bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline expression of immune gene modules in blood is associated with primary response to anti-TNF therapy in Crohn’s disease patients
Authors: Bai Benjamin Y. H. , Reppell Mark , Smaoui Nizar , Waring Jeffery F. , Pivorunas Valerie , Guay Heath , Lin Simeng , Chanchlani Neil , Bewshea Claire , Goodhand James R. ,   UK Inflammatory Bowel Disease Pharmacogenetics Study Group, Kennedy Nicholas A. , Ahmad Tariq , Anderson Carl A. 
Published: April 2023

AbstractBackground and AimsAnti-TNF therapy is widely used for treatment of inflammatory bowel disease (IBD), yet many patients are primary non-responders (PNR), failing to respond to induction therapy. We aimed to identify blood gene expression differences between primary responders (PR) and primary non-responders to anti-TNF monoclonal antibodies (infliximab and adalimumab); and to predict response status from blood gene expression and clinical data.MethodsThe Personalised Anti-TNF Therapy in Crohn’s Disease (PANTS) study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF naive Crohn’s disease (CD) patients (ClinicalTrials.govidentifier:NCT03088449). Blood gene expression in 324 unique patients was measured by RNA-seq at baseline (week 0), and at weeks 14, 30, and 54 after treatment initiation (total sample size = 814).ResultsAfter adjusting for clinical covariates and estimated blood cell composition, baseline expression of MHC, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders. Expression changes from baseline to week 14 were generally of consistent direction across patients but with greater magnitude in responders, with the exception of interferon-related genes that were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at week 30 and week 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor.ConclusionsBaseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these expression differences were insufficient for clinically useful prediction of response.
Assessing Willingness to receive COVID-19 Vaccines, associated factors and reasons for hesitancy among persons aged 13-80 years in Central Uganda. A population-based surveillance Cohort
Authors: Daama Alex , Rashid Naziru , Asani Kasango , Nalwoga Grace Kigozi , Nalugoda Fred , Bulamba Robert , Kyasanku Emmanuel , Nakigozi Gertrude , Kigozi Godfrey , Kagaayi Joseph , Mugamba Stephen 
Published: April 2023

ABSTRACTBackgroundVaccination is essential for controlling the COVID-19 pandemic. However adequate vaccine coverage is a critical to the effectiveness of the vaccine at a population level. Data on to acceptability of the vaccine in Urban areas are limited. This study examined the prevalence, factors associated with willingness to receive COVID-19 vaccine and reasons for hesitancy in the predominantly urban in central Uganda (Wakiso)MethodsData were obtained from a cross-sectional study conducted from March 1st, 2021, to September 30th, 2021 in the urban population-based cohort of the Africa Medical and behavioral Sciences Organization (AMBSO). Multivariable modified Poisson regression analysis was used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals of willingness to accept the COVID-19 vaccine.ResultsA total of 1,903 participants were enrolled in the study; 61% of whom were females. About 63% of participants indicated willingness to accept the COVID-19 vaccine. Younger age groups (13-19 and 20-29) were less likely to accept the vaccine compared to the persons ages 40-49 years (aPR=0.79; 95% CI: 0.74, 0.84 for the 13-19 years and 0.93; 95% CI: 0.88, 0.98 for age group 20-29, compared to those ages 40–49 years. Post-primary education (aPR=1.05; 95% CI: 1.02, 1.09 compared to primary level), being a students and government staff (APR=1.13; 95% CI: 1.04, 1.23 compared to construction and Mechanic workers) were associated with willingness to receive COVID-19 vaccine. Some of the reported reasons for hesitancy included; concerns about side effects 154(57.0%), about 64(23.7%) did not think the vaccines were effective, and those who did not like the vaccines 32(11.9%).ConclusionA substantial proportion of individuals were not willingness to receive the COVID-19 vaccine. More effort is needed to reduce vaccine hesitancy, especially among the young and people with lower formal education.
Performance of a diagnostic model for the presence of unruptured intracranial aneurysms in the general population
Authors: Klieverik Vita M. , Roozenbeek Bob , Cras Tim Y. , Vernooij Meike W. , Geerlings Mirjam I. , Bos Daniel , Ruigrok Ynte M. 
Published: April 2023

AbstractBackgroundThe prevalence of unruptured intracranial aneurysms (UIAs) in the general population is 3%. Aneurysmal subarachnoid hemorrhage can be prevented by screening for UIAs followed by preventive treatment of identified UIAs. We developed a diagnostic model for presence of UIAs in the general population to help identify persons at high risk of having UIAs.MethodsBetween 2005-2015, middle aged and elderly participants from the population-based Rotterdam Study underwent brain magnetic resonance imaging at 1.5 Tesla, on which presence of incidental UIAs was evaluated. A multivariable logistic regression model with diagnostic markers sex, age, hypertension, smoking, hypercholesterolemia, diabetes, and alcohol, and their interactions, was developed. We corrected for overfitting using bootstrapping. Model performance was assessed with discrimination, calibration, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).Results5835 persons were included (55.0% women, mean age 64.9±10.9 years) with a 2.2% UIA prevalence. Sex, age, hypertension, smoking, diabetes, and interactions of sex with age, hypertension, and smoking were independent diagnostic markers. The resulting model had a c-statistic of 0.65 (95% confidence interval [CI] 0.60–0.68) and 56% sensitivity, 52% specificity, 98% PPV, and 3% NPV for UIA presence at a cut-off value of 4% prevalence. Because of interactions with sex, additional models for men and women separately were developed. The model for men had a c-statistic of 0.70 (95%CI 0.62–0.78) with age, hypertension, and smoking as diagnostic markers and comparable additional performance values as for the full model. The model for women had a c-statistic of 0.58 (95%CI 0.52–0.63) with smoking as the only diagnostic marker.ConclusionOur diagnostic model had insufficient performance to help identify persons at high risk of having UIAs in the general population. Rather, it provides insight in risk factors contributing to UIA risk and shows that these may be in part sex-specific.
Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes
Authors: Ramessur Anisha , Ambasager Bana , Aramburu Iker Valle , Peakman Freddie , Gleason Kelly , Lehmann Christoph , Papayannopoulos Venizelos , Coombes Raoul Charles , Malanchi Ilaria 
Published: April 2023

AbstractPurposeA high number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear.Patients and MethodsHere, we investigate changes in circulating neutrophils from newly diagnosed breast cancer patients before any therapeutic interventions. To do this, we assessed their lifespan and their broader intracellular kinase network activation states by using the Pamgene Kinome assay which measures the activity of neutrophil kinases.ResultsWe found sub-type specific L-selectin (CD62L) changes in circulating neutrophils as well as perturbations in their overall global kinase activity. Strikingly, breast cancer patients of different subtypes (HR+, HER2+, triple negative) exhibited distinct neutrophil kinase activity patterns indicating that quantifiable perturbations can be detected in circulating neutrophils from early breast cancer patients, that are sensitive to both hormonal and HER-2 status. We also detected an increase in neutrophils lifespan in cancer patients, independently of tumour subtype.ConclusionsOur results suggest that the tumour-specific kinase activation patterns in circulating neutrophils may be used in conjunction with other markers to identify patients with cancer from those harbouring only benign lesions of the breast. Given the important role neutrophil in breast cancer progression, the significance of this sub-type of specific priming warrants further investigation.Clinical RelevanceThe current study aims to investigate cancer-specific changes in circulating neutrophils in patients with newly diagnosed early breast cancer before any therapeutic intervention. We found L-selectin (CD62L) changes in circulating neutrophils from patients with early-stage breast cancer compared to healthy volunteers, which is an indication of an early phenotypical change. Moreover, these changes in CD62L were dependent on the breast cancer sub-type, showing opposing trends according to the hormonal receptor status of the tumour. Importantly, this subtype dependent phenotypic alteration was reflected in broader intracellular signalling perturbation when measuring intracellular kinase activity. Moreover, those cancer perturbed neutrophils, show expanded life span when cultured ex vivo, suggesting an alteration in their physiologic state. The tumour-specific kinase activation patterns in circulating neutrophils may be useful in conjunction with other markers to distinguish patients with cancer from those with benign lesions of the breast.
Retinoids and EZH2 inhibitors cooperate to orchestrate cytotoxic effects on bladder cancer cells
Authors: Ozgun Gizem , Yaras Tutku , Landman Nick , Karakülah Gökhan , van Lohuizen Maarten , Senturk Serif , Ozhan Serap Erkek 
Published: April 2023

ABSTRACTEmerging evidence has highlighted the importance of targeting EZH2 in bladder cancer owing to the highly mutated nature of bladder cancers harboring mutations in chromatin regulatory genes opposing Polycomb-mediated repression. Besides, enhanced expression of EZH2 contributes to pathogenesis. Furthermore, the critical role of the retinoic acid signaling pathway in the development and homeostasis of the urothelium is well established. Here we report that coordinated targeting of EZH2 and the retinoic acid signaling pathway caused cytotoxic effects on bladder cancer cells by inducing a synergistic reduction in proliferative potential that was associated with increased apoptosis and cell cycle arrest in a cooperative and orchestrated manner. Moreover, combined treatment caused the modulation of the expression of genes associated with an anti-oncogenic profile, as reflected by the stimulation of marker genes associated with apoptosis and differentiation. We further portrayed a molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of certain genes associated with unfolded protein response and some metabolic processes. This work also characterized an apoptotic program centered on the master transcriptional regulators C/EBPβ and CHOP. These findings highlight the importance of co-targeting the EZH2/retinoic acid pathway in bladder cancers and encourage the design of novel treatments employing retinoids coupled with EZH2 inhibitors in bladder carcinoma.
RhoA GEF Mcf2lb regulates rosette integrity during collective cell migration
Authors: Olson Hannah M. , Maxfield Amanda , Calistri Nicholas L. , Heiser Laura M. , Nechiporuk Alex V. 
Published: April 2023

ABSTRACTDuring development, multicellular rosettes serve as important cellular intermediates in the formation of diverse organ systems. Multicellular rosettes are transient epithelial structures that are defined by the apical constriction of cells towards the rosette center. Due to the important role these structures play during development, understanding the molecular mechanisms by which rosettes are formed and maintained is of high interest. Utilizing the zebrafish posterior lateral line primordium (pLLP) as a model system, we identify the RhoA GEF Mcf2lb as a regulator of rosette integrity. The pLLP is a group of ∼150 cells that migrates along the zebrafish trunk and is organized into epithelial rosettes; these are deposited along the trunk and will differentiate into sensory organs called neuromasts (NMs). Using single-cell RNA sequencing and whole-mount in situ hybridization, we showed thatmcf2lbis expressed in the pLLP during migration. Given the known role of RhoA in rosette formation, we asked whether Mcf2lb plays a role in regulating apical constriction of cells within rosettes. Live imaging and subsequent 3D analysis ofmcf2lbmutant pLLP cells showed disrupted apical constriction and subsequent rosette organization. This in turn resulted in a unique posterior Lateral Line phenotype: an excess number of deposited NMs along the trunk of the zebrafish. Cell polarity markers ZO-1 and Par-3 were apically localized, indicating that pLLP cells are normally polarized. In contrast, signaling components that mediate apical constriction downstream of RhoA, Rock-2a and non-muscle Myosin II were diminished apically. Altogether our results suggest a model whereby Mcf2lb activates RhoA, which in turn activates downstream signaling machinery to induce and maintain apical constriction in cells incorporated into rosettes.
Context-Aware Stress Monitoring using Wearable and Mobile Technologies in Everyday Settings
Authors: Aqajari Seyed Amir Hossein , Labbaf Sina , Tran Phuc Hoang , Nguyen Brenda , Mehrabadi Milad Asgari , Levorato Marco , Dutt Nikil , Rahmanit Amir M. 
Published: April 2023

AbstractBackgroundDaily monitoring of stress is a critical component of maintaining optimal physical and mental health. Physiological signals and contextual information have recently emerged as promising indicators for detecting instances of heightened stress. Nonetheless, developing a real-time monitoring system that utilizes both physiological and contextual data to anticipate stress levels in everyday settings while also gathering stress labels from participants represents a significant challenge.ObjectiveWe present a monitoring system that objectively tracks daily stress levels by utilizing both physiological and contextual data in a daily-life environment. Additionally, we have integrated a smart labeling approach to optimize the ecological momentary assessment (EMA) collection, which is required for building machine learning models for stress detection. We propose a three-tier Internet-of-Things-based system architecture to address the challenges.MethodsA group of university students (n=11) consisting of both males (n=4) and females (n=7) with ages ranging from 18 to 37 years (Mean = 22.91, SD = 5.05) were recruited from the University of California, Irvine. During a period of two weeks, the students wore a smartwatch that continuously monitored their physiology and activity levels. A context-logging application was also installed on their smartphone. They were asked to respond to several EMAs daily through a smart EMA query system. We employed three different machine learning algorithms to evaluate the performance of our system. The mean decrease impurity approach was employed to identify the most significant features. The k-nearest neighbor imputation technique was used to fill out the missing contextual features.ResultsF1-score is the performance metric used in our study. We utilized a cross-validation technique to accurately estimate the performance of our stress models. We achieved the F1-score of 70% with a Random Forest classifier using both PPG and contextual data, which is considered an acceptable score in models built for everyday settings. Whereas using PPG data alone, the highest F1-score achieved is approximately 56%, emphasizing the significance of incorporating both PPG and contextual data in stress detection tasks.ConclusionWe proposed a system for monitoring daily-life stress using both physiological and smartphone data. The system includes a smart query module to capture high-quality labels. This is the first system to employ both physiology and context data for stress monitoring and to include a smart query system for capturing frequent self-reported data throughout the day.
The extent of regeneration is impacted by the stage of amputation in ladybird beetles: a case study inCheilomenes sexmaculata
Authors: Alam Hera , Rai Shriza , Verma Praveen C , Mishra Geetanjali 
Published: April 2023

AbstractRegeneration is a topic of interest for centuries and arthropods are no exception. Trade-offs associated with regeneration are likely to indicate the reallocation of resources from other metabolic activities such as growth, development, or reproduction to regrowth of the lost body part. This may confer negative selection to some of the developmental traits of the organism despite regeneration being overall advantageous. Our hypothesis for the study was that the extent of regeneration and trade-offs associated with it may be stage-specific. To test this hypothesis, the right forelimb of all four larval stages of the ladybird beetle (Cheilomenes sexmaculata) was amputated. The amputated stages were reared till adulthood and all developmental transitions were recorded. Leg size was measured and compared with control. The result showed that the regenerated legs of all the treatments were smaller than the control and the regenerative potency of early larval stage was higher than late larval stages. Regeneration causes delay in post-amputation duration in all the treatments, increasing their total development period. However, insignificant difference was observed between the fresh body weight of regenerated and control adults. The length of unamputated left foreleg was reduced in regenerated beetles, showing some internal trade-off.
Multiscalar electrical spiking inSchizophyllum commune
Authors: Adamatzky Andrew , Schunselaar Ella , Wösten Han A. B. , Ayres Phil 
Published: April 2023

AbstractGrowing colonies of the split-gill fungusSchizophyllum communeshow action potential-like spikes of extracellular electrical potential. We analysed several days of electrical activity recording of the fungus and discovered three families of oscillatory patterns. Very slow activity at a scale of hours, slow activity at a scale of tens minutes and very fast activity at scale of half-minute. We simulated the spiking behaviour using FitzHugh-Nagume model, uncovered mechanisms of spike shaping. We speculated that spikes of electrical potential might be associated with transportation of nutrients and metabolites.
Protein-lipid charge interactions control the folding of OMPs into asymmetric membranes
Authors: Machin Jonathan , Kali Antreas C. , Ranson Neil A. , Radford Sheena E. 
Published: April 2023

AbstractBiological membranes consist of two leaflets of phospholipid molecules that form a bilayer, and typically the composition of lipids in each leaflet is distinct. This asymmetry is created and maintainedin vivoby dedicated biochemical pathways, but difficulties in creating stable asymmetric membranesin vitrohave restricted our understanding of how bilayer asymmetry modulates the folding, stability and function of membrane proteins. Here we employ cyclodextrin mediated lipid exchange to generate asymmetric liposomes and use these to characterize the stability and folding kinetics of two bacterial outer membrane proteins (OMPs). We show that excess negative charge in the outer leaflet of a liposome impedes the membrane insertion and folding of OmpA and BamA, while excess negative charge in the inner leaflet accelerates their folding, relative to symmetric liposomes with the same membrane composition. Three positively charged residues in the extracellular loops of OmpA that play a critical role in folding are identified using molecular dynamics simulations and mutational analyses. Bioinformatic analysis was then used to identify a conserved patch of positive residues in the extracellular loops of OMPs generally that lies 6-8Å from the membrane surface. Together, the the results rationalise the well known ‘positive outside’ rule for OMP sequences and suggest new insights into the mechanisms that drive OMP folding and assemblyin vitroandin vivo.
Acceptability of the Venting Wisely Pathway for use in Critically ill Adults with Hypoxemic Respiratory Failure and Acute Respiratory Distress Syndrome (ARDS): A qualitative study protocol
Authors: Krewulak Karla , Knight Gwen , Irwin Andrea , Morrissey Jeanna , Stelfox Henry T. , Bagshaw Sean , Zuege Danny J. , des Ordons Amanda Roze , Fiest Kirsten M. , Parhar Ken Kuljit S 
Published: April 2023

ABSTRACTIntroductionHypoxemic respiratory failure (HRF) affects nearly 15% of critically ill adults admitted to an intensive care unit (ICU). An evidence based, stakeholder informed multidisciplinary care pathway (Venting Wisely) was created to standardize the diagnosis and management of patients with HRF and Acute Respiratory Distress Syndrome (ARDS). Successful adherence to the pathway requires a coordinated team-based approach by the clinician team. The overall aim of this study is to describe the acceptability of theVenting Wiselypathway among critical care clinicians. Specifically, this will allow us to: 1) better understand the user’s experience with the intervention and 2) determine if the intervention was delivered as intended.Methods and analysisThis qualitative study will conduct focus groups with nurse practitioners, physicians, registered nurses, and registered respiratory therapists from 17 Alberta ICUs. We will use template analysis to describe the acceptability of a multi component care pathway according to seven constructs of acceptability: 1) Affective attitude; 2) Burden; 3) Ethicality; 4) Intervention coherence; 5) Opportunity costs; 6) Perceived effectiveness; and 7) Self-efficacy. This study will contribute to a better understanding of the acceptability of theVenting Wiselypathway. Identification of areas of poor acceptability will be used to refine the pathway and implementation strategies as ways to improve adherence to the pathway and promote its sustainability.Ethics and disseminationThe study was approved by the University of Calgary Conjoint Health Research Ethics Board (CHREB). The results will be submitted for publication in a peer-reviewed journal and presented at a scientific conference.STRENGTHS AND LIMITATIONSThis qualitative study will provide vital information about why the implementation of theVenting Wiselypathway may or may not have worked as anticipated.Findings will identify opportunities to improve pathway adherence and provide insights on how to sustain the intervention and scale to other sites.Acceptance and adherence of theVenting Wiselypathway has the potential to increase and standardize the use of evidence-informed, life-saving therapies for mechanically ventilated patients; this may improve outcomes and save costs to the healthcare system.Focus groups will be conducted with a wide variety of clinicians (nurse practitioners, physicians, registered nurses, registered respiratory therapists), and within various intensive care units (general systems, cardiovascular surgery, and neurosciences), and hospitals (regional, community, and tertiary).The study is being conducted in one province in Canada, which may limit generalizability.