bluuebunny/crossref_metadata_2025_split huggingface dataset:
FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs
Authors: Griffith Billie G. C. , Upstill-Goddard Rosanna , Brunton Holly , Grimes Graeme R. , Biankin Andrew V. , Serrels Bryan , Byron Adam , Frame Margaret C. 
Published: July 2020

AbstractFocal adhesion kinase (FAK) localizes to focal adhesions and is overexpressed in many cancers. FAK can also translocate to the nucleus, where it binds to, and regulates, several transcription factors, including MBD2, p53 and IL-33, to control gene expression by unknown mechanisms. We have used ATAC-seq to reveal that FAK controls chromatin accessibility at a subset of regulated genes. Integration of ATAC-seq and RNA-seq data showed that FAK-dependent chromatin accessibility is linked to differential gene expression, including of the FAK-regulated cytokine and transcriptional regulator interleukin-33 (Il33), which controls anti-tumor immunity. Analysis of the accessibility peaks on theIl33gene promoter/enhancer regions revealed sequences for several transcription factors, including ETS and AP-1 motifs, and we show that c-Jun, a component of AP-1, regulatesIl33gene expression by binding to its enhancer in a FAK kinase-dependent manner. This work provides the first demonstration that FAK controls transcription via chromatin accessibility, identifying a novel mechanism by which nuclear FAK regulates biologically important gene expression.
TATA and paused promoters active in differentiated tissues have distinct expression characteristics
Authors: Ramalingam Vivekanandan , Natarajan Malini , Johnston Jeff , Zeitlinger Julia 
Published: July 2020

AbstractCore promoter types differ in the extent to which RNA polymerase II (Pol II) pauses after initiation, but how this difference affects their tissue-specific gene expression characteristics is not well understood. While promoters with Pol II pausing elements are active at all stages of development, TATA promoters are highly active in differentiated tissues. We therefore used a genomics approach on late-stageDrosophilaembryos to analyze the properties of promoter types. Using tissue-specific Pol II ChIP-seq, we found that paused promoters have high levels of paused Pol II throughout the embryo, even in tissues where the gene is not expressed, while TATA promoters only show Pol II occupancy when the gene is active. This difference between promoter types is associated with different chromatin accessibility in ATAC-seq data and different expression characteristics in single-cell RNA data. The results suggest that promoter types have optimized different promoter properties: paused promoters show more consistent expression when active, while TATA promoters have lower background expression when inactive. We propose that tissue-specific effector genes have evolved to use two different strategies for their differential expression across tissues.
Organizational culture, quality of care and leadership style in government general hospitals in Kuwait: a multimethod study
Authors: ALFadhalah Talal , Elamir Hossam 
Published: July 2020

AbstractPurposeTo investigate the organizational culture, assess the quality of care, and measure their association with a transformational/transactional leadership style in six hospitals.Materials and methodsWe used cross-sectional and retrospective quantitative approaches in government-sponsored secondary-care hospitals. A sample of 1,626 was drawn from a frame of 9,863 healthcare workers in six hospitals. Followers were surveyed using the Multifactor Leadership Questionnaire and the Organizational Description Questionnaire. We reviewed and analyzed one year (2012) of quarterly and annual quality indicators from the hospitals. Data were analyzed using suitable statistical analyses.ResultsWe collected 1,626 responses from six hospitals. 66.4% to 87.1% of participants in each hospital identified their hospital’s organizational culture as transformational, whereas 41 out of 48 departments were identified as having a transformational culture. The percentage of participants at each hospital rating their leader and organizational culture as transformational ranged from 60.5% to 80.4%. The differences between leadership style and organizational culture were statistically significant for four of the hospitals. For most of the quality indicators, there was a positive, but nonsignificant, correlation with leadership style.ConclusionLeaders define and influence organizational culture. The prevailing transformational leadership style creates and maintains a transformational organizational culture. The effect of transformational leadership on the quality of care delivered by the organization was measured in this study, and showed a positive and nonsignificant relationship between generic quality indicators and the transformational style.
SARS-COV-2 THREE FORCING SEASONALITIES: POLICIES, ENVIRONMENT AND URBAN SPACES
Authors: Telles Charles Roberto 
Published: July 2020

AbstractThis research investigated if pandemic of SARS-COV-2 follows the Earth seasonality ε comparing countries cumulative daily new infections incidence over Earth periodic time of interest for north and south hemisphere. It was found that no seasonality in this form ε occurs as far as a seasonality forcing behavior ε′ assumes most of the influence in SARS-COV-2 spreading patterns. Putting in order ε′ of influence, there were identified three main forms of SARS-COV-2 of transmission behavior: during epidemics growth, policies are the main stronger seasonality forcing behavior of the epidemics followed by secondary and weaker environmental and urban spaces driving patterns of transmission. At outbreaks and control phase, environmental and urban spaces are the main seasonality forcing behavior due to policies/ALE limitations to address heterogeneity and confounding scenario of infection. Finally regarding S and R compartments of SIR model equations, control phases are the most reliable phase to predictive analysis.These seasonality forcing behaviors cause environmental driven seasonality researches to face hidden or false observations due to policy/ALE interventions for each country and urban spaces characteristics. And also, it causes policies/ALE limitations to address urban spaces and environmental seasonality instabilities, thus generating posterior waves or uncontrolled patterns of transmission (fluctuations).All this components affect the SARS-COV-2 spreading patterns simultaneously being not possible to observe environmental seasonality not associated intrinsically with policies/ALE and urban spaces, therefore conferring to these three forms of transmission spreading patterns, specific regions of analysis for time series data extraction.
Reconstitution of human kinetochore in mitotic cell extracts reveals permitted and restricted assembly steps
Authors: Tarasovetc Ekaterina V. , Allu Praveen Kumar , Cheeseman Iain M. , Black Ben E. , Grishchuk Ekaterina L. 
Published: July 2020

AbstractAssembly of a functional kinetochore is critical for accurate chromosome segregation. Hierarchical recruitment of soluble components during kinetochore assembly is a highly regulated mitotic event, but the underlying steps are not well understood. In yeast andXenopusegg extracts, soluble kinetochore components can spontaneously assemble into microtubule-binding subcomplexes. Although the molecular interactions among specific kinetochore components are evolutionary conserved in eukaryotes, it remains unclear whichde novoassembly steps are permitted in extracts of mitotic human cells. By analyzing the recruitment of GFP-fused kinetochore proteins from human mitotic cell extracts to inner kinetochore components immobilized on microbeads, we reconstructed the interaction between CENP-C and CENP-A–containing nucleosomes. However, subsequent phospho-dependent binding of the Mis12 complex was less efficient, whereas binding of the Ndc80 complex was inhibited. Consistently, the microtubule-binding activity of native kinetochore components, as well as those assembled using a combination of native and recombinant human proteins, was weaker than that of recombinant Ndc80 complex alone. Such inhibitory mechanisms that prevent interactions between different kinetochore components are likely to guard against spurious formation of kinetochores in the cytosol of mitotic human cells, and imply existence of specific regulatory mechanisms that permit these interactions at the assembling kinetochore.
AraC mutations that suppress inactivating mutations in the C-terminal domain of the RpoA subunit ofEscherichia coliRNA polymerase
Authors: Belin Dominique , Silva Filo 
Published: July 2020

AbstractInE. coli, transcriptional activation is often mediated by the C-terminal domain of RpoA, the α subunit of RNA polymerase. Mutations that prevent activation of the arabinose PBADpromoter are clustered in a small region of the α–CTD domain around K271. To determine the target(s) of RpoA in the PBADpromoter, we have isolated suppressors ofrpoAα–CTD mutations. The suppressors map to the N-terminal domain of AraC, the main transcriptional regulator ofaragene expression. No mutation was found in the large DNA regulatory region betweenaraCand PBAD, suggesting that, in this system, RpoA does not activate transcription through its direct DNA binding. One class ofaraCmutations result in substitutions in the core of the N-terminal domain suggesting that they may affect its conformation. Another class of suppressors define genetically a domain that potentially interacts with the C-terminal domain of RpoA. Surprisingly, inrpoA+strains lacking CRP, thearaCmutations largely restore arabinose gene expression, suggesting that they somehow strengthen the AraC:α–CTD interaction. Thus, the N-terminal domain of AraC exhibits at least three activities: dimerization, arabinose binding and transcriptional activation via RpoA.ImportanceGene expression is most often controlled at the level of transcription by regulators that interact with RNA polymerase. The C-terminal domain ofEscherichia coliRpoA is attached to the core enzyme by a flexible linker and serves as a hub that interacts with many regulators and even with DNA sites to activate transcription. Mutations in a RpoA subdomain interfere with activation of the main arabinose promoter by AraC, the regulator that either activates or represses expression of the arabinose operons. We define here genetically the target of RpoA in the main arabinose promoter. Suppressors of most RpoA mutations map to the N-terminal domain of AraC that promotes its dimerization and binds to arabinose, the inducer. Thus, our results identify a third function for this AraC domain. Some suppressors define a potential binding site for RpoA, while others, at internal residues, probably affect the conformation of the AraC domain.
Fruit presence induces polar auxin transport in citrus and olive stem and represses hormone release from the bud
Authors: Haim Dor , Shalom Liron , Simhon Yasmin , Shlizerman Lyudmila , Kamara Itzhak , Morozov Michael , Albacete Moreo Alfonso Ant , Rivero Rosa M , Sadka Avi 
Published: July 2020

ABSTRACTIn many fruit trees, heavy fruit load in one year reduces flowering in the following year, creating a biennial fluctuation in yield termed alternate bearing (AB). In subtropical trees, where flowering induction is mostly governed by the accumulation of cold hours, fruit load is thought to generate a signal (AB signal) that blocks the perception of the cold induction. Fruit removal during a heavy-fruit-load year (On-Crop) is effective at inducing flowering only if performed one to a few months prior to onset of the flowering-induction period. We previously showed that following fruit removal, content of the auxin indoleacetic acid (IAA) in citrus buds is reduced, suggesting that the hormone plays a role in the AB signal. Here, we demonstrate that fruit presence generates relatively strong polar auxin transport (PAT) in citrus and olive stems. Upon fruit removal, PAT is reduced and allows auxin release from the bud. Furthermore, using immunolocalization, hormone and gene expression analyses, we show that in citrus, IAA level in the bud and, specifically, in the apical meristem is reduced upon fruit removal. Overall, our data provide support for the notion that fruit presence generates an auxin signal in the bud which may affect flowering induction.HIGHLIGHTSHeavy fruit load can reduce flowering intensity the following year. Fruit presence, inducing polar auxin transport in stems and inhibiting auxin release from buds, may be a fruit-load signal.
The diagnostic value of RASSF1A promoter methylation in prostate cancer: A systematic review and meta-analysis
Authors: Li Su-Liang , Li Ye-Xing , Ye Yun , Yuan Xiao-Hua , Wang Jian-Jun , Yan Hong-Lin 
Published: July 2020

AbstractBackgroundRASSF1A promoter methylation is consistent with clinicopathological data and has good accuracy in distinguishing tumors. However, the diagnostic parameters vary among previous studies. A systematic review was conducted to explore the diagnostic value of RASSF1A promoter methylation in prostate cancer.MethodsA comprehensive search of the literature in the PubMed, Medline, Cochrane Library, Embase and ISI Web of Science databases up to May 21, 2020 was performed. STATA software version 12.0 and Meta-disc version 1.4 were used to analyze the data.ResultsThe pooled sensitivity was 0.64 (95% CI 0.61–0.66), the pooled specificity was 0.80 (95% CI 0.77–0.83), the PLR was 3.82 (95% CI 1.96–7.44), and the NLR was 0.29 (95% CI 0.16–0.52). Furthermore, the pooled DOR of RASSF1A promoter methylation for prostate cancer was 13.08 (95% CI: 6.56–26.08). The area under the summary ROC curve was 0.87 (95% CI: 0.84–0.90). The results of the meta-regression suggested that heterogeneity was mainly derived from publication year. Fagan’s nomogram showed that the predictive accuracy was increased significantly by detecting RASSF1A promoter methylation for diagnosing prostate cancer.ConclusionThis meta-analysis suggests that detection of the RASSF1A promoter methylation status can be used for the diagnosis of PCa. In the future, further analyses and studies of larger sample sizes in large centers are needed to confirm our conclusion.
On the Emergence of P-Loop NTPase and Rossmann Enzymes from a Beta-Alpha-Beta Ancestral Fragment
Authors: Longo Liam M. , Jabłońska Jagoda , Vyas Pratik , Kanade Manil , Kolodny Rachel , Ben-Tal Nir , Tawfik Dan S. 
Published: July 2020

AbstractDating back to the last universal common ancestor (LUCA), the P-loop NTPases and Rossmanns now comprise the most ubiquitous and diverse enzyme lineages. Intriguing similarities in their overall architecture and phosphate binding motifs suggest common ancestry; however, due to a lack of sequence identity and some fundamental structural differences, these families are considered independent emergences. To address this longstanding dichotomy, we systematically searched for ‘bridge proteins’ with structure and sequence elements shared by both lineages. We detected homologous segments that span the first βαβ segment of both lineages and include two key functional motifs: (i) a phosphate binding loop – the ‘Walker A’ motif of P-loop NTPases or the Rossmann equivalent, both residing at the N-terminus of α1; and (ii) an Asp at the tip of β2. The latter comprises the ‘Walker B’ aspartate that chelates the catalytic metal in P-loop NTPases, or the canonical Rossmann β2-Asp that binds the cofactor’s ribose moiety. Tubulin, a Rossmann GTPase, demonstrates the potential of the β2-Asp to take either one of these two roles. We conclude that common P-loops/Rossmann ancestry is plausible, although convergence cannot be completely ruled out. Regardless, both lineages most likely emerged from a polypeptide comprising a βαβ segment carrying the above two functional motifs, a segment that comprises the core of both enzyme families to this very day.
Optimizing the use of gene expression data to predict plant metabolic pathway memberships
Authors: Wang Peipei , Moore Bethany M. , Uygun Sahra , Lehti-Shiu Melissa D. , Barry Cornelius S. , Shiu Shin-Han 
Published: July 2020

AbstractPlant metabolites produced via diverse pathways are important for plant survival, human nutrition and medicine. However, the pathway memberships of most plant enzyme genes are unknown. While co-expression is useful for assigning genes to pathways, expression correlation may exist only under specific spatiotemporal and conditional contexts. Utilizing >600 expression values and similarity data combinations from tomato, three strategies for predicting membership in 85 pathways were explored: naive prediction (identifying pathways with the most similarly expressed genes), unsupervised and supervised learning. Optimal predictions for different pathways require distinct data combinations that, in some cases, are indicative of biological processes relevant to pathway functions. Naive prediction produced higher error rates compared with machine learning methods. In 52 pathways, unsupervised learning performed better than a supervised approach, which may be due to the limited availability of training data. Furthermore, using gene-to-pathway expression similarities led to prediction models that outperformed those based simply on gene expression levels. Our study highlights the need to extensively explore expression-based features and prediction strategies to maximize the accuracy of metabolic pathway membership assignment. We anticipate that the prediction framework outlined here can be applied to other species and also be used to improve plant pathway annotation.
Presenilin-deficient neurons and astrocytes display normal mitochondrial phenotypes
Authors: Contino Sabrina , Vrancx Céline , Suelves Nuria , Vadukul Devkee M. , Payen Valery L. , Stanga Serena , Bertrand Luc , Kienlen-Campard Pascal 
Published: July 2020

AbstractPresenilins 1 and 2 (PS1 and PS2) are predominantly known as the catalytic subunits of the γ-secretase complex which generates the amyloid-β (Aβ) peptide, the major constituent of the senile plaques found in the brain of Alzheimer’s disease (AD) patients. Apart from their role in γ-secretase activity, a growing number of cellular functions have been recently attributed to PSs. They are involved in synaptic transmission, endo-lysosomal function and calcium homeostasis. PSs were also found to be enriched in mitochondria-associated membranes (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more specifically reported to regulate calcium shuttling between the ER and mitochondria by controlling the formation of functional MAMs through its interaction with the Mitofusin2 protein. We have previously demonstrated that the absence of PS2 (PS2KO) alters mitochondrial morphology and function. Indeed, a PS2KO cell line showed reduced mitochondrial respiration along with disrupted mitochondrial cristae and increased glycolysis. This phenotype is restored by the stable re-expression of human PS2. Still, all these results were obtained in immortalized Mouse Embryonic Fibroblasts (MEF) and one bottom-line question is to know whether these observations hold true for the Central Nervous System (CNS) cells, and in particular neurons and astrocytes. To that end, we carried out primary PS1KO, PS2KO and PS1/PS2KO (PSdKO) neuronal and astrocyte cultures. All the conditions were obtained in the same litter by crossing PS2 heterozygous and PS1 floxed (PS2+/−; PS1flox/flox) animals. Indeed, contrary to PS2KO mice, PS1KO are not viable and therefore require the use of the Cre-LoxP system to achieve gene deletionin vitro. Strikingly, we did not observe any mitochondrial phenotype in PS1KO, PS2KO or PSdKO primary cultures. Mitochondrial respiration and membrane potential were similar in all models, as were the glycolytic flux and NAD+/NADH ratio. We further investigated the discrepancies between these results and the ones previously reported in the MEF PS2KO cell line by analyzing PS2KO primary fibroblasts. No mitochondrial dysfunction was observed in this model, in line with observations in PS2KO primary neurons and astrocytes. These results indicate that the mitochondrial phenotype observed in immortalized PS2-deficient cell lines cannot be extrapolated to primary neurons, astrocytes and even to primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far might be the consequence of a cell immortalization process and, therefore, should be critically reconsidered regarding its relevance to AD.
Characterization of exosome release and extracellular vesicle-associated miRNAs for human bronchial epithelial cells irradiated with high charge and energy ions
Authors: Li Zhentian , Jella Kishore K. , Jaafar Lahcen , Moreno Carlos S. , Dynan William S. 
Published: July 2020

ABSTRACTExosomes are extracellular vesicles that mediate transport of nucleic acids, proteins, and other molecules. Prior work has implicated exosomes in the transmission of radiation nontargeted effects. Here we investigate the ability of energetic heavy ions, representative of species found in galactic cosmic rays, to stimulate exosome release from human bronchial epithelial cellsin vitro. Immortalized human bronchial epithelial cells (HBEC3-KT F25F) were irradiated with 1.0 Gy of high linear energy transfer (LET)48Ti,28Si, or16O ions, or with 10 Gy of low-LET reference γ-rays, and extracellular vesicles were collected from conditioned media. Preparations were characterized by single particle tracking analysis, transmission electron microscopy, and immunoblotting for the exosomal marker, TSG101. Irradiation with high-LET ions, but not γ-rays, stimulated exosome release by about 3-fold, relative to mock-irradiated controls. The exosome-enriched vesicle preparations contained pro-inflammatory damage-associated molecular patterns, including HSP70 and calreticulin. Additionally, miRNA profiling was performed for vesicular RNAs using NanoString technology. The miRNA profile was skewed toward a small number of species that have previously been shown to be involved in cancer initiation and progression, including miR-1246, miR-1290, miR-23a, and miR-205. Additionally, a set of 24 miRNAs was defined as modestly over-represented in preparations from HZE ion-irradiated versus other cells. Gene set enrichment analysis based on the over-represented miRNAs showed highly significant association with nonsmall cell lung and other cancers.
Probabilistic estimation of identity by descent segment endpoints and detection of recent selection
Authors: Browning Sharon R. , Browning Brian L. 
Published: July 2020

AbstractMost methods for fast detection of identity by descent (IBD) segments report identity by state segments without any quantification of the uncertainty in the endpoints and lengths of the IBD segments. We present a method for determining the posterior probability distribution of IBD segment endpoints. Our approach accounts for genotype errors, recent mutations, and gene conversions which disrupt DNA sequence identity within IBD segments. We find that our method’s estimates of uncertainty are well calibrated for homogeneous samples. We quantify endpoint uncertainty for 7.7 billion IBD segments from 408,883 individuals of White British ancestry in the UK Biobank, and use these IBD segments to find regions showing evidence of recent natural selection. We show that many spurious selection signals are eliminated by the use of unbiased estimates of IBD segment endpoints and a pedigree-based genetic map. Nine of the top ten regions with the greatest evidence for recent selection in our scan have been identified as selected in previous analyses using different approaches. Our computationally efficient method for quantifying IBD segment endpoint uncertainty is implemented in the open source ibd-ends software package.