bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating dietary quality among individuals aged 15 years and over by diabetes status in South Africa
Authors: Burgess Matthew , McGrath Nuala
Published: October 2024

Analysis of the 2016 South African Demographic and Health Survey (SADHS) estimated that 11.7% of individuals aged 15+ years had poor glycaemic control, despite only 4.7% reporting a previous diabetes diagnosis, and a further 64.5% had prediabetes. Diet-related lifestyle change has an important role in diabetes prevention and management, however entrenched racial and socioeconomic inequalities and increasing urbanisation may present barriers to a healthy diet. Using data from the 2016 SADHS we investigated whether dietary choices differ by diabetes status defined by previous diagnosis and survey HbA1c, and whether the diet of people living with diabetes (PLWD) differs by age, gender, ethnicity and wealth quintile. Reporting of fruit, vegetable, sugar-sweetened beverage, fruit juice and fast-food consumption was used to create an index of healthy diet. Ordered logistic regression modelling considering the proportional odds assumption was used to investigate the effect of diabetes status and sociodemographic status on healthy diet among the general population and PLWD. Concurrent low consumption of fruit, vegetables and fruit juice was the most common dietary pattern among both the general population and people living with diabetes, with high consumption of fast-food and sugar-sweetened beverage less common. Among the general population, previous diabetes diagnosis, age ≥55 years, non-black African ethnicity and being in the wealthiest quintile were significantly associated with increased odds of a healthier diet. Among PLWD, there was no association between previous diabetes diagnosis and healthy diet, high wealth remained significantly associated with a healthier diet, whilst female gender and having health insurance also became significantly associated with a healthier diet. Future public health interventions should focus on making fruit and vegetables more accessible to younger, black and socioeconomically poor populations, irrespective of diabetes status.
The illicit cigarette market in the Democratic Republic of the Congo (DRC): findings from a cross-sectional study of empty cigarette packs
Authors: Mdege Noreen Dadirai , Tchoupe Christelle , Pokothoane Retselisitsoe , Mirindi Didier , Miderho Christus Cito , Sams Kelley , Shamba Patrick , Kandate Emmanuel , Milambo Patrice , Ross Hana
Published: October 2024

This study aimed to estimate the proportion of cigarettes consumed in the Democratic Republic of the Congo (DRC) that are illicit and the extent of cigarette tax evasion; and to identify the origins of and factors associated with illicit cigarettes. Data were collected from May 15 to June 9, 2023. Stratified, multistage sampling was used to select 32 health areas from which empty cigarette packs were collected. Each collected pack was examined and classified as licit if it complied, or illicit if it did not comply, with the DRC’s tax stamp or written health warning requirements, or the requirements to have a notice indicating the prohibition of sale by/to minors or information on tar and nicotine content. We reported frequencies as numbers and percentages, and means for continuous variables. We performed regression analysis and used adjusted odds ratios (aOR) and their 95% confidence intervals (CI) to measure associations. 8.6% of the 10622 empty cigarette packs collected were illicit. All of the illicit packs were also identified as having evaded cigarette tax. Approximately 8.0% of the collected packs did not comply with written health warning requirements, 5.6% did not indicate the prohibition of sale by/to minors, and 4.5% did not have information on tar and nicotine content. Packs from low-income areas were more likely to be illicit than those collected from high-income areas (aOR 1.90; [95% CI: 1.48-2.43]). The likelihood of being an illicit cigarette increased with increasing susceptibility to armed conflict/insecurity. Packs from border provinces were less likely to be illicit than those from non-border provinces (aOR 0.48; [95% CI: 0.25-0.90]). Our results show that the illicit cigarette trade market in the DRC is currently small, and most illicit cigarettes are imported from other countries. There is a need to secure the cigarette supply chain, including strengthening border controls.
Analysis of the progression of cervical cancer in Guatemala- from pre-malignancy to invasive disease
Authors: Robinson Emma , Rodriguez Isabel , Argueta Victor , Xie Yi , Lou Hong , Milano Rose , Lee Hyo Jung , Burdett Laurie , Mishra Sambit K. , Yeager Meredith , Mirabello Lisa , Dean Michael , Orozco Roberto
Published: October 2024

To better understand cervical cancer progression, we analyzed RNA from 262 biopsies from women referred for colposcopy We determined HPV type and analyzed the expression of 51 genes. HPV31 was significantly more prevalent in precancer than stage 1 cancer and invasive cancer (p < 0.0001) and HPV16 increased in invasive disease (p < 0.0001).CCNE1, MELTF, andULBP2were significantly increased in HPV16-positive compared to HPV31 precancers whileNECTIN2andHLA-Eexpression decreased. Markers of the innate immune system, DNA repair genes, and cell cycle genes are significantly increased during cancer progression (p = 0.0001). In contrast, theTP53andRB1tumor suppressor gene expression is significantly decreased in cancer cells. TheT cell markersCD28andFLT3LGexpression decreased in cancer whileFOXP3, IDO1, andULBP2expression increased. There is a significantly higher survival rate in individuals with increased expression ofCD28(p = 0.0005),FOXP3(p = 0.0002),IDO1(p = 0.038),FLT3LG(p = 0.026),APOBEC3B(p = 0.0011), andRUNX3(p = 0.019), and a significantly lower survival rate in individuals with increased expression ofULBP2(p = 0.035). These results will help us understand the molecular factors influencing the progression of cervical precancer to cancer.
Age Prediction based on Blood DNA Methylation
Authors: Rui Liu , Pu Fan , Jing Zhang , Zhao Liu , Hao-yuan Mi
Published: October 2024

Objective

In the judicial field, traditional DNA methylation age prediction models have low accuracy and poor stability. Additionally, the use of linear regression models for detection is inefficient and costly. This study aims to utilize the prediction principles of the Support Vector Regression (SVR) model, based on preliminary laboratory data from blood DNA methylation detection using the Illumina 850K chip. By selecting low-dimensional and highly linear loci, we aim to establish a highly stable and accurate blood DNA methylation age prediction model.

Methods

This research is based on Illumina 850K chip technology. We conducted a literature review to select CpG sites and related primers, then employed SVR for model construction and age prediction. The model was built on the Matlab2022a platform. Standard parameters were selected, and optimal values for C and g were determined using grid search and cross-validation methods. During data processing, numerical values were normalized before calculation and de-normalized to obtain the predicted values.

Results

The constructed model achieved an R2of 0.91563 and a Mean Absolute Error (MAE) of 2.77 years. This indicates that the prediction accuracy for blood samples reached 91.56%, with an error of 2.77 years. Moreover, the accuracy of the model’s predictions decreases with increasing age.
Slow-wave sleep is associated with nucleus accumbens volume in elderly adults
Authors: Bán Kitti , Nárai Ádám , Báthori Noémi , Bankó Éva M. , Bihari Adél , Tomacsek Vivien , Kovács Tibor , Weiss Béla , Hermann Petra , Simor Péter , Vidnyánszky Zoltán
Published: October 2024

Slow-wave sleep (SWS) is essential for restorative neural processes, and its decline is associated with both healthy and pathological ageing. Building on previous rodent research, this longitudinal study identified a significant association between nucleus accumbens (NAcc) volume and SWS duration in cognitively unimpaired older adults. Our findings support the involvement of the NAcc in ageing-related modulation of SWS and suggest potential therapeutic targets for improving SWS.
Adiponectin Signaling Regulates Urinary Bladder Function by Blunting Smooth Muscle Purinergic Contractility
Authors: Luo Zhaobo , Wu Ali , Robson Simon , Alper Seth , Yu Weiqun
Published: October 2024

Lower urinary tract symptoms (LUTS) affect ∼ 50% of the population aged >40 years and are strongly associated with obesity and metabolic syndrome. Adipose tissue plays a key role in obesity/metabolic syndrome by releasing adipokines that regulate systemic energy/lipid metabolism, insulin resistance, and inflammation. Adiponectin (ADPN), the most abundant adipokine, modulates energy/metabolism homeostasis through its insulin-sensitizing and anti-inflammatory effects. Human plasma ADPN levels are inversely associated with obesity and diabetes. The role of adipokines such as ADPN in the LUTS associated with obesity/metabolic syndrome remains unknown. We have tested such a possible role in a global ADPN knockout mouse model (Adpn−/−).Adpn−/−mice exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle (BSM) contractility with absence of purinergic contraction. Molecular examination indicated significantly altered metabolic and purinergic pathways. The ADPN receptor agonist AdipoRon was found to abolish acute BSM contraction. Intriguingly, both AMPK activators and inhibitors also abolished BSM purinergic contraction. These data indicate the important contribution of a novel ADPN signaling pathway to the regulation of BSM contractility. Dysregulation of this ADPN signaling pathway might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome.

ARTICLE HIGHLIGHTS

Lower urinary tract symptom (LUTS) is strongly associated with obesity and metabolic syndrome, however, the underlying molecular mechanisms are missing. Dysregulation of adipokine signaling could be the link for this association.

Whether adiponectin, the most abundant adipokine, plays a role in regulating bladder function and dysfunction.

Mice null for adiponectin exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle contractility, with corresponding metabolic and purinergic pathway changes.

Dysregulation of adiponectin signaling might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome.
Optical Clearing with Tartrazine Enables Deep Transscleral Imaging with Optical Coherence Tomography
Authors: Narawane Amit , Trout Robert , Viehland Christian , Kuo Anthony N. , Vajzovic Lejla , Dhalla Al-Hafeez , Toth Cynthia A.
Published: October 2024

Suprachoroidal injections are a relatively new method of drug delivery to treat retinal disease. At present, it is difficult to visualize the distribution of injection-delivered product beneath the sclera into the suprachoroidal space. Imaging the suprachoroidal space with OCT is hindered by scattering of light from densely packed collagen fibers of the sclera, limiting depth penetration of the OCT light. In this Letter, we demonstrate the first use of tartrazine (Yellow 5) as an optical clearing agent for suprachoroidal research imaging with OCT in anex vivoeye model. Our results show that this clearing agent dramatically improves visualization of the choroid and suprachoroidal space with transscleral OCT and allows for improved imaging of the location and extent of delivered suprachoroidal fluid. We believe these methods will enable use of optical techniques such as OCT to image through a variety of previously optically inaccessible, highly scattering tissue samples.
Dietary control of peripheral adipose storage capacity through membrane lipid remodelling
Authors: Tol Marcus J. , Shimanaka Yuta , Bedard Alexander H. , Sapia Jennifer , Cui Liujuan , Colaço-Gaspar Mariana , Hofer Peter , Ferrari Alessandra , Qian Kevin , Kennelly John P. , Lee Stephen D. , Gao Yajing , Xiao Xu , Gao Jie , Mack Julia J. , Weston Thomas A. , Pan Calvin , Lusis Aldons J. , Williams Kevin J. , Su Baolong , Pike Daniel P. , Reed Alex , Milosevich Natalia , Cravatt Benjamin F. , Arita Makoto , Young Stephen G. , Ford David A. , Zechner Rudolf , Vanni Stefano , Tontonoz Peter
Published: October 2024

Complex genetic and dietary cues contribute to the development of obesity, but how these are integrated on a molecular level is incompletely understood. Here, we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, a membrane-bound O-acyltransferase that enriches diet-derived omega-6 (n-6) polyunsaturated fatty acids (PUFAs) in the phospholipidome. In high-fat diet–fed mice, lowering membranen-6 PUFA levels by adipocyte-specificLpcat3knockout (Lpcat3AKO) or by dietary lipid manipulation leads to dysfunctional triglyceride (TG) storage, ectopic fat deposition and insulin resistance. Aberrant lipolysis of stored TGs inLpcat3AKOadipose tissues instigates a non-canonical adaptive response that engages a futile lipid cycle to increase energy expenditure and limit further body weight gain. Mechanistically, we find that adipocyte LPCAT3 activity promotes TG storage by selectively enrichingn-6 arachidonoyl-phosphatidylethanolamine at the ER–lipid droplet interface, which in turn favours the budding of large droplets that exhibit greater resistance to ATGL-dependent hydrolysis. Thus, our study highlights the PPARγ–LPCAT3 pathway as a molecular link between dietaryn-6 PUFA intake, adipose expandability and systemic energy balance.
Evaluation of current practice of antimicrobial use and clinical outcome in the management of children with pneumonia admitted to Jimma Medical Center, Southwest Ethiopia: A prospective observational study
Authors: Wariyo Guyo Abduba , Teshome Derese Berhanu
Published: October 2024

Background

Antimicrobial resistance is a global crisis that threatens to reverse a century of medical progress; threatening the effective prevention and treatment of common infectious diseases.

Objectives

To evaluate the current practices of antimicrobial utilization and clinical outcomes of children with pneumonia admitted to Jimma Medical Center, Ethiopia.

Method

A prospective observational study design was conducted on children admitted to the pediatric wards of Jimma Medical Center. The study was conducted from February 03, 2022, to June 03, 2022, and patients aged < 18 years and diagnosed with pneumonia were included. A chart review supplemented by a self-administered questionnaire was used to collect data. Descriptive statistics and binary logistic regressions were performed for data analyses.

Results

Among the total of 146 patients, 61.6% were male, and the mean age was 40.95 (+47.61) months. Microbiologically and radiologically examined patients were 47(32.19%) and 64 (43.8%), respectively. All the treatment approaches were found to be initiated empirically. Ceftriaxone was the most commonly prescribed antimicrobial. In-hospital mortality was 7.5%. Pre-admission antimicrobial use (AOR =3.87; 95% CI:1.34-11.16; P=0.012), antimicrobial change (AOR = 3.74; 95% CI: 1.522-9.22; P=0.004), and hospital stay (> 10 days) (AOR = 6.00; 95% CI: 2.53-14.22; P=0.029) were all independent predictors of poor clinical outcome.

Conclusion

An empirically initiated antimicrobial was completed without sufficient evidence of indication, such as microbiological and radiographic findings. More than one-fourth of the patients treated for pneumonia experienced poor outcomes, implicating the need for more attention during treatment.
At-home wearables and machine learning capture motor impairment and progression in adult ataxias
Authors: Manohar Rohin , Yang Faye X. , Stephen Christopher D. , Schmahmann Jeremy D. , Eklund Nicole M. , Gupta Anoopum S.
Published: October 2024

A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behavior.

Here we test whether movement-building block characteristics (i.e., submovements), obtained from the wrist and ankle during natural behavior at home, can sensitively capture disease progression in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis (ALS) and ataxia telangiectasia (A-T).

Remotely collected cross-sectional (n= 76) and longitudinal data (n= 27) were analyzed from individuals with ataxia (SCAs 1, 2, 3, and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal ALS data to optimize sensitivity to change, were also evaluated.

All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, strongly separated ataxia and control populations, and had high within-week reliability. The composite outcomes trained on longitudinal ALS data most strongly captured disease progression over time.

These data demonstrate that outcome measures based on accelerometers worn at home can accurately capture the ataxia phenotype and sensitively measure disease progression. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.
Knowledge, Attitude, and Practices Regarding Dengue Infection: A Community-Based Study in Rural Cox’s Bazar
Authors: Prue Ely , Husna Al Asmaul , Rokony Shazia , Thowai Aung Sain , Moulee Shahra Tanjim , Jahan Afsana , Khatun Aysha , Sarkar Moloy , Bibi Saima , Tabassum Tahsin Tasneem , Nurunnabi Mohammad
Published: October 2024

Introduction

Dengue, an emerging infectious disease spread by mosquitoes, poses a significant public health challenge, especially in tropical and subtropical areas like Bangladesh.

Methods

We conducted a community-based cross-sectional study to assess the levels of knowledge, attitude, and practice (KAP) towards dengue infection among 484 adult rural people in the purposively selected Shikderpara and Muhuripara villages, Cox’s Bazar. Face-to-face interviews were performed at the convenience of study participants using a pretested, semi-structured questionnaire.

Results

The mean age of participants were 33.3±13.5 years, with the majority (53.9%) extending between 18 and 34 years. About two-thirds (72.9%) of the residents were literate. Most participants demonstrated average knowledge (84.3%), a positive attitude towards dengue infection (63.0%), and average prevention practices (57.2%). There was a significant association between participants’ practice levels and their knowledge and attitude (p<0.05), along with a statistically significant correlation between their knowledge and dengue prevention practices (p<0.05).

Conclusion

Although the attitude toward dengue infection was positive, knowledge and practices were average. This can be improved by promoting community participation and implementing comprehensive public health measures at all levels.

Categories

Communicable Disease, Emerging Public Health Issue.
Combination of radiosensitivity index and PD-L1 status predicts overall survival of endometrial cancer patients treated with radiotherapy: A study based on TCGA data
Authors: Xu Shaohua
Published: October 2024

Identifying biomarker for the clinical outcome of patients with endometrial cancer (EC) after radiotherapy is helpful to optimize treatment. The predictive efficacy of the combination of radiosensitivity index (RSI) and programmed cell death ligand 1 (PD-L1) should be investigated. The endometrial cancer cohort contained 225 patients received radiotherapy, and 285 patients who did not receive radiotherapy was downloaded from The Caner Genome Atlas (TCGA) and divided into radiosensitive (RS) and radioresistant (RR) groups according RSI. The EC patients were further classified into PD-L1-high and PD-L1-low groups according to the median value of CD274 mRNA expression. Cox proportional hazards regression and Kaplan-Meier analysis for overall survival were performed. The differently expressed analysis, gene set enrichment analysis and immune cell infiltration were performed. Among EC patients in the TCGA dataset, a group characterized by radioresistance and low PD-L1 status (PD-L1-high-RR group) was identified. Kaplan-Meier analysis showed EC patients in the RR-PD-L1-low group had significantly worse overall survival than those in the other groups when received radiotherapy (p=0.0006). Cox proportional hazards regression showed patients in the RR-PD-L1-low group were significantly associated with a poor of overall survival (HR=3.79; 95% CI=1.43-6.23; p=0.007) when received radiotherapy. MAPK signaling pathway was differently enriched in RR-PD-L1-high group. CD8+ T cell and M1 macrophage were lower infiltration in RR-PD-L1-high group, whereas M2 macrophage was more infiltration in RR-PD-L1-high group. The combination of RSI and PD-L1 may serve a predictive tool to identify EC patients who benefit from radiotherapy, especially combined immunotherapy.
BOLD Amplitude Correlates of Preclinical Alzheimer’s Disease
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Brown Christopher A. , Flamporis Melissa , Lane Jacqueline , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A.
Published: October 2024

Alzheimer’s disease (AD) is characterized by a long preclinical stage during which molecular markers of amyloid beta and tau pathology rise, but there is minimal neurodegeneration or cognitive decline. Previous literature suggests that measures of brain function might be more sensitive to neuropathologic burden during the preclinical stage of AD than conventional measures of macrostructure, such as cortical thickness. However, among studies that used resting-state functional Magnetic Resonance Imaging (fMRI) acquisitions with Blood Oxygenation Level Dependent (BOLD) contrast, most employed connectivity-based analytic approaches, which discard information about the amplitude of spontaneous brain activity. Consequently, little is known about the effects of amyloid and tau pathology on BOLD amplitude. To address this knowledge gap, we characterized the effects of preclinical and prodromal AD on the amplitude of low-frequency fluctuations (ALFF) of the BOLD signal both at the whole-brain level and, at a more granular level, focused on subregions of the medial temporal lobe. We observed reduced ALFF in both preclinical and prodromal AD. In preclinical AD, amyloid positivity was associated with a spatially diffuse ALFF reduction in the frontal, medial parietal, and lateral temporal association cortices, while tau pathology was negatively associated with ALFF in the entorhinal cortex. These ALFF effects were observed in the absence of observable macrostructural changes in preclinical AD and remained after adjusting for structural atrophy in prodromal AD, indicating that ALFF offers additional sensitivity to early disease processes beyond what is provided by traditional structural imaging biomarkers of neurodegeneration. We conclude that ALFF may be a promising imaging-based biomarker for assessing the effects of amyloid-clearing immunotherapies in preclinical AD.
NAD+- and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models
Authors: Ai Ruixue , Mao Lipeng , Jin Xurui , Zhang Shi-qi , Pan Junping , Lagartos Maria Jose Donate , Cao Shu-Qin , Yang Guang , Xie Chenglong , Kang Xiongbin , Wang Pingjie , Hu Yang , Bergersen Linda Hildegard , Storm-Mathisen Jon , Kuroyanagi Hidehito , Doncel Beatriz Escobar , González Noemí Villaseca , Chaudhry Farrukh Abbas , Wang Zeyuan , Zhang Qiang , Niu Zhangming , Chen Guobing , Luo Oscar Junhong , Fang Evandro Fei
Published: October 2024

Aberrant alternative splicing (ASEs) is an aging hallmark to Alzheimer’s Disease (AD). Although NAD+and related metabolites can slow down AD, NAD+on ASEs in AD remain unclear. Mouse transcriptomic data revealed NR-induced ASEs, focusing on the Eva1-C locus. AI-based algorithms predicted EVA1-C protein structures and protein-protein interactions. AD postmortem brain samples and tauopathy models including transgenic mice and worm was used for validation. NAD+abundance/metabolic status modulates ASEs and the expression of EVA1-C isoforms, which in turn regulate the interaction with BAG-1 and HSP70 proteins. Importantly, EVA1-C is dramatically reduced in 20 Braak 5/6 AD patients compared to cognitive normal humans in different brain regions. NAD+metabolism modulates abundance of specific mRNA isoforms, and that ASEs influence disease progression in model tauopathies and potentially AD. These results could facilitate future development of NAD+-based splice-switching therapeutics for AD.

Teaser

Unveiling the Link Between NAD+Metabolism and Alzheimer’s Disease: Discovering the Role of Alternative RNA Splicing in Disease Progression and Potential Therapeutic Targets
Evaluation of Tumor-colonizingSalmonellaStrains using the Chick Chorioallantoic Membrane Model
Authors: Mon Khin K. Z. , Kenney Linda J.
Published: October 2024

The chick embryo chorioallantoic membrane (CAM) tumor model is a valuable preclinical model for studying the tumor colonizing process ofSalmonella entericaserovar Typhimurium. It offers advantages such as cost-effectiveness, rapid turnaround, reduced engraftment issues, and ease of observation. In this study, we explored and validated the applicability of the partially immune-deficient CAM tumor model. Herein, we demonstrate thatSalmonellapreferentially colonizes tumors and directly causes tumor cell death. Bacterial migration, tumor colonization, and intra-tumor distribution did not require flagellar-mediated motility. The vast majority ofSalmonellathat colonized the CAM tumor were extracellular. Thus, tumor invasion was independent of both SPI1– and SPI2-encoded type three secretion systems. Surprisingly, the extracellular residence ofSalmonellaon CAM tumors did not require biofilm formation. We evaluated our wild-type parental strain compared to the attenuated clinical strain VNP20009 and discovered a reduced tumor colonization capability of VNP20009. The inability to effectively colonize CAM tumors potentially explains the reduced anti-tumor efficacy of VNP20009. Our work establishes the xenograft CAM model as an informative and predictive screening platform for studying tumor-colonizingSalmonella.

IMPORTANCE

Cancer has a major impact on society, as it poses a significant health burden to human populations worldwide.SalmonellaTyphimurium has demonstrated promise in cancer treatment by exerting direct tumoricidal effects and enhancing host-mediated anti-tumor immunity in xenograft mouse studies. A general understanding of its pathogenesis and the relative ease of genetic manipulation support the development of attenuated strains for therapeutic use. Alternativein ovomodels such as the CAM tumor model present a suitable screening platform to accelerate the development of therapeutic strains. It allows for rapid evaluation ofSalmonellastrains to assess their efficacy and potential as oncolytic agents. The present study establishes that thein ovotumor model can be utilized as a preclinical tool for evaluating oncolyticSalmonella, bridging the gap betweenin vitroandin vivoscreening.
The Role of Ethics in Physiotherapy: A Scoping Review Protocol
Authors: Bertoni Gianluca , Patuzzo Manzati Sara , Pagani Federica , Testa Marco , Battista Simone
Published: October 2024

Background and aims

Ethical considerations play a crucial role in physiotherapy, influencing patient care, professional conduct, and clinical decision-making. Despite its significance, there is a limited comprehensive understanding of how ethical principles are applied in physiotherapy practice. The evolving nature of the field, alongside advancements in treatment approaches, presents new ethical challenges that require systematic investigation. This scoping review aims to map the existing literature on ethical issues within physiotherapy, identify research methodologies, and highlight knowledge gaps.

Method

This review will follow the methodological framework proposed by the Joanna Briggs Institute (JBI) for scoping reviews and will be reported following the PRISMA for Scoping Reviews guidelines. A comprehensive search will be conducted on PubMed, Medline, Embase, CINAHL, PsychInfo, Cochrane Central, and Pedro. The gray literature will be consulted. Studies involving physiotherapists and those addressing ethical issues in physiotherapy practice will be included. Data extraction will be based on a standardized form, and a narrative synthesis will categorize the ethical issues and principles.

Discussion

The review will provide a broad overview of ethical issues and principles in physiotherapy. It will inform future research priorities, guide ethical training for practitioners, and support the development of policies and guidelines to improve ethical shared decision-making in physiotherapy practice.
How the COVID-19 pandemic affected lifestyle and wellbeing factors associated with dementia risk in older adults with Subjective Cognitive Decline and Mild Cognitive Impairment participating in the APPLE-Tree (Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce) in England
Authors: Wright Annie Mae , Demnitz-King Harriet , Burton Alexandra , Morse Rachel M. , Alberts Sweedal , Kenten Charlotte , Jeraldo Rosario Isabel Espinoza , Poppe Michaela , Barber Julie , Cooper Claudia
Published: October 2024

The COVID-19 pandemic negatively affected known dementia risk factors and cognition in older adults. We invited adults with mild cognitive concerns without dementia, aged ≥60 years participating in a randomised controlled trial of a psychosocial, secondary dementia prevention intervention, to complete a co-designed, semi-structured qualitative survey, regarding how the pandemic impacted their lifestyle and wellbeing in areas relevant to dementia risk: social connections, activities, diet, mental and physical health, community and family support. Data was collected between October 2020 and December 2022; we conducted manifest content analysis.

551/746 trial participants completed the survey. Most (n=530, 96%) described pandemic-related changes to lifestyle or wellbeing; two thirds (n=369/545, 67.7%) reported less activities. A quarter (n=145, 26.8%) identified no change in social connections, with others reporting less in-person meetings (n=139, 25.7%) or speaking to less people (n=99; 18.2%); a minority engaged in compensatory online activities (n=31, 5.7%) and online (n=63, 11.6%) or phone (n=90, 16.6%) social contact. Relatively few reported weight gain (n=22, 4.0%); two-thirds reported no change in their diet (n=360, 66.1%), with others eating more unhealthy food (n=31, 4.8%), more food (n=21, 3.9%) and/or snacks (n=11, 2.0%); others reporting more healthy eating (n=26, 4.8%) and/or more home cooking (n=57, 10.5%). Modes of support changed, with reliance on food parcels, online services and shopping by neighbours. Over half reported (almost exclusively negative) mental health pandemic-related changes (n=307, 56.9%), including depression, stress, fear and loneliness; many reported declines in physical health (n=153, 28.1%) and/or fitness (n=70, 12.8%).

Stoical accounts of adaptation and resilience, enabled by technology and community support predominated, but were not possible for all. Reducing the digital divide, tackling loneliness and developing inclusive online/in-person support programmes that are more resilient in future lockdowns could protect cognitively frail people now and in any future pandemic, and contribute to national dementia prevention strategy.

Trial registration:ISRCTN17325135;https://doi.org/10.1186/ISRCTN17325135(27.11.19)
Disentangling the relationship between fibromyalgia and insomnia: A bidirectional two-sample Mendelian random analysis
Authors: Gao Jin , Pan Liangke , Pan Zhenglun
Published: October 2024

Objective

Fibromyalgia (FM) and insomnia frequently coexist, but whether FM is an independent causal risk factor for insomnia, and/or vice versa, remains unclear. We investigated the bidirectional causal relationship between FM and insomnia.

Methods

Genome-wide association studies (GWAS) summary statistics on FM [sample size = 416,757 (2689 cases; 299,606 controls) (FinnGen)] and insomnia [sample size = 462,341 (UK Biobank)] were used. The possible causal relationships were assessed by bi-directional MR analysis. The major analysis method of MR was performed using inverse-variance weighted (IVW), supplemented by MR-Egger, weighted median, weighted mode and simple mode approaches. In addition, sensitivity analyses including Cochran’s Q test, MR-Egger intercept test, and the leave-one-out test were conducted to ensure the stability of the results.

Results

There was strong evidence to suggest insomnia is a risk factor for FM (odds ratio (OR) 7.65, 95% confidence interval (CI) 3.17-18.45, p = 5.85E-06). We found no evidence that genetic liability to FM increases insomnia (OR = 1.00, 95% CI 0.99-1.01, p = 0.99)

Conclusions

This study provides evidence in support of a causal relationship between insomnia and increased risk of FM, whilst overcoming the major limitations of previous epidemiological studies. Interventions for insomnia may be an effective strategy to prevent or reduce the burden of FM. Extended study needs to be performed with multi-center, large-scale GWAS cohort studies to re-evaluate the association between FM and insomnia in future.
Genome Analyses of A Worldwide Multisource Collection ofKlebsiella variicolaReveal Adaptation Relevant for Human Infection
Authors: Wang Jiayu , Coipan Claudia E. , Franz Eelco , Kuiper Ed , Wessels Els , Gally David L. , Vasudevan Karthick , Veerarhagavan Balaji , Farzana Refath , Holden Nicola , Zadoks Ruth , Higgins Paul G. , Schneiders Thamarai
Published: October 2024

Abstract

Klebsiella variicola(K.var), part of theKlebsiella pneumoniae(K.pne) species complex, is an emerging human pathogen originally associated with plants. Phylogenomic analyses of a global dataset of isolates categorised as human, animal, plant, or environmental strains suggest thatK.varare broadly disseminated regardless of hosts or habitats and exhibit genomic variability that is relevant for occupying and transmitting within and across multiple sources. Ancestral state analyses confirm thatK.varare originally derived from non-human sources. Genome-wide association analyses of human versus non-human isolates ofK.varindicate isolates from human origins are linked to the loss of cold-shock response genes such aslpxPandcspB. Importantly, humanK.varisolates also showed enriched antimicrobial resistance gene content and diversity acquired through mobile genetic elements, horizontal gene transfer and mutations within the chromosomal loci which underscore the impact of antimicrobial exposure and proximity to antibiotic resistantK.pnein nosocomial environments. Capsular profiles ofK.varsuggest high levels of variability in gene composition and indicate that gene functionality forwcaJin capsule formation differs betweenK.varandK.pne. Although capsular specialisation was not observed in a host/habitat or lineage-dependent manner, human isolates harbour, on average, a higher siderophore gene content in addition tomrkDmutations which impact on fimbriae and biofilm formation. There is limited evidence of any specificK.varlineages exhibiting convergence of both virulence and antimicrobial resistance genotypes which suggest that these attributes are evolving independently in clinical strains. Our work highlights that gene attrition and acquisition provide a basis for adaptation ofK.varas human pathogens. The broad distribution and evolution ofK.varhighlight the need for improved diagnostic precision and surveillance under a One Health framework.
Operate a Cell-Free Biofoundry using Large Language Models
Authors: Hérisson J. , Hoang A. N. , El-Sawah A. , Khalil M. M. , Faulon J.-L.
Published: October 2024

In this paper, we present a novel approach to optimizing cell-free protein synthesis (CFPS) systems using artificial intelligence (AI), specifically leveraging ChatGPT-4 for code generation and active learning (AL). This study aims to automate and enhance the process of producing antimicrobial proteins, namely colicin M and colicin E1, in CFPS systems. We developed an automated workflow that employs an iterative Design-Build-Test-Learn (DBTL) cycle, integrating a newly implemented AL method with cluster margin (CM) selection to efficiently explore experimental conditions. The workflow components, including modules for sampling, plate design, instruction generation, and data analysis, were coded using ChatGPT-4 without further human modification. By employing this automated approach, significant improvements in protein yields were achieved, with a 9-fold increase for colicin M and a 3-fold increase for colicin E1 compared to standard buffer compositions. The use of LLMs in conjunction with AL demonstrated the potential of AI-driven methodologies to accelerate the optimization of complex biological processes and reduce manual intervention. The study also discusses limitations such as variability in CFPS and suggests future improvements in automation, reproducibility, and integration of diverse liquid handling systems to further enhance the scalability and efficiency of cell-free biofoundries.
Soluble guanylyl cyclase, the NO-receptor, regulates endothelium-dependent vascular relaxation via its transnitrosation activity
Authors: Younis Waqas , Cui Chuanlong , Sadeghian Tanaz , Burboa Pia , Shu Ping , Qin Yong , Xie Lai-Hua , Gallardo Mauricio Lillo , Beuve Annie
Published: October 2024

We previously demonstrated that the NO-receptor soluble guanylyl cyclase (GC1) has the ability to transnitrosate other proteins in a reaction that involves, in some cases, oxidized Thioredoxin 1 (oTrx1). This transnitrosation cascade was establishedin vitroand we identified by mass spectrometry and mutational analysis Cys 610 (C610) of GC1 α-subunit as a major donor of S-nitrosothiols (SNO). To assay the relevance of GC1 transnitrosation under physiological conditions and in oxidative pathologies, we studied a knock-in mouse in which C610 was replaced with a serine (KI αC610S) under basal or angiotensin II (Ang II)–treated conditions. Despite similar GC1 expression and NO-stimulated cGMP-forming activity, the Ang II-treated KI mice displayed exacerbated oxidative pathologies including higher mean arterial pressure and more severe cardiac dysfunctions compared to the Ang II-treated WT. These phenotypes were associated with a drastic decrease in global S-nitrosation and in levels of SNO-Trx1 and SNO-RhoA in the KI mice. To investigate the mechanism underlying the dysregulation of blood pressure despite an intact NO-cGMP axis, pressure myography andin vivointravital microscopy were conducted to analyze the vascular resistance tone. Both approaches indicated that, even in the absence of oxidative stress, the single mutation C610S led to a significant deficiency in acetylcholine-induced vasorelaxation while smooth muscle relaxation in response to NO remained unchanged. These findings indicate that the C610S mutation uncoupled the two NO signaling pathways involved in the endothelium and smooth muscle vasorelaxation and suggest that GC1-dependent S-nitrosation is a key player in endothelium-derived hyperpolarization.
Frem2Knockout Mice Exhibit Fraser Syndrome Phenotypes and Neonatal Lethality Due to Bilateral Renal Agenesis
Authors: Simikyan Rubina G. , Zhang Xinyuan , Strelkova Olga , Li Nathan , Zhu MengYu , Eckhard Andreas , Baranov Petr Y. , Wu Xudong , Richey Lauren , Indzhykulian Artur A.
Published: October 2024

Fraser syndrome is a rare autosomal recessive disorder characterized by multiple congenital malformations, including cryptophthalmos, syndactyly, and renal agenesis, which can lead to severe complications beginning at the embryonic stage. Mutations in genes encoding extracellular matrix proteins such as FRAS1, FREM1, FREM2, and the associated trafficking protein GRIP1, are implicated in Fraser syndrome. These proteins are critical for maintaining epithelial integrity during embryogenesis, with deficiencies leading to tissue detachment and blistering phenotypes in mouse models. The FREM2 protein is a single-pass membrane protein of 3169 amino acids. While FREM2-deficient mouse models encoding missense variants found in patients, or a truncated FREM2 protein product were previously reported, it has not been studied in a constitutive knockout (KO) mouse model.

Here, we developed constitutiveFrem2-KOmice exhibiting neonatal lethality, mainly due to bilateral renal agenesis, along with blood-filled blisters, cryptophthalmos, and syndactyly. Only one mouse survived to adulthood exhibiting unilateral renal agenesis and Fraser syndrome-like phenotypes. These findings confirm FREM2’s crucial role in the development of the kidneys, skin, and eyes and provide an animal model for further studies of FREM2-related developmental disorders.
Combinatorial effector targeting (COMET) for transcriptional modulation and locus-specific biochemistry
Authors: Wilson Caroline M. , Pommier Greg C. , Richman Daniel D. , Sambold Nicholas , Hussmann Jeffrey A. , Weissman Jonathan S. , Gilbert Luke A.
Published: October 2024

Understanding how human gene expression is coordinately regulated by functional units of proteins across the genome remains a major biological goal. Here, we present COMET, a high-throughput screening platform forcombinatorialeffector targeting for the identification of transcriptional modulators. We generate libraries of combinatorial dCas9-based fusion proteins, containing two to six effector domains, allowing us to systematically investigate more than 110,000 combinations of effector proteins at endogenous human loci for their influence on transcription. Importantly, we keep full proteins or domains intact, maintaining catalytic cores and surfaces for protein-protein interactions. We observe more than 5800 significant hits that modulate transcription, we demonstrate cell type specific transcriptional modulation, and we further investigate epistatic relationships between our effector combinations. We validate unexpected combinations as synergistic or buffering, emphasizing COMET as both a method for transcriptional effector discovery, and as a functional genomics tool for identifying novel domain interactions and directing locus-specific biochemistry.
Reduced Folate Carrier 1 (RFC1/Slc19a1) Suppression Exacerbates Blood-Brain Barrier Breakdown in Experimental Ischemic Stroke in Adult Mice
Authors: Gurler Gokce , Bozanoglu Dilan , Leon Christelle , Belder Nevin , Bahcekapili Melike Sever , Bolbos Radu , Karatas Hulya , Wiart Marlene , Chauveau Fabien , Yemisci Muge
Published: October 2024

The Reduced Folate Carrier 1 (RFC1), also called solute carrier family 19 member 1 (SLC19A1/SLC19a1), is recognized for transporting folates across the blood-brain barrier (BBB). RFC1 has recently been defined as a hypoxia-immune related gene whose expression levels were induced by acute retinal ischemia, suggesting that RFC1 may have a role in the response of the brain to ischemic injury. Despite a recent human meta-analysis suggesting an association between certain RFC1 polymorphisms and the risk of silent brain infarctions, preclinical evidence concerning the potential role of RFC1 in acute ischemic stroke has yet to be presented. To investigate this, we first characterized RFC1 protein expression in mouse microvessels and pericytes which play significant roles in stroke pathophysiology. Then, we examined the temporal (1-h, 24-h, and 48-h) and spatial (infarct, periinfarct, contralateral) expression of RFC1 protein in the intraluminal transient middle cerebral artery occlusion mouse model. Finally, we knocked down RFC1 protein with RFC1-siRNA in the potential periinfarct region before induction of ischemia and investigated BBB integrity and infarct sizein vivovia 7T-MRI. Moreover, we utilized a pharmacological modulation-methotrexate, a non-covalent inhibitor of RFC1- to further investigate the role of RFC1 in maintaining BBB integrity. Our study revealed that, i) RFC1 protein levels were dynamic throughout the acute phases of ischemic stroke, ii) RFC1 suppression aggravated the BBB leakage during ischemia. These results emphases the role of RFC1 in the pathophysiology of ischemic stroke and supports the evidence from human studies.
Awakening prime editing for precision engineering of probioticEscherichia coliNissle 1917
Authors: Chen Pei-Ru , Wei Ying , Li Xin , Yu Hai-Yan , Wang Shu-Guang , Yuan Xian-Zheng , Xia Peng-Fei
Published: October 2024

CRISPR-Cas systems are transforming precision medicine with engineered probiotics as next-generation diagnostics and therapeutics. To promote human health and treat disease, engineering probiotic bacteria demands maximal versatility to enable non-natural functionalities while minimizing undesired genomic interferences. Here, we present a streamlined prime editing approach tailored for probioticEscherichia coliNissle 1917 utilizing only essential genetic modules and an optimized workflow. This was realized by assembling a prime editor consisting of the CRISPR-Cas system fromStreptococcus pyogeneswith its native codons and a codon-optimized reverse transcriptase, and by orchestrating the induction levels. As a result, we achieved all types of prime editing in every individual round of experiments with efficiencies of 25.0%, 52.0% and 66.7% for DNA deletion, insertion, and substitution, respectively. A comprehensive evaluation of off-target effects revealed a significant reduction in unintended mutations, particularly in comparison to two different base editing methods. Leveraging the prime editing system, we developed a barcoding system for strain tracking and an antibiotic-resistance-gene-free platform to enable non-natural functionalities. Our prime editing strategy awakens back-to-basics CRISPR-Cas systems devoid of complex or extraneous designs, paving the way for future innovations in engineered probiotics.
The aberrant language network dynamics in autism ages 5–40 years
Authors: Hu Zhe , Guo Xiaolin , Yang Junjie , Qu Zhiheng , Li Zhongqi , Li Junjing , Gao Xiaowei , Liu Jiaxuan , Wang Yaling , Li Wanchun , Li Wanjing , Huang Yien , Chen Jiali , Wang Xin , Yuan Binke
Published: October 2024

Background

Language impairments, which affect both structural aspects of language and pragmatic use, are frequently observed in autism spectrum disorder (ASD). These impairments are often associated with atypical brain development and unusual network interaction patterns. However, a neurological framework remains elusive to explain them.

Methods

In this study, we utilized the dynamic "meta-networking" framework of language—a theoretical model that describes the domain-segregation dynamics during resting states—to investigate cortical language network abnormalities in ASD aged 5–40 years.

Results

Our findings revealed distinct developmental trajectories for three domain-specific language subnetworks in ASD, characterized by unique patterns of hypo-and hyper-connectivity that vary with age. Notably, these language network abnormalities proved to be strong predictors of verbal Intelligence Quotient and communication deficits, though they did not predict social abilities or stereotypical behaviors.

Limitations

Due to the limited availability of linguistic data, our study was unable to assess the language deficit profiles of individuals with ASD.

Conclusions

Collectively, these findings refined our understanding of the network mechanisms for language and communication deficits in ASD.