bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage-derived miR-21 drives overwhelming glycolytic and inflammatory response during sepsis via repression of the PGE2/IL-10 axis
Authors: Melo Paulo , Alvarez Annie Rocio Pineros , Serezani C. Henrique 
Published: May 2020

AbstractMyeloid cells play a critical role in the development of systemic inflammation and organ damage during sepsis. The mechanisms the development of aberrant inflammatory response remains to be elucidated. MicroRNAs are small non-coding RNAs that could prevent the expression of inflammatory molecules. Although the microRNA-21 (miR-21) is abundantly expressed in macrophages, the role of miR-21 in sepsis is controversial. Here we showed that miR-21 is upregulated in neutrophils and macrophages from septic mice. We found that myeloid-specific miR-21 deletion enhances animal survival, followed by decreased bacterial growth and organ damage during sepsis. Increased resistance against sepsis was associated with a reduction of aerobic glycolysis (as determined by reduced extracellular acidification rate (ECAR) and expression of glycolytic enzymes) and systemic inflammatory response (IL-1βTNFα and IL-6). While miR-21-/- macrophages failed to induce aerobic glycolysis and production of pro-inflammatory cytokines, we observed increased levels of the anti-inflammatory mediators’ prostaglandin E2(PGE2) and IL10. Using blocking antibodies and pharmacological tools, we further discovered that increased survival and decreased systemic inflammation in miR21Δmyelduring sepsis is dependent on the PGE2/IL10-mediated glycolysis inhibition. Together, we are showing a heretofore unknown role of macrophage miR21 in the orchestrating the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm and tissue damage during sepsis.
Sensitivity of Gene Sets to miRNA Regulation: A Cell-Based Probabilistic Approach
Authors: Mahlab-Aviv Shelly , Linial Nathan , Linial Michal 
Published: May 2020

AbstractMature microRNAs (miRNAs) are small, non-coding RNA molecules that function by base-pairing with mRNAs. In multicellular organisms, miRNAs lead to mRNA destabilization and translation arrest. Importantly, the quantities and stichometry of miRNAs/mRNAs determine the miRNA regulation characteristics of specific cells. In this study, we used COMICS (Competition of miRNA Interactions in Cell Systems), a stochastic computational iterative framework to characterize genes by their sensitivity and robustness to miRNA regulation. We monitor the cell state by quantifying the retention level for all mRNAs, at the end of 100,000 simulation iterations. In HeLa cells, we partitioned all genes to five classes according to their decay rates. We show that the largest class (69% of genes) is apparently resistant to miRNA regulation. We created in silico perturbations using overexpressing of all major miRNAs (248 types) at various levels relative to the basal level (x1 to x1000). We further classified genes according to the differential behaviour for any pair of conditions of miRNA expression profile. Based on such measure (OvereXpression Ratio, OXR), we identified a small number of gene sets that are especially sensitive to OXR. Our results expose an overlooked quantitative dimension for set of genes and miRNA regulation in living cells.
Binding partners regulate unfolding of myosin VI to activate the molecular motor
Authors: dos Santos Ália , Fili Natalia , Hari-Gupta Yukti , Gough Rosemarie E. , Wang Lin , Martin-Fernandez Marisa , Aaron Jesse , Wait Eric , Chew Teng-Leong , Toseland Christopher P. 
Published: May 2020

ABSTRACTMyosin VI is the only minus-end actin motor and is coupled to various cellular processes ranging from endocytosis to transcription. This multi-potent nature is achieved through alternative isoform splicing and interactions with a network of binding partners. There is a complex interplay between isoforms and binding partners to regulate myosin VI. Here, we have compared the regulation of two myosin VI splice isoforms by two different binding partners. By combining biochemical and single-molecule approaches, we propose that myosin VI regulation follows a generic mechanism, independently of the spliced isoform and the binding partner involved. We describe how myosin VI adopts an autoinhibited backfolded state which is released by binding partners. This unfolding activates the motor, enhances actin binding and can subsequently trigger dimerization. We have further expanded our study by using single molecule imaging to investigate the impact of binding partners upon myosin VI molecular organisation and dynamics.
The Starlet Sea Anemone,Nematostella vectensis, possesses body region-specific bacterial associations with spirochetes dominating the capitulum
Authors: Bonacolta A. M. , Connelly M. T. , Rosales S. , del Campo J. , Traylor-Knowles N. 
Published: May 2020

AbstractSampling of different body regions can reveal highly specialized bacterial associations within the holobiont and facilitate identification of core microbial symbionts that would otherwise be overlooked by bulk sampling methods. Here we characterized compartment-specific associations present within the model cnidarianNematostella vectensisby dividing its morphology into three distinct body regions. This sampling design allowed us to uncover a capitulum-specific dominance of spirochetes withinN. vectensis. Bacteria from the family Spirochaetaceae made up 66% of the community in the capitulum, while only representing 1.2% and 0.1% of the communities in the mesenteries and physa, respectively. A phylogenetic analysis of the predominant spirochete sequence recovered fromN. vectensisshowed a close relation to spirochetes previously recovered from wildN. vectensis. These sequences clustered closer to the recently described genusOceanispirochaeta, rather thanSpirochaeta perfilievii, supporting them as members of this clade. This suggests a consistent and potentially important association betweenN. vectensisand spirochetes from the order Spirochaetales.
TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage
Authors: Gianini Marta , Sproviero Daisy , Bayona-Feliu Aleix , Cereda Cristina , Aguilera Andrés 
Published: May 2020

AbstractTDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. Here, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, and R loop-dependent increased DSBs and Fanconi Anemia repair centers. Similar results were observed in a non-neuronal model of HeLa cells depleted of TDP-43. These results uncover a new role of TDP-43 in the control of co-transcriptional R-loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R-loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies.
DONSON, a gene responsible for microcephalic primordial dwarfism, ensures proper centriole duplication cycle by maintaining centriole engagement during interphase
Authors: Matsuhashi Kyohei , Watanabe Koki , Ito Kei K. , Chinen Takumi , Hata Shoji , Stewart Grant S. , Kitagawa Daiju 
Published: May 2020

AbstractMicrocephalic primordial dwarfism (MPD) is a genetic disorder characterized by short stature and microcephaly. MPD-related genes are known to regulate centrosome biogenesis, DNA replication or the DNA damage response. Although some of the MPD-related proteins that are implicated in DNA replication localize to centrosomes, how these proteins affect centrosome biogenesis remains mostly elusive. Here, we revisit the potential function of these DNA replication mediators in human centrosome biogenesis. Among these proteins, depletion of DONSON leads to excessive number of centrosomes in interphase, caused by precocious centriole disengagement. Such disengaged centrioles are converted to centrosomes, followed by centriole reduplication during interphase. These extra centrosomes lead to abnormal spindle formation and chromosome segregation errors. Importantly, similar defects are observed in MPD patients’ cells withDONSONmutations, suggesting a possible cause of the disease. Overall, these results indicate that DONSON is involved in regulating the centriole duplication cycle by ensuring the maintenance of centriole engagement during interphase.
Pioneer factor GAF cooperates with PBAP and NURF to regulate transcription
Authors: Judd Julius , Duarte Fabiana M. , Lis John T. 
Published: May 2020

SummaryTranscriptionally silent genes must be activated throughout development. This requires nucleosomes be removed from promoters and enhancers to allow transcription factor binding (TFs) and recruitment of coactivators and RNA Polymerase II (Pol II). Specialized pioneer TFs bind nucleosome-wrapped DNA to perform this chromatin opening by mechanisms that remain incompletely understood1–3. Here, we show that GAGA-factor (GAF), aDrosophilapioneer factor4, interacts with both SWI/SNF and ISWI family chromatin remodelers to allow recruitment of Pol II and entry to a promoter-proximal paused state, and also to promote Pol II’s transition to productive elongation. We found that GAF functions with PBAP (SWI/SNF) to open chromatin and allow Pol II to be recruited. Importantly this activity is not dependent on NURF as previously proposed5–7; however, GAF also functions with NURF downstream of this process to ensure efficient Pol II pause release and transition to productive elongation apparently through its role in precisely positioning the +1 nucleosome. These results demonstrate how a single sequence-specific pioneer TF can synergize with remodelers to activate sets of genes. Furthermore, this behavior of remodelers is consistent with findings in yeast8–10and mice11–13, and likely represents general, conserved mechanisms found throughout Eukarya.
Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact
Authors: Chiasson Melissa A. , Rollins Nathan J. , Stephany Jason J. , Sitko Katherine A. , Matreyek Kenneth A. , Verby Marta , Sun Song , Roth Frederick P. , DeSloover Daniel , Marks Debora , Rettie Allan E. , Fowler Douglas M. 
Published: May 2020

ABSTRACTVitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin Despite VKOR’s pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency 2 or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an evolutionary coupling analysis, supports a four transmembrane domain topology, with variants in transmembrane domains exhibiting strongly deleterious effects on abundance and activity. Functionally constrained regions of the protein define the active site, and we find that, of four conserved cysteines putatively critical for function, only three are absolutely required. Finally, 25% of human VKOR missense variants show reduced abundance or activity, possibly conferring warfarin sensitivity or causing disease.
Synthetic Maturation of Multilineage Human Liver Organoids via Genetically Guided Engineering
Authors: Velazquez Jeremy J. , LeGraw Ryan , Moghadam Farzaneh , Tan Yuqi , Kilbourne Jacquelyn , Hislop Joshua , Liu S , Cats Davy , Chuva de Sousa Lopes Susana M. , Plaisier Christopher , Cahan Patrick , Kiani Samira , Ebrahimkhani Mo R. 
Published: May 2020

SUMMARYPluripotent stem cell (PSC)-derived organoids are emerging as novel human-based microphysiological models but display immature phenotypes with limited subsets of endothelial or stromal cells. Here we demonstrate thatin vitromanipulation of gene regulatory networks (GRNs) in PSC-derived liver organoids selected either through computational analysis or targeted tissue design can advance tissue maturationin vitro. Through an unbiased comparison with the genetic signature of mature livers, we identify downregulated GRNs in fetal liver organoids compared to adult livers. We demonstrate that overexpression ofPROX1andATF5, together with targeted CRISPR-based transcriptional activation of endogenousCYP3A4, drives maturationin vitro. Single cell analyses reveal hepatobiliary-, endothelial-, and stellate-like cell populations. The engineered organoids demonstrate enhanced vasculogenesis, capture native liver characteristics (e.g. FXR signaling, CYP3A4 activity), and exhibit therapeutic potential in mice. Collectively, our approach provides a genetically guided framework for engineering developmentally advanced multilineage tissues from hiPSCs.HIGHLIGHTSIn vitrotissue maturation via genetically encoded molecular programsComputational analysis to identify maturation transcription factors in liver organoidsPromoting vascularization of organoids via genetically encoded molecular programsSingle cell analysis of parenchymal and non-parenchymal cellsModeling of native liver functions andin vivotherapeutic potentialGraphical Abstract
The association between health-related individual traits and dairy avoidance
Authors: Mishali Moshe , Kisner Mirit , Tal Naama 
Published: May 2020

PurposeThe purpose of this research is to examine whether health-related personal traits such as hypochondriasis, health behavior and health locus of control can predict dairy avoidance.Design/methodology/approachThe empirical study took place in Israel. The researchers administered questionnaires to gather self-reported data concerning the consumption dairy products in general without making a distinction among different types of dairy (fermented/nonfermented, low fat/high fat etc.). A random sample of 77 participants was recruited from among students at the University of Haifa, after culling out those who declared to have been medically diagnosed with lactose intolerance or dairy allergy.FindingsHigh health behavior scores were associated with increased likelihood of avoiding milk and dairy products by a factor of 3.92 (OR = 3.92, 95% CI: 1.54–10.02, p = 0.004), whereas external health locus of control was associated with decreased likelihood of shunning milk and dairy (OR = 0.136, 95% CI: 0.032–0.580, p = 0.007). The connection between hypochondriasis and milk avoidance turned out insignificant.Practical implicationsThe medical establishment should devise ways, means and measures to purvey well-established dietary guidelines for those who are willing to make an effort and invest in their health.Originality/valueThis study adds to the burgeoning body of literature seeking to relate personal traits or individual characteristics to a host of lifestyle choices. The most salient finding is that many individuals who perform an array of behaviors they deem beneficial to their health and well-being in an attempt to exercise control over their health, paradoxically run the risk of making uninformed lifestyle decisions including dietary choices – ones that might prove detrimental to their health over the long haul.
Dietary supplements versus functional foods: consumers' attitudes to their consumption
Authors: Chaloupkova Petra , Petrtyl Miloslav , Verner Vladimir , Kokoska Ladislav 
Published: May 2020

PurposeThe popularity of dietary supplements (DSs) and functional foods (FFs) is currently widespread worldwide. In general, European countries represent one of the most important markets for both two groups; however, regional differences were reported in their consumption and preferences. The main objective was to determine the attitudes of Czech adult consumers towards DSs and FFs and to find out which ones are most commonly used and for what reasons.Design/methodology/approachThe data were collected from 1,049 respondents using a questionnaire survey. A Pearson Chi-squared test was used to determine the association between consumer preferences and selected socio-economic characteristics. A multiple correspondence analysis was used to compare relations among 13 categories of DSs and FFs and the socio-demographic variables.FindingsThe authors’ findings showed a high prevalence of awareness regarding the terms DSs and FFs (79%) and use (99%) of both these categories among the respondents. Data indicated that average consumption of FFs was slightly higher (56.7%) than that of DSs (48.6%). The most popular FFs were identified as dietary fibre, unsaturated fatty acids, followed by probiotics and prebiotics, whereas vitamins, minerals and herbal products were mentioned as the most preferred DSs. The most frequent reasons for consumption of both food products were stress relief, digestive care and immunity boosting.Originality/valueThe authors report for the first time on consumer attitudes to and preferences for the use of DSs and FFs. The findings can contribute to an understanding of general attitudes and preferences regarding both food categories in the EU population.
Are all innovation modes beneficial to firms’ innovation performance? New findings from an emerging market
Authors: Hu Shilei , Wang Xiaohong , Zhang Ben 
Published: May 2020

Purpose
This paper aims to examine the influence of individual and combined effects of the mode focused on scientific and technological-based innovation (STI) and the mode based on learning by doing, by using and by interacting (DUI) on firms’ innovation performance and whether information technology (IT) moderates the relation between different innovation modes and firms’ innovation performance.

Design/methodology/approach
A conceptual model linking innovation modes, IT (including IT infrastructure and the frequency of IT usage) and firms’ innovation performance was developed, and the proposed hypotheses were tested empirically using World Bank’s micro survey data collected from manufacturing firms in an emerging market (China).

Findings
The results show that individually both STI mode of innovation and DUI mode of innovation have a significant positive effect on firms’ innovative performance, whereas the combined STI and DUI mode of innovation has a negative impact. IT infrastructure moderates the relation between STI (or STI and DUI) mode of innovation and firms’ innovation performance, while the frequency of IT usage has no moderating effects on the relationship between any kind of innovation modes and firms’ innovation performance.

Research limitations/implications
Although some results are quite different from what is expected, these are insightful for both academics and policymakers. The use of cross-sectional data has its limitations. Therefore, future studies based on longitudinal data should be conducted. This study points toward the need to conduct the meta-analysis to better explain the existing inconsistencies in the findings of relevant quantitative studies.

Practical implications
This study provides firm managers with practical implications. The conclusions of this study imply that the impact of the combined STI and DUI mode of innovation is likely to be contextual, so firms should make contingent decisions on whether to engage in STI mode of innovation and DUI mode of innovation simultaneously according to their own organizational conditions. Moreover, face-to-face contacts are particularly important when a firm engages in DUI mode of innovation. In addition, the focus of IT strategy of firms engaged in STI mode of innovation should be on perfecting their IT infrastructure rather than increasing the frequency of IT usage.

Originality/value
This paper provides new evidence for the relation between business innovation modes and firms’ innovation performance, and it is one of the few empirical studies that focus on emerging markets. More importantly, this paper proposes a persuasive explanation framework for understanding the heterogeneous impacts of the combined STI and DUI mode of innovation on firms’ innovation performance. This is the first study that examines the moderating effect of IT on the relationship between business innovation modes and a firm’s innovation performance.
Parametric dependence of lightning impulse behavior of grounding electrodes buried in a dispersive and ionized lossy soil under first- and subsequent-stroke currents
Authors: Sajadi Seyed Sajad , Ostadzadeh Saeed Reza , Sadeghi Seyed Hossein Hesamedin 
Published: May 2020

Purpose
The purpose of this paper is to investigate the simultaneous effects of ionization and dispersion of soil on the impulse behavior of grounding electrodes under first and subsequent stroke currents.

Design/methodology/approach
A recently introduced technique called improved multi-conductor transmission line (MTL) is simplified for grounding electrodes buried in both-affected soils.

Findings
The simulation results show that including the two effects simultaneously in highly resistive soils under high-valued subsequent stroke current is recommended. Otherwise, simultaneous effects can be disregard.

Originality/value
To the best of the authors’ knowledge, there is no research on sensitivity analyses for the simultaneous inclusion of the two effects on the effective length and the induced voltage on the soil surface. To this end, the simplified MTL is applied to the grounding electrodes. The simulation results show that the computational efficiency in comparison with previous methods is, first, considerably increased. Second, the simultaneous effects result in decreasing the soil surface voltage with respect to situations where either ionization or dispersion is taken into account (single-affected soils). In other words, the performance of grounding systems is improved. Third, the effective length in both-affected soil is has a middle value with respect to the single-affected soil. Such findings practically and financially are of importance.