bluuebunny/crossref_metadata_2025_split huggingface dataset:
DeepsmirUD: Precise prediction of regulatory effects on miRNA expression mediated by small molecular compounds using competing deep learning frameworks
Authors: Sun Jianfeng , Ru Jinlong , Chen Zihao , Qi Fei , Ramos-Mucci Lorenzo , Chen Suyuan , Cribbs Adam P. , Deng Li , Wang Xia 
Published: July 2022

AbstractAberrant miRNA expression has pervasively been found to relate to a growing number of human diseases. Therefore, targeting miRNAs to regulate their expression levels has become an important therapy against diseases that stem from the dysfunction of oncogenic pathways regulated by the miRNAs. In recent years, small molecule compounds have demonstrated enormous potential as drugs to regulate miRNA expression (i.e., SM-miR). A clear understanding of the mechanism of action of small molecules on down- and up-regulating miRNA expression allows precise diagnosis and treatment of oncogenic pathways. However, outside of a slow and costly process of experimental determination, computational strategies to assist this in an ad hoc manner have still not been enabled. In this work, we develop, to the best of our knowledge, the first prediction tool, DeepsmirUD, to infer small molecule-mediated regulatory effects on miRNA expression. This method is powered by an ensemble of 12 cutting-edged deep learning frameworks and achieves state-of-the-art performance with AUC values of 0.840/0.969 and AUCPR values of 0.866/0.983 on two independent test datasets. With a complementarily constructed network inference approach based on similarity, we report a significantly improved accuracy of 0.813 in determining regulatory effects of nearly 650 SM-miR relations formed with either novel small molecules or novel miRNAs. By further integrating miRNA-cancer relations, we established a database of potentially pharmaceutical drugs to aid in understanding the drug mechanisms of action in diseases and to offer novel insight into drug repositioning. Taken together, our method shows great promise to assist and accelerate the therapeutic development of potential miRNA targets and small molecule drugs. Furthermore, we have employed DeepsmirUD to predict regulatory effects of a large number of high-confidence SM-miR relations curated from Psmir, which are publicly available through https://github.com/2003100127/deepsmirud and https://rujinlong.github.io/deepsmirud/ alongside the DeepsmirUD standalone package.
Arabidopsis FIBRILLIN6 regulates carotenoid biosynthesis by directly promoting phytoene synthase activity
Authors: Iglesias-Sanchez Ariadna , Morelli Luca , Rodriguez-Concepcion Manuel 
Published: July 2022

AbstractCarotenoids are health-promoting plastidial isoprenoids with essential functions in plants as photoprotectants and photosynthetic pigments in chloroplasts. They also accumulate in specialized plastids named chromoplasts, providing color to non-photosynthetic tissues such as flower petals and ripe fruit. Carotenoid accumulation in chromoplast requires specialized structures and proteins such as fibrillins. Although fibrillins were first reported as structural components of carotenoid sequestering structures in chromoplasts, later work revealed roles in chloroplasts and other plastid types. However, the association of fibrillins with carotenoids in plastids other than chromoplasts has remained unexplored. Here we show that a member of the fibrillin family, FBN6, interacts with phytoene synthase (PSY, the first committed and rate-determining step of the carotenoid pathway) to promote its enzymatic activity. Transient overexpression of FBN6 in Nicotiana benthamiana leaves results in a higher production of phytoene, the product of PSY activity, whereas loss of FBN6 activity in Arabidopsis thaliana mutants dramatically reduces the production of carotenoids during seedling deetiolation and after exposure to high light. Our work hence demonstrates that fibrillins not only promote the accumulation of carotenoids but also their biosynthesis.
Endothelial NCK2 Promotes Atherosclerosis Progression in Male but not Female Nck1-null Atheroprone Mice
Authors: Bywaters Briana C. , Pedraza Gladys , Trache Andreea , Rivera Gonzalo M. 
Published: July 2022

AbstractA better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, has been implicated in cardiovascular development and postnatal angiogenesis but its role in vascular disease remains incompletely understood. Here, we report stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development. Male and female Nck1-null atheroprone mice enabling inducible, endothelial-specific Nck2 inactivation were fed a high fat diet (HFD) for 8 or 16 weeks to model atherosclerosis initiation and progression, respectively. Analysis of aorta preparations en face during disease progression, but not initiation, showed a significant reduction in plaque burden in males, but not females, lacking endothelial NCK2 relative to controls. Markers of vascular inflammation were reduced by endothelial NCK2 deficiency in both males and females during atherosclerosis progression but not initiation. At advanced stages of disease, plaque size and severity of atherosclerotic lesions were reduced by abrogation of endothelial NCK2 signaling only in males. Collectively, our results demonstrate stage- and sex-dependent modulation of atherosclerosis development by endothelial NCK2 signaling.
Protein structure prediction in the era of AI: challenges and limitations when applying toin-silicoforce spectroscopy
Authors: Gomes Priscila S. F. C. , Gomes Diego E. B. , Bernardi Rafael C. 
Published: July 2022

AbstractMechanoactive proteins are essential for a myriad of physiological and pathological processes. Guided by the advances in single-molecule force spectroscopy (SMFS), we have reached a molecular-level understanding of how several mechanoactive proteins respond to mechanical forces. However, even SMFS has its limitations, including the lack of detailed structural information during force-loading experiments. That is where molecular dynamics (MD) methods shine, bringing atomistic details with femtosecond time-resolution. However, MD heavily relies on the availability of high-resolution structures, which is not available for most proteins. For instance, the Protein Data Bank currently has 192K structures deposited, against 231M protein sequences available on Uniprot. But many are betting that this gap might become much smaller soon. Over the past year, the AI-based AlphaFold created a buzz on the structural biology field by being able to, for the first time, predict near-native protein folds from their sequences. For some, AlphaFold is causing the merge of structural biology with bioinformatics. In this perspective, using anin silicoSMFS approach, we investigate how reliable AlphaFold structure predictions are to investigate mechanical properties of staph bacteria adhesins proteins. Our results show that AlphaFold produce extremally reliable protein folds, but in many cases is unable to predict high-resolution protein complexes accurately. Nonetheless, the results show that AlphaFold can revolutionize the investigation of these proteins, particularly by allowing high-throughput scanning of protein structures. Meanwhile, we show that the AlphaFold results need to be validated and should not be employed blindly, with the risk of obtaining an erroneous protein mechanism.
Riboflavin Depletion Promotes Longevity and Metabolic Hormesis in Caenorhabditis elegans
Authors: Yerevanian Armen , Murphy Luke , Emans Sinclair , Zhou Yifei , Ahsan Fasih , Baker Daniel , Li Sainan , Adedoja Adebanjo , Cedillo Lucydalila , Gnanatheepam Einstein , Dao Khoi , Jain Mohit , Georgakoudi Irene , Soukas Alexander 
Published: July 2022

SummaryRiboflavin is an essential cofactor in many enzymatic processes and in the production of flavin adenine dinucleotide (FAD). Here we report that the partial depletion of riboflavin through knockdown of the C. elegans riboflavin transporter 1 (rft-1) promotes metabolic health by reducing intracellular flavin concentrations. Knockdown of rft-1 significantly increases lifespan in a manner dependent on FOXO/daf-16, AMP-activated protein kinase (AMPK)/aak-2, the mitochondrial unfolded protein response, and mTOR complex 2 (mTORC2). Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin depleted animals also exhibit activation of caloric restriction reporters without a reduction in TORC1 signaling. Our findings indicate that riboflavin depletion activates an integrated, hormetic response that promotes lifespan and healthspan in C. elegans.
Predicting protease networks through human genetics
Authors: Iwamoto Kazunari , Eriksson Tore 
Published: July 2022

AbstractBy utilizing functional genetic variation within the participants of the UK Biobank project for a largescale PheWAS study we attempted to get a better understanding of how the set of human proteases and their endogenous inhibitors are involved in common diseases. Focusing on known human proteases, their inhibitors, and known substrates, we computed their ranked-biased similarity from phenome-wide association results. Putative regulatory networks were constructed from 250 high-scoring pairs of proteases and related genes. This analysis suggested thirteen network modules, five diagnosis-based and eight biomarker-based. Through genetic associations and published literature on module members, the modules could be classified into different disease modalities including cholesterol homeostasis and high blood pressure.
Senescent cell-derived extracellular vesicles inhibit cancer recurrence by coordinating immune surveillance
Authors: Ziglari Tahereh , Calistri Nicholas L. , Finan Jennifer M. , Derrick Daniel , Nakayasu Ernesto S. , Burnet Meagan C. , Kyle Jennifer E. , Hoare Matthew , Heiser Laura M. , Pucci Ferdinando 
Published: July 2022

AbstractExtracellular vesicles (EVs) are key signaling mediators. To explore the role of senescent cell-derived extracellular vesicles (senEVs) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. Our results demonstrate that senEVs are both necessary and sufficient to trigger immune-mediated clearance of senescent cells, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II+ antigen-presenting cells to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of senescent cell signaling from antigen-presenting cells to neutrophils.Through comprehensive transcriptional and proteomic analyses, we identified six ligands specific to senEVs, highlighting their role in promoting antigen-presenting cell–T cell adhesion and synapse formation. Antigen-presenting cells activated CCR2+CD4+ TH17cells, which appeared to inhibit B cell activation. CD4 T cells were essential for preventing tumor recurrence, indicating that CCR2+ TH17cells function downstream of senEVs during senescence surveillance.Our findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thereby enhancing the efficient clearance of senescent cells. These conclusions may have implications not only for tumor recurrence but also for understanding senescence during de novo carcinogenesis. Consequently, this work could inform the development of novel cancer early detection strategies based on the biology of cellular senescence.
A review of socioeconomic inequalities in HIV infections among women in Low and Middle-income countries
Authors: Adegbosin Adeoluwa P , Adegbosin Adeyinka E 
Published: July 2022

AbstractBackgroundEvidence shows that HIV is more prevalent among women in low and middle-income countries, this disparity is partly due to biological and socioeconomic factors. In this study we synthesised evidence on the relationship between socioeconomic factors and HIV prevalence among women.MethodWe searched PubMed, Cochrane, Scopus, and Embase, for articles published between 2010 and 2020 that investigated the relationship between socioeconomic factors and HIV prevalence among women in low and middle-income countries. We analysed and reported our findings based on the PRISMA guidelines.FindingsA total of 14 studies were included in the final analysis. Six studies explored the effect of disparity in level of education on the prevalence of HIV among women. The effect of income disparity was explored in eight studies, while two studies each explored the effects of occupation and employment status. Overall, evidence shows that women with low socioeconomic status were more at risk of HIV infection.InterpretationTargeted Interventions aimed at improving the socioeconomic status of women in low and middle-income countries will play a significant role in reducing the prevalence of HIV infection in these settings.
A Measurement Invariance Analysis of Selected Opioid Overdose Knowledge Scale (OOKS) Items among Bystanders and First Responders
Authors: Swartz James A. , Lin Qiao , Kim Yerim 
Published: July 2022

AbstractThe Opioid Overdose Knowledge Scale (OOKS) is widely used as an adjunct to opioid education and naloxone distribution (OEND) for assessing pre- and post-training knowledge. However, the extent to which the OOKS performs comparably for bystander and first responder groups has not been well determined. We used exploratory structural equation modeling (ESEM) to assess the measurement invariance of an OOKS item subset when used as an OEND training pre-test. We used secondary analysis of pre-test data collected from 446 first responders and 1,349 bystanders (N=1,795) attending OEND trainings conducted by two county public health departments. Twenty-four items were selected by practitioner/trainer consensus from the original 45-item OOKS instrument with an additional 2 removed owing to low response variation. We used exploratory factor analysis (EFA) followed by ESEM to identify a factor structure, which we assessed for configural, metric, and scalar measurement invariance by participant group using the 22 dichotomous items (correct/incorrect) as factor indicators. EFA identified a 3-factor model consisting of items dealing with: basic overdose risk information, signs of an overdose, and rescue procedures/advanced overdose risk information.Model fit by ESEM estimation versus confirmatory factor analysis showed the ESEM model afforded a better fit. Measurement invariance analyses indicated the 3-factor model fit the data across all levels of invariance per standard fit statistic metrics. The reduced set of 22 OOKS items appears to offer comparable measurement of pre-training knowledge on opioid overdose risks, signs of an overdose, and rescue procedures for both bystanders and first responders.
Using the sanitation safety planning tool to improve the occupational health and safety of de-sludging operators in Uganda: a protocol for a controlled before and after study
Authors: Ssekamatte Tonny , Nalugya Aisha , Fuhrimann Samuel , Mugambe Richard K. , Kansiime Winnifred K. , Tigaiza Arnold , Nakalembe Doreen , Moodley Nishai , Nuwagaba Fred , Kimbugwe Ceaser , Mselle Jane Sembuche , Tamale Bridget Nagawa , Halage Abdullah Ali , Isunju John Bosco 
Published: July 2022

AbstractBackgroundDe-sludging operators play a critical role in ensuring access to safe sanitation services. De-sludging activities, however, increase the operators’ risk of exposure to physical, chemical, ergonomic, psychological, and biological hazards, which eventually affect their health-related quality of life (HRQoL). Despite immense exposure to occupational hazards, only a few evidence-based interventions have been implemented to improve the occupational health and safety (OHS) of de-sludging operators.ObjectiveThe proposed study intends to utilise the sanitation safety planning (SSP) tool to improve the OHS of de-sludging operators in Uganda. The study aims to generate evidence of the prevalence of exposure to occupational hazards and the associated health outcomes, knowledge, attitude and uptake of OHS measures, as well as the HRQoL of de-sludging operators. The facilitators and barriers to the promotion of OHS shall also be explored.MethodsA mixed-methods study will be conducted among 356 desludging operators in the Greater Kampala Metropolitan Area. A structured questionnaire pre-loaded on the KoboCollect mobile data collection application will be used to obtain information on socio-demographic characteristics, history of work-related accidents and diseases, uptake of safety measures, and health-related quality of life. A total of 10 focus group discussions (FGDs) will be conducted among desludging operators, to understand how they cope with associated occupational hazards. In addition, 25 in-depth interviews (IDIs) will be conducted among purposively selected employers to understand the barriers and facilitators of provision and implementation of safety measures among desludging operators. Quantitative data will be analyzed using STATA version 15 while qualitative data will be transcribed verbatim and the analysis aided by the NVIVO software.Expected outcomesThe study will generate evidence of the occupational health and safety of desludging operators and the effectiveness of the SSP tool. These findings will be critical in informing the design and implementation of occupational health and safety programmes among desludging operators.
A multimodal neuroimaging study of brain abnormalities and clinical correlates in post treatment Lyme disease
Authors: Marvel Cherie L. , Alm Kylie H. , Bhattacharya Deeya , Rebman Alison W. , Bakker Arnold , Morgan Owen P. , Creighton Jason A. , Kozero Erica A. , Venkatesan Arun , Nadkarni Prianca A. , Aucott John N. 
Published: July 2022

AbstractLyme disease is the most common vector-borne infectious disease in the United States. Post-treatment Lyme disease (PTLD) is a condition affecting 10-20% of patients in which symptoms persist despite antibiotic treatment. Cognitive complaints are common among those with PTLD, suggesting that brain changes are associated with the course of the illness. However, there has been a paucity of evidence to explain the cognitive difficulties expressed by patients with PTLD.This study administered a working memory task to a carefully screened group of 12 patients with well-characterized PTLD and 18 healthy controls while undergoing functional MRI (fMRI). A subset of 12 controls and all 12 PTLD participants also received diffusion tensor imaging (DTI) to measure white matter integrity. Clinical variables were also assessed and correlated with these multimodal MRI findings.On the working memory task, the patients with PTLD responded more slowly, but no less accurately, than did controls. FMRI activations were observed in expected regions by the controls, and to a lesser extent, by the PTLD participants. The PTLD group also hypoactivated several regions relevant to the task. Conversely, novel regions were activated by the PTLD group that were not observed in controls, suggesting a compensatory mechanism. Notably, three activations were located in white matter of the frontal lobe. DTI measures applied to these three regions of interest revealed that higher axial diffusivity correlated with fewer cognitive and neurological symptoms. Whole-brain DTI analyses revealed several frontal lobe regions in which higher axial diffusivity in the patients with PTLD correlated with longer duration of illness. Together, these results show that the brain is altered by PTLD, involving changes to white matter within the frontal lobe. Higher axial diffusivity may reflect white matter repair and healing over time, rather than pathology, and cognition appears to be dynamically affected throughout this repair process.
The impact of residency training in family medicine on hospital admissions due to Ambulatory-care Sensitive Conditions in Rio de Janeiro
Authors: Jantsch Adelson Guaraci , Burström Bo , Nilsson Gunnar , de Leon Antônio Ponce 
Published: July 2022

ABSTRACTBACKGROUNDLack of skilled human resources in primary care remains a major concern for policymakers in low- and middle-income countries. There is little evidence supporting the impact of residency training in family medicine in the quality of care, and it perpetuates misconceptions among policymakers that the provision of primary care can be easily done by any physician without special training.METHODSThis article compares the risk of patients being hospitalized due to Ambulatory care sensitive conditions and the odds of having follow-up visits in primary care after hospital discharge, according to the type of their medical provider: (1) Generalists (reference), (2) Family physicians; and, (3) patients with no consultations prior to the event. Multilevel multivariate binomial regression models estimated the relative risks of a patient being hospitalized in a given month and the relative risks for the occurrence of a follow-up visit in primary care in a retrospective cohort of 636.640 patients between January 2013 and July 2018 in Rio de Janeiro.FINDINGSFor all 14 conditions, there was a higher risk of hospitalization when patients had no consultation in primary care prior to the event. Except for Ear, Nose and Throat infections, patients seen by family physicians had a lower risk of being hospitalized, compared to patients seen by Generalists. Follow-up visits were more likely to happen among patients treated by family physicians for almost every condition analyzed.CONCLUSIONWith two years of training in family medicine, Family physicians can reduce the risk of their patients being hospitalized and increase the likelihood of those patients having a follow-up consultation in primary care. Investments in residency training in family medicine should be made to fix the shortage of skilled physicians in primary care, reduce hospitalizations and improve quality and continuity of care.