bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reciprocal connectivity of the periaqueductal gray with the ponto-medullary respiratory network in rat
Authors: Trevizan-Baú Pedro , Furuya Werner I. , Mazzone Stuart B. , Stanić Davor , Dhingra Rishi R. , Dutschmann Mathias 
Published: September 2020

AbstractSynaptic activities of the periaqueductal gray (PAG) can modulate or appropriate the respiratory motor activities in the context of behavior and emotion via descending projections to nucleus retroambiguus. However, alternative anatomical pathways for the mediation of PAG-evoked respiratory modulation via core nuclei of the brainstem respiratory network remains only partially described. We injected the retrograde tracer Cholera toxin subunit B (CT-B) in the pontine Kölliker-Fuse nucleus (KFn,n=5), medullary Bötzinger (BötC,n=3) and pre-Bötzinger complexes (pre-BötC;n=3), and the caudal raphé nuclei (n=3), and quantified the ascending and descending connectivity of the PAG. CT-B injections in the KFn, pre-BötC, and caudal raphé, but not in the BötC, resulted in CT-B-labeled neurons that were predominantly located in the lateral and ventrolateral PAG columns. In turn, CT-B injections into the lateral and ventrolateral PAG columns (n=4) yield the highest numbers of CT-B-labeled neurons in the KFn and far fewer numbers of labeled neurons in the pre-BötC and caudal raphé. Analysis of the relative projection strength revealed that the KFn shares the densest reciprocal connectivity with the PAG (ventrolateral and lateral columns, in particular). Overall, our data imply that the PAG may engage a distributed respiratory rhythm and pattern generating network beyond the nucleus retroambiguus to mediate downstream modulation of breathing. However, the reciprocal connectivity of the KFn and PAG suggests specific roles for synaptic interaction between these two nuclei that are most likely related to the regulation of upper airway patency during vocalization or other volitional orofacial behaviors.HighlightsThe lateral and ventrolateral PAG project to the primary respiratory network.The Kölliker-Fuse nucleus shares the densest reciprocal connectivity with the PAG.The Bötzinger complex appears to have very little connectivity with the PAG.
Smad3Regulates Smooth Muscle Cell Fate and Governs Adverse Remodeling and Calcification of Atherosclerotic Plaque
Authors: Cheng Paul , Wirka Robert C. , Kim Juyong Brian , Nguyen Trieu , Kundu Ramendra , Zhao Quanyi , Pedroza Albert , Nagao Manabu , Iyer Dharini , Fischbein Michael P. , Quertermous Thomas 
Published: September 2020

AbstractAtherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC biology can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD, and is associated with expression ofSMAD3in SMC, but the mechanism by which this gene modifies CAD risk remains poorly understood. SMC-specific deletion ofSmad3in a murine atherosclerosis model resulted in greater plaque burden, positive remodeling, and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss ofSmad3altered SMC progeny phenotype toward the previously described chondromyocyte fate, but importantly also promoted transition to a novel cell-state that governs remodeling and recruitment of inflammatory cells. This new remodeling population was marked by uniquely highMmp3andCxcl12expression, and its appearance correlated with higher-risk plaque features such as increased positive remodeling and macrophage content. Further, investigation of transcriptional mechanisms by which Smad3 alters SMC cell-fate revealed novel roles for Hox and Sox transcription factors whose direct interaction with Smad3 regulate an extensive transcriptional program balancing remodeling and vascular ECM with significant implications for human Mendelian aortic aneurysmal diseases. Together, these data suggest thatSmad3expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including positive remodeling, monocyte recruitment, and vascular calcification.
Amazonian soil metagenomes indicate different physiological strategies of microbial communities in response to land use change
Authors: Khan Md Abdul Wadud , Bohannan Brendan J. M. , Meyer Kyle M. , Klein Ann M. , Nüsslein Klaus , Grover James P. , Rodrigues Jorge L. Mazza 
Published: September 2020

ABSTRACTDespite the global importance in ecological processes, the Amazon rainforest has been subjected to high rates of deforestation, mostly for pasturelands, over the last few decades. In this study, we used a combination of deep shotgun metagenomics and a machine learning approach to compare physiological strategies of microbial communities between contrasting forest and pasture soils. We showed that microbial communities (bacteria, archaea and viruses), and the composition of protein-coding genes are distinct in each ecosystem. The diversities of these metagenomic datasets are strongly correlated, indicating that the protein-coding genes found in any given sample of these soil types are predictable from their taxonomic lineages. Shifts in metagenome profiles reflected potential physiological differences caused by forest-to-pasture conversion with alterations in gene abundances related to carbohydrate and energy metabolisms. These variations in these gene contents are associated with several soil factors including C/N, temperature and H++Al3+ (exchangeable acidity). These data underscore that microbial community taxa and protein-coding genes co-vary. Differences in gene abundances for carbohydrate utilization, energy, amino acid, and xenobiotic metabolisms indicate alterations of physiological strategy with forest-to-pasture conversion, with potential consequences to C and N cycles. Our analysis also indicated that soil virome was altered and shifts in the viral community provide insights into increased health risks to human and animal populations.
Development of the Pre-Gnathal Segments of the Insect Head Indicates They Are Not Serial Homologues of Trunk Segments
Authors: Lev Oren , Chipman Ariel D. 
Published: September 2020

AbstractThe three anterior-most segments in arthropods contain the ganglia that make up the arthropod brain. These segments, the pre-gnathal segments, are known to exhibit many developmental differences to other segments, believed to reflect their divergent morphology. We have analyzed the expression and function of the genes involved in the segment-polarity network in the pre-gnathal segments compared with the trunk segments in the hemimetabolous insectOncopeltus fasciatus. We show that there are fundamental differences in the way the pre-gnathal segments are generated and patterned, relative to all other segments, and that these differences are general to all arthropods. We argue that given these differences, the pre-gnathal segments should not be considered serially homologous to trunk segments. This realization has important implications for our understanding of the evolution of the arthropod head. We suggest a novel scenario for arthropod head evolution that posits duplication of an ancestral single-segmented head into three descendent segments. This scenario is consistent with what we know of head evolution from the fossil record, and helps reconcile some of the debates about early arthropod evolution.
An expanded gene catalog of the mouse gut metagenome
Authors: Zhu Jiahui , Ren Huahui , Zhong Huanzi , Li Xiaoping , Zou Yuanqiang , Han Mo , Li Minli , Madsen Lise , Kristiansen Karsten , Xiao Liang 
Published: September 2020

AbstractHigh-quality and comprehensive reference gene catalogs are essential for metagenomic research. The rather low diversity of samples used to construct existing catalogs of mouse gut metagenomes limits the size and numbers of identified genes in existing catalogs. We therefore established an expanded gene catalog of genes in the mouse gut metagenomes (EMGC) containing >5.8 million genes by integrating 88 newly sequenced samples, 86 mouse-gut-related bacterial genomes and 3 existing gene catalogs. EMGC increases the number on non-redundant genes by more than one million genes compared to the so far most extensive catalog. More than 50% of the genes in EMGC were taxonomically assigned and 30% were functionally annotated. 902 Metagenomic species (MGS) assigned to 122 taxa are identified based on the EMGC. The EMGC-based analysis of samples from groups of mice originating from different animal providers, housing laboratories and genetic strains substantiated that diet is a major contributor to differences in composition and functional potential of the gut microbiota irrespective of differences in environment and genetic background. We envisage that EMGC will serve as an efficient and resource-saving reference dataset for future metagenomic studies in mice.
Extracellular DJ-1 induces sterile inflammation in the ischemic brain
Authors: Nakamura Koutarou , Sakai Seiichiro , Tsuyama Jun , Nakamura Akari , Otani Kento , Kurabayashi Kumiko , Yogiashi Yoshiko , Masai Hisao , Shichita Takashi 
Published: September 2020

AbstractInflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP), and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow-derived macrophages (BMMs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 hours after stroke onset and makes direct contact with the surfaces of infiltrating myeloid cells. Administration of an antibody against DJ-1 suppresses the expression of inflammatory cytokines in infiltrating immune cells and attenuates ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases.Significance statementDJ-1 has been thoroughly investigated as a cytoprotective antioxidant protein in neurons. However, here we demonstrate that extracellularly released DJ-1 triggers neurotoxic inflammation after ischemic stroke. Intracellular DJ-1 increases in response to oxidative stress in ischemic neurons, but if ischemic stresses result in necrotic cell death, DJ-1 is released extracellularly. Released DJ-1 interacts with TLR2 and TLR4 on the surface of infiltrating myeloid cells and triggers post-ischemic inflammation, leading to the exacerbated pathologies of ischemic stroke. Thus, extracellular DJ-1 is a previously unknown inflammatogenic DAMP, and may be a putative target for therapeutic intervention to prevent progression of inflammatory and neurodegenerative diseases.
Tissue Level Profiling of SARS-CoV-2 antivirals in mice to predict their effects: comparing Remdesivir’s active metabolite GS-441 524 vs. the clinically failed Hydroxychloroquine
Authors: Scherf-Clavel Oliver , Kaczmarek Edith , Kinzig Martina , Friedl Bettina , Feja Malte , Höhl Rainer , Nau Roland , Holzgrabe Ulrike , Gernert Manuela , Richter Franziska , Sörgel Fritz 
Published: September 2020

AbstractBackground and ObjectivesRemdesivir and hydroxychloroquine are or were among the most promising therapeutic options to tackle the current SARS-CoV-2 pandemic. Besides the use of the prodrug remdesivir itself, the direct administration of GS-441 524, the resulting main metabolite of remdesivir, could be advantageous and even more effective. All substances were not originally developed for the treatment of COVID-19 and especially for GS-441 524 little is known about its pharmacokinetic and physical-chemical properties. To justify the application of new or repurposed drugs in humans, pre-clinical in vivo animal models are mandatory to investigate relevant PK and PD properties and their relationship to each other. In this study, an adapted mouse model was chosen to demonstrate its suitability to provide sufficient information on the model substances GS-441 524 and HCQ regarding plasma concentration and distribution into relevant tissues a prerequisite for treatment effectiveness.MethodsGS-441 524 and HCQ were administered intravenously as a single injection to male mice. Blood and organ samples were taken at several time points and drug concentrations were quantified in plasma and tissue homogenates by two liquid chromatography/tandem mass spectrometry methods. In vitro experiments were conducted to investigate the degradation of remdesivir in human plasma and blood. All pharmacokinetic analyses were performed with R Studio using non-compartmental analysis.ResultsHigh tissue to plasma ratios for GS-441 524 and HCQ were found, indicating a significant distribution into the examined tissue, except for the central nervous system and fat. For GS-441 524, measured tissue concentrations exceeded the reported in vitro EC50values by more than 10-fold and in consideration of its high efficacy against feline infectious peritonitis, GS-441 524 could indeed be effective against SARS-CoV-2 in vivo. For HCQ, relatively high in vitro EC50values are reported, which were not reached in all tissues. Facing its slow tissue distribution, HCQ might not lead to sufficient tissue saturation for a reliable antiviral effect.ConclusionThe mouse model was able to characterise the PK and tissue distribution of both model substances and is a suitable tool to investigate early drug candidates against SARS-CoV-2. Furthermore, we could demonstrate a high tissue distribution of GS-441 524 even if not administered as the prodrug remdesivir.
Lopinavir-ritonavir is not an effective inhibitor of the main protease activity of SARS-CoV-2in vitro
Authors: Jang Minsu , Park Yea-In , Park Rackhyun , Cha Yeo-Eun , Namkoong Sim , Lee Jin I. , Park Junsoo 
Published: September 2020

ABSTRACTCOVID-19 has caused over 900,000 deaths worldwide as of September 2020, and effective medicines are urgently needed. Lopinavir was identified as an inhibitor of the HIV protease, and a lopinavir-ritonavir combination therapy was reported to be beneficial for the treatment of SARS and MERS. However, recent clinical tests could not prove that lopinavir-ritonavir therapy was an effective treatment for COVID-19. In this report, we examined the effect of lopinavir and ritonavir to the activity of the purified main protease (Mpro) protein of SARS- CoV-2, the causative virus of COVID-19. Unexpectedly, lopinavir and ritonavir did not inhibit Mpro activity. These results will aid the drug candidate selection for ongoing and future COVID-19 clinical trials.
GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers
Authors: Li Yapeng , Gao Junfeng , Kamran Mohammad , Harmacek Laura , Danhorn Thomas , Leach Sonia M. , O’Connor Brian P. , Hagman James R. , Huang Hua 
Published: September 2020

AbstractMast cells (MCs) are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the MC lineage-determining factors (LDTFs). However, it is unclear whether these LDTFs regulate chromatin accessibility at MC enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of MC identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We found that the number and densities of GATA2-but not MITF-bound sites at the super-enhancers were several folds higher than that at the typical enhancers. Our studies revealed that GATA2 promotes robust gene transcription to maintain MC identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key MC genes.
Evaluation of nafamostat mesylate safety and inhibition of SARS-CoV-2 replication using a 3-dimensional human airway epithelia model
Authors: Kirkpatrick D. Lynn , Millard Jeffrey 
Published: September 2020

AbstractIn the current COVID-19 pandemic context, Ensysce and its subsidiary Covistat have been working to repurpose nafamostat mesylate as an effective oral and inhalation treatment against SARS-CoV-2 infection. Prior reports used cell lines to demonstrate the antiviral potential of nafamostat against coronaviral infections and determined its mechanism of action through inhibition of transmembrane protease serine 2 (TMPRSS2). We selected a biologically relevant pre-clinical experimental model of SARS-CoV-2 lung infection using a 3D human reconstituted airway epithelial model of nasal origin to characterize the effects of nafamostat on tissue-level cellular ultrastructure and viral infection kinetics. Our results confirm the not only the relevance of this model for the preclinical evaluation of safety and efficacy of antiviral candidates, but also the highly potent nature of nafamostat SARS-CoV-2 antiviral activity. The studies described herein provided evidence demonstrating the therapeutic potential of nafamostat against COVID-19, as well as its safety upon exposure to lung airway cellular.One Sentence SummaryUsing a human airway model, study demonstrates the powerful inhibitory effect of nafamostat on SARS-CoV-2 genome copy detection when applied apically.
Computational Circuit Mechanisms Underlying Thalamic Control of Attention
Authors: Gu Qinglong L. , Lam Norman H. , Wimmer Ralf D. , Halassa Michael M. , Murray John D. 
Published: September 2020

SummaryThe thalamus engages in attention by amplifying relevant signals and filtering distractors. Whether architectural features of thalamic circuitry offer a unique locus for attentional control is unknown. We developed a circuit model of excitatory thalamocortical and inhibitory reticular neurons, capturing key observations from task-engaged animals. We found that top-down inputs onto reticular neurons regulate thalamic gain effectively, compared to direct thalamocortical inputs. This mechanism enhances downstream readout, improving detection, discrimination, and cross-modal performance. The model revealed heterogeneous thalamic responses that enable decoding top-down versus bottom-up signals. Spiking activity from task-performing mice supported model predictions, with a similar coding geometry in auditory thalamus and readout strategy in auditory cortex. Dynamical systems analysis explained why reticular neurons are potent sites for control, and how lack of excitatory connectivity among thalamocortical neurons enables separation of top-down from bottom-up signals. Our work reveals mechanisms for attentional control and connects circuit architectures to computational functions.
The influence of corporate governance on intellectual capital efficiency: evidence from Islamic banks of OIC countries
Authors: Aslam Ejaz , Haron Razali 
Published: September 2020

PurposeThe purpose of this study is to examine the impact of corporate governance (CG) on intellectual capital efficiency (ICE) in Islamic banks (IBs) of Organisation of Islamic Cooperation (OIC) countries.Design/methodology/approachA sample of 129 IBs is drawn from the 29 OIC countries from 2008 to 2017. A two-step system of the generalised method of moments has been employed to account for the unobserved endogeneity and heteroscedasticity issue that arose due to time-variant and time-invariant variables.FindingsThe results revealed that CG measures, namely board size, non-executive directors do explain the extent and quality of ICE in the expected direction. In contrast, CEO duality, Shariah board and audit committee are negatively associated with the ICE. Moreover, the authors observed that male CEO in IBs has negative, but foreign ownership has a positive association with ICE in determining the extent of ICE in IBs. This study contributes specifically to the stakeholder theory and the literature of ICE and CG.Research limitations/implicationsThe findings of the study provide insight into how a larger board can overcome skill deficiency and how making more investment in ICE would help to enhance productivity. Hence, bank managers, regulators, policymakers and shareholders have strong interest in designing the appropriate CG structure to develop ICE in banks.Originality/valueThis is one of the few studies which provide empirical evidence of CG mechanism to boost the ICE in the perspective of IBs of the OIC countries.
Recency effects in the buffering of negative news by corporate social responsibility advertising
Authors: Han Joon Hye , Davies Gary , Grimes Anthony 
Published: September 2020

PurposeDrawing from the theory of how relevant items are processed in memory when making judgements, this study aims to test for recency effects between CSR advertising and related, negative news on how a company is perceived and the explanatory roles of environmentalism, attribution and both feelings and attitudes towards the advertising itself.Design/methodology/approachThis study uses between-subjects experimental design with pretests.FindingsOrder effects exist, which, when ads and news are similarly influential, evidence a recency effect. The process is explained by both the mediating influence of attribution of blame and the moderation of this influence by attitude towards the environment. Differences between the effectiveness of ads are explained by the mediating influence of attitudes towards and feelings about the ad together with the moderation of this influence by involvement in the ad context.Practical implicationsCorporate social responsibility (CSR) ads should be pretested in the context of related but negative news, and not just on their own, to ensure they can buffer such news. CSR ads can be more effective when following rather than preceding such news and should not be withdrawn if such a crisis occurs.Originality/valueThe research first attempts to explain recency effects theoretically from the influence of CSR ads on negative CSR-related news. It also shows the determining factors in how such effects influence consumers by considering attribution, environmentalism, attitude to the context and attitude and feelings towards CSR ads.
The “Right” recipes for security culture: a competing values model perspective
Authors: Kam Hwee-Joo , Mattson Thomas , Kim Dan J. 
Published: September 2020

PurposeThis study argues that the effect of perceived organizational culture on the formation of security-related subjective norms and the level of compliance pressure will vary based on how the employees perceive their organization's cultural values. These perceptions reflect on the assumptions and principles that organizations use to guide their security-related behaviors. To make these arguments, we adopt the competing values model (CVM), which is a model used to understand the range of organizational values and resulting cultural archetypes.Design/methodology/approachThis study conducted a survey of working professionals in the banking and higher education industries and used partial least squares (PLS)-structural equation model (SEM) to analyze the data. In a series of post hoc analyses, we ran a set of multi-group analyses to compare the perceived organizational cultural effects between the working professionals in both industries.FindingsOur study reveals that perceived organizational cultures in favor of stability and control promoted more positive security-related behaviors. However, the different effects were more pronounced when comparing the effects between the working professionals in both industries.Originality/valueThis study is one of the few that examines which cultural archetypes are more effective at fostering positive security behaviors. These findings suggest that we should be cautious about generalizing the effects of organizational culture on security-related actions across different contexts and industries.