bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does capacity to elevate androgens underlie variation in female ornamentation and territoriality in White-shouldered Fairywren (Malurus alboscapulatus)?
Authors: Boersma Jordan , Enbody Erik D. , Ketaloya Serena , Watts Heather E. , Karubian Jordan , Schwabl Hubert 
Published: February 2023

AbstractHistoric bias toward study of male sex hormones and sexual signals currently constrains our perspective of hormone—behavior—phenotype relationships. Resolving how ornamented female phenotypes evolve is particularly important for understanding the diversity of social signals across taxa. Studies of both males and females in taxa with variable female phenotypes are needed to establish whether sexes share mechanisms underlying expression of signaling phenotypes and behavior. White-shouldered Fairywren (Malurus alboscapulatus) subspecies vary in female ornamentation, baseline circulating androgens, and response to territorial intrusion. Themoretoniornamented female subspecies show higher female, but lower male androgens, and a stronger pair territorial response relative to pairs from thelorentziunornamented female subspecies. Here we address whether subspecific differences in female ornamentation, baseline androgens, and pair territoriality are associated with ability to elevate androgens following gonadotropin releasing hormone (GnRH) challenge and in response to simulated territorial intrusion. We find that subspecies do not differ in their capacity to circulate androgens in either sex following GnRH or territorial intrusion challenges. Whereas pre-GnRH androgens were somewhat predictive of degree of response to territorial intrusions, higher androgens were associated with lower territorial aggression. Post-GnRH androgens were not predictive of response to simulated intruders, nor did females sampled during intrusion elevate androgens relative to flushed controls, suggesting that increased androgens are not necessary for the expression of territorial defense behaviors. Collectively, our results suggest that capacity to produce and circulate androgens does not underlie subspecific patterns of female ornamentation, territoriality, and baseline androgens.
Prospectively predicting BPaMZ Phase IIb outcomes using a translational preclinical mouse to human platform
Authors: Wang Qianwen , Goh Janice JN , Zhang Nan , Nuermberger Eric , Savic Rada 
Published: February 2023

AbstractDespite known treatments, tuberculosis (TB) remains the world’s top infectious killer, highlighting the pressing need for new drug regimens. To prioritize the most efficacious drugs for clinical testing, we previously developed a PK-PD translational platform with bacterial dynamics that reliably predicted short-term monotherapy outcomes in Phase IIa trials from preclinical mouse studies. In this study, we extended our platform to include PK-PD models that account for drug-drug interactions in combination regimens and bacterial regrowth in our bacterial dynamics model to predict cure at end of treatment and relapse 6 months post-treatment. The Phase III trial STAND, testing new regimen pretomanid (Pa), moxifloxacin (M), and pyrazinamide (Z) (PaMZ), predicted to shorten treatment duration by 2 months was put on hold after a separate ongoing trial showed adding bedaquiline (B) to the PaMZ regimen (SimpliciTB) suggested superior efficacy. To forecast if the addition of B would indeed benefit the PaMZ regimen, we applied an extended translational platform to both regimens. We predicted currently available short- and long-term clinical data well for drug combinations related to BPaMZ. We predict the addition of B to PaMZ will shorten treatment duration by 2 months and be non-inferior compared to control HRZE, both at the end of treatment for treatment efficacy and 6 months after treatment has ended in relapse prevention. Using BPaMZ as a case study, we have demonstrated our translational platform can predict Phase II and III outcomes prior to actual trials, allowing us to better prioritize the regimens most likely to succeed.
Cardiomyocyte Pdk4 response is associated with metabolic maladaptation in aging
Authors: Fatmi Mohammad Kasim , Ren Di , Fedorova Julia , Zoungrana Linda Ines , Wang Hao , Davitt Kayla , Li Zehui , Iglesias Migdalia , Lesnefsky Edward J. , Krause‐Hauch Meredith , Li Ji 
Published: February 2023

AbstractIschemic heart disease (IHD) is the leading cause of death, with age range being the primary factor for development. The mechanisms by which aging increases vulnerability to ischemic insult are not well understood. We aim to use single‐cell RNA sequencing to discover transcriptional differences in various cell types between aged and young mice, which may contribute to aged‐related vulnerability to ischemic insult. Utilizing 10× Genomics Single‐Cell RNA sequencing, we were able to complete bioinformatic analysis to identity novel differential gene expression. During the analysis of our collected samples, we detected Pyruvate Dehydrogenase Kinase 4 (Pdk4) expression to be remarkably differentially expressed. Particularly in cardiomyocyte cell populations, Pdk4 was found to be significantly upregulated in the young mouse population compared to the aged mice under ischemic/reperfusion conditions. Pdk4 is responsible for inhibiting the enzyme pyruvate dehydrogenase, resulting in the regulation of glucose metabolism. Due to decreased Pdk4 expression in aged cardiomyocytes, there may be an increased reliance on glucose oxidization for energy. Through biochemical metabolomics analysis, it was observed that there is a greater abundance of pyruvate in young hearts in contrast to their aged counterparts, indicating less glycolytic activity. We believe that Pdk4 response provides valuable insight towards mechanisms that allow for the young heart to handle ischemic insult stress more effectively than the aged heart.
Impact of alcohol use disorder severity on human immunodeficiency virus (HIV) viral suppression and CD4 count in three international cohorts of people with HIV
Authors: Bertholet Nicolas , Saitz Richard , Hahn Judith A. , Heeren Timothy C. , Emenyonu Nneka I. , Freiberg Matthew , Winter Michael R. , Kim Theresa W. , Magane Kara M. , Lloyd‐Travaglini Christine , Fatch Robin , Bryant Kendall , Forman Leah S. , Rateau Lindsey , Blokhina Elena , Muyindike Winnie R. , Gnatienko Natalia , Samet Jeffrey H. 
Published: February 2023

AbstractBackgroundAlcohol use has been linked to worse human immunodeficiency virus (HIV) immunologic/virologic outcomes, yet few studies have explored the effects of alcohol use disorder (AUD). This study assessed whether AUD severity is associated with HIV viral suppression and CD4 count in the three cohorts of the Uganda Russia Boston Alcohol Network for Alcohol Research Collaboration on HIV/AIDS (URBAN ARCH) Consortium.MethodsPeople with HIV (PWH) in Uganda (n = 301), Russia (n = 400), and Boston (n = 251), selected in‐part based on their alcohol use, were included in analyses. Logistic and linear regressions were used to assess the cross‐sectional associations between AUD severity (number of DSM‐5 diagnostic criteria) and (1) HIV viral suppression, and (2) CD4 count (cells/mm3) adjusting for covariates. Analyses were conducted separately by site.ResultsThe proportion of females was 51% (Uganda), 34% (Russia), and 33% (Boston); mean age (SD) was 40.7 (9.6), 38.6 (6.3), and 52.1 (10.5), respectively. All participants in Uganda and all but 27% in Russia and 5% in Boston were on antiretroviral therapy. In Uganda, 32% met criteria for AUD, 92% in Russia, and 43% in Boston. The mean (SD) number of AUD criteria was 1.6 (2.4) in Uganda, 5.6 (3.3) in Russia, and 2.4 (3.1) in Boston. Most participants had HIV viral suppression (Uganda 92%, Russia 57%, Boston 87%); median (IQR) CD4 count was 673 (506, 866), 351 (201, 542), and 591 (387, 881), respectively. In adjusted models, there were no associations between AUD severity and HIV viral suppression: adjusted odds ratios (AOR) (95%CI) per 1 additional AUD criterion in Uganda was 1.08 (0.87, 1.33); Russia 0.98 (0.92, 1.04); and Boston 0.95 (0.84, 1.08) or CD4 count: mean difference (95%CI) per 1 additional criterion: 5.78 (−7.47, 19.03), −3.23 (−10.91, 4.44), and −8.18 (−24.72, 8.35), respectively.ConclusionsIn three cohorts of PWH, AUD severity was not associated with HIV viral suppression or CD4 count. PWH with AUD in the current era of antiretroviral therapy can achieve virologic control.
Compound heterozygous splicing variants expand the genotypic spectrum of EMC1‐related disorders
Authors: Bryen Samantha J. , Zhang Katharine , Dziaduch Gregory , Bommireddipalli Shobhana , Naseri Take , Reupena Muagututi'a Sefuiva , Viali Satupa'itea , Minster Ryan L. , Waddell Leigh B. , Charlton Amanda , O'Grady Gina L. , Evesson Frances J. , Cooper Sandra T. 
Published: February 2023

AbstractEMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice‐site variant in intron‐3 of EMC1 (NM_015047.3:c.287‐1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron‐20 of EMC1 (NM_015047.3:c.2588‐771C>G) that was poorly predicted by in silico programs to disrupt pre‐mRNA splicing. Reverse Transcription‐PCR (RT‐PCR) revealed stochastic activation of a pseudo‐exon associated with the c.2588‐771C>G variant and mis‐splicing arising from the c.287‐1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1‐related disorders.
Opening of mitochondrial permeability transition pore in cardiomyocytes: Is ferutinin a suitable tool for its assessment?
Authors: Bréhat Juliette , Panel Mathieu , Ghaleh Bijan , Morin Didier 
Published: February 2023

AbstractMitochondrial permeability transition pore (mPTP) opening is a critical event leading to cell injury during myocardial ischemia–reperfusion but having a reliable cellular model to study the effect of drugs targeting mPTP is an unmet need. This study evaluated whether the Ca2+ electrogenic ionophore ferutinin is a relevant tool to induce mPTP in cardiomyocytes. mPTP opening was monitored using the calcein/cobalt fluorescence technique in adult cardiomyocytes isolated from wild‐type and cyclophylin D (CypD) knock‐out mice. Concomitantly, the effect of ferutinin was assessed in isolated myocardial mitochondria. Our results confirmed the Ca2+ ionophoric effect of ferutinin in isolated mitochondria and cardiomyocytes. Ferutinin induced all the hallmarks of mPTP opening in cells (loss of calcein, of mitochondrial potential and cell death), but none of them could be inhibited by CypD deletion or cyclosporine A, indicating that mPTP opening was not the major contributor to the effect of ferutinin. This was confirmed in isolated mitochondria where ferutinin acts by different mechanisms dependent and independent of the mitochondrial membrane potential. At low ferutinin/mitochondria concentration ratio, ferutinin displays protonophoric‐like properties, lowering the mitochondrial membrane potential and limiting oxidative phosphorylation without mitochondrial swelling. At high ferutinin/mitochondria ratio, ferutinin induced a sudden Ca2+ independent mitochondrial swelling, which is only partially inhibited by cyclosporine A. Together, these result show that ferutinin is not a suitable tool to investigate CypD‐dependent mPTP opening in isolated cardiomyocytes because it possesses other mitochondrial properties such as swelling induction and mitochondrial uncoupling properties which impede its utilization.
Spermidine reduced neuropathic pain in chronic constriction injury‐induced peripheral neuropathy in rats
Authors: Yousefi‐Manesh Hasan , Shirooie Samira , Noori Tayebeh , Sheibani Mohammad , Tavangar Seyed Mohammad , Hemmati Sara , Sadeghi Mohammad Amin , Akbarniakhaky Hassan , Mohammadi Zohreh , Foroutani Laleh , Dehpour Ahmad Reza 
Published: February 2023

AbstractNeuropathic pain is one of the most critical types of chronic pain despite the increasing advances in medical science. Spermidine (SPD) is a natural polyamine that has wide roles in several cellular processes inducing autophagy and reducing oxidative stress. This study aimed to investigate the effects of SPD on oxidative stress markers and pain threshold in the neuropathic rat model of chronic constriction injury (CCI) model. Eighteen adult male rats were divided into three groups: sham, CCI and CCI+SPD. After induction of neuropathy via CCI model in the CCI and CCI+SPD groups, SPD (1 mg/kg/day, orally) was administered to the CCI+SPD group for 3 weeks. The behavioral tests (von Frey, hot plate) were done four times during the experiment. At the end of the study, electrophysiological tests, the H & E staining, and oxidative stress assay of the prefrontal cortex (PFC), spinal cord, and sciatic nerve were performed. The threshold of pain in hot plate and von Frey tests was significantly lower in the CCI group than in the sham group, which was reversed by SPD treatment in the CCI+ SPD group. In addition, nerve conduction was considerably lower in the CCI group than in the sham and CCI+SPD groups (P < 0.01, P < 0.05, respectively). The CCI group showed neuronal degeneration and fibrosis in the different tissues in the H & E assay; elevated tissues level of nitrite, decreased levels of superoxide dismutase (SOD), glutathione (GPx), and catalase were also observed. However, SPD treatment modulated the pathological changes and oxidative stress biomarkers. In conclusion, SPD showed beneficial effects in decreasing neuropathic pains. SPD treatment reduced oxidative stress and improved histopathological changes and behavioral tests in the CCI‐induced neuropathic pain in in vivo model.
X‐ray crystallographic and mutational analysis of the NylC precursor: catalytic mechanism of autocleavage and substrate hydrolysis of nylon hydrolase
Authors: Negoro Seiji , Shibata Naoki , Kato Dai‐ichiro , Tanaka Yusuke , Yasuhira Kengo , Nagai Keisuke , Oshima Shohei , Furuno Yoko , Yokoyama Risa , Miyazaki Kaito , Takeo Masahiro , Hengphasatporn Kowit , Shigeta Yasuteru , Lee Young‐Ho , Higuchi Yoshiki 
Published: February 2023

Nylon hydrolase (NylC), a member of the N‐terminal nucleophile (Ntn) hydrolase superfamily, is responsible for the degradation of various aliphatic nylons, including nylon‐6 and nylon‐66. NylC is initially expressed as an inactive precursor (36 kDa), but the precursor is autocatalytically cleaved at Asn266/Thr267 to generate an active enzyme composed of 27 and 9 kDa subunits. We isolated various mutants with amino acid changes at the catalytic centre. X‐ray crystallographic analysis revealed that the NylC precursor forms a doughnut‐shaped quaternary structure composed of four monomers (molecules A‐D) with D2 symmetry. Catalytic residues in the precursor are covered by loop regions at the A/B interface (equivalent to the C/D interface). However, the catalytic residues are exposed to the solvent environment through autocleavage followed by movements of the loop regions. T267A, D306A and D308A mutations resulted in a complete loss of autocleavage. By contrast, in the T267S mutant, autocleavage proceeded slowly at a constant reaction rate (k = 2.8 × 10−5 s−1) until complete conversion, but the reaction was inhibited by K189A and N219A mutations. Based on the crystallographic and molecular dynamic simulation analyses, we concluded that the Asp308‐Asp306‐Thr267 triad, resembling the Glu‐Ser‐Ser triad conserved in Ntn‐hydrolase family enzymes, is responsible for autocleavage and that hydrogen‐bonding networks connecting Thr267 with Lys189 and Asn219 are required for increasing the nucleophilicity of Thr267‐OH in both the water accessible and water inaccessible systems. Furthermore, we determined that NylC employs the Asp308‐Asp306‐Thr267 triad as catalytic residues for substrate hydrolysis, but the reaction requires Lys189 and Tyr146 as additional catalytic/substrate‐binding residues specific for nylon hydrolysis.
Developing the Resident Measure of Safety in Care Homes (RMOS): A Delphi and Think Aloud Study
Authors: Tyler Natasha , Planner Claire , Shears Bethany , Hernan Andrea , Panagioti Maria , Giles Sally 
Published: February 2023

AbstractObjectiveThis study aimed to develop a measure of contributory factors to safety incidents in care homes to be completed by residents and/or their unpaid carers.IntroductionCare home residents are particularly vulnerable to patient safety incidents, due to higher likelihood of frailty, multimorbidity and cognitive decline. However, despite residents and their carers wanting to be involved in safety initiatives, there are few mechanisms for them to contribute and make meaningful safety improvements to practice.MethodsWe developed 73 evidence‐based items from synthesis and existing measures, which we presented to a panel of stakeholders (residents/carers, health/social care professionals and researchers). We used two online rounds of Delphi to generate consensus (80%) on items important to include in the Resident Measure of Safety in Care Homes (RMOS); a consensus meeting was later held. The draft RMOS developed through the Delphi was presented to participants during ‘Think Aloud' interviews using cognitive testing techniques.ResultsThe 29‐item RMOS was developed. Forty‐three participants completed Delphi round 1, and 27 participants completed round 2, 11 participants attended the consensus meeting and 12 ‘Think Aloud’ interviews were conducted. Of the 73 original items, 42 items that did not meet consensus in Delphi round 1 were presented in round 2. After the consensus meeting, it was agreed that 35 items would comprise the RMOS questionnaire and were presented in the ‘Think Aloud’ interviews. Participants suggested numerous changes to items mostly to improve comprehension and ability to answer.ConclusionWe have a developed an evidence‐based RMOS, with good face validity, to assess contributory factors to safety in care homes from a resident/carer perspective. Future work will involve psychometrically testing the items in a pilot and developing a complementary simplified, dementia‐friendly version to promote inclusivity.Patient or Public InvolvementFour patient and public contributors worked with researchers to develop the online questionnaires. Patients (residents) and carers participated on the consensus panel. One member of the research team is an expert by lived experience and was involved in design and analysis decisions. The item list and instructions for the questionnaires were reviewed for face validity, understanding and acceptability by a patient and public involvement group and modified.
Management of COVID‐19 and vaccination in Nepal: A qualitative study
Authors: Karki Alisha , Rijal Barsha , Koirala Bikash , Makai Prabina , KC Pramod , Adhikary Pratik , Joshi Saugat , Basnet Srijana , Bhattarai Sunita , Karki Jiban 
Published: February 2023

AbstractObjectiveThe aim of this research is to investigate the perspective of citizens of Nepal on the management COVID‐19, the roll‐out of the vaccine, and to gain an understanding of attitudes towards the governments' handling of the COVID‐19 pandemic.MethodA qualitative methodology was used. In‐depth interviews were conducted with 18 males and 23 females aged between 20 and 86 years old from one remote and one urban district of Nepal. Interviews were conducted in November and December 2021. A thematic approach was used to analyse the data, utilising NVivo 12 data management software.ResultThree major themes were identified: (1) Peoples' perspective on the management of COVID‐19, (2) people's perception of the management of COVID‐19 vaccination and (3) management and dissemination of information. It was found that most participants had heard of COVID‐19 and its mitigation measures, however, the majority had limited understanding and knowledge about the disease. Most participants expressed their disappointment concerning poor testing, quarantine, vaccination campaigns and poor accountability from the government towards the management of COVID‐19. Misinformation and stigma were reported as the major factors contributing to the spread of COVID‐19. People's knowledge and understanding were mainly shaped by the quality of the information they received from various sources of communication and social media. This heavily influenced their response to the pandemic, the preventive measures they followed and their attitude towards vaccination.ConclusionOur study concludes that the study participants' perception was that testing, quarantine centres and vaccination campaigns were poorly managed in both urban and rural settings in Nepal. Since people's knowledge and understanding of COVID‐19 are heavily influenced by the quality of information they receive, we suggest providing contextualised correct information through a trusted channel regarding the pandemic, its preventive measures and vaccination. This study recommends that the government proactively involve grassroots‐level volunteers like Female Community Health Volunteers to effectively prepare for future pandemics.Patient and Public ContributionThis study was based on in‐depth interviews with 41 people from diverse socioeconomic backgrounds. This study would not have been possible without their participation.
Cap allocation rules for an online platform supply chain under cap‐and‐trade regulation
Authors: Zhang Mengying , Wang Ningning , Liu Hongwei , Zhang Zihao 
Published: February 2023

AbstractCap‐and‐trade regulation is increasingly adopted by countries and governments to curb carbon emissions. This regulation can be implemented based on two rules, that is, the traditional cap allocation rule and the linear cap allocation rule. Considering the impact of online channel structure on the manufacturer's production and low‐carbon investment strategy, this paper aims to explore the economic and environmental performances of the two rules. The results show that the linear rule encourages the government to allocate less cap to each unit product as the emission abatement level increases, preventing the manufacturer from gaining a windfall profit from the free carbon credits. Besides, the government could use the traditional cap allocation rule to better control the total carbon emissions but use the linear cap allocation rule to obtain more social welfare as well as economic benefit. No matter which cap allocation rule is implemented, the manufacturer always performs better in reseller mode, and the e‐tailer might perform better in reseller (marketplace) mode given a high (low) low‐carbon investment efficiency. This study enriches the literature on the interplay between the cap allocation rule and selling mode and provides insights into decision‐making for governments and firms.