bluuebunny/crossref_metadata_2025_split huggingface dataset:
Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition
Authors: Abraham Antony D. , Casello Sanne M. , Schattauer Selena S. , Wong Brenden A. , Mizuno Grace O. , Mahe Karan , Tian Lin , Land Benjamin B. , Chavkin Charles 
Published: June 2021

AbstractFollowing repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre- and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdynCre neurons using Channelrhodopsin-2 (ChR2) disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence.
The phosphatidylglycerol phosphate synthase PgsA utilizes a trifurcated amphipathic cavity for catalysis at the membrane-cytosol interface
Authors: Yang Bowei , Yao Hebang , Li Dianfan , Liu Zhenfeng 
Published: June 2021

AbstractPhosphatidylglycerol is a crucial phospholipid found ubiquitously in biological membranes of prokaryotic and eukaryotic cells. The phosphatidylglycerol phosphate (PGP) synthase (PgsA), a membrane-embedded enzyme, catalyzes the primary reaction of phosphatidylglycerol biosynthesis. Mutations in pgsA frequently correlate with daptomycin resistance in Staphylococcus aureus and other prevalent infectious pathogens. Here we report the structures of S. aureus PgsA (SaPgsA) captured at two distinct states of the catalytic process, with lipid substrate (cytidine diphosphate-diacylglycerol, CDP-DAG) or product (PGP) bound to the active site within a trifurcated amphipathic cavity. The hydrophilic head groups of CDP-DAG and PGP occupy two different pockets in the cavity, inducing local conformational changes. An elongated membrane-exposed surface groove accommodates the fatty acyl chains of CDP-DAG/PGP and opens a lateral portal for lipid entry/release. Remarkably, the daptomycin resistance-related mutations mostly cluster around the active site, causing reduction of enzymatic activity. Our results provide detailed mechanistic insights into the dynamic catalytic process of PgsA and structural frameworks beneficial for development of antimicrobial agents targeting PgsA from pathogenic bacteria.
Genetic diversity in chimpanzee transcriptomics does not represent wild populations
Authors: Shukla Navya , Shaban Bobbie , Romero Irene Gallego 
Published: June 2021

AbstractChimpanzees (Pan troglodytes) are a genetically diverse species, consisting of 4 highly distinct subspecies. As humans’ closest living relative they have been a key model organism in the study of human evolution, and comparisons of human and chimpanzee transcriptomes have been widely used to characterise differences in gene expression levels that could underlie the phenotypic differences between the two species. However, the subspecies from which these transcriptomic datasets have been derived is not recorded in metadata available in the public NCBI Sequence Read Archive (SRA). Furthermore, labelling of RNA-seq samples is for the most part inconsistent across studies, and the true number of individuals from whom transcriptomic data is available is difficult to ascertain. Thus we have evaluated genetic diversity at the subspecies and individual level in 486 public RNA-seq samples available in the SRA, spanning the vast majority of public chimpanzee transcriptomic data. Using multiple population genetics approaches we find that nearly all samples (96.6%) have some degree of Western chimpanzee ancestry. At the individual donor level, we identify multiple samples that have been repeatedly analysed across different studies, and identify a total of 135 genetically distinct individuals within our data, a number that falls to 89 when we exclude likely first and second-degree relatives. Altogether, our results show that current transcriptomic data from chimpanzees is capturing low levels of genetic diversity relative to what exists in wild chimpanzee populations. These findings provide important context to current comparative transcriptomics research involving chimpanzees.
Mutation in Abl kinase with altered drug binding kinetics indicates a novel mechanism of imatinib resistance
Authors: Lyczek Agatha , Berger Benedict Tilman , Rangwala Aziz M. , Paung YiTing , Tom Jessica , Philipose Hannah , Guo Jiaye , Albanese Steven K. , Robers Matthew B. , Knapp Stefan , Chodera John D. , Seeliger Markus A. 
Published: June 2021

AbstractProtein kinase inhibitors are potent anti-cancer therapeutics (1). For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for Chronic Myeloid Leukemia (CML) by 80% (2, 3), but 22-41% of patients acquire resistance to imatinib (4). About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain (5), in which more than a hundred different mutations have been identified (6–8). Some mutations are located near the imatinib binding site and cause resistance through altered interactions with the drug. However, many resistance mutations are located far from the drug binding site (9) and it remains unclear how these mutations confer resistance. Additionally, earlier studies on small sets of patient-derived imatinib resistance mutations indicated that some of these mutant proteins were in fact sensitive to imatinib in cellular and biochemical studies (10). Here, we surveyed the resistance of 94 patient-derived Abl kinase domain mutations annotated as disease-relevant or resistance-causing using an engagement assay in live cells. We found that only two-thirds of mutations weaken imatinib affinity by more than two-fold compared to Abl wild type. Surprisingly, one-third of mutations in Abl kinase domain still remain sensitive to imatinib and bind with similar or higher affinity than wild type. Intriguingly, we identified a clinical Abl mutation that binds imatinib with wild type-like affinity but dissociates from imatinib three times faster. Given the relevance of residence time for drug efficacy (11–14), mutations that alter binding kinetics could cause resistance in the non-equilibrium environment of the body where drug export and clearance play critical roles.SignificanceWe performed the first in cell screen of imatinib binding against a library of Abl kinase mutants derived from patients with imatinib-resistant CML. The majority of mutations readily bind imatinib, posing the question of how these mutations cause resistance in patients. We identified a kinetic mutant that binds imatinib with wild type affinity but dissociates considerably faster from the mutant kinase. Using NMR and molecular dynamics, we found that this mutation increases the conformational dynamics of the mutant protein, linking conformational dynamics of the protein to drug dissociation. The results underline the importance of drug dissociation kinetics for drug efficacy and propose a novel kinetic resistance mechanism that may be targetable by altering drug treatment schedules.
TRIOBP promotes bidirectional radial stiffness gradients within the organ of Corti
Authors: Babahosseini Hesam , Belyantseva Inna A. , Yousaf Rizwan , Tona Risa , Hadi Shadan E. , Wilson Elizabeth , Kitajiri Shin-ichiro , Frolenkov Gregory I. , Friedman Thomas B. , Cartagena-Rivera Alexander X. 
Published: June 2021

AbstractHearing depends on complex mechanical properties of the inner ear sensory epithelium. Yet, the individual contributions of different cell types to the stiffness spectrum of the sensory epithelium have not been thoroughly investigated. Using sub-100 nanometer spatial resolution PeakForce Tapping Atomic Force Microscopy (PFT-AFM), we mapped the Young’s modulus (stiffness) of the apical surface of different cells of freshly-dissected cochlear epithelium from wild-type mice and mice lacking the F-actin bundling protein TRIOBP-5 or TRIOBP-4 and TRIOBP-5. Variants of the genes encoding human and mouse TRIOBP are associated with deafness. We show that TRIOBP deficiency affects formation of supporting cell apical phalangeal microfilaments and bundled cortical F-actin of hair cell cuticular plates, softening the apical surface of the sensory epithelium. Unexpectedly, high-resolution PFT-AFM-mapping also revealed previously unrecognized reticular lamina radial stiffness gradients of opposite orientations in wild-type supporting and hair cells. Deafness-associated TRIOBP deficiencies significantly modified these bidirectional radial stiffness gradients.
Oct4 primarily controls enhancer activity rather than accessibility
Authors: Xiong Le , Tolen Erik A. , Choi Jinmi , Caizzi Livia , Adachi Kenjiro , Lidschreiber Michael , Cramer Patrick , Schöler Hans R. 
Published: June 2021

AbstractThe transcription factor Oct4 is essential for maintaining stem cell pluripotency and for efficient cell reprogramming, but its functional roles are far from being understood. Here, we investigate the functions of Oct4 by rapidly depleting Oct4 from mouse embryonic stem cells and conducting a time-resolved multiomics analysis. Oct4 depletion leads to an immediate loss of its binding to putative enhancers that are accessible in chromatin. Loss of Oct4 is accompanied by a concomitant decrease in mRNA synthesis from putative target genes that are part of the transcriptional network that maintains pluripotency. Oct4 binding to enhancers does not correlate with chromatin accessibility, whereas Sox2 can apparently retain accessibility after Oct4 depletion even in the absence of eRNA synthesis. These results are consistent with the model that Sox2 primarily acts as a pioneer factor that renders enhancers accessible, whereas Oct4 acts primarily as a transcriptional activator that stimulates transcription of pluripotency enhancers and their target genes.
Residual errors in visuomotor adaptation persist despite extended motor preparation periods
Authors: Weightman Matthew , Brittain John-Stuart , Miall R. Chris , Jenkinson Ned 
Published: June 2021

AbstractA consistent finding in sensorimotor adaptation is a persistent undershoot of full compensation, such that performance asymptotes with residual errors greater than seen at baseline. This behaviour has been attributed to limiting factors within the implicit adaptation system, which reaches a sub-optimal equilibrium between trial-by-trial learning and forgetting. However, recent research has suggested that allowing longer motor planning periods prior to movement eliminates these residual errors. The additional planning time allows required cognitive processes to be completed before movement onset, thus increasing accuracy. Here we looked to extend these findings by investigating the relationship between increased motor preparation time and the size of imposed visuomotor rotation (30°, 45° or 60°), with regards to the final asymptotic level of adaptation. We found that restricting preparation time to 0.35 seconds impaired adaptation for moderate and larger rotations, resulting in larger residual errors compared to groups with additional preparation time. However, we found that even extended preparation time failed to eliminate persistent errors, regardless of magnitude of cursor rotation. Thus, the asymptote of adaptation was significantly less than the degree of imposed rotation, for all experimental groups. Additionally, there was a positive relationship between asymptotic error and implicit retention. These data suggest that a prolonged motor preparation period is insufficient to reliably achieve complete adaptation and therefore our results provide support for the proposal that limitations within the implicit learning system contributes to asymptotic adaptation levels.New & NoteworthyResidual errors in sensorimotor adaptation are commonly attributed to an equilibrium between trial-by-trial learning and forgetting. Recent research suggested that allowing sufficient time for mental rotation eliminates these errors. In a number of experimental conditions, we show that while restricted motor preparation time does limit adaptation - consistent with mental rotation - extending preparation time fails to eliminate the residual errors in motor adaptation.
LncRNAs of Saccharomyces cerevisiae dodge the cell cycle arrest imposed by the ethanol stress
Authors: Lázari Lucas C. , Wolf Ivan R. , Schnepper Amanda Piveta , Valente Guilherme T. 
Published: June 2021

ABSTRACTEthanol impairs many subsystems of Saccharomyces cerevisiae, including the cell cycle. Cyclins and damage checkpoints drive the cell cycle. Two ethanol-responsive lncRNAs in yeast interact with cell cycle proteins, and here we investigated the role of these RNAs on the ethanol-stressed cell cycle. Our network dynamic modeling showed that the higher and lower ethanol tolerant strains undergo a cell cycle arrest during the ethanol stress. However, lower tolerant phenotype arrest in a later phase leading to its faster population rebound after the stress relief. Two lncRNAs can skip the arrests mentioned. The in silico overexpression of lnc9136 of SEY6210 (a lower tolerant strain), and CRISPR-Cas9 partial deletions of this lncRNA, evidenced that the one induces a regular cell cycle even under ethanol stress; this lncRNA binds to Gin4 and Hsl1, driving the Swe1p, Clb1/2, and cell cycle. Moreover, the lnc10883 of BY4742 (a higher tolerant strain) interacts to the Mec1p and represses Bub1p, circumventing the DNA and spindle damage checkpoints keeping a normal cell cycle even under DNA damage. Overall, we present the first evidence of the direct roles of lncRNAs on cell cycle proteins, the dynamics of this system in different ethanol tolerant phenotypes, and a new cell cycle model.
Analysis at single-cell resolution identifies a stable mammalian tRNA-mRNA interface and increased translation efficiency in neurons
Authors: Gao William , Gallardo-Dodd Carlos J. , Kutter Claudia 
Published: June 2021

AbstractThe correlation between codon and anticodon pools influences the efficiency of translation, but whether differences exist in these pools across individual cells is unknown. We determined that codon usage and amino acid demand are highly stable across different cell types using single-cell RNA-sequencing atlases of adult mouse and fetal human. After demonstrating the robustness of ATAC-sequencing for analysis of tRNA gene usage, we quantified anticodon usage and amino acid supply in adult mouse and fetal human single-cell ATAC-seq atlases. We found that tRNA gene usage is overall coordinated across cell types, except in neurons which clustered separately from other cell types. Integration of these datasets revealed a strong and statistically significant correlation between amino acid supply and demand across almost all cell types. Neurons have an enhanced translation efficiency over other cell types, driven by an increased supply of tRNAAla (AGC) anticodons. This results in faster decoding of the Ala-GCC codon, as determined by cell-type specific ribosome profiling, and a reduction of tRNAAla (AGC) anticodon pools may be implicated in neurological pathologies. This study, the first such examination of codon usage, anticodon usage, and translation efficiency at single-cell resolution, identifies conserved features of translation elongation across mammalian cellular diversity and evolution.
Baicalein suppresses Tau fibrillization by sequestering oligomers
Authors: Sonawane Shweta Kishor , Balmik Abhishek Ankur , Boral Debjyoti , Ramasamy Sureshkumar , Chinnathambi Subashchandrabose 
Published: June 2021

Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder caused by protein
misfolding, aggregation and accumulation in the brain. A large number of
molecules are being screened against these pathogenic proteins but the focus for
therapeutics is shifting towards the natural compounds as aggregation
inhibitors, mainly due to their minimum adverse effects. Baicalein is a natural
compound belonging to the class of flavonoids isolated from the Chinese herb
Scutellaria baicalensis. Here we applied
fluorescence, absorbance, microscopy, MALDI-TOF spectrophotometry and other
biochemical techniques to investigate the interaction between Tau and Baicalein
in vitro. We found the aggregation inhibitory
properties of Baicalein for the repeat Tau. Overall, the potential of Baicalein
in dissolving the preformed Tau oligomers as well as mature fibrils can be of
utmost importance in therapeutics for Alzheimer’s disease.
Conditional gene expression reveals stage-specific functions of the unfolded protein response in theUstilago maydis/maize pathosystem
Authors: Schmitz Lara , Kronstad James W. , Heimel Kai 
Published: June 2021

SummaryUstilago maydisis a model organism to study biotrophic plant-pathogen interactions. Sexual and pathogenic development of the fungus are tightly connected since fusion of compatible haploid sporidia is prerequisite for infection of the host plant, maize (Zea mays). After plant penetration, the unfolded protein response (UPR) is activated and required for biotrophic growth. The UPR is continuously active throughout all stages of pathogenic developmentin planta. However, since development of UPR deletion mutants stops directly after plant penetration, the role of an active UPR at later stages of development has/could not be examined, yet. Here, we establish a gene expression system forU. maydisthat uses endogenous, conditionally active promoters to either induce or repress expression of a gene of interest during different stages of plant infection. Integration of the expression constructs into the native genomic locus and removal of resistance cassettes were required to obtain a wild type-like expression pattern. This indicates that genomic localization and chromatin structure are important for correct promoter activity and gene expression. By conditional expression of the central UPR regulator, Cib1, inU. maydis, we show that a functional UPR is required for continuous plant defense suppression after host infection and thatU. maydisrelies on a robust control system to prevent deleterious UPR hyperactivation.
Increasing rice productivity in Ghana: Do savings with rural and community banks matter?
Authors: Vukey Enoch Yao , Egyir Irene S. , Asiedu Edward , Kwapong Nana Afranaa 
Published: June 2021

PurposeThis paper analysed the motives behind farmers' savings with Rural and Community Banks (RCBs) and the effect of these savings on rice yield in the Hohoe Municipality of the Volta region of Ghana.Design/methodology/approachA multi-stage sampling approach was used to draw a random sample of 222 rice farmers, and a structured questionnaire was employed to collect cross-sectional data. A Likert scale was used to rank the motive behind farmers' savings while the endogenous switching regression model was used to estimate the effect of savings on rice yield.FindingsThe results of the study showed that most farmers mobilise savings to enhance farm investment which is critical to increasing rice productivity. Improved labour and fertiliser use had a positive influence on rice yield, while farm size had an inverse relation with rice yield. Further, the findings show that savings with RCBs help mobilise the necessary finance to enhance rice productivity. In terms of the treatment effect of savings, the results indicate that farmers who patronise saving products of RCBs recorded a statistically significant average yield of 1.41 Mt/ha more than those not patronising saving products from any bank.Practical implicationsWhile the literature on agricultural finance focuses largely on credit, this study demonstrates that savings hold significant benefits for the development of agriculture through productivity gains. The importance of this demonstration is further shown by the fact that credit access depends on the ability to save in most developing countries.Social implicationsThere is a need to educate farmers about the essence of patronising formal savings products.Originality/valueThis study represents the first attempt at linking farmers' savings to agricultural productivity using an econometric methodology in Ghana. The study serves as a foundation paper and for that matter will serve as a guide to future research on savings mobilisation and agricultural productivity nexus.
Challenges faced by youth social entrepreneurs in Malaysia: career transition to become a social entrepreneur
Authors: Che Nawi Nur Raihan , Arshad Mohd Mursyid , Krauss Steven Eric , Ismail Ismi Arif 
Published: June 2021

PurposeThe practice of social entrepreneurship has grown rapidly around the world, including in Malaysia where it is still considered to be at an early stage. Nevertheless, little is known about the career transition among youth who choose careers as social entrepreneurs. The purpose of this study is to explore the challenges faced by youth social entrepreneurs who run social enterprises in Malaysia.Design/methodology/approachThis study used a qualitative approach to collect and analyse data to answer the research questions. Seven youth social entrepreneurs were interviewed until data saturation was met. An interview guide was created for the purposes of conducting the interviews. The interviews were recorded using a voice recorder. Data were transcribed verbatim and grouped in order to identify the codings, categories and themes.FindingsThe findings show the career transition to become a social entrepreneur, as well as the major challenges that youth social entrepreneurs face, which include acclimatising to the life and career of a social entrepreneur and not getting support from family.Practical implicationsThe study findings are also significant for presenting valuable data on the experience of the developing social entrepreneur. The qualitative nature of the study provides valuable experiential insight into the lives and struggles of young social entrepreneurs in Malaysia. The findings will allow local authorities and social entrepreneurship regulatory agencies to design initiatives and plan actions intended to overcome the challenges.Originality/valueThis study makes an original contribution by showing that the process of career development as a social entrepreneur has given meaning to the informants. Despite presenting many challenges, social entrepreneurship has reinforced the role of youth social entrepreneurs, especially in relation to social responsibility.