bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Osteoclast Differentiation and Activation by Leukotriene B4 Loaded in Microspheres
Authors: Lorencetti-Silva Francine , Manfrin Arnez Maya Fernanda , de Queiroz Thomé João Pedro , de Carvalho Fabrício Kitazono , Faccioli Lúcia Helena , Paula-Silva Francisco Wanderley Garcia 
Published: May 2020

AbstractAimLeukotriene B4(LTB4) is a labile inflammatory lipid mediator important for host defense. We hypothesised that sustained delivery of LTB4would be a therapeutic strategy to prevent osteoclast cell differentiation in bone resorption in inflammatory diseases. Therefore, the aim of this study was to investigate the role of LTB4in differentiation of monocytic lineage cells into osteoclasts after stimulation with LTB4loaded in microspheres (MS).DesignLTB4-MS were prepared using an oil-in-water emulsion solvent extraction-evaporation process. Sterility, LPS contamination, characterization and efficiency of LTB4encapsulation were investigated. J774A.1 cells were cultured in the presence of monocyte colony stimulating factor (M-CSF) and ligand for receptor activator of nuclear factor kappa B (RANKL) and then stimulated with LTB4-MS. Cytotoxicity was determined by lactate dehydrogenase assay, osteoclast formation by means of the activity of tartrate-resistant acid phosphatase enzyme and gene expression was measured by quantitative reverse transcription polymerase chain reaction to investigate regulation ofAlox5, Alox5ap, Acp5, Mmp9, CalcrandCtsk.ResultsWe found that 5-lipoxygenase pathway is involved in the osteoclastic differentiation hematopoietic lineage cells and that exogenous addition of LTB4-MS inhibited osteoclastogenesis induced by M-CSF and RANKL. The mechanism of LTB4-MS involved induction ofMmp9gene expression and inhibition ofCalcrandCtsk, without changingAcp5.ConclusionLTB4-MS inhibited differentiation of macrophages into an osteoclastic phenotype and cell activation under M-CSF and RANKL stimulus shedding light on a potential therapeutic strategy to prevent osteoclast differentiation.
A conserved amino acid in the C-terminus of HPV E7 mediates binding to PTPN14 and repression of epithelial differentiation
Authors: Hatterschide Joshua , Brantly Alexis C. , Grace Miranda , Munger Karl , White Elizabeth A. 
Published: May 2020

ABSTRACTThe human papillomavirus (HPV) E7 oncoprotein is a primary driver of HPV-mediated carcinogenesis. The E7 proteins from diverse HPV bind to the host cellular non-receptor protein tyrosine phosphatase type 14 (PTPN14) and direct it for degradation through the activity of the E7-associated host E3 ubiquitin ligase UBR4. Herein we show that a highly conserved arginine residue in the C-terminal domain of diverse HPV E7 mediates interaction with PTPN14. We found that disruption of PTPN14 binding through mutation of the C-terminal arginine did not impact the ability of several high-risk HPV E7 proteins to bind and degrade the retinoblastoma tumor suppressor or activate E2F target gene expression. HPVs infect human keratinocytes and we previously reported that both PTPN14 degradation by HPV16 E7 and PTPN14 CRISPR knockout repress keratinocyte differentiation-related genes. Now we have found that blocking PTPN14 binding through mutation of the conserved C-terminal arginine rendered both HPV16 and HPV18 E7 unable to repress differentiation-related gene expression. We then confirmed that the HPV18 E7 variant that could not bind PTPN14 was also impaired in repressing differentiation when expressed from the complete HPV18 genome. Finally, we found that the ability of HPV18 E7 to extend the lifespan of primary human keratinocytes required PTPN14 binding. CRISPR/Cas9 knockout of PTPN14 rescued keratinocyte lifespan extension in the presence of the PTPN14 binding-deficient HPV18 E7 variant. These results support the model that PTPN14 degradation by high-risk HPV E7 leads to repression of differentiation and contributes to its carcinogenic activity.IMPORTANCEHuman papillomavirus (HPV)-positive carcinomas account for nearly 5% of the global human cancer burden. The E7 oncoprotein is a primary driver of HPV-mediated carcinogenesis. HPV E7 binds and degrades the putative tumor suppressor, PTPN14. However, the impact of PTPN14 binding by E7 on cellular processes is not well defined. Here, we show that PTPN14 binding is mediated by a conserved C-terminal arginine residue of HPV E7in vivo. Additionally, we found that PTPN14 binding contributes to the carcinogenic activity of HPV18 E7 (the second most abundant HPV type in cancers). Finally, we determined that PTPN14 binding by HPV16 E7 and HPV18 E7 represses keratinocyte differentiation. HPV-positive cancers are frequently poorly differentiated and the HPV life cycle is dependent upon the keratinocyte differentiation program. The finding that PTPN14 binding by HPV E7 impairs differentiation has significant implications for both HPV-mediated carcinogenesis and the HPV life cycle.
Association of country-wide coronavirus mortality with demographics, testing, lockdowns, and public wearing of masks (Update August 4, 2020)
Authors: Leffler Christopher T. , Ing Edsel , Lykins Joseph D. , Hogan Matthew C. , McKeown Craig A. , Grzybowski Andrzej 
Published: May 2020

AbstractPurposeTo determine sources of variation between countries in per-capita mortality from COVID-19 (caused by the SARS-CoV-2 virus).MethodsPotential predictors of per-capita coronavirus-related mortality in 200 countries by May 9, 2020 were examined, including age, sex, obesity prevalence, temperature, urbanization, smoking, duration of infection, lockdowns, viral testing, contact tracing policies, and public mask-wearing norms and policies. Multivariable linear regression analysis was performed.ResultsIn univariate analyses, the prevalence of smoking, per-capita gross domestic product, urbanization, and colder average country temperature were positively associated with coronavirus-related mortality. In a multivariable analysis of 196 countries, the duration of infection in the country, and the proportion of the population 60 years of age or older were positively associated with per-capita mortality, while duration of mask-wearing by the public was negatively associated with mortality (all p<0.001). International travel restrictions and a lower prevalence of obesity were independently associated with mortality in a model which controlled for testing policy. Internal lockdown requirements and viral testing policies and levels were not associated with mortality. The association of contact tracing policy with mortality approached statistical significance (p=0.06). In countries with cultural norms or government policies supporting public mask-wearing, per-capita coronavirus mortality increased on average by just 15.8% each week, as compared with 62.1% each week in remaining countries.ConclusionsSocietal norms and government policies supporting the wearing of masks by the public, as well as international travel controls, are independently associated with lower per-capita mortality from COVID-19.
Importations of COVID-19 into African countries and risk of onward spread
Authors: Sun Haoyang , Dickens Borame L , Cook Alex R , Clapham Hannah E 
Published: May 2020

AbstractBackgroundThe emergence of a novel coronavirus (SARS-CoV-2) in Wuhan, China, at the end of 2019 has caused widespread transmission around the world. As new epicentres in Europe and America have arisen, of particular concern is the increased number of imported coronavirus disease 2019 (COVID-19) cases in Africa, where the impact of the pandemic could be more severe. We aim to estimate the number of COVID-19 cases imported from 12 major epicentres in Europe and America to each African country, as well as the probability of reaching 10,000 infections in total by the end of March, April, and May following viral introduction.MethodsWe used the reported number of cases imported from the 12 major epicentres in Europe and America to Singapore, as well as flight data, to estimate the number of imported cases in each African country. Under the assumption that Singapore has detected all the imported cases, the estimates for Africa were thus conservative. We then propagated the uncertainty in the imported case count estimates to simulate the onward spread of the virus, until 10,000 infections are reached or the end of May, whichever is earlier. Specifically, 1,000 simulations were run separately under two scenarios, where the reproduction number under the stay-at-home order was assumed to be 1.5 and 1.0 respectively.FindingsWe estimated Morocco, Algeria, South Africa, Egypt, Tunisia, and Nigeria as having the largest number of COVID-19 cases imported from the 12 major epicentres. Based on our 1,000 simulation runs, Morocco and Algeria’s estimated probability of reaching 10,000 infections by end of March was close to 100% under both scenarios. In particular, we identified countries with less than 100 cases in total reported by end of April whilst the estimated probability of reaching 10,000 infections by then was higher than 50% even under the more optimistic scenario.ConclusionOur study highlights particular countries that are likely to reach (or have reached) 10,000 infections far earlier than the reported data suggest, calling for the prioritization of resources to mitigate the further spread of the epidemic.
Outcomes from COVID-19 across the range of frailty: excess mortality in fitter older people
Authors: Miles Amy , Webb Thomas E , Mcloughlin Benjamin C , Mannan Imran , Rather Arshad , Knopp Paul , Davis Daniel 
Published: May 2020

AbstractPurposeOur aim was to quantify the mortality from COVID-19 and identify any interactions with frailty and other demographic factors.MethodsHospitalised patients aged ≥70 were included, comparing COVID-19 cases with non-COVID-19 controls admitted over the same period. Frailty was prospectively measured and mortality ascertained through linkage with national and local statutory reports.ResultsIn 217 COVID-19 cases and 160 controls, older age and South Asian ethnicity, though not socioeconomic position, were associated with higher mortality. For frailty, differences in effect size were evident between cases (HR 1.02, 95%CI 0.93-1.12) and controls (HR 1.99, 95%CI 1.46-2.72), with an interaction term (HR 0.51, 95%CI 0.37-0.71) in multivariable models.ConclusionsOur findings suggest that (i) frailty is not a good discriminator of prognosis in COVID-19 and (ii) pathways to mortality may differ in fitter compared with frailer older patients.Key summary pointsAimTo describe associations between frailty, ethnicity, socioeconomic position and mortality in a cohort of older patients presenting to hospital with COVID-19.
Effects of Age and Knee Osteoarthritis on the Modular Control of Walking: A Pilot Study
Authors: Roelker Sarah A. , Koehn Rebekah R. , Caruthers Elena J. , Schmitt Laura C. , Chaudhari Ajit M.W. , Siston Robert A. 
Published: May 2020

ABSTRACTOlder adults and individuals with knee osteoarthritis (KOA) often exhibit reduced locomotor function and altered muscle activity. Identifying age- and KOA-related changes to the modular control of gait may provide insight into the neurological mechanisms underlying reduced walking performance in these populations. The purpose of this pilot study was to determine if the modular control of walking differs between younger and older adults without KOA and adults with end-stage KOA. Kinematic, kinetic, and electromyography data were collected from ten younger (23.5 ± 3.1 years) and ten older (63.5 ± 3.4 years) adults without KOA and ten adults with KOA (64.0 ± 4.0 years) walking at their self-selected speed. Separate non-negative matrix factorizations of 500 bootstrapped samples determined the number of modules required to reconstruct each participant’s electromyography. The number of modules required in the younger adults (3.2 ± 0.4) was greater than in the individuals with KOA (2.3 ± 0.7;p= 0.002), though neither cohorts’ required number of modules differed significantly from the unimpaired older adults (2.7 ± 0.5;p≥ 0.113). A significant association between module number and walking speed was observed (r= 0.532;p= 0.003) and individuals with KOA walked significantly slower (0.095 ± 0.21 m/s) than younger adults (1.24 ± 0.15 m/s;p= 0.005). Individuals with KOA also exhibited altered module activation patterns and composition (which muscles are associated with each module) compared to unimpaired adults. These findings suggest aging alone may not significantly alter modular control; however, the combined effects of knee osteoarthritis and aging may together impair the modular control of gait.
Predictors of misconceptions, knowledge, attitudes, and practices of COVID-19 pandemic among a sample of Saudi population and its impact: a cross-sectional study
Authors: Baig Mukhtiar , Jameel Tahir , Alzahrani Sami H , Mirza Ahmad A , Gazzaz Zohair J , Ahmad Tauseef , Baig Fizzah , Almurashi Saleh H 
Published: May 2020

ABSTRACTObjectivesTo explore the predictors of misconceptions, knowledge, attitudes, and practices of the COVID-19 pandemic among a sample of the Saudi population and its impact.DesignAn online cross-sectional study.SettingJeddah, Saudi Arabia.ParticipantsA total of 2006 participants [953(47.5%) females, and 1053(52.5%) males], and more than 18 years of age were included in the study.Data collection and analysisThis cross-sectional survey was conducted at the Faculty of Medicine, Rabigh, King Abdulaziz University (KAU). The participants were approached by social media (SM). An online questionnaire was administered, and the data were analyzed on SPSS-26.ResultsThe SM was the leading source of information 889(43.9%). Two-thirds of the participants, 1250(66.9%) had various misconceptions, and about one-third of the study participants 637(31.7%) had disturbed social, mental, and psychological wellbeing, and many participants became more religious. Two-thirds of the study participants, 1292(68.1%) had good knowledge score. The attitude was highly positive in 1867(93.1%) participants’, and the practice score was adequate in 1939(97.7%). The participants’ educational status was the predictor of good knowledge. Male gender and divorced ones were the predictor of poor practice scores and age 51-60 years, private jobholders, and students were the predictors of the good practice scores. The Saudi nationality was the predictor of participants’ positive attitude, while the male gender and divorced ones were predictors of a negative attitude. The male gender and higher education status were the predictors of good concepts, while the older age and job (own business) were the predictors of misconceptions.ConclusionOur study observed several predictors of misconceptions, knowledge, attitudes, and practices among the Saudi population. Our participants had a good realization of the impact of this pandemic.Strengths and limitationsOurs is the first study involving the general population of Saudi Arabia at a time when COVID-19 has tremendously affected the society.The use of a validated questionnaire has strengthened the study results.The sample size is adequate and representing different segments of society.One of the limitations is the convenience sampling method.Besides, the study used an online questionnaire, so we could not reach the section of society that is not using the internet.
Winner-Takes-All Resource Competition Redirects Cascading Cell Fate Transitions
Authors: Zhang Rong , Goetz Hanah , Melendez-Alvarez Juan , Li Jiao , Ding Tian , Wang Xiao , Tian Xiao-Jun 
Published: May 2020

AbstractFailure of modularity remains a significant challenge for synthetic gene circuits assembled with tested modules as they often do not function as expected. Competition over shared limited gene expression resources is a crucial underlying reason. Here, we first built a synthetic cascading bistable switches (Syn-CBS) circuit in a single strain with two coupled self-activation modules to achieve two successive cell fate transitions. Interestingly, we found that thein vivotransition path was redirected as the activation of one switch always prevailed against the other instead of the theoretically expected coactivation. This qualitatively different type of resource competition between the two modules follows a ‘winner-takes-all’ rule, where the winner is determined by the relative connection strength between the modules. To decouple the resource competition, we constructed a two-strain circuit, which achieved successive activation and stable coactivation of the two switches. We unveiled a nonlinear resource competition within synthetic gene circuits and provided a division of labor strategy to minimize unfavorable effects.
COVIDep platform for real-time reporting of vaccine target recommendations for SARS-CoV-2: Description and connections with COVID-19 immune responses and preclinical vaccine trials
Authors: Ahmed Syed Faraz , Quadeer Ahmed A. , McKay Matthew R. 
Published: May 2020

AbstractWe introduce COVIDep (https://COVIDep.ust.hk), a web-based platform that provides immune target recommendations for guiding SARS-CoV-2 vaccine development. COVIDep implements a protocol that pools together publicly-available genetic data for SARS-CoV-2 and epitope data for SARS-CoV to identify B cell and T cell epitopes that present potential immune targets for SARS-CoV-2. Correspondences between outputs of COVIDep and immune responses recorded in COVID-19 patients and preclinical vaccine trials are also indicated. The platform is user-friendly, flexible, and based on up-to-date data. It may help guide vaccine designs and associated experimental studies for SARS-CoV-2.
Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice
Authors: Menendez-Montes Ivan , Escobar Beatriz , Gomez Manuel J. , Albendea-Gomez Teresa , Palacios Beatriz , Bonzon Elena , Alonso Ana Vanessa , Ferrarini Alessia , Jimenez-Borreguero Luis Jesus , Vázquez Jesus , Martin-Puig Silvia 
Published: May 2020

ABSTRACTHypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1α elimination in cardiac tissue. Here, we used a new conditional knock out ofHif1ain NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1α loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2α and ATF4 by E12.5.Hif1amutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.
The TFIID subunit Taf4 is required for pancreatic beta cell function and identity
Authors: Kleiber Thomas , Davidson Guillaume , Mengus Gabrielle , Martianov Igor , Davidson Irwin 
Published: May 2020

AbstractWe selectively inactivated the Taf4 subunit of general transcription factor TFIID in adult murine pancreatic beta cells (BCs). Taf4 inactivation rapidly diminishes expression of critical genes involved in BC function leading to increased glycaemia, lowered plasma insulin levels, defective glucose-stimulated insulin secretion and in the longer term reduced BC mass through apoptosis of a subpopulation of BCs. Nevertheless, glycaemia and blood insulin levels are stabilised after 11 weeks with mutant animals showing long term survival. Bulk RNA-seq and ATAC-seq together with single cell RNA-seq on isolated Langerhans islets show that Taf4 loss leads to a remodelling of chromatin accessibility and gene expression not only in targeted BCs, but also alpha and delta cells. One week after Taf4-loss, cells with mixed BC, alpha and/or delta cell identities were observed as well as a BC population trans-differentiating into alpha-like cells. Computational analysis defines how known critical BC and alpha cell determinants may act in combination with additional transcription factors and the NuRF chromatin remodelling complex to promote BC trans-differentiation.
Common genetic variation influencing human white matter microstructure
Authors: Zhao Bingxin , Li Tengfei , Yang Yue , Wang Xifeng , Luo Tianyou , Shan Yue , Zhu Ziliang , Xiong Di , Hauberg Mads E. , Bendl Jaroslav , Fullard John F. , Roussos Panagiotis , Li Yun , Stein Jason L. , Zhu Hongtu 
Published: May 2020

AbstractBrain regions communicate with each other via tracts of myelinated axons, commonly referred to as white matter. White matter microstructure can be measured in the living human brain using diffusion based magnetic resonance imaging (dMRI), and has been found to be altered in patients with neuropsychiatric disorders. Although under strong genetic control, few genetic variants influencing white matter microstructure have ever been identified. Here we identified common genetic variants influencing white matter microstructure using dMRI in 42,919 individuals (35,741 in the UK Biobank). The dMRIs were summarized into 215 white matter microstructure traits, including 105 measures from tract-specific functional principal component analysis. Genome-wide association analysis identified many novel white matter microstructure associated loci (P< 2.3 × 10−10). We identified shared genetic influences through genetic correlations between white matter tracts and 62 other complex traits, including stroke, neuropsychiatric disorders (e.g., ADHD, bipolar disorder, major depressive disorder, schizophrenia), cognition, neuroticism, chronotype, as well as non-brain traits. Common variants associated with white matter microstructure alter the function of regulatory elements in glial cells, particularly oligodendrocytes. White matter associated genes were enriched in pathways involved in brain disease pathogenesis, neurodevelopment process, and repair of white matter damage (P< 1.5 × 10−8). In summary, this large-scale tract-specific study provides a big step forward in understanding the genetic architecture of white matter and its genetic links to a wide spectrum of clinical outcomes.
A viral genome packaging motor transitions between cyclic and helical symmetry to translocate dsDNA
Authors: Woodson Michael , Pajak Joshua , Zhao Wei , Zhang Wei , Arya Gaurav , White Mark A. , Jardine Paul. J. , Morais Marc C. 
Published: May 2020

SUMMARYMolecular segregation and biopolymer manipulation require the action of molecular motors to do work by applying directional forces to macromolecules. The additional strand conserved E (ASCE) ring motors are an ancient family of molecular motors responsible for diverse tasks ranging from biological polymer manipulation (e.g. protein degradation and chromosome segregation) to establishing and maintaining proton gradients across mitochondrial membranes. Viruses also utilize ASCE segregation motors to package their genomes into their protein capsids and serve as accessible experimental systems due to their relative simplicity. We show by CryoEM focused image reconstruction that ASCE ATPases in viral dsDNA packaging motors adopt helical symmetry complementary to their dsDNA substrates. Together with previous data, including structural results showing these ATPases in planar ring conformations, our results suggest that these motors cycle between helical and planar cyclical symmetry, providing a possible mechanism for directional translocation of DNA. We further note that similar changes in quaternary structure have been observed for proteasome and helicase motors, suggesting an ancient and common mechanism of force generation that has been adapted for specific tasks over the course of evolution.