bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebral glucagon‐like peptide‐1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice
Authors: Lv Chuanxiang , Han Shuai , Sha Zhuang , Liu Mingqi , Dong Shiying , Zhang Chunyun , Li Zean , Zhang Kang , Lu Shouyong , Xu Zhiyang , Bie Li , Jiang Rongcai 
Published: June 2023

AbstractAimWe aimed to assess the effects of cerebral glucagon‐like peptide‐1 receptor (GLP‐1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI).MethodsImmunofluorescence was employed to evaluate glymphatic system function. The blood–brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests.ResultsCerebral GLP‐1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN‐020 abolished the protective effect of the GLP‐1R agonist against cognitive impairment.ConclusionCerebral GLP‐1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.
Cdk5 phosphorylation‐dependent C9orf72 degradation promotes neuronal death in Parkinson's disease models
Authors: Xu Xingfeng , Li Mao , Su Yan , Wang Qi , Qin Peifang , Huang Haitao , Zhang Yuting , Zhou Yali , Yan Jianguo 
Published: June 2023

AbstractAimsChromosome 9 open reading frame 72 (C9orf72) is one of the most dazzling molecules in neurodegenerative diseases, albeit that its role in Parkinson's disease (PD) remains unknown. This article aimed to explore the potential mechanism of C9orf72 involved in the pathogenesis of PD.MethodsThe expression and phosphorylation levels of C9orf72 were examined by Western blotting, RT‐PCR, and immunoprecipitation using PD models. Multiple bioinformatics software was used to predict the potential phosphorylation sites of C9orf72 by Cdk5, followed by verification of whether Cdk5‐inhibitor ROSCOVITINE could reverse the degradation of C9orf72 in PD. By constructing the sh‐C9orf72‐knockdown adenovirus and overexpressing the FLAG‐C9orf72 plasmid, the effects of C9orf72 knockdown and overexpression, respectively, were determined. A short peptide termed Myr‐C9orf72 was used to verify whether interfering with Cdk5 phosphorylation at the Ser9 site of the C9orf72 protein could alleviate autophagy disorder, neuronal death, and movement disorder in PD models.ResultsThe expression level of the C9orf72 protein was significantly reduced, albeit the mRNA expression was not changed in the PD models. Moreover, the phosphorylation level was enhanced, and its reduction was mainly degraded by the ubiquitin‐proteasome pathway. The key nervous system kinase Cdk5 directly phosphorylated the S9 site of the C9orf72 protein, which promoted the degradation of the C9orf72 protein. The knockdown of C9orf72 aggravated autophagy dysfunction and increased neuronal loss and motor dysfunction in substantia nigra neurons of PD mice. The overexpression of C9orf72 alleviated autophagy dysfunction in PD neurons. Specifically, interference with Cdk5 phosphorylation at the S9 site of C9orf72 alleviated autophagy dysfunction, neuronal death, and motor dysfunction mediated by C9orf72 protein degradation during PD.ConclusionsCumulatively, our findings illustrate the importance of the role of C9orf72 in the regulation of neuronal death during PD progression via the Cdk5‐dependent degradation.
MiR‐199a‐5p enhances neuronal differentiation of neural stem cells and promotes neurogenesis by targeting Cav‐1 after cerebral ischemia
Authors: Jin Hua‐Qian , Jiang Wei‐Feng , Zheng Xin‐Tian , Li Lin , Fang Yan , Yang Yan , Hu Xiao‐Wei , Chu Li‐Sheng 
Published: June 2023

AbstractAimsMicroRNAs (miRs) are involved in endogenous neurogenesis, enhancing of which has been regarded as a potential therapeutic strategy for ischemic stroke treatment; however, whether miR‐199a‐5p mediates postischemic neurogenesis remains unclear. This study aims to investigate the proneurogenesis effects of miR‐199a‐5p and its possible mechanism after ischemic stroke.MethodsNeural stem cells (NSCs) were transfected using Lipofectamine 3000 reagent, and the differentiation of NSCs was evaluated by immunofluorescence and Western blotting. Dual‐luciferase reporter assay was performed to verify the target gene of miR‐199a‐5p. MiR‐199a‐5p agomir/antagomir were injected intracerebroventricularly. The sensorimotor functions were evaluated by neurobehavioral tests, infarct volume was measured by toluidine blue staining, neurogenesis was detected by immunofluorescence assay, and the protein levels of neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), caveolin‐1 (Cav‐1), vascular endothelial growth factor (VEGF), and brain‐derived neurotrophic factor (BDNF) were measured by Western blotting.ResultsMiR‐199a‐5p mimic enhanced neuronal differentiation and inhibited astrocyte differentiation of NSCs, while a miR‐199a‐5p inhibitor induced the opposite effects, which can be reversed by Cav‐1 siRNA. Cav‐1 was through the dual‐luciferase reporter assay confirmed as a target gene of miR‐199a‐5p. miR‐199a‐5p agomir in rat stroke models manifested multiple benefits, such as improving neurological deficits, reducing infarct volume, promoting neurogenesis, inhibiting Cav‐1, and increasing VEGF and BDNF, which was reversed by the miR‐199a‐5p antagomir.ConclusionMiR‐199a‐5p may target and inhibit Cav‐1 to enhance neurogenesis and thus promote functional recovery after cerebral ischemia. These findings indicate that miR‐199a‐5p is a promising target for the treatment of ischemic stroke.
Poor dental service utilization in those with clinically severe obesity: A neglected issue with solutions needed
Authors: Malik Zanab , Sohn Woosung , Nanayakkara Shanika , Williams Kathryn 
Published: June 2023

SummaryData linking body mass index (BMI) and dental service utilization with oral and general health, quality of life, wellbeing, and mental health are lacking. Adult patients with clinically severe obesity attending a hospital‐based obesity service in Greater Western Sydney were invited to participate in a cross‐sectional survey that collected data on dental utilization and visiting patterns, dental anxiety, and oral health‐related quality of life (OHRQoL). General health data were obtained from participants' medical records. Of the 82 individuals who consented to participate, 81 (98.8%) completed the study questionnaire, and 74 (91.3%) answered additional screening questions related to their general wellbeing and mental health. Of the participants, 50 (61.7%) reported that their last dental visit was more than 1 year ago, 43 (53.1%) visited only as needed and 22 (27.2%) participants reported favourable dental visiting patterns. Twenty‐four (29.6%) participants reported high levels of dental anxiety, and low levels of OHRQoL compared with national data. Screening questions suggested low general wellbeing and poor mental health in this patient cohort. Within this group, BMI was not significantly correlated with any of the variables of dental service utilization, dental anxiety, OHRQoL, wellbeing, or mental health (p > .05). There was a negative correlation between dental anxiety and dental utilization (p < .05). Patients with clinically severe obesity reported poor dental utilization, low OHRQoL, and high levels of dental anxiety. This study highlighted the frequency of medical complications, lack of wellbeing, and poor mental health, which were evident in this cohort and may complicate dental management.
“It's like a forgotten issue sometimes …”: Qualitative study of individuals living and caring for people with chronic breathlessness
Authors: Sunjaya Anthony , Martin Allison , Arnott Clare , Marks Guy , Jenkins Christine 
Published: June 2023

AbstractIntroductionThis study aims to explore the perspectives of patients and carers with chronic breathlessness on current provision of care, care expectations, and self‐management needs to develop relevant health services and resources to improve clinical outcomes.MethodsIn‐depth semistructured interviews were conducted on patients living with chronic breathlessness and carers.ResultsThirteen patients (cardiac, respiratory, and noncardiorespiratory) and two carers were interviewed (mean age 57 years, 47% female, median duration with breathlessness 5 years). Four main themes were identified: (1) living with breathlessness, (2) diagnosis delays, misdiagnosis, and knowledge gaps, (3) beyond curing disease: symptom relief and improving quality of life, and (4) self‐management and limited support for it.ConclusionBreathlessness has a high personal impact but remains a neglected condition in Australia. Patients suffer from lack of personal, community, and provider awareness, discontinuity of care, and too few clinical and self‐management options.
First‐in‐human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC‐2394, in healthy volunteers
Authors: Tang Fei , Kunder Rebecca , Chu Tom , Hains Avis , Nguyen Allen , McBride Jacqueline M. , Zhong Yu , Santagostino Sara , Wilson Maria , Trenchak Abigail , Chen Liuxi , Ly Justin , Moein Anita , Lewin‐Koh Nicholas , Raghavan Vibha , Osaghae Uyi , Wynne Chris , Owen Ryan , Place David 
Published: June 2023

AbstractInappropriate and chronic activation of the cytosolic NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first‐in‐human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150–1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC‐2394, a small‐molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC‐2394 and its CYP3A4 induction potential in food‐effect (FE) and drug–drug interaction (DDI) stages, respectively. Although GDC‐2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug‐induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC‐2394 was rapidly absorbed; exposure increased in an approximately dose‐proportional manner with low‐to‐moderate intersubject variability. The mean terminal half‐life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high‐fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC‐2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole‐blood stimulation assays showed rapid, reversible, and near‐complete inhibition of the selected PD biomarkers, IL‐1β and IL‐18, across all tested doses. Despite favorable PK and target engagement PD, the GDC‐2394 safety profile precludes its further development.
Longitudinal estimated glomerular filtration rate (eGFR) modeling in long‐term renal function to inform clinical trial design in kidney transplantation
Authors: Kosinski Luke , Frey Eric , Klein Amanda , O'Doherty Inish , Romero Klaus , Stegall Mark , Helanterä Ilkka , Gaber Ahmed Osama , Fitzsimmons William E. , Aggarwal Varun ,   Transplant Therapeutics Consortium (TTC)
Published: June 2023

AbstractKidney transplantation is the preferred treatment for individuals with end‐stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post‐transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post‐transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well‐known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post‐transplant. Our model is a nonlinear, mixed‐effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long‐term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long‐term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post‐transplant in various clinically relevant populations.
Estimating potential global sources and secondary spread of freshwater invasions under historical and future climates
Authors: Hubbard Justin A. G. , Drake D. Andrew R. , Mandrak Nicholas E. 
Published: June 2023

AbstractAimWe employed a climate‐matching method to evaluate potential source regions of freshwater invasive species to an introduced region and their potential secondary spread under historical and future climates.LocationGlobal source regions, with primary introductions to the Laurentian Great Lakes and secondary introductions throughout North America.MethodsWe conducted a climate‐match analysis using the CLIMATE algorithm to estimate global source freshwater ecoregions under historical and future climates with an ensemble of global climate models for climate‐change scenario SSP5‐8.5. Given existing research, we use a climate match of ≥71.7% between ecoregions to indicate climatic conditions that will not inhibit the survival of introduced freshwater organisms. Further, we estimate the secondary spread of freshwater invaders to the ecoregions of North America under historical and future climates.ResultsWe identified 54 global freshwater ecoregions with a climate match ≥71.7% to the recipient Laurentian Great Lakes under historical climatic conditions, and 11 additional ecoregions were predicted to exceed the threshold under climate change. Three of the 11 ecoregions were located in South America, a continent where no matches existed under historical climates and eight were located in the southern United States, southern Europe, Japan and New Zealand. Further, we identify 34 North American ecoregions of potential secondary spread of freshwater invasions from the Great Lakes under historical climatic conditions, and five ecoregions were predicted to exceed the threshold under climate change.Main ConclusionWe provide a climate‐match method that can be employed to assess the sources and spread of freshwater invasions under historical and future climate scenarios. Our climate‐match method predicted increases in climate match between the recipient region and several potential source regions, and changes in areas of potential spread under climate change. The identified ecoregions are candidates for detailed biosecurity risk assessments and related management actions.
Social versus non‐social behavioral inhibition: Differential prediction from early childhood of long‐term psychosocial outcomes
Authors: Tan Enda , Zeytinoglu Selin , Morales Santiago , Buzzell George A. , Almas Alisa N. , Degnan Kathryn A. , Chronis‐Tuscano Andrea , Henderson Heather , Pine Daniel S. , Fox Nathan A. 
Published: June 2023

AbstractBehavioral inhibition (BI) is a temperamental style characterized by cautious and fearful behaviors in novel situations. The present multi‐method, longitudinal study examined whether young children's observed and parent‐reported BI in social versus non‐social contexts predicts different long‐term psychosocial outcomes. Participants (N = 279) were drawn from a longitudinal study of socioemotional development. BI in social contexts (“social BI”) was measured via children's observed wariness toward unfamiliar adults and peers at 24 and 36 months and parents’ reports of children's social fear/shyness at 24, 36, and 48 months. BI in non‐social contexts (“non‐social BI”) was measured via children's observed fearful responses to masks and novel toys, and parents’ reports of children's distress to non‐social novelty at 9 months and non‐social fear at 48 months. At 15 years, anxiety was assessed via adolescent‐ and parent‐reports, and global internalizing and externalizing problems were assessed via parent‐reports. Confirmatory factor analysis showed that a two‐factor model fit the BI data significantly better than a single‐factor model, providing evidence for the dissociation of BI in social versus non‐social contexts. Social BI was uniquely associated with adolescent social anxiety, whereas non‐social BI was specifically associated with adolescent separation anxiety. Neither social BI nor non‐social BI predicted global internalizing and externalizing problems, providing evidence for the specific relations between BI and anxiety problems. Together, these results suggest that young children's inhibited responses in social versus non‐social situations predict different subtypes of anxiety problems in adolescence, highlighting the multifaceted nature of BI and the divergent trajectories of different anxiety problems.
Tirzepatide 10 and 15 mg compared with semaglutide 2.4 mg for the treatment of obesity: An indirect treatment comparison
Authors: le Roux Carel W. , Hankosky Emily R. , Wang Duzhe , Malik Raleigh , Yu Maria , Hickey Ana , Kan Hong , Bunck Mathijs C. , Stefanski Adam , Garcia‐Perez Luis‐Emilio , Wharton Sean 
Published: June 2023

AbstractAimTo compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison.Materials and MethodsUsing SURMOUNT‐1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching‐adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points.ResultsGreater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: −4.67% [95% CI −5.91%, −3.43%]; tirzepatide 15 mg mean difference: −5.92% [95% CI −7.16%, −4.68%]; both P < .001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P < .001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P < .001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P = .074).ConclusionsCurrently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching‐adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg.
How did COVID‐19 lockdowns affect firms and workers? Evidence from Jordan and Morocco
Authors: Baltaji Rihab , Fakih Ali , Sayour Nagham 
Published: June 2023

AbstractMotivationThe COVID‐19 pandemic harmed business and employment in two ways: ill health reduced consumer demand for goods and services; and lockdowns to control disease prevented businesses from operating. This article is concerned with the latter effect.PurposeThis article assesses the losses of full‐time and part‐time jobs as well as wage cuts in Jordan and Morocco as a result of businesses having to close down under lockdowns.Methods and approachWe compared firms that closed down under lockdown to those that did not in the two countries. We used propensity score matching to balance the two sets of firms.We drew on data from two rounds of the COVID‐19 World Bank Enterprise Survey, carried out in June–August 2020 for both countries; and November–December 2020 for Jordan and January–February 2021 for Morocco. The surveys included 601 firms in Jordan and 1,096 in Morocco. We used results from the first round to estimate short‐term effects, and those from the second round to estimate medium‐term effects.The survey differentiated firms by sector—manufacturing, retailing, and other services—by firm size, by whether they were under foreign ownership, and by whether they were engaged in exporting.FindingsFirst we checked the likelihood that firms closed: larger firms and non‐exporting firms were significantly less likely than smaller and exporting firms to close down.When firms closed, they shed jobs, but with marked differences across sectors.Manufacturing firms laid workers off in the short term, an effect that did not increase in the medium term. However, manufacturing firms did reduce wages in the medium term.Retail firms shed fewer jobs in the short term but cut more jobs in the medium term—mainly of part‐time workers. They also cut wages in the medium term.For other services, job losses were observed for part‐time workers in both the short term and the medium term.Policy implicationsPolicy‐makers should consider promoting digitization of the economy; programmes to reform and repurpose businesses; and targeted unemployment benefits to protect workers from loss of jobs and earnings from lockdowns.
Tacit knowledge and the role of the dental educator
Authors: Matharu Karanveer Singh , Wareing Mark Philip 
Published: June 2023

AbstractIntroductionThis article seeks to explore tacit knowledge in the context of the practice and the role of a dental educator in a workplace learning environment.Material and MethodsThe key theoretical ideologies which underpin the definition of tacit knowledge have been outlined and practical examples to enable conceptualisation. The role tacit knowledge plays in procedural knowledge, performance of a skill and diagnosis and decision‐making has been explained in further detail. Approaches to maximise the educational output of learning opportunities by using tacit knowledge and how an awareness of tacit knowledge can complement reflection have been considered.ResultsIt is acknowledged that workplace learning is of mutual benefit to the dental educator, trainee and clinical team and that the development of the educator to make tacit knowledge explicit, can be achieved through peer observation, amongst other methods.ConclusionTacit knowledge is a key element underpinning learning in the workplace; the use of this knowledge can be applied in an advantageous manner, from both an educational and a personal developmental perspective.