bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Activity Behaviors of Female Adolescents in Saudi Arabia
Authors: Alali Muna Ali , Robbins Lorraine B. , Kao Tsui-Sui Annie , Ling Jiying , Pathak Dola , Smith Alan L.
Published: July 2024

Background

Saudi Arabia has one of the highest childhood obesity rates worldwide. The primary factor associated with the high prevalence of obesity among adolescents is a lack of physical activity (PA). Compared to male adolescents, very few Saudi female adolescents meet the World Health Organization recommendation of achieving 60 minutes of moderate-to-vigorous PA per day, putting them at a higher risk of overweight and obesity.

Objective

This cross-sectional study aimed to examine the relationship between the theory of planned behavior and psychosocial factors, including attitude toward PA, subjective norms, perceived behavioral control (PBC), PA intention, and self-reported PA among Saudi female adolescents.

Methods

A convenience sample of 329 Saudi female adolescents was recruited from all-female public intermediate and high schools in the Eastern Region of Saudi Arabia. Data were collected using online self-administered questionnaires. The theoretical model was examined using structural equation modeling.

Results

The findings revealed a higher prevalence of overweight compared to obesity among participants. About half the participants were from families with a medium monthly income. The mean PA score indicated a low level of PA. The model demonstrated significant explanatory power for both PA intention and PA behavior, respectively. The strongest predictor of adolescents' intention was attitude, followed by PBC.

Moreover, the female adolescents' attitudes and PBC had significant indirect effects on self-reported PA through intention, whereas intention had a direct effect on PA. The model did not support a direct or indirect relationship between subjective norms and PA.

Discussion

The findings provide essential support for targeting attitude and perceived behavior control of female adolescents in order to enhance their PA intention. This theoretical understanding can help design effective theory-based interventions that promote PA among Saudi female adolescents.
Child Firearm-Related Homicide and Suicide by State Legislation in the US (2009 to 2020)
Authors: Haines Krista L , Gorenshtein Laura , Kaur Kavneet , Grisel Braylee , Kawano Bradley , Leraas Harold , Freeman Jennifer , Tripoli Todd , Fernandez-Moure Joseph , Agarwal Suresh
Published: July 2024

BACKGROUND:

Firearms are the leading cause of death among US children and adolescents. This study evaluates whether state gun laws are associated with firearm suicides and homicides in children.

STUDY DESIGN:

This is a cross-sectional database study comparing childhood firearm mortality with 36 state firearm laws using data from CDC WONDER and the RAND State Firearm Law Database. Primary outcomes were firearm-related suicide and homicide mortalities per 100,000 persons. We examined suicide deaths by all firearms, including intentional self-harm by handguns only, intentional self-harm by rifles, shotguns, or large firearms only, and intentional self-harm by other or unspecified firearms, as well as homicide deaths for the same firearm types in each state. Welch’s t-tests compared mean rates of suicide and homicide mortality between states with and without these laws. States that either enacted or rescinded firearm legislation during this period were excluded.

RESULTS:

From 2009 to 2020, there were 6,735 suicides and 10,278 homicides by firearm totaling 17,013 child deaths (younger than 18 years of age) by firearm. States with “child access prevention-negligent storage” laws demonstrated lower suicide mortality rates across all firearm types (handguns: N 13, M [mean per 100,000] 0.68, SD 0.27, p < 0.001; long guns: N 12, M 0.65, SD 0.25, p < 0.001). There were no significant differences in mean suicide death rates across all firearm types when comparing states with or without firearm laws related to “minimum age youth possession,” “minimum age youth purchase and sale,” or “child access prevention intentional.” Comparing homicide mortality rates for all firearm types revealed no notable distinctions between states with and without the identified laws.

CONCLUSIONS:

Firearm legislation is associated with decreased suicide rates for individuals younger than 18 years of age, but its influence on homicides is less certain. Comprehensive research and thoughtful policy formulation are essential for addressing this pressing public health concern.
Modelling SARS-CoV-2 infection in a human alveolus microphysiological system
Authors: Šuligoj Tanja , Coombes Naomi , Booth Catherine , Savva George M. , Bewley Kevin R , Funnell Simon GP , Juge Nathalie
Published: July 2024

The COVID-19 pandemic has highlighted the importance of physiologically relevant in vitro models to assist preclinical research. Here, we describe the adaptation of a human alveolus microphysiological system (MPS) model consisting of primary human alveolar epithelial and lung microvascular endothelial cells to study infection with SARS-CoV-2 at Biosafety Level 3 (BSL3) facility. This infection model recapitulates breathing-like stretch and culture of epithelial cells at the air-liquid interface (ALI) and resulted in clinically relevant cytopathic effects including cell rounding of alveolar type 2 cells (AT2) and disruption of the tight junction protein occludin (OCLN). Viral replication was confirmed by immunocytochemical nucleocapsid staining in the epithelium and increased shedding of SARS-CoV-2 virus within two days post-infection, associated with changes in innate host immune responses. Together, these data demonstrate that, under the experimental conditions used in this work, this human alveolus MPS chip can successfully model SARS-CoV-2 infection of human alveolar lung cells.
Lung Microbiome Intervention Attenuates Herpesvirus-Induced Post-HCT Pulmonary Fibrosis Through PD-L1 Upregulation on Dendritic Cells
Authors: Perkins Joshua B. , Ravi Keerthikka , Guo Chunfang , Oh Gina J. , Rodriguez Bellmary G. , Gurczynski Stephen J. , Weinberg Jason B. , Huffnagle Gary B. , O’Dwyer David N. , Moore Bethany B. , Zhou Xiaofeng
Published: July 2024

Alterations in the lung microbiome frequently accompany adverse pulmonary outcomes. Hematopoietic cell transplantation (HCT) markedly affects the lung microbiome corresponding with a high incidence of post-HCT pulmonary complications. In a preclinical mouse model of HCT, we observed a reduction inLactobacillus johnsoniiwithin the lung microbiome following transplantation. Intranasal administration of live or heat-killed (HK)L. johnsoniiat low doses reduced gammaherpesvirus-induced pulmonary fibrosis in HCT mice, in which IL-17A plays an essential role. HKL. johnsoniitreatment of HCT mice suppressed inflammatory cytokine production by lung macrophages and decreasedIl17aexpression in T helper 17 (Th17) cells. HKL. johnsoniiincreased PD-L1 expression on the surface of type II conventional dendritic cells (cDC2) in HCT mice andin vitroin bone marrow-derived dendritic cells (BMDCs). HKL. johnsonii-exposed BMDCs also inhibited IL-17A secretion from co-cultured Th17 cells in a PD-1-dependent manner. Notably, when HKL. johnsoniiwas administered to HCT mice reconstituted with bone marrow cells from PD-1 knockout (KO) mice, which lack a PD-L1 mediated response, HKL. johnsonii-mediated reduction of pulmonary fibrosis was negated. Collectively, our findings demonstrate that HKL. johnsoniimitigates herpesvirus-induced pulmonary fibrosis in HCT mice by modulating cDC2 surface expression of PD-L1, which subsequently suppressesIl17aexpression in Th17 cells, pointing towards a potential postbiotic-based strategy for immunomodulation to address pulmonary complications of HCT.
3D bioprinting of low-viscosity phase-separated food-grade bioinks byin situself-assembly
Authors: Oliveira Sara M. , DeSantis Gabriel , Pastrana Lorenzo M.
Published: July 2024

There is a notable gap in the scientific understanding of the cellular role in cultured cell-based foods. Unravelling the effects of the interactions between ingredient micro/nanostructure and cells and their significance on nutrition and texture is of great importance. In addition, bioprinting methods face notable limitations in animal-free formulations and scale. Herein, we introduce a proof-of-concept bioprinting method based on thein situintegration of self-assembling events, allowing printing without supporting baths. Our approach enabled a food-grade 3D bioprinted model with 8.5 mm height and a hardness of 284 mN, supporting the early differentiation of myoblasts producing embryonic myosin heavy chain, after 7 days of differentiation. Cellular protein content increased up to 18-fold per initial cell without changes in construct texture. The method provides a novel concept to produce robust, cell-dense platforms for further research on food-grade bioprinted foods.
Xenon and nitrous oxide induced changes in resting EEG activity can be explained by systematic increases in the relaxation rates of stochastically driven alpha band oscillatory activity
Authors: Evertz Rick , Pelentritou Andria , Cormack John , Hicks Damien G , Liley David T. J.
Published: July 2024

Resting electroencephalographic activity is typically indistinguishable from a filtered linear random process across a diverse range of behavioural and pharmacological states, suggesting that the power spectral density of the resting electroencephalogram (EEG) can be modelled as the superposition of multiple, stochastically driven and independent, alpha band (8 - 13 Hz) relaxation oscillators. This simple model can account for variations in alpha band power and `1/f scaling' in eyes-open/eyes-closed conditions in terms of alterations in the distribution of the alpha band oscillatory relaxation rates. As changes in alpha band power and `1/f scaling' have been reported in anaesthesia we hypothesise that such changes may also be accounted for by alterations in alpha band relaxation oscillatory rate distributions. On this basis we choose to study the EEG activity of xenon and nitrous oxide, gaseous anaesthetic agents that have been reported to produce different EEG effects, notable given they are both regarded as principally acting via N-methyl-D-aspartate (NMDA) receptor antagonism. By recording high density EEG from participants receiving equilibrated step-level increases in inhaled concentrations of xenon (n = 24) and nitrous oxide (n = 20), alpha band relaxation rate (damping) distributions were estimated by solving an inhomogeneous integral equation describing the linear superposition of multiple alpha-band relaxation oscillators having a continuous distribution of dampings. For both agents, level-dependent reductions in alpha band power and spectral slope exponent (15-40 Hz) were observed, that were accountable by increases in mean alpha band damping. These shared increases suggest that, consistent with their identified molecular targets of action, xenon and nitrous oxide are mechanistically similar, a conclusion further supported by neuronal population modelling in which NMDA antagonism is associated with increases in damping and reductions in peak alpha frequency. Alpha band damping may provide an important link between experiment and theories of consciousness, such as the global neuronal network theory, where the likelihood of a globally excited state (`conscious percept'), is inversely related to mean damping.
Quantifying social roles in multi-animal videos using subject-aware deep-learning
Authors: Goss Kelly , Bueno-Junior Lezio S. , Stangis Katherine , Ardoin Théo , Carmon Hanna , Zhou Jie , Satapathy Rohan , Baker Isabelle , Jones-Tinsley Carolyn E. , Lim Miranda M. , Watson Brendon O. , Sueur Cédric , Ferrario Carrie R. , Murphy Geoffrey G. , Ye Bing , Hu Yujia
Published: July 2024

Analyzing social behaviors is critical for many fields, including neuroscience, psychology, and ecology. While computational tools have been developed to analyze videos containing animals engaging in limited social interactions under specific experimental conditions, automated identification of the social roles of freely moving individuals in a multi-animal group remains unresolved. Here we describe a deep-learning-based system – named LabGym2 – for identifying and quantifying social roles in multi-animal groups. This system uses a subject-aware approach: it evaluates the behavioral state of every individual in a group of two or more animals while factoring in its social and environmental surroundings. We demonstrate the performance of subject-aware deep-learning in different species and assays, from partner preference in freely-moving insects to primate social interactions in the field. Our subject-aware deep learning approach provides a controllable, interpretable, and efficient framework to enable new experimental paradigms and systematic evaluation of interactive behavior in individuals identified within a group.
Mutational Constraint Analysis Workflow for Overlapping Short Open Reading Frames and Genomic Neighbours
Authors: Danner Martin , Begemann Matthias , Kraft Florian , Elbracht Miriam , Kurth Ingo , Krause Jeremias
Published: July 2024

Understanding the dark genome is a priority task following the complete sequencing of the human genome. Short open reading frames (sORFs) are a group of largely unexplored elements of the dark genome with the potential for being translated into microproteins. The definitive number of coding and regulatory sORFs is not known, however they could account for up to 1-2% of the human genome. This corresponds to an order of magnitude in the range of canonical coding genes. For a few sORFs a clinical relevance has already been demonstrated, but for the majority of potential sORFs the biological function remains unclear. A major limitation in predicting their disease relevance using large-scale genomic data is the fact that no population-level constraint metrics for genetic variants in sORFs are yet available. To overcome this, we used the recently released gno-mAD 4.0 dataset and analysed the constraint of a consensus set of sORFs and their genomic neighbours. We demonstrate that sORFs are mostly embedded into a moderately constraint genomic context, but within the gencode dataset we identified a subset of highly constrained sORFs comparable to highly constrained canonical genes.
Characterization of eight newHydractiniai-cell markers reveals underlying heterogeneity in the adult pluripotent stem cell population
Authors: Waletich Justin , de Jong Danielle , Schnitzler Christine E.
Published: July 2024

Adult pluripotent stem cells are found in diverse animals, including cnidarians, acoels, and planarians, and confer remarkable abilities such as whole-body regeneration. The mechanisms by which these pluripotent stem cells orchestrate the replacement of all lost cell types, however, remains poorly understood. Underlying heterogeneity within the stem cell populations of these animals is often obscured when focusing on certain tissue types or life history stages, which tend to have indistinguishable spatial expression patterns of stem cell marker genes. Here, we focus on the adult pluripotent stem cells (i-cells) ofHydractinia symbiolongicarpus, a colonial marine cnidarian with distinct polyp types and stolonal tissue. Recently, a single-cell expression atlas was generated forH. symbiolongicarpuswhich revealed two distinct clusters with i-cell signatures, potentially representing heterogeneity within this species’ stem cell population. Considering this finding, we investigated eight new putative stem cell marker genes from the atlas including five expressed in both i-cell clusters (Pcna,Nop58,Mcm4,Ubr7, andUhrf1) and three expressed in one cluster or the other (Pter, FoxQ2-like,andZcwpw1). We characterized their expression patterns in various contexts–feeding and sexual polyps, juvenile feeding polyps, stolon, and during feeding polyp head regeneration–revealing context-dependent gene expression patterns and a transcriptionally dynamic i-cell population. We uncover previously unknown differences within the i-cell population ofHydractiniaand demonstrate that its colonial nature serves as an excellent system for investigating and visualizing heterogeneity in pluripotent stem cells.
Sexually dimorphic auditory representation inAedes aegyptibrains
Authors: Ohashi Takuro S. , Xu Yifeng Y.J. , Shigaki Shunsuke , Nakamura Yukiko , Lee Tai-Ting , Loh YuMin M. , Mishiro-Sato Emi , Eberl Daniel F. , Su Matthew P. , Kamikouchi Azusa
Published: July 2024

Male attraction to female flight sounds is a vital, reproducible component of courtship in many species of mosquitoes; however, female acoustic behaviours have proven challenging to define. To investigate sexual dimorphisms in acoustic behaviours, previous reports have largely focused on differences in mosquito peripheral ear anatomy and function. Whilst molecular investigations have recently begun on the auditory periphery, sexual dimorphisms in central processing of acoustic information have not yet been explored. Here we used a combination of neurotracing, calcium imaging and molecular analyses to examine sexual dimorphisms in auditory processing in the yellow fever mosquitoAedes aegypti. We identified shared and dimorphic neurons connecting male and female ears to the primary auditory processing centre in the brain, and defined multiple distinct neuronal clusters based on responses to auditory stimulation. We finally used transcriptomic and proteomic analyses to investigate the molecular factors underlying these differences, with motile ciliary-related terms significantly enriched in males.
A cancer immunotherapy modality based on dendritic cell reprogrammingin vivo
Authors: Ascic Ervin , Åkerström Fritiof , Sreekumar Nair Malavika , Rosa André , Kurochkin Ilia , Zimmermannova Olga , Catena Xavier , Rotankova Nadezhda , Veser Charlotte , Rudnik Michal , Ballocci Tommaso , Schärer Tiffany , Huang Xiaoli , de Rosa Torres Maria , Renaud Emilie , Velasco Santiago Marta , Met Özcan , Askmyr David , Lindstedt Malin , Greiff Lennart , Ligeon Laure-Anne , Agarkova Irina , Svane Inge Marie , Pires Cristiana F. , Rosa Fábio F. , Pereira Carlos-Filipe
Published: July 2024

Immunotherapy leads to long-term survival of cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cellsin vivoby adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced complete tumor regressions, and established long-term systemic immunity in different mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for first-in-human trials and other applications of immune cell reprogrammingin vivo.

One-Sentence Summary

Reprogramming of tumor cells to cDC1-like cellsin vivoelicits systemic and long-term antitumor immunity.
Unveiling Clonal Cell Fate and Differentiation Dynamics: A Hybrid NeuralODE-Gillespie Approach
Authors: Gao Mingze , Barile Melania , Chabra Shirom , Haltalli Myriam , Calderbank Emily F. , Chao Yiming , Laurenti Elisa , Gottgens Bertie , Huang Yuanhua
Published: July 2024

Recent lineage tracing single-cell techniques (LT-scSeq), e.g., the Lineage And RNA RecoverY (LARRY) barcoding system, have enabled clonally resolved interpretation of differentiation trajectories. However, the heterogeneity of clone-specific kinetics remains understudied, both quantitatively and in terms of interpretability, thus limiting the power of bar-coding systems to unravel how heterogeneous stem cell clones drive overall cell population dynamics. Here, we present CLADES, a NeuralODE-based framework to faithfully estimate clone-specific kinetics of cell states from newly generated and publicly available human cord blood LARRY LT-scSeq data. By incorporating a stochastic simulation algorithm (SSA) and differential expression gene (DEGs) analysis, CLADES yields cell division dynamics across differentiation timecourses and fate bias predictions for the early progenitor cells. Moreover, clone-level quantitative behaviours can be grouped into characteristic types by pooling individual clones into meta-clones. By benchmarking with CoSpar, we found that CLADES improves fate bias prediction accuracy at the meta-clone level. In conclusion, we report a broadly applicable approach to robustly quantify differentiation kinetics using meta-clones while providing valuable insights into the fate bias of cellular populations for any organ system maintained by a pool of heterogeneous stem and progenitor cells.
QuickFit: A high-throughput RT-qPCR-based assay to quantify viral growth and fitnessin vitro
Authors: Galvez Nicolas M.S. , Sheehan Maegan L. , Lin Allen Z. , Cao Yi , Lam Evan C. , Jackson Abigail M. , Balazs Alejandro B.
Published: July 2024

The quantification of viral growth rates is key to understanding evolutionary dynamics and the potential for mutants to escape antiviral drugs. Defining evolutionary escape paths and their impact on viral fitness allows for the development of drugs that are resistant to escape. In the case of HIV, combination antiretroviral therapy can successfully prevent or treat infection, but it relies on strict adherence to prevent escape. Here, we present a method that enables the quantification of viral fitness termed QuickFit, which employs large numbers of parallel viral cultures to accurately measure growth rates. QuickFit consistently recapitulated HIV growth measurements obtained by traditional approaches but with significantly higher throughput and lower error. This method represents a promising tool for rapid and consistent evaluation of viral fitness.
The Role of the Clinical Pharmacist in Addressing Drug-Related Problems in Stroke Patients in a Tertiary Care Centre
Authors: Philip Susan , George Jeesa , Kumar A Pramod , Begum Foujia , Divya Bharathi K
Published: July 2024

The morbidity, mortality, and diminished quality of life of patients are all impacted by drug-related problems. Stroke is one of the leading causes of disability and death in India and since the stroke patients are at an increased risk of DRPs (Drug Related Problems), early identification, prevention and resolution of the same is important for improving the quality of life of stroke patients. The aim of the study was to assess the incidence of DRPs in stroke patients by using Hepler-strand classification and the acceptance rate by the multidisciplinary team. The relevant information were documented using a predefined data collection form and was analyzed for drug related problems and categorized according to Hepler–Strand classification. A total of 510 DRPs from 130 participants with an average incidence of 3.92 DRPs per patient. Drug-drug interaction was found to be 23.53% and ADRs accounted for 12.55 % of total DRPs. The study found a high acceptance rate of recommendations by healthcare professionals at 97.36%, with changes in therapy being made 68.13% of the time. Early detection and resolution of DRP by clinical pharmacist may improve the therapeutic outcomes in stroke patients. This also helps in preventing complications and unnecessary hospitalization, high cost of treatment and deaths among stroke patients.
Psychometric characteristics of ADHD-T-5 in its Dari version among public primary school students in Kabul City, Afghanistan
Authors: Azimi Ziauddin , Wang Seok Mui , Khan Jesmine , Ismail Zaliha , Isa Mohamad Rodi
Published: July 2024

Introduction

One of the key instruments used to assess attention-deficit/hyperactivity disorder (ADHD) in children and adolescents is the ADHD Rating Scale-5. This study aimed to test the psychometric characteristics of the ADHD Rating Scale-5 teacher version (ADHD-T) in Dari among school-aged children in Kabul City.

Methods

Face and content validity, explanatory factor analysis (EFA), confirmatory factor analysis (CFA) and reliability of the questionnaire were conducted. The structure, validity, and reliability of the scales were evaluated using the translated versions of the ADHD-T questionnaires for the assessment of ADHD in children. Teachers completed the ADHD-T-Dari on behalf of three hundred and fifty-eight public primary school students.

Results

Face validity, content quality, and internal consistency of the ADHD-T-Dari were excellent. Significant collinearity was found between the items of the inattention and/or hyperactivity-impulsivity domains of the ADHD-T-Dari. The Kaiser-Meyer-Olkin index was 0.913 and was satisfactory. The two-factor model of the scale showed a better fit with an RMSEA of 0.065, a CMIN/dfof 20.501, and a CFI of 905 compared to the one- and three-factor models of ADHD-T-Dari. The Cronbach’s alpha for the total ADHD-T-Dari scale with 18 items was 0.898, while it was 0.851 and 0.847 for the inattention and/or hyperactivity-impulsivity subscales with 9 items each.

Conclusion

The exploratory and CFA showed that the psychometric qualities have strong concept validity and very good psychometric properties with good reliability. Therefore, the ADHD-T-Dari is valid, reliable, and suitable for the assessment of ADHD symptoms in Afghan school children and adolescents.
Self-Supervised Data-Driven Approach Defines Pathological High-Frequency Oscillations in Human
Authors: Zhang Yipeng , Daida Atsuro , Liu Lawrence , Kuroda Naoto , Ding Yuanyi , Oana Shingo , Kanai Sotaro , Monsoor Tonmoy , Duan Chenda , Hussain Shaun A. , Qiao Joe X , Salamon Noriko , Fallah Aria , Sim Myung Shin , Sankar Raman , Staba Richard J. , Engel Jerome , Asano Eishi , Roychowdhury Vwani , Nariai Hiroki
Published: July 2024

Objective

Interictal high-frequency oscillations (HFOs) are a promising neurophysiological biomarker of the epileptogenic zone (EZ). However, objective criteria for distinguishing pathological from physiological HFOs remain elusive, hindering clinical application. We investigated whether the distinct mechanisms underlying pathological and physiological HFOs are encapsulated in their signal morphology in intracranial EEG (iEEG) recordings and whether this mechanism-driven distinction could be simulated by a deep generative model.

Methods

In a retrospective cohort of 185 epilepsy patients who underwent iEEG monitoring, we analyzed 686,410 HFOs across 18,265 brain contacts. To learn morphological characteristics, each event was transformed into a time-frequency plot and input into a variational autoencoder. We characterized latent space clusters containing morphologically defined putative pathological HFOs (mpHFOs) using interpretability analysis, including latent space disentanglement and time-domain perturbation.

Results

mpHFOs showed strong associations with expert-defined spikes and were predominantly located within the seizure onset zone (SOZ). Discovered novel pathological features included high power in the gamma (30–80 Hz) and ripple (>80 Hz) bands centered on the event. These characteristics were consistent across multiple variables, including institution, electrode type, and patient demographics. Predicting 12-month postoperative seizure outcomes using the resection ratio of mpHFOs outperformed unclassified HFOs (F1=0.72 vs. 0.68) and matched current clinical standards using SOZ resection (F1=0.74). Combining mpHFO data with demographic and SOZ resection status further improved prediction accuracy (F1=0.83).

Interpretation

Our data-driven approach yielded a novel, explainable definition of pathological HFOs, which has the potential to further enhance the clinical use of HFOs for EZ delineation.
Gasdermin D-Mediated Neutrophil Pyroptosis drives Inflammation in Psoriasis
Authors: Liu Jian , Jiang YuYing , Diao ZiYue , Chen DanDan , Xia RuiYuan , Wang BingWei , Yang Shuo , Yin ZhiQiang
Published: July 2024

Psoriasis is a multifactorial immune-mediated inflammatory disease. Its pathogenesis involves abnormal accumulation of neutrophils and T-cell related abnormalities. Pyroptosis is a type of regulated cell death associated with innate immunity, but its role in psoriasis is unclear. In this study, we found thatgasdermin D (Gsdmd)is higher in human psoriatic skin than that in normal skin, and in imiquimod-induced psoriasis-like mouse skin, the expression ofGsdmdwas most significantly altered in neutrophils andIl1bwas also mainly expressed in neutrophils. Immunohistochemical staining of serial sections of skin lesions from psoriasis patients and healthy control also showed that GSDMD expression is higher in psoriasis lesion, especially in neutrophils.Gsdmddeficiency mitigates psoriasis-like inflammation in mice. GSDMD in neutrophils contributes to psoriasis-like inflammation, whileGsdmddepletion in neutrophils attenuates the development of skin inflammation in psoriasis and reduces the release of the inflammatory cytokines. We found that neutrophil pyroptosis is involved in and contributes to psoriasis inflammation, which provides new insights into the treatment of psoriasis by targeting neutrophil pyroptosis.
CAF to the rescue! Potential and challenges of combination antifungal therapy for reducing morbidity and mortality in hospitalized patients with serious fungal infections
Authors: Jacobs Samantha E. , Chaturvedi Vishnu
Published: July 2024

The global burden of invasive fungal disease (IFD) is substantial and escalating. Combination antifungal therapy (CAF) may improve patient outcomes by reducing development of resistance, improving drug penetration and rate of fungal clearance, and allowing for lower, less toxic antifungal drug doses; yet, increased cost, antagonism, drug-drug interactions, and toxicity are concerns. Clinical practice guidelines recommend antifungal monotherapy, rather than CAF, for most IFDs due to a lack of comparative randomized clinical trials. An examination of the existing body of CAF research should frame new hypotheses and determine priorities for future CAF clinical trials. We performed a systematic review of CAF clinical studies for invasive candidiasis, cryptococcosis, invasive aspergillosis, and mucormycosis. Additionally, we summarize findings from animal models of CAF and assess laboratory methods available to evaluate CAF efficacy. Future CAF trials should be prioritized according to animal models showing improved survival and observational clinical data supporting efficacy and safety.
Silence in physician clinical practice: a scoping review protocol
Authors: Kelly Martina Ann , Rivera Stefanie , McClurg Caitlin , Sweeney Catherine , Mosca Stephen , McLeod Ellen , Bennett Deirdre , Brown Megan
Published: July 2024

Objective

The objective of this review is to map, describe and conceptualize how silence is discussed within literature on interactions between physicians and patients, in clinical settings.

Methods

We will use the methodological framework of Arksey & O’Malley, adapted by Levac et al and Joanna Briggs Institute. Empirical studies including quantitative, qualitative, mixed methods, observational studies and reviews will be included. Commentaries, editorials, and grey literature will also be examined. The databases MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Scopus and Web of Science will be searched. A two-part study selection strategy will be applied. First, reviewers will follow inclusion and exclusion criteria based on ‘Population-Concept-Context’ framework to independently screen titles and abstracts. Next, full texts will be screened. Data will be extracted, collated, and charted to summarize methods, outcomes and key findings from the articles included.

Expected results and implications

This scoping review will provide an extensive description of how physicians engage with silence in clinical settings. Findings will identify how silence is perceived in physician patient interactions, the roles it plays, what factors influence use of silence and guide development of educational initiatives on use of silence in clinical settings.
Traditional Chinese Medicine Research Activity in Switzerland. A Systematic Review and Bibliometric Analysis
Authors: Chen Bingjun , Lyu Xiaoying , Lottenbach Koryna , Zeier Chantal , Jaminet Dominic , Solongo Sarangoo , Timo Hummel , Talia Wicker , Sevik Ahmet , Wang Xiaying , Hammes Michael , Li Yiming , Pradhan Saroj K. , Furian Michael
Published: July 2024

Importance

Traditional Chinese Medicine (TCM) becomes popular in Switzerland, however, Swiss TCM research activity and scientific output have not been investigated.

Objective

To describe the Swiss TCM research activities and main health conditions studied.

Data Source

A systematic literature search of PubMed and Embase was performed from database inception to December 31st, 2023.

Study Selection

Articles describing a TCM-related therapy modality in humans with at least one author affiliated with a Swiss institution.

Data Extraction

Primary and secondary outcomes, as well as study and author characteristics were extracted from included articles.

Main Outcomes and Measures

The main outcome was the main health condition studied. Secondary outcomes are the total number of articles published over time, the TCM therapies used, and the Swiss institutions involved.

Results

Of the 223 articles included, 68.2% of published articles originated from the top 3 of 73 (4.1%) Swiss institutions, namely the University of Zurich (32.3%), University of Bern (30.0%) and University of Basel (7.6%). Overall, 116 (52.0%) articles described original studies including 36 (31.0%) articles reporting findings from randomized clinical trials, 29 (25.0%) from cross-sectional studies, 20 (17.2%) from prospective cohort studies, 19 (16.4%) from case reports and 12 (10.3%) from retrospective studies. The top health categories studied were Pain Management (16.4%), Psychology and Behaviour (8.6%), Neurology (6.9%), and Oncology (6.9%). The most used TCM therapies were acupuncture or moxibustion (61.2%), combination of several treatments (15.5%), herbal medicine (10.3%), and Qi Gong or martial arts (9.5%).

Conclusion and Relevance

Until 2023, the total number of scientific TCM output by Swiss authors is steadily increasing but remains small. More effort to conducted TCM research and to elucidate the TCM therapy effects in Switzerland is warranted.

Registration

PROSPERO No. CRD42023432693.
Inhibitor-induced supercharging of kinase turnover via endogenous proteolytic circuits
Authors: Scholes Natalie S. , Bertoni Martino , Comajuncosa-Creus Arnau , Kladnik Katharina , Frommelt Fabian , Hinterndorfer Matthias , Razumkov Hlib , Prokofeva Polina , Schwalm Martin P. , Imrichova Hana , Barone Eleonora , Schätz Caroline , Rukavina Andrea , Koren Anna , Kubicek Stefan , Knapp Stefan , Gray Nathanael S. , Superti-Furga Giulio , Kuster Bernhard , Aloy Patrick , Winter Georg E.
Published: July 2024

Targeted protein degradation has emerged as a promising new pharmacological strategy. Traditionally, it relies on small molecules that induce proximity between a target protein and an E3 ubiquitin ligase to prompt target ubiquitination and degradation by the proteasome. Sporadic reports indicated that ligands designed to inhibit a target can also induce its destabilization. Among others, this has repeatedly been observed for kinase inhibitors. However, we lack an understanding of the frequency, generalizability, and mechanistic underpinnings of these phenomena. To address this knowledge gap, we generated dynamic abundance profiles of 98 kinases after cellular perturbations with 1570 kinase inhibitors, revealing 160 selective instances of inhibitor-induced kinase destabilization. Kinases prone to degradation are frequently annotated as HSP90 clients, thus affirming chaperone deprivation as an important route of destabilization. However, detailed investigation of inhibitor-induced degradation of LYN, BLK and RIPK2 revealed a differentiated, common mechanistic logic where inhibitors function by inducing a kinase state that is more efficiently cleared by endogenous degradation mechanisms. Mechanistically, effects can manifest by ligand-induced changes in cellular activity, localization, or multimerization which may be triggered by direct target engagement or network effects. Collectively, our data suggest that inhibitor-induced kinase degradation is a common event and positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.
Functional ultrasound imaging and neuronal activity: how accurate is the spatiotemporal match?
Authors: Lambert Théo , Niknejad Hamid Reza , Kil Dries , Brunner Clément , Nuttin Bart , Montaldo Gabriel , Urban Alan
Published: July 2024

Over the last decade, functional ultrasound (fUS) has risen as a critical tool in functional neuroimaging, leveraging hemodynamic changes to infer neural activity indirectly. Recent studies have established a strong correlation between neural spike rates (SR) and functional ultrasound signals. However, understanding their spatial distribution and variability across different brain areas is required to thoroughly interpret fUS signals. In this regard, we conducted simultaneous fUS imaging and Neuropixels recordings during stimulus-evoked activity in awake mice within three regions the visual pathway. Our findings indicate that the temporal dynamics of fUS and SR signals are linearly correlated, though the correlation coefficients vary among visual regions. Conversely, the spatial correlation between the two signals remains consistent across all regions with a spread of approximately 300 micrometers. Finally, we introduce a model that integrates the spatial and temporal components of the fUS signal, allowing for a more accurate interpretation of fUS images.
Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)
Authors: Sbrocco Kaelin , Borgenheimer Ella , Zhang Ying , Koob Mike , Cvetanovic Marija
Published: July 2024

The cerebellum role in cognition and its functional bi-directional connectivity with prefrontal cortex (PFC) is well recognized. However, how chronic cerebellar dysfunction affects PFC function and cognition remains less understood. Spinocerebellar ataxia type 1 (SCA1), is an inherited, fatal neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1) and characterized by severe loss of Purkinje cells (PCs) in the cerebellum. Patients with SCA1 suffer from movement and balance deficits, cognitive decline and premature lethality. Cognitive deficits significantly impact patients quality of life, yet how exactly cerebellar degeneration contributes to cognitive deficits and PFC dysfunction in SCA1 is unknown. We have previously demonstrated that expression of mutant ATXN1 only in cerebellar Purkinje cells (PCs) is sufficient to cause cognitive deficits in a transgenic ATXN1[82Q] mouse line. To understand how cerebellar dysfunction impacts the PFC, we examined neuronal activity, synaptic density, and gene expression changes in the PFC of ATXN1[82Q] mice. Remarkably, we found decreased neuronal activity, reduced synaptic density, and altered expression of immediate early genes and pathways involved in glucose metabolism, inflammation and amphetamine in the PFC of ATXN1[82Q] mice. Furthermore, we characterized cellular and molecular PFC dysfunction in a novel conditional knock-in SCA1 line, f-ATXN1146Q mice, expressing floxed human expanded ATXN1 throughout the brain. Intriguingly, we found an increased number of neurons, increased synaptic density and large gene expression alterations in the PFC of f-ATXN1146Q mice. Finally, to precisely determine the role of cerebellar dysfunction in cognitive deficits and PFC dysfunction in SCA1, we crossed f-ATXN1146Q mice with Pcp2-Cre mice expressing Cre recombinase in PCs to delete expanded ATXN1 only in PCs. Surprisingly, we have found that deleting expanded ATXN1 in PCs exacerbated cognitive deficits and PFC dysfunction in these mice. Our findings demonstrate that circumscribed cerebellar dysfunction is sufficient to impact PFC activity and synaptic connectivity impairing cognition. However, when multiple brain regions are impacted in disease, cerebellar dysfunction may ameliorate PFC pathology and cognitive performance.
In vivotests of theE. coliTonB system working model—interaction of ExbB with unknown proteins, identification of TonB-ExbD transmembrane heterodimers and PMF-dependent ExbD structures
Authors: Postle Kathleen , Kopp Dale , Jana Bimal
Published: July 2024

The TonB system ofEscherichia coliresolves the dilemma posed by its outer membrane that protects it from a variety of external threats, but also constitutes a diffusion barrier to nutrient uptake. Our working model involves interactions among a set of cytoplasmic membrane-bound proteins: tetrameric ExbB that serves as a scaffold for a dimeric TonB complex (ExbB4-TonB2), and also engages dimeric ExbD (ExbB4-ExbD2). Through a set of synchronized conformational changes and movements these complexes are proposed to cyclically transduce cytoplasmic membrane protonmotive force to energize active transport of nutrients through TonB-dependent transporters in the outer membrane (described in Gresock etal., J. Bacteriol. 197:3433). In this work, we provide experimental validation of three important aspects of the model. The majority of ExbB is exposed to the cytoplasm, with an ∼90-residue cytoplasmic loop and an ∼50 residue carboxy terminal tail. Here we found for the first time, that the cytoplasmic regions of ExbB served asin vivocontacts for three heretofore undiscovered proteins, candidates to move ExbB complexes within the membrane. Support for the model also came from visualization ofin vivoPMF-dependent conformational transitions in ExbD. Finally, we also show that TonB forms homodimers and heterodimers with ExbD through its transmembrane domainin vivo. This trio ofin vivoobservations suggest how and why solvedin vitrostructures of ExbB and ExbD differ significantly from thein vivoresults and submit that future inclusion of the unknown ExbB-binding proteins may bring solved structures into congruence with proposedin vivoenergy transduction cycle intermediates.
Prevalence of the Cefazolin Inoculum Effect (CzIE) in Nasal Colonizing Methicillin-SusceptibleStaphylococcus aureusin Patients from Intensive Care Units in Colombia and Use of a Modified Rapid Nitrocefin Test for Detection
Authors: Carvajal Lina P. , Rincon Sandra , Gomez-Villegas Sara I. , Matiz-González Juan M. , Ordoñez Karen , Santamaria Alejandra , Ospina-Navarro Leonardo , Beltran Jaime , Guevara Fredy , Mendez Yardany R. , Salcedo Soraya , Porras Alexandra , Valencia-Moreno Albert , Grennia Haley , Deyanov Alexander , Baptista Rodrigo , Tam Vincent H. , Panesso Diana , Tran Truc T. , Miller William R. , Arias Cesar A. , Reyes Jinnethe
Published: July 2024

The cefazolin inoculum effect (CzIE) has been associated with poor clinical outcomes in patients with MSSA infections. We aimed to investigate the point prevalence of the CzIE among nasal colonizing MSSA isolates from ICU patients in a multicenter study in Colombia (2019-2023). Patients underwent nasal swabs to assess forS. aureuscolonization on admission to the ICU and some individuals had follow-up swabs. We performed cefazolin MIC by broth-microdilution using standard and high-inoculum and developed a modified nitrocefin-based rapid test to detect the CzIE. Whole genome sequencing was carried out to characterize BlaZ types and allotypes, phylogenomics and Agr-typing. All swabs were subjected to 16S-rRNA metabarcoding sequencing to evaluate microbiome characteristics associated with the CzIE. A total of 352 patients were included; 46/352 (13%) patients were colonized withS. aureus; 22% (10/46) and 78% (36/46) with MRSA and MSSA, respectively. Among 36 patients that contributed with 43 MSSA colonizing isolates, 21/36 (58%) had MSSA exhibiting the CzIE. BlaZ type A and BlaZ-2 were the predominant type and allotype in 56% and 52%, respectively. MSSA belonging to CC30 were highly associated with the CzIE and SNP analyses supported transmission of MSSA exhibiting the CzIE among some patients of the same unit. The modified nitrocefin rapid test had 100%, 94.4% and 97.7% sensitivity, specificity and accuracy, respectively. We found a high prevalence point prevalence of the CzIE in MSSA colonizing the nares of critically-ill patients in Colombia. A modified rapid test was highly accurate in detecting the CzIE in this patient population.
Harnessing confounding and genetic pleiotropy to identify causes of disease through proteomics and Mendelian randomisation – ‘MR Fish’
Authors: Warwick Alasdair N , Hingorani Aroon D , Khawaja Anthony P , Gordillo-Marañón María , Olvera-Barrios Abraham , Stuart Kelsey V , Egan Catherine , Tufail Adnan , Sofat Reecha , Kuan Po Ai Valerie , Finan Chris , Schmidt Amand F
Published: July 2024

We propose an extension of the Mendelian randomisation (MR) paradigm (‘MR-Fish’) in which the confounded disease association of an index protein (‘the bait’) is harnessed to identify the causal role of different proteins (‘the catch’) for the same disease. Using C-reactive protein (CRP) as the bait,cis-MR analyses refuted a causal relationship of CRP with a wide range of diseases that associate with CRP in observational studies, including type 2 diabetes (T2DM) and coronary heart disease (CHD), suggesting these associations are confounded. Using ‘MR-Fish’, and leveraging large-scale proteomics data, we find evidence of a causal relationship with multiple diseases for several proteins encoded by genes that aretranshits in genome wide association analysis of CRP. These include causal associations of IL6R and FTO with CHD and T2DM; as well as ZDHHC18 with several circulating blood lipid fractions. Among the proteins encoded by genes that aretrans-for-CRP we identified 28 that are druggable. Our findings point to a general approach using MR analysis with proteomics data to identify causal pathways and therapeutic targets from non-causal observational associations of an index protein with a disease.
Out-of-pocket prescription medicine expenditure amongst community-dwelling adults: findings from The Irish Longitudinal Study on Ageing (TILDA) in 2016
Authors: Larkin James , Prendergast Ciaran , Murry Logan T. , Flood Michelle , Clyne Barbara , Burke Sara , Keegan Conor , Boland Fiona , Fahey Tom , Persaud Nav , Kenny Rose Anne , Moriarty Frank
Published: July 2024

Background The number of prescription medicines prescribed to older adults is increasing in Ireland and other countries. This is leading to higher out-of-pocket prescription medicine expenditure for older adults, which has several negative consequences including cost-related non-adherence. This study aimed to characterise out-of-pocket prescription medicine payments, and examine their relationship with entitlements, multimorbidity and adherence. Methods This cross-sectional study used 2016 data from a nationally-representative sample of adults in Ireland aged 50 years or less. Descriptive statistics and regression models were used to describe out-of-pocket prescription medicine payments and assess the association between out-of-pocket prescription medicine payments and the following variables: healthcare entitlements, multimorbidity, and cost-related non-adherence. Results There were 5,668 eligible participants. Median annual out-of-pocket prescription medicine expenditure was 144 euro (IQR: 0-312 euro). A generalised linear model showed that, amongst those with out-of-pocket prescription medicine expenditure, having fewer healthcare entitlements was associated with 4.74 (95% CI: 4.37-5.15) times higher out-of-pocket prescription medicine expenditure. Overall, 1.7% (n=89) of participants reported cost-related non-adherence in the previous year. A multivariable model found no significant associations between any variables and cost-related non-adherence. Conclusions Those with entitlements to subsidised prescription medicines had much lower out-of-pocket prescription medicine expenditure. This highlights the benefits of expanding healthcare entitlements and ensuring uptake of entitlements by those with eligibility.