bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Dimensionality Reduction by Matrix Factorization for Systems Pharmacology
Authors: Mehrpooya Adel , Saberi-Movahed Farid , Azizizadeh Najmeh , Rezaei-Ravari Mohammad , Saberi-Movahed Farshad , Eftekhari Mahdi , Tavassoly Iman 
Published: May 2021

AbstractThe extraction of predictive features from the complex high-dimensional multi-omic data is necessary for decoding and overcoming the therapeutic responses in systems pharmacology. Developing computational methods to reduce high-dimensional space of features inin vitro, in vivoand clinical data is essential to discover the evolution and mechanisms of the drug responses and drug resistance. In this paper, we have utilized the Matrix Factorization (MF) as a modality for high dimensionality reduction in systems pharmacology. In this respect, we have proposed three novel feature selection methods using the mathematical conception of a basis for features. We have applied these techniques as well as three other matrix factorization methods to analyze eight different gene expression datasets to investigate and compare their performance for feature selection. Our results show that these methods are capable of reducing the feature spaces and find predictive features in terms of phenotype determination. The three proposed techniques outperform the other methods used and can extract a 2-gene signature predictive of a Tyrosine Kinase Inhibitor (TKI) treatment response in the Cancer Cell Line Encyclopedia (CCLE).Key PointsMatrix Factorization (MF) is a useful framework for high dimensionality reduction in systems pharmacology.Novel feature selection methods using the incorporation of the mathematical conception of a basis for features into MF increases the performance of feature selection process.Feature selection based on the basis-concept in MF can provide predictive gene signatures for therapeutic responses in systems pharmacology.
Interaction between perineuronal nets and ketamine in antidepressant action
Authors: Young Calvin K. , Kinley Kachina G. , McNaughton Neil 
Published: May 2021

AbstractDepression is highly prevalent, increases suicide risk, and is now the leading cause of disability worldwide. Our ability to treat depression is hampered by the lack of understanding of its biological underpinnings and of the mode of action of effective treatments. We hypothesised that the scaffolding proteins in the medial frontal cortex play a major role in effective antidepressant action. We implanted cannulae into the infralimbic cortex to inject chABC and locally remove perineuronal nets and then tested for antidepressant effects with the forced swim test. We further tested if systemic injections of ketamine had an additive effect. Our preliminary data indicate that neither the removal of these scaffolding proteins nor ketamine were sufficient to decrease depression-like behaviour, but may interact synergistically to decrease immobility time in the forced swim test.
"Smart Tanks": An Intelligent High-Throughput Intervention Testing Platform in Daphnia
Authors: Cho Yongmin , Jonas-Closs Rachael A. , Yampolsky Lev Y. , Kirschner Marc W. , Peshkin Leonid 
Published: May 2021

AbstractWe present a novel platform for testing the effect of interventions on life- and health-span of a short-lived semi transparent freshwater organism, sensitive to drugs with complex behavior and physiology – the planktonic crustacean Daphnia magna. Within this platform, dozens of complex behavioural features of both routine motion and response to stimuli are continuously accurately quantified for large homogeneous cohorts via an automated phenotyping pipeline. We build predictive machine learning models calibrated using chronological age and extrapolate onto phenotypic age. We further apply the model to estimate the phenotypic age under pharmacological perturbation. Our platform provides a scalable framework for drug screening and characterization in both life-long and instant assays as illustrated using long term dose response profile of metformin and short term assay of such well-studied substances as caffeine and alcohol.
Obesity-instructed TREM2high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution
Authors: Subramanian Ayshwarya , Vernon Katherine , Zhou Yiming , Marshall Jamie L. , Alimova Maria , Zhang Fan , Slyper Michal , Waldman Julia , Montesinos Monica S. , Dionne Danielle , Nguyen Lan T. , Cuoco Michael S. , Dubinsky Dan , Purnell Jason , Heller Keith , Sturner Samuel H. , Grinkevich Elizabeth , Ghoshal Ayan , Weins Astrid , Villani Alexandra-Chloe , Chang Steven L. , Rosenblatt-Rosen Orit , Shaw Jillian L. , Regev Aviv , Greka Anna 
Published: May 2021

AbstractMouse models are a tool for studying the mechanisms underlying complex diseases; however, differences between species pose a significant challenge for translating findings to patients. Here, we used single-cell transcriptomics and orthogonal validation approaches to provide cross-species taxonomies, identifying shared broad cell classes and unique granular cellular states, between mouse and human kidney. We generated cell atlases of the diabetic and obese kidney using two different mouse models, a high-fat diet (HFD) model and a genetic model (BTBR ob/ob), at multiple time points along disease progression. Importantly, we identified a previously unrecognized, expanding Trem2high macrophage population in kidneys of HFD mice that matched human TREM2high macrophages in obese patients. Taken together, our cross-species comparison highlights shared immune and metabolic cell-state changes.
Pseudo-mutant p53 as a targetable phenotype of DNMT3A-mutated pre-leukemia
Authors: Tuval Amos , Brilon Yardena , Azogy Hadas , Moshkovitz Yoni , Biezuner Tamir , Leshkowitz Dena , Salame Tomer M , Minden Mark D , Tal Perry , Rotter Varda , Oren Moshe , Kaushansky Nathali , Shlush Liran I 
Published: May 2021

AbstractPre-leukemic clones carrying DNMT3A mutations have a selective advantage and an inherent chemo-resistance, however the basis for this phenotype has not been fully elucidated.Mutations affecting the gene TP53 occur in pre-leukemic hematopoietic stem/progenitor cells (preL-HSPCs) and lead to chemo-resistance. Many of these mutations cause a conformational change and some of them were shown to enhance self-renewal capacity of preL-HSPCs.Intriguingly, a misfolded p53 was described in AML blasts that do not harbor mutations in TP53, emphasizing the dynamic equilibrium between a wild-type (WT) and a “pseudomutant” conformations of p53.By combining single cell analyses and p53 conformation-specific monoclonal antibodies we studied preL-HSPCs from primary human DNMT3A AML samples. We found that while leukemic blasts express mainly the WT conformation, in preL-HSPCs the pseudomutant conformation is the dominant. HSPCs from non-leukemic samples expressed both conformations to a similar extent.Treatment with a short peptide that can shift the dynamic equilibrium favoring the WT conformation of p53, specifically eliminated preL-HSPCs that had dysfunctional canonical p53 pathway activity as reflected by single cell RNA sequencing.Our observations shed light upon a possible targetable p53 dysfunction in human preL-HSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.
Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi
Authors: Bernatchez Jean A. , Kil Yun-Seo , da Silva Elany Barbosa , Thomas Diane , McCall Laura-Isobel , Wendt Karen L. , Souza Julia M. , Ackermann Jasmin , McKerrow James H. , Cichewicz Robert H. , Siqueira-Neto Jair L. 
Published: May 2021

ABSTRACTSafe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac and gastrointestinal pathology and caused by the kinetoplastid parasite Trypanosoma cruzi, have yet to be developed. Benznidazole and nifurtimox, which are currently the only available drugs against T. cruzi, are associated with severe adverse effects and questionable efficacy in the late stage of the disease. Natural products have proven to be a rich source of new chemotypes for other infectious agents. We utilized a microscopy-based high-throughput phenotypic screen to identify inhibitors of T. cruzi from a library of natural product samples obtained from fungi procured through a Citizen Science Soil Collection Program (https://whatsinyourbackyard.org/), and the Great Lakes (USA) benthic environment. We identified five leucinostatins (A, B, F, NPDG C and NPDG D) as potent inhibitors of the intracellular amastigote form of T. cruzi. Leucinostatin B also showed in vivo efficacy in a mouse model of Chagas disease. Given prior reports that leucinostatins A and B have antiparasitic activity against the related kinetoplastid T. brucei, our findings suggest a potential cross-trypanocidal compound class and provide a platform for further chemical derivatization of a potent chemical scaffold against T. cruzi.
BrainEXP-NPD: a database of transcriptomic profiles of human brains of six neuropsychiatric disorders
Authors: Xia Cuihua , Ma Teng , Jiao Chuan , Chen Chao , Liu Chunyu 
Published: May 2021

AbstractBackgroundSpatio-temporal gene expression has been widely used to study gene functions and biological mechanisms in diseases. Numerous microarray and RNA sequencing data focusing on brain transcriptomes in neuropsychiatric disorders have accumulated. However, their consistency, reproducibility has not been properly evaluated. Except for a few psychiatric disorders, like schizophrenia, bipolar disorder and autism, most have not been compared to each other for cross-disorder comparisons.MethodsWe organized 48 human brain transcriptome datasets from six sources. The original brain donors include patients with schizophrenia (SCZ, N=427), bipolar disorder (BD, N=312), major depressive disorder (MDD, N=219), autism spectrum disorder (ASD, N=53), Alzheimer’s disease (AD, N=765), Parkinson’s disease (PD, N=163) as well as controls as unaffected by such disorders (CTRL, N=6,378), making it a total of 8,317 samples. Raw data included multiple brain regions of both sexes, with ages ranging from embryonic to seniors. After standardization, quality control, filtering and removal of known and unknown covariates, we performed comprehensive meta- and mega-analyses, including gene differential expression and gene co-expression network.ResultsA total of 6922, 3011, 2703, 4389, 3507, 4279 significantly differentially expressed genes (FDR q < 0.05) were detected in the comparisons of 6 brain regions of SCZ-CTRL, 5 brain regions of BD-CTRL, 6 brain regions of MDD-CTRL, 4 brain regions of ASD-CTRL, 7 brain regions of AD-CTRL, and 6 brain regions of PD-CTRL, respectively. Most differentially expressed genes were brain region-specific and disease-specific. SCZ and BD have a maximal transcriptome similarity in striatum (ρ=0.42) among the four brain regions, as measured by Spearman’s correlation of differential expression log2 FC values. SCZ and MDD have a maximal transcriptome similarity in hippocampus (ρ=0.30) among the five brain regions. BD and MDD have a maximal transcriptome similarity in frontal cortex (ρ=0.45) among the five brain regions. Other disease pairs have a less transcriptome similarity (ρ<0.1) in all brain regions. PD is negatively correlated with SCZ, BD, and MDD in cerebellum and striatum. We also performed coexpression network analyses for different disorders and controls separately. We developed a database named BrainEXP-NPD (http://brainexpnpd.org:8088/BrainEXPNPD/), to provide a userfriendly web interface for accessing the data, and analytical results of meta- and mega-analyses, including gene differential expression and gene co-expression networks between cases and controls on different brain regions, sexes and age groups. Discussion: BrainEXP-NPD compiled the largest collection of brain transcriptomic data of major neuropsychiatric disorders and presented lists of differentially expressed genes and coexpression modules in multiple brain regions of six major disorders.
Micromorphy Offers Effective Defence Against Predation: Insights From The Cost-Benefit Analyses Of Micro Gastropod Predation Record
Authors: Chandroth Anupama , Chattopadhyay Devapriya 
Published: May 2021

ABSTRACTPredation, an important driver of natural selection, is studied in the fossil record using quantifiable traces like drill holes produced by gastropods and repair scars produced after durophagous attacks. Despite the abundance of such records in molluscan prey, predation records of micromolluscs (<5mm) remained unexplored. Using a Miocene assemblage of microgastropods from the Quilon Limestone, India, we established the predatory-prey dynamics with the help of cost-benefit analyses. The overall predation intensity is low (DF = 0.06, RF= 0.04) and does not depend on the relative abundance of prey groups suggesting a non-random prey selection regardless of the encounter frequency. The predation is selective in terms of taxonomy, ornamentation, and size of the prey. The smallest size class has the lowest DF and RF supporting a negative size refugia. Higher IDF in larger size class and ornamented groups implies morphological defense resulting in higher failure. Microgastropods show a lower predation intensity than their regular-sized counterparts in a global comparison of coeval records. Results of the cost-benefit analyses explain this difference; the net energy gain from predatory drilling is found to increase monotonically with increasing prey size making the small prey less beneficial. Because the predators try to maximize net energy gain from a predatory attack, the microgastropod prey characterized by relatively low net energy yield is not preferred in the presence of larger prey. Micromorphy, therefore, appears a viable strategy for the prey group to be adopted as an evolutionary response against predation, especially in resource-limited conditions that fail to support large body size.
Gene surfing of underdominant alleles promotes formation of hybrid zones
Authors: Gilbert Kimberly J. , Moinet Antoine , Peischl Stephan 
Published: May 2021

AbstractThe distribution of genetic diversity over geographic space has long been investigated in population genetics and serves as a useful tool to understand evolution and history of populations. Within some species or across regions of contact between two species, there are instances where there is no apparent ecological determinant of sharp changes in allele frequencies or divergence. To further understand these patterns of spatial genetic structure and potential species divergence, we model the establishment of clines that occur due to the surfing of underdominant alleles during range expansions. We provide analytical approximations for the fixation probability of underdominant alleles at expansion fronts and demonstrate that gene surfing can lead to clines in 1D range expansions. We extend these results to multiple loci via a mixture of analytical theory and individual-based simulations. We study the interaction between the strength of selection against heterozygotes, migration rates, and local recombination rates on the formation of stable hybrid zones. A key result of our study is that clines created by surfing at different loci can attract each other and align after expansion, if they are sufficiently close in space and in terms of recombination distance. Our findings suggest that range expansions can set the stage for parapatric speciation due to the alignment of multiple selective clines, even in the absence of ecologically divergent selection.
Early Disruption of Photoreceptor Cell Architecture and Loss of Vision in a Humanized Pig Model of Usher Syndrome
Authors: Grotz Sophia , Schäfer Jessica , Wunderlich Kirsten A. , Ellederova Zdenka , Auch Hannah , Bähr Andrea , Runa-Vochozkova Petra , Plutniok Janet , Arnold Vanessa , Ardan Taras , Veith Miroslav , Santamaria Gianluca , Dhom Georg , Hitzl Wolfgang , Kessler Barbara , Kurome Mayuko , Zakharchenko Valeri , Linnert Joshua , Fischer Andrea , Blutke Andreas , Döring Anna , Suchankova Stepanka , Popelar Jiri , May-Simera Helen , Laugwitz Karl-Ludwig , Vandenberghe Luk H. , Wolf Eckhard , Nagel-Wolfrum Kerstin , Motlik Jan , Fischer M. Dominik , Wolfrum Uwe , Klymiuk Nikolai 
Published: May 2021

AbstractUsher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and, so far, there are no suitable animal models for testing therapeutic strategies. By introducing a human mutation into the harmonin-encodingUSH1Cgene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Primary cells from those animals and USH1C patients showed significantly elongated primary cilia, compared to wild-type, confirming the nature of USH as a true and general ciliopathy and proving the therapeutic capacity of gene supplementation and gene repair approaches.
gcaPDA: A Haplotype-resolved Diploid Assembler
Authors: Xie Min , Yang Linfeng , Jiang Chenglin , Wu Shenshen , Luo Cheng , Yang Xin , He Lijuan , Chen Shixuan , Deng Tianquan , Ye Mingzhi , Yan Jianbing , Yang Ning 
Published: May 2021

AbstractGenerating chromosome-scale haplotype resolved assembly is important for functional studies. However, current de novo assemblers are either haploid assemblers that discard allelic information, or diploid assemblers that can only tackle genomes of low complexity. Here, we report a diploid assembler, gcaPDA (gamete cells assisted Phased Diploid Assembler), which exploits haploid gamete cells to assist in resolving haplotypes. We generate chromosome-scale phased diploid assemblies for the highly heterozygous and repetitive genome of a maize F1 hybrid using gcaPDA and evaluate the assembly result thoroughly. With applicability of coping with complex genomes and fewer restrictions on application than other diploid assemblers, gcaPDA is likely to find broad applications in studies of eukaryotic genomes.
Single-Cell Profiling Resolved Transcriptional Alterations and Lineage Dynamics of Subventricular Zone after Mild Traumatic Brain Injury
Authors: Chen Xiameng , Cao Shuqiang , Wang Yinji , Li Manrui , Guo Yadong , Ye Yi , Wang Zheng , Dai Hao , Yang Wenjie , Sun Yuwen , Ou Xiaofeng , He Min , Xie Xiaoqi , Liang Weibo 
Published: May 2021

AbstractMild traumatic brain injury (mTBI) is the most common form of brain trauma caused by physical impact. The subventricular zone (SVZ) is a neurogenetic niche that contributes to homeostasis and repair after brain injury. It is particularly challenging to fully elucidate the molecular alterations in the SVZ occurring in response to injury due to its cell diversity and the complex network. In this study, we aimed to address this issue using a novel transcriptomic technique- unbiased single-cell RNA sequencing. We resolved previous unknown cell subpopulations harbored in the niche, and uncovered cell type-specific alterations in gene expression, enriched pathways, and cell-cell crosstalk following mTBI. Notably, we also report novel lineage trajectories and molecular hallmarks that govern neurogenesis. This study dissects the delicate transcriptome changes of individual cell types as well as the reprogramming process of cells in the SVZ niche after mTBI, and our findings are expected to facilitate the development of therapeutic interventions or diagnostic tests for mTBI.
Nuclear and cytoplasmic RNA exosomes and PELOTA1 prevent miRNA-induced secondary siRNA production in Arabidopsis
Authors: Vigh Maria Louisa , Thieffry Axel , Arribas-Hernández Laura , Brodersen Peter 
Published: May 2021

ABSTRACTAmplification of short interfering RNA (siRNAs) via RNA dependent RNA Polymerases (RdRPs) is of fundamental importance in RNA silencing. In plants, silencing by microRNAs (miRNAs) generally does not lead to engagement of RdRPs, in part thanks to an as yet poorly understood activity of the cytoplasmic exosome adaptor SKI2. Here, we show that mutation of the cytoplasmic exosome subunit RRP45B results in siRNA production very similar to what is observed inski2mutants. Furthermore, loss of the nuclear exosome adaptor HEN2 leads to secondary siRNA production from miRNA targets largely distinct from those producing siRNAs inski2. Importantly, mutation of the Release Factor paralogue PELOTA1 required for subunit dissociation of stalled ribosomes causes siRNA production from miRNA targets overlapping with, but distinct from, those affected inski2andrrp45bmutants. We also show that miRNA-induced illicit secondary siRNA production correlates with miRNA levels rather than accumulation of stable 5’-cleavage fragments. We propose that stalled RNA-induced Silencing Complex (RISC) and ribosomes, but not stable target mRNA cleavage fragments released from RISC, trigger secondary siRNA production, and that the exosome limits siRNA amplification by reducing RISC dwell time on miRNA target mRNAs while PELOTA1 does so by reducing ribosome stalling.
Corporate disclosures on curbing bribery and the UK Bribery Act 2010: evidence from UK companies
Authors: Islam Muhammad Azizul , Haque Shamima , Henderson Sharon , Jones Michael John , Semeen Homaira 
Published: May 2021

PurposeThis study aims to investigate whether United Kingdom (UK)-based companies have changed their voluntary disclosures on curbing the bribery of foreign officials in response to the UK Bribery Act 2010, and if so whether and how such disclosure changes substantively reflected allegations of bribery of foreign officials by news media.Design/methodology/approachBy using the notions of institutional pressure and decoupling and applying content and thematic analysis, the authors examined, in particular, disclosures on curbing bribery by the largest 100 companies listed on the London Stock Exchange in periods before and after the Bribery Act (2007–2012). News media reports covering incidents of bribery of foreign officials and related corporate disclosures before and after the Act were thoroughly examined to problematise corporate anti-bribery disclosure practices.FindingsThe study finds a significant change in disclosure on curbing bribery before and after the enactment of the UK Bribery Act, consistent with the notion of institutional coercive pressure. However, decoupling is also found: organisations' disclosures did not substantively reflect incidents of bribing foreign public officials, mostly from underprivileged developing nations.Research limitations/implicationsThis study acknowledges a limitation stemming from using media reports that focus on bribery incidents in identifying actual cases or incidents of bribery. As some of the incidents identified from news media reports appeared to be allegations, not convictions for bribery, companies could have defensible reasons for not disclosing some aspects of them.Practical implicationsRegulators should think why new or more regulations without substantive requirement are not helpful to curb corporate decoupling and injustice. The regulators should address the crisis that multinational companies (MNCs) being suppliers of bribery are much more harmful for the underprivileged communities in developing nations. Accordingly, this paper provides practical insights into how stakeholders ought to critically interpret MNCs' accounts of their involvement in bribery.Originality/valueThis study contributes to the accounting literature by problematising MNCs' operations in underprivileged countries. The findings suggest that not only public officials in developing countries as creators of bribery but also Western-based MNCs as the suppliers of bribery contribute to perpetuating unethical practices and injustices to the underprivileged communities in developing countries. This research is imperative as this is one of the first known studies that provides evidence of the actions including disclosure-related actions companies have taken in response to the UK Bribery Act.