bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population structure and transmission ofMycobacterium bovisin Ethiopia
Authors: Almaw Gizat , Mekonnen Getnet Abie , Mihret Adane , Aseffa Abraham , Taye Hawult , Conlan Andrew JK , Gumi Balako , Zewude Aboma , Aliy Abde , Tamiru Mekdes , Olani Abebe , Lakew Matios , Sombo Melaku , Gebre Solomon , Diguimbaye Colette , Hilty Markus , Fané Adama , Müller Borna , Hewinson R Glyn , Ellis Richard J , Nunez-Garcia Javier , Palkopoulou Eleftheria ,   the ETHICOBOTS consortium, Abebe Tamrat , Ameni Gobena , Parkhill Julian , Wood James LN , Berg Stefan , van Tonder Andries J 
Published: November 2020

AbstractBovine tuberculosis (bTB) is endemic in cattle in Ethiopia, a country that hosts the largest national cattle herd in Africa. The intensive dairy sector, most of which is peri-urban, has the highest prevalence of disease. Previous studies in Ethiopia have demonstrated that the main cause isMycobacterium bovis(M. bovis), which has been investigated using conventional molecular tools including deletion typing, spoligotyping and Mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR). Here we use whole genome sequencing (WGS) to examine the population structure ofM. bovisin Ethiopia. A total of 134M. bovisisolates were sequenced including 128 genomes from 85 mainly dairy cattle and six genomes isolated from humans, originating from 12 study sites across Ethiopia. These genomes provided a good representation of the previously described population structure ofM. bovis, based on spoligotyping and demonstrated that the population is dominated by the clonal complexes African 2 (Af2) and European 3 (Eu3). A range of within-host diversity was observed amongst the isolates and evidence was found for both short- and long-distance transmission. Detailed analysis of available genomes from the Eu3 clonal complex combined with previously published genomes revealed two distinct introductions of this clonal complex into Ethiopia between 1950 and 1987, likely from Europe. This work is important to help better understand bTB transmission in cattle in Ethiopia and can potentially inform national strategies for bTB control in Ethiopia and beyond.
TC10 regulates breast cancer invasion and metastasis by controlling membrane type-1 matrix metalloproteinase at invadopodia
Authors: Hülsemann M. , Donnelly S.K. , Verkhusha P.V. , Mao S.P.H. , Segall J.E. , Hodgson L. 
Published: November 2020

AbstractDuring breast cancer metastasis, cancer cell invasion is driven by actin-rich protrusions called invadopodia, which mediate the extracellular matrix degradation required for the success of the invasive cascade. In this study, we demonstrated that TC10, a member of a Cdc42 subfamily of p21 small GTPases, regulates the membrane type 1 matrix metalloproteinase (MT1-MMP)-driven extracellular matrix degradation at invadopodia. We show that TC10 is required for the plasma membrane surface exposure of MT1-MMP at invadopodia. By utilizing our new Förster resonance energy transfer (FRET) biosensor, we demonstrated the p190RhoGAP-dependent regulation of spatiotemporal TC10 activity at invadopodia. We identified a pathway that regulates TC10 activity and function at invadopodia through the activation of p190RhoGAP and the downstream interacting effector Exo70 at the invadopodia sites. Our findings reveal the role of a previously unknown regulator of vesicular fusion at invadopodia, TC10, on the invasive potential of breast cancer cells during invasion and metastasis.
Quantitative analysis of Histone modifications in gene silencing
Authors: Wu Kenneth , Dhillon Namrita , Du Kelvin , Kamakaka Rohinton T. 
Published: November 2020

AbstractGene silencing in budding yeast is mediated by Sir protein binding to unacetylated nucleosomes to form a chromatin structure that inhibits transcription. This transcriptional silencing is characterized by the high-fidelity transmission of the silent state. Despite its relative stability, the constituent parts of the silent state are in constant flux giving rise to a model that silent loci can tolerate such fluctuations without functional consequences. However, the level of tolerance is unknown and we developed a method to measure the threshold of histone acetylation that causes the silent chromatin state to switch to the active state. We show that loss of silencing required between 50% and 75% of the unacetylated histones to be replaced with acetylated histone mimics. The precise levels of unacetylated nucleosomes required varied from locus to locus and was influenced by both silencer strength and UAS enhancer/promoter strength. Simple calculations suggest that an approximately 50% reduction in the ability of acetylases to acetylate individual nucleosomes across a large domain may be sufficient to generate a transcriptionally silent region in the nucleus.
Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2
Authors: Touret Franck , Driouich Jean-Sélim , Cochin Maxime , Petit Paul Rémi , Gilles Magali , Barthélémy Karine , Moureau Grégory , Mahon Francois-Xavier , Malvy Denis , Solas Caroline , de Lamballerie Xavier , Nougairède Antoine 
Published: November 2020

AbstractFollowing the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of Imatinib in multiple models. Our results indicated that Imatinib and another TKI, the Masitinib, exhibit an antiviral activity in VeroE6 cells. However, Imatinib was inactive in a reconstructed bronchial human airway epithelium model.In vivo, Imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of Imatinib and similar TKIs as antivirals in the treatment of Covid-19.
“Multiplex” rheostat positions cluster around allosterically critical regions of the lactose repressor protein
Authors: Bantis Leonidas E. , Parente Daniel J. , Fenton Aron W. , Swint-Kruse Liskin 
Published: November 2020

AbstractAmino acid variation at “rheostat” positions provides opportunity to modulate various aspects of protein function – such as binding affinity or allosteric coupling – across a wide range. Previously a subclass of “multiplex” rheostat positions was identified at which substitutions simultaneously modulated more than one functional parameter. Using the Miller laboratory’s dataset of ∼4000 variants of lactose repressor protein (LacI), we compared the structural properties of multiplex rheostat positions with (i) “single” rheostat positions that modulate only one functional parameter, (ii) “toggle” positions that follow textbook substitution rules, and (iii) “neutral” positions that tolerate any substitution without changing function. The combined rheostat classes comprised >40% of LacI positions, more than either toggle or neutral positions. Single rheostat positions were broadly distributed over the structure. Multiplex rheostat positions structurally overlapped with positions involved in allosteric regulation. When their phenotypic outcomes were interpreted within a thermodynamic framework, functional changes at multiplex positions were uncorrelated. This suggests that substitutions lead to complex changes in the underlying molecular biophysics. Bivariable and multivariable analyses of evolutionary signals within multiple sequence alignments could not differentiate single and multiplex rheostat positions. Phylogenetic analyses – such as ConSurf – could distinguish rheostats from toggle and neutral positions. Multivariable analyses could also identify a subset of neutral positions with high probability. Taken together, these results suggest that detailed understanding of the underlying molecular biophysics, likely including protein dynamics, will be required to discriminate single and multiplex rheostat positions from each other and to predict substitution outcomes at these sites.
Single-colony sequencing reveals phylosymbiosis, co-phylogeny, and horizontal gene transfer between the cyanobacteriumMicrocystisand its microbiome
Authors: Pérez-Carrascal Olga M. , Tromas Nicolas , Terrat Yves , Moreno Elisa , Giani Alessandra , Marques Laisa Corrêa Braga , Fortin Nathalie , Shapiro B. Jesse 
Published: November 2020

AbstractCyanobacteria from the genusMicrocystiscan form large mucilaginous colonies with attached heterotrophic bacteria – their microbiome. However, the nature of the relationship betweenMicrocystisand its microbiome remains unclear. Is it a long-term, evolutionarily stable association? Which partners benefit? Here we report the genomic diversity of 109 individualMicrocystiscolonies – including cyanobacteria and associated bacterial genomes – isolatedin situand without culture from Lake Champlain, Canada and Pampulha Reservoir, Brazil. We found 14 distinctMicrocystisgenotypes from Canada, of which only two have been previously reported, and four genotypes specific to Brazil.Microcystisgenetic diversity was much greater between than within colonies, consistent with colony growth by clonal expansion rather than aggregation ofMicrocystiscells. We also identified 72 bacterial species in the microbiome. EachMicrocystisgenotype had a distinct microbiome composition, and more closely-related genotypes had more similar microbiomes. This pattern of phylosymbiosis could be explained by co-phylogeny in two out of the nine most prevalent associated bacterial genera,RoseomonasandRhodobacter, suggesting long-term evolutionary associations.RoseomonasandRhodobactergenomes encode functions which could complement the metabolic repertoire ofMicrocystis, such as cobalamin and carotenoid biosynthesis, and nitrogen fixation. In contrast, other colony-associated bacteria showed weaker signals of co-phylogeny, but stronger evidence of horizontal gene transfer withMicrocystis. These observations suggest that acquired genes are more likely to be retained in both partners (Microcystisand members of its microbiome) when they are loosely associated, whereas one gene copy is sufficient when the association is physically tight and evolutionarily long-lasting.
Assessment of protein-protein interfaces in cryo-EM derived assemblies
Authors: Malhotra Sony , Joseph Agnel Praveen , Thiyagalingam Jeyan , Topf Maya 
Published: November 2020

AbstractStructures of macromolecular assemblies derived from cryo-EM maps often contain errors that become more abundant with decreasing resolution. Despite efforts in the cryo-EM community to develop metrics for the map and atomistic model validation, thus far, no specific scoring metrics have been applied systematically to assess the interface between the assembly subunits. Here, we have assessed protein-protein interfaces in macromolecular assemblies derived by cryo-EM. To this end, we developed PI-score, a density-independent machine learning-based metric, trained using protein-protein interfaces’ features in high-resolution crystal structures. Using PI-score, we were able to identify errors at interfaces in the PDB-deposited cryo-EM structures (including SARS-CoV-2 complexes) and in the models submitted for cryo-EM targets in CASP13 and the EM model challenge. Some of the identified errors, especially at medium-to-low resolution structures, were not captured by density-based assessment scores. Our method can therefore provide a powerful complementary assessment tool for the increasing number of complexes solved by cryo-EM.
Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB
Authors: Chou Tsui-Wen , Chang Nydia P , Krishnagiri Medha , Patel Aisha P , Atkins Colm , Daniels Brian P. 
Published: November 2020

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.
Palmitoylation Couples DLK to JNK3 to Facilitate Pro-degenerative Axon-to-Soma Signaling
Authors: Niu Jingwen , Holland Sabrina M. , Ketschek Andrea , Collura Kaitlin M. , Hayashi Takashi , Gallo Gianluca , Thomas Gareth M. 
Published: November 2020

SummaryDual Leucine-zipper Kinase (DLK, a MAP3K) mediates neuronal responses to diverse injuries and insults via c-Jun N-terminal Kinase (JNK) family Mitogen-activated Protein Kinases (MAPKs). It is unclear why DLK couples to JNKs in mammalian neurons versus other MAPKs, especially because some invertebrate DLK orthologs couple instead to the related p38 family MAPKs. Here we identify two mechanisms that potentially explain this DLK-JNK coupling. First, neural-specific JNK3, but not p38-MAPK, catalyzes positive feedback phosphorylation of DLK that further activates DLK and locks the DLK-JNK3 module in a highly active state. Furthermore, the pro-degenerative JNK2 and JNK3, but not the related JNK1, are endogenously palmitoylated. Moreover, palmitoylation targets both DLK and JNK3 to the same axonal vesicles and JNK3 palmitoylation is essential for pro-degenerative axonal retrograde signalingin vivo. These findings provide insights into DLK-JNK signaling relevant to multiple neuropathological conditions and answer long-standing questions regarding the selective pro-degenerative roles of JNK2/3.
Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity
Authors: Underwood Rachel , Wang Bing , Pathak Aneesh , Volpicelli-Daley Laura , Yacoubian Talene A. 
Published: November 2020

SUMMARYParkinson’s disease and Dementia with Lewy Bodies are two common neurodegenerative disorders marked by proteinaceous aggregates composed primarily of the protein α-synuclein. α-Synuclein is hypothesized to have prion-like properties, by which misfolded α-synuclein induces the pathological aggregation of endogenous α-synuclein and neuronal loss. Rab27a and Rab27b are two highly homologous Rab GTPases that regulate α-synuclein secretion, clearance, and toxicityin vitro. In this study, we tested the impact of Rab27a/b on the transmission of pathogenic α-synuclein. Double knockout of both Rab27 isoforms eliminated α-synuclein aggregation and neuronal toxicity in primary cultured neurons exposed to fibrillary α-synuclein.In vivo, Rab27 double knockout mice lacked fibril-induced α-synuclein inclusions, dopaminergic neuron loss, and behavioral deficits seen in wildtype mice with fibril-induced inclusions. Studies using AlexaFluor488-labeled α-synuclein fibrils revealed that Rab27a/b knockout prevented α-synuclein internalization without affecting bulk endocytosis. Rab27a/b knockout also blocked the cell-to-cell spread of α-synuclein pathology in multifluidic, multichambered devices. This study provides critical insight into the role of Rab GTPases in Parkinson’s disease and identifies Rab27s as key players in the progression of synucleinopathies.
Human Pumilio proteins directly bind the CCR4-NOT deadenylase complex to regulate the transcriptome
Authors: Enwerem Isioma I.I. , Elrod Nathan D. , Chang Chung-Te , Lin Ai , Ji Ping , Bohn Jennifer A. , Levdansky Yevgen , Wagner Eric J. , Valkov Eugene , Goldstrohm Aaron C. 
Published: November 2020

AbstractPumilio paralogs, PUM1 and PUM2, are sequence-specific RNA-binding proteins that are essential for vertebrate development and neurological functions. PUM1&2 negatively regulate gene expression by accelerating degradation of specific mRNAs. Here, we determined the repression mechanism and impact of human PUM1&2 on the transcriptome. We identified subunits of the CCR4-NOT (CNOT) deadenylase complex required for stable interaction with PUM1&2 and to elicit CNOT-dependent repression. Isoform-level RNA sequencing revealed broad co-regulation of target mRNAs through the PUM-CNOT repression mechanism.Functional dissection of the domains of PUM1&2 identified a conserved N-terminal region that confers the predominant repressive activity via direct interaction with CNOT. In addition, we show that the mRNA decapping enzyme, DCP2, has an important role in repression by PUM1&2 N-terminal regions. Our results support a molecular model of repression by human PUM1&2 via direct recruitment of CNOT deadenylation machinery in a decapping-dependent mRNA decay pathway.
KDM2B promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma
Authors: Gulay Kevin Christian M. , Aoshima Keisuke , Shibata Yuki , Yasui Hironobu , Yan Qin , Kobayashi Atsushi , Kimura Takashi 
Published: November 2020

AbstractEpigenetic regulators have been implicated in tumorigenesis of many types of cancer; however, their roles in endothelial cell cancers such as canine hemangiosarcoma (HSA) have not been studied. In this study, we found that lysine-specific demethylase 2B (Kdm2b) was highly expressed in HSA cell lines compared to normal canine endothelial cells. Silencing of Kdm2b in HSA cells resulted to increased cell deathin vitrocompared to the scramble control by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage. Similarly, doxycycline-induced Kdm2b silencing in tumor xenografts resulted to decreased tumor sizes compared to the scramble control. Furthermore, Kdm2b was also highly expressed in clinical cases of HSA, and its expression levels was higher than in hemangioma, a benign counterpart of HSA. Based on these results, we hypothesized that pharmacological Kdm2b inhibition can also induce HSA cell death and can be used as an alternative treatment for HSA. We treated HSA cells with GSK-J4, a histone demethylase inhibitor, and found that GSK-J4 treatment also induced apoptosis and cell death. On top of that, GSK-J4 treatment in HSA tumor-bearing mice decreased tumor sizes without any obvious side-effects. In this study, we demonstrated that Kdm2b acts as an oncogene in HSA by enhancing DNA damage response and can be used as a biomarker to differentiate HSA from hemangioma. Moreover, we indicated that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment.
Accounting comparability, financial reporting quality and audit opinions: evidence from Iran
Authors: Golmohammadi Shuraki Mojtaba , Pourheidari Omid , Azizkhani Masoud 
Published: November 2020

PurposeType of audit opinion is important for all stakeholders. Firm-specific characteristics have a direct impact on the type of audit opinion. The purpose of this study is to examine the association between accounting comparability (as a micro level characteristic), financial reporting quality (as a macro level characteristic) and audit opinions.Design/methodology/approachThis study uses a multivariate regression analysis to tests it hypotheses to a sample of firms listed in Tehran Stock Exchange during 2015–2019. To measure accounting comparability, the authors use De Franco et al. (2011) model, and Hutton et al. (2009) model to measure financial reporting quality. The authors use type of audit opinion, and auditor's remarks (explanatory notes) as the measure for audit opinions.FindingsThe authors find a negative association between accounting comparability, and the proxies for audit opinion. The authors also find that a negative association between financial reporting quality and audit opinions. These results suggest that higher accounting comparability, and higher financial reporting quality (proxied by earnings quality) increases auditor tendency to issue unmodified audit opinion.Originality/valueTo the authors' best knowledge, this is the first study that empirically examines the association between accounting comparability, financial reporting quality and audit opinion. This study provides empirical support for the theoretical views on the association between financial reporting quality and audit opinion. The results could be of interest of both auditors and managers, especially in emerging capital markets, who seek to improve financial reporting quality.
A study of Open Access research data repositories developed by BRICS countries
Authors: Misgar Safat Mushtaq , Bhat Ajra , Wani Zahid Ashraf 
Published: November 2020

Purpose
In the present era, research data is a concern for researchers, as they are trying to find new ways to communicate their research findings and conclusions to other researchers in order to increase visibility and credibility. BRICS nations are fast emerging economies and contribute significantly in research output. This study makes an effort to analyze and explore the role of BRICS nations towards open access research data repository registered with Registry of Research Data Repositories.

Design/methodology/approach
The data were gathered from re3data repository, and the search was limited to BRICS nations. The data were further analyzed and tabulated as per set parameters, namely, country-wise distribution, types of contents, subject coverage and language diversity.

Findings
The findings depict that in terms of strength, India has the highest number of data repositories, thereby achieved the first rank among BRICS nations, and South Africa has the least number of data repositories, whereas in terms of content type and subject coverage, India again is leading among BRICS nations. The English language is used by repositories as the main language of the interface.

Practical implications
The study helps to understand the development of research data repositories by BRICS nations. The study is further beneficial to researchers, as Registry of Research Data Repository provides a single platform to access repositories from various disciplines. Readily available data saves time, money and efforts of researchers and helps the researcher in completing their research activity in a very short span of time.

Originality/value
The paper has investigated open access data repositories of BRICS nation that has not been attempted earlier. This gives readers comprehensive overview of research data repositories developed in fast emerging economies of the global. The paper can be very helpful for information managers, OA promoters and education and research policy makers to devise plans and policy bearing in mind the evolving research channels in emerging economies.