was abrogated by GAD-inhibition. Further, NK cells expressed GABA-A receptor subunits and GABA signaling regulators, with transcriptional modulations taking place upon challenge withT. gondii. Exogenous GABA and GABA-containing supernatants from parasitized dendritic cells (DCs) impacted NK cell function by reducing the degranulation and cytotoxicity of NK cells. Conversely, GABA-containing supernatants from NK cells enhanced the migratory responses of parasitized DCs. This enhanced DC migration was abolished by GABA-A receptor antagonism or GAD-inhibition and was reconstituted by exogenous GABA. Jointly, the data show that NK cells are GABAergic cells and that GABA hampers NK cell cytotoxicityin vitro. We hypothesize that GABA secreted by parasitized immune cells modulates the immune responses toT. gondiiinfection.Summary sentenceIn response to infection challenge, NK cells synthesize and secreteγ-aminobutyric acid (GABA), which impacts NK cell and dendritic cell functions via GABA-A receptors.
Machine learning prediction of Antibody-Antigen binding: dataset, method and testing
Authors: Ye Chao , Hu Wenxing , Gaeta Bruno 
Published: March 2021

AbstractDNA sequencing technologies are providing new insights into the immune response by allowing the large scale sequencing of rearranged immunoglobulin gene present in an individual, however the applications of this approach are limited by the lack of methods for determining the antigen(s) that an immunoglobulin encoded by a given sequence binds to. Computational methods for predicting antibody-antigen interactions that leverage structure prediction and docking have been proposed, however these methods require knowledge of the 3D structures.As a step towards the development of a machine learning method suitable for predicting antibody-antigen binding affinities from sequence data, a weighted nearest neighbor machine learning approach was applied to the problem. A prediction program was coded in Python and evaluated using cross-validation on a dataset of 600 antibodies interacting with 50 antigens. The classification predicting accuracy was around 76% for this dataset. These results provide a useful frame of reference as well as protocols and considerations for machine learning and dataset creation in this area.Both the dataset (in csv format) and the machine learning program (coded in python) are freely available for download.
γδ-Thymocyte Maturation and Emigration
Authors: Joannou K. , Golec D.P. , Wang H. , Henao-Caviedes L.M. , May J.F. , Kelly R.G. , Chan R. , Jameson S.C. , Baldwin T.A. 
Published: March 2021

AbstractThe thymus is the site of both αβ and γδ-T cell development. After several unique waves of γδ-T cells are generated in, and exported from, the fetal/neonatal thymus, the adult thymus continues to produce a stream of γδ-T cells throughout life. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus, however, it is less clear whether this paradigm holds true in adult animals. To investigate the relationship between maturation and time since V(D)J recombination in adult-derived γδ-thymocytes, we used the Rag2pGFP model. Immature (CD24+) γδ-thymocytes expressed high levels of GFP while only a small minority of mature (CD24-) γδ-thymocytes were GFP+. Similarly, most GFP+γδ-splenocytes were immature, while some were mature. Analysis of γδ-recent thymic emigrants (RTEs) indicated that most γδ-T cell RTEs were CD24+and GFP+and adoptive transfer experiments showed that immature γδ-thymocytes could be maintained in the periphery for at least 3 days over which time they matured. With respect to the mature γδ-thymocytes that were GFP-, parabiosis experiments demonstrated that mature γδ-T cells did not recirculate from the periphery. Instead, a population of mature γδ-thymocytes remained resident in the thymus for at least 60 days while mature γδ-thymocytes derived solely from adult hematopoiesis were mostly lost from the thymus within 60 days. Collectively, these data demonstrate two streams of actively developing γδ-T cells in adult mice: an immature subset that quickly leaves the thymus and matures in the periphery, and one that completes maturation within the thymus over a longer period of time. Furthermore, there is a fetal-derived and heterogeneous population of resident γδ-thymocytes of unknown functional importance.
Optogenetic manipulation of individual or whole populationCaenorhabditis elegansworms with an under hundred-dollar tool: the OptoArm
Authors: Koopman M. , Janssen L. , Nollen E.A.A. 
Published: March 2021

AbstractOptogenetic tools have revolutionized the study of neuronal circuits inCaenorhabditis elegans.The expression of light-sensitive ion channels or pumps under specific promotors allows researchers to modify the behavior of excitable cells. Several optogenetic systems have been developed to spatially and temporally photoactivate light-sensitive actuators inC. elegans. Nevertheless, their high costs and low flexibility have limited wide access to optogenetics. Here, we developed an inexpensive, easy-to-build, and adjustable optogenetics device for use on different microscopes and worm trackers, called the OptoArm. The OptoArm allows for single- and multiple-worm illumination and is adaptable in terms of light intensity, lighting profiles and light-color. We demonstrate the OptoArm’s power in a population-based study on contributions of motor circuit cells to age-related motility decline. We find that functional decline of cholinergic neurons mirrors motor decline, while GABAergic neurons and muscle cells are relatively age-resilient, suggesting that rate-limiting cells exist and determine neuronal circuit aging.
A strategic sampling design revealed the local genetic structure of cold-water fluvial sculpin: a focus on groundwater-dependent water temperature heterogeneity
Authors: Nakajima Souta , Sueyoshi Masanao , Hirota Shun K. , Ishiyama Nobuo , Matsuo Ayumi , Suyama Yoshihisa , Nakamura Futoshi 
Published: March 2021

AbstractA key piece of information for ecosystem management is the relationship between the environment and population genetic structure. However, it is difficult to clearly quantify the effects of environmental factors on genetic differentiation because of spatial autocorrelation and analytical problems. In this study, we focused on stream ecosystems and the environmental heterogeneity caused by groundwater and constructed a sampling design in which geographic distance and environmental differences are not correlated. Using multiplexed ISSR genotyping by sequencing (MIG-seq) method, a fine-scale population genetics study was conducted in fluvial sculpinCottus nozawae, for which summer water temperature is the determinant factor in distribution and survival. There was a clear genetic structure in the watershed. Although a significant isolation-by-distance pattern was detected in the watershed, there was no association between genetic differentiation and water temperature. Instead, asymmetric gene flow from relatively low-temperature streams to high-temperature streams was detected, indicating the importance of low-temperature streams and continuous habitats. The groundwater-focused sampling strategy yielded unexpected results and provided important insights for conservation.