bluuebunny/crossref_metadata_2025 huggingface dataset:
EDA Fibronectin Microarchitecture and YAP Translocation During Wound Closure
Authors: Patten Jennifer , Halligan Patrick , Bashiri Ghazal , Kegel Michael , Bonadio Jacob D , Wang Karin
Published: September 2024

Fibronectin (Fn) is an extracellular matrix glycoprotein with mechanosensitive structure-function. EDA Fn, a Fn isoform, is not present in adult tissue but is required for tissue repair. Curiously, EDA Fn is linked to both regenerative and fibrotic tissue repair. Given that Fn mechanoregulates cell behavior, Fn EDA organization during wound closure might play a role in mediating these differing responses. One mechanism by which cells sense and respond to their microenvironment is by activating a transcriptional co-activator, Yes-associated protein (YAP). Interestingly, YAP activity is not only required for wound closure, but similarly linked to both regenerative and fibrotic repair. Therefore, this study aims to evaluate how, during normal and fibrotic wound closure, EDA Fn organization might modulate YAP translocation by culturing human dermal fibroblasts on polydimethylsiloxane (PDMS) substrates mimicking normal (soft: 18 kPa) and fibrotic (stiff: 146 kPa) wounded skin. On stiffer substrates mimicking fibrotic wounds, fibroblasts assembled an aligned EDA Fn matrix comprising thinner fibers, suggesting increased microenvironmental tension. To evaluate if cell binding to the EDA domain of Fn was essential to overall matrix organization, fibroblasts were treated with Irigenin, which inhibits binding to the EDA domain within Fn. Blocking adhesion to EDA led to randomly organized EDA Fn matrices with thicker fibers, suggesting reduced microenvironmental tension even during fibrotic wound closure. To evaluate if YAP signaling plays a role in EDA Fn organization, fibroblasts were treated with CA3, which suppresses YAP activity in a dose-dependent manner. Treatment with CA3 also led to randomly organized EDA Fn matrices with thicker fibers, suggesting a potential connected mechanism of reducing tension during fibrotic wound closure. Next, YAP activity was assessed to evaluate the impact of EDA Fn organization. Interestingly, fibroblasts migrating on softer substrates mimicking normal wounds increased YAP activity but on stiffer substrates, decreased YAP activity. When fibroblasts on stiffer substrates were treated with Irigenin or CA3, fibroblasts increased YAP activity. These results suggest there may be disrupted signaling between EDA Fn organization and YAP translocation during fibrotic wound closure that could be restored when reestablishing normal EDA Fn matrix organization to instead drive regenerative wound repair.
High-Dimensional Mediation Analysis with Network Mediators: Applications to Pediatric Acute Lymphoblastic Leukemia
Authors: Wang Jade Xiaoqing , Lu Zhao-Hua , Reddick Wilburn E , Conklin Heather M , Glass John O , Jacola Lisa , Onar-Thomas Arzu , Jeha Sima , Cheng Cheng , Zhou Xiang , Li Yimei
Published: September 2024

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with survivors frequently experiencing long-term neurocognitive morbidities. Here, we utilize the TOTXVI clinical trial data to elucidate the mechanisms underlying treatment-related neurocognitive side effects in pediatric ALL patients by incorporating brain connectivity network data. To enable such analysis, we propose a high-dimensional mediation analysis method with a novel network mediation structural shrinkage (NMSS) prior, which is particularly suited for analyzing high-dimensional brain structural connectivity network data that serve as mediators. Our method is capable of addressing the structural dependencies of brain connectivity networks including sparsity, effective degrees of nodes, and modularity, yielding accurate estimates of the high-dimensional coefficients and mediation effects. We demonstrate the effectiveness and superiority of the proposed NMSS method through simulation studies and apply it to the TOTXVI data, revealing significant mediation effects of brain connectivity on visual processing speed directed by IT intensity. The findings shed light on the potential of targeted interventions to mitigate neurocognitive deficits in pediatric ALL survivors.
Cadherin 16 promotes sensory gating via the endocrine corpuscles of Stannius
Authors: Schloss Susannah S. , Marshall Zackary Q. , Santistevan Nicholas J. , Gjorcheska Stefani , Stenzel Amanda , Barske Lindsey , Nelson Jessica C.
Published: September 2024

Sensory thresholds enable animals to regulate their behavioral responses to environmental threats. Despite the importance of sensory thresholds for animal behavior and human health, we do not yet have a full appreciation of the underlying molecular-genetic and circuit mechanisms. The larval zebrafish acoustic startle response provides a powerful system to identify molecular mechanisms underlying establishment of sensory thresholds and plasticity of thresholds through mechanisms like habituation. Using this system, we identify Cadherin 16 as a previously undescribed regulator of sensory gating. We demonstrate that Cadherin 16 regulates sensory thresholds via an endocrine organ, the corpuscle of Stannius (CS), which is essential in zebrafish for regulating Ca2+homeostasis. We further show that Cadherin 16 regulates whole-body calcium and ultimately behavior through the hormone Stanniocalcin 1L, and the IGF-regulatory metalloprotease, Papp-aa. Finally, we demonstrate the importance of the CS through ablation experiments that reveal its role in promoting normal acoustic sensory gating. Together, our results uncover a previously undescribed brain non-autonomous pathway for the regulation of behavior and establish Ca2+homeostasis as a critical process underlying sensory gatingin vivo.
Genetics of Motor Neuron Disease in New Zealand
Authors: Mrkela Miran , Rodrigues Miriam , Naidoo Serey , Devaux Jules B.L. , Kirk Siobhan E. , Vinnakota Chitra , Buchanan Christina M. , Mulroy Dympna , Fraser Harry , Jacobsen Jessie C. , Wyatt Hannah , Drake Kylie , Parker Elsa , Potter Howard , Henden Lyndal , McCann Emily P. , Williams Kelly L. , Henders Anjali K. , Roxburgh Richard H. , Scotter Emma L.
Published: September 2024

Motor neuron disease (MND) is a group of neurodegenerative diseases characterised by adult-onset progressive degeneration of motor neurons, of which amyotrophic lateral sclerosis (ALS) is the most common. MND is clinically heterogenous with complex aetiology, being caused by or associated with over 40 different genes, along with multiple environmental risk factors. Although New Zealand has one of the highest incidence and mortality rates of MND globally, the reasons for this are yet to be determined.

In light of this lack of systematic genetic MND research in New Zealand, we sought to identify the frequencies of genetic variants in known MND-linked genes in people in New Zealand with MND. A total of 184 participants were enrolled; 149 with a clinical diagnosis of MND and 35 who were clinically unaffected but at risk of familial MND. Of the 149 affected, 128 had sporadic MND, and 21 had familial MND. Participants’ DNA was screened for genetic variation in 46 MND-associated genes using a combination of Sanger sequencing, Illumina single nucleotide polymorphism (SNP) microarray, repeat-primed PCR forC9orf72, and an Invitae gene panel.

Clinical phenotypes of participants with MND recapitulated the trends seen in European reference populations with both males, and individuals with spinal onset, having earlier disease onset. Thirty three of the 184 participants (17.9%) carried known pathogenic variants; the majority hadC9orf72hexanucleotide repeat expansion (24/34), and the remainder had previously reported pathogenic genetic variants inSOD1(9/34; p.(Ile114Thr) and p.(Glu101Gly)). All NZSOD1p.(Ile114Thr) cases (n=4) were distantly related (identical-by- descent) to one another and a cluster of >30 MND cases from Australia with the same variant. Variants of interest were identified in 14 participants, of which splicing variantsDCTN1:c.279+1G>C andATP13A2p.(Lys804=) are subject to ongoing study. Of the pathogenic variants, 48.4% were identified in pre-symptomatic unaffected individuals with a family history, highlighting the importance of offering cascade testing and symptom surveillance for families, particularly as gene-specific treatments are becoming available.
Implementation of Male-Specific Motivational Interviewing in Malawi: An Assessment of Intervention Fidelity and Barriers to Scale-Up
Authors: Holland Katherine Ničev , Hubbard Julie , Mphande Misheck , Robson Isabella , Phiri Khumbo , Onoya Dorina , Chikuse Elijah , Dovel Kathryn , Choko Augustine
Published: September 2024

Introduction

Treatment interruption (TI), defined as >28 days late for ART appointment, is one of the greatest challenges in controlling southern African HIV epidemics. Negative client-provider interactions remain a major reason for TI and barrier for return to care, especially for men. Motivational interviewing (MI) facilitates client-driven counseling and improves client-provider interactions by facilitating equitable, interactive counseling that helps clients understand and develop solutions for their unique needs. Fidelity of MI counseling in resource-constrained health systems is challenging.

Methods

We developed a male-specific MI curriculum for Malawian male TI clients. Four psychosocial counselors (PCs, a high-level Malawian counseling cadre) received a 2.5-day curriculum training and job-aid to guide MI counseling approaches. They participated in monthly phone-based discussions with their manager about MI-based solutions to challenges faced. PCs implemented the MI curriculum with men >15 years who were actively experiencing TI. Clients were found at home (through tracing) or at the facility (for those who returned to care on their own). MI counseling sessions were recorded, transcribed, translated into English, and coded in Atlas.ti v9. MI quality was assessed using a modified version of the validated Motivational Interviewing Treatment Integrity tool. The tool has two measures: 1) counts of key MI behaviors throughout the session (questions, reflections, etc.); and 2) overarching scores (using a five-point scale) that characterize three MI dimensions for an entire counseling session (cultivating change talk, partnership, and empathy).

Results

44 MI sessions were recorded and analyzed between 4/1/22-8/1/22. 64% of counseling sessions focused on work and travel as the main reason for TI. 86% of sessions yielded client-driven, tailored solutions for overcoming TI. PCs implemented multiple MI behaviors very well: asking questions, giving information, simple reflections, and client affirmation. Few PCs used complex reflection, emphasized autonomy, or sought collaboration with clients. Among overarching MI dimensions, HCWs scored high in partnership (promoting client-driven discussions) and cultivating change talk (encouraging client-driven language and behavior change confidence) but scored sub-optimal in empathy. Only 5 sessions had confrontational/negative PC attitudes.

Conclusions

PCs implemented MI with fidelity and quality resulting in tailored, actionable plans for male re-engagement in HIV treatment in Malawi.

Clinical Trial Number

NCT05137210 andNCT04858243
A Large Language Model-based Approach for Analyzing Covariates of Health Equity in Registered Research Projects
Authors: Nananukul Navapat , Kejriwal Mayank
Published: September 2024

Large language models (LLMs) have made significant advancements in natural language processing, offering broad applications in multiple domains. This study explores the use of the GPT-3.5 LLM to conduct efficient and robust computational analysis of registered research projects on theAll of Usplatform. Specifically, we explore the association between projects pursuing health equity research and: the project’s use of demographic categories (whichAll of Usenables), the multi-institutional composition of the team leading the project, and the involvement of R2 institutions (compared to only R1 institutions). We demonstrate the utility of GPT-3.5 in automating tasks ranging from generating Python scripts for extracting attributes from free text (such as project description and goals) to identifying and classifying institutions as R1 and R2, and summarizing project details into Unified Medical Language System (UMLS)-coded medical keywords. These contributions significantly reduced manual workload, allowing researchers to focus on more in-depth analysis. Our results reveal health equity insights not readily available in the originalAll of Usresearch hub. Specifically, we find a strong positive association between the use of demographic data and projects focused on health equity, while other associations such as health equity projects conducted by institutions were positive but weaker and more dependent on specific project topics.
Sedentary Habits and Obesity: The Role of TV, Unemployment, and White-Collar Work on Obesity in Reproductive-Aged Women in Bangladesh
Authors: Alam Md. Zakiul , Sheoti Isna Haque
Published: September 2024

Introduction

In Bangladesh, overweight and obesity are increasingly alarming, especially among women. Thus, this paper aims to explore whether television watching, white-collar jobs, and unemployment are working as sedentary behavior to increase overweight and obesity in Bangladesh.

Data and methods

We utilized cross-sectional data from the Bangladesh Demographic and Health Survey, 2017-2018. The dependent variable of the study was the nutritional status of women using three different measures: body mass index (BMI), Asian body mass index (ABMI), and tri-ponderal mass index (TMI). The frequency of watching television (TV) and types of employment were the two predictors of overweight and obesity in this study. The Multilevel Ordered Logistic Regression Analysis was used in this study.

Results

Women who have watched television at least once a week are more likely to have a BMI ≥25 and become overweight (30.3%) and obese (9.3%) than those who did not watch TV at all (20.1% and 3%). This same pattern of BMI is discernible among unemployed women (28.7% and 8.2%) compared to women in agricultural work (16% and 2.9%). Professional women have the highest risk of being overweight and obese (35.4% and 10.9%). The pattern of overweight and obese is consistent for ABMI and PMI. However, these indicators (ABMI & PMI) report a higher prevalence of overweight and obesity than BMI.

Conclusion

In this era of technology, TV watching, and other technology will increase with time. More and more women are engaging in white-collar jobs or looking for jobs. In these circumstances, policymakers need to focus on how this use of technology can decrease overweight and obesity among women. More studies need to be conducted to explore the effect of other sedentary behaviors and take steps based on those studies to reduce the increasing rate of overweight and obesity.
p53motifDB: integration of genomic information and tumor suppressor p53 binding motifs
Authors: Baniulyte Gabriele , Hicks Sawyer M. , Sammons Morgan A.
Published: September 2024

The tumor suppressor geneTP53encodes the DNA binding transcription factor p53 and is one of the most commonly mutated genes in human cancer. Tumor suppressor activity requires binding of p53 to its DNA response elements and subsequent transcriptional activation of a diverse set of target genes. Despite decades of close study, the logic underlying p53 interactions with its numerous potential genomic binding sites and target genes is not yet fully understood. Here, we present a database of DNA and chromatin-based information focused on putative p53 binding sites in the human genome to allow users to generate and test new hypotheses related to p53 activity in the genome. Users can query genomic locations based on experimentally observed p53 binding, regulatory element activity, genetic variation, evolutionary conservation, chromatin modification state, and chromatin structure. We present multiple use cases demonstrating the utility of this database for generating novel biological hypotheses, such as chromatin-based determinants of p53 binding and potential cell type-specific p53 activity. All database information is also available as a precompiled sqlite database for use in local analysis or as a Shiny web application.
Characteristics of ectopic alveolar basal cells relative to airway basal cells in fibrosis
Authors: Blumer Sabrina , Khan Petra , Roux Julien , Artysh Nataliia , Plappert Linda , Prasse Antje , Hostettler Katrin E.
Published: September 2024

Rationale

Basal cells (BC) appear ectopically within the lung parenchyma of interstitial lung disease (ILD) patients, potentially through migration of airway BC or though trans-differentiation of alveolar epithelial type 2 (AT2) cells. The exact origin and function of these ectopic alveolar BC remains elusive. By comparing ectopic alveolar to “classical” airway BC, we aimed to get a better understanding of the origin and characteristics of alveolar BC in ILD.

Methods

Alveolar and airway BC were isolated from transbronchial and airway mucosal biopsies, respectively, from the same ILD patients and expanded in culture. Samples were analyzed by single cell RNA sequencing (scRNA-seq), TaqMan RT-PCR, and immunochemistry.

Results

scRNA-seq analysis revealed several differences in gene expression that suggested a shift to a more mesenchymal-like phenotype and a decrease in keratinization genes in alveolar compared to airway BC. Specific AT2 cell marker genes were not expressed in either BC type. While the morphology, wound repair and proliferation capacities of BC from both origins were not significantly different, alveolar BC formed significantly fewer organoids, expressing more MUC5B. After instillation into bleomycin-injured mice, alveolar and airway BC showed similar engraftment, differentiation capacity and effects on fibrosis.

Conclusion

Despite similar overall functionality in vitro and after instillation into bleomycin-injured mice, alveolar and airway BC differed in their transcriptomes and in their capacities to form and to differentiate in organoids. Our data provide no evidence to support their potential derivation from AT2 cells.

Take home message

Alveolar and airway basal cells differ in their transcriptomes and in their capacities to form and to differentiate in organoids, although with no indication of an AT2 cell origin.
Evolvoid: A genetic algorithm for shaping optimal cellular constructs
Authors: Mancini P. , Fontana F. , Botte E. , Magliaro C. , Ahluwalia A.
Published: September 2024

We describe anin-silicopipeline, Evolvoid, based on Genetic Algorithms (GAs) for identifying the optimal morphologies of cell-laden constructs. Driven by an ad hoc selection rule (i.e., the so-called fitness function (FF)), Evolvoid iteratively identifies the characteristics (i.e., the genome) of the ‘survival of the fittest’ individual of a given population throughout generations. The FF is based on universally observed biophysical laws, representing the optimal trade-off betweeni)high cell viability and robustness to changes in environmental oxygen andii)a low surface energy. The Shannon entropy is used to evaluate genome complexity, with the most complex fittest individuals showing quantitative and qualitative biological resemblance toin vitroconstructs. Evolvoid paves the way for the development of “lab on a laptop”: high-fidelity and cost-effective digital twins of cellular constructs which could augment or even substitute costlyin vitromodels.
Assessment of drive efficiency and resistance allele formation of a homing gene drive in the mosquitoAedes aegypti
Authors: Yang Xiaozhen , Xu Xuejiao , Chen Yixian , Wei Jiajia , Huang Wanting , Wu Songqing , Champer Jackson , Wang Junxiang
Published: September 2024

Aedes aegypti, known for transmitting viruses such as dengue, zika, and yellow fever, poses a significant public health threat. Conventional insecticides give rise to a range of issues, including ecological contamination and insect resistance. Hence, there is a pressing demand for environmentally friendly, safer, and more efficacious strategies for mosquito control. With the rapid advancement of the CRISPR/Cas9 system in gene function exploration and pest population control, substantial progress has been achieved in utilizing CRISPR/Cas9-based gene drive systems across various mosquito species. Only a few studies on gene drive technology have been conducted inA. aegypti. In this study, we constructed two complete drives forA. aegyptiwith different Cas9 promoters, each targetingkmo. Our drive based onPub-Cas9 had limited activity, but one withexu-Cas9 exhibited super-Mendelian inheritance rates of approximately 60%. We observed low but detectable somatic activity of the drive and no evidence of maternally deposited Cas9. Germline resistance allele formation rates were similar to drive conversion rates, but most wild-type alleles in the germline remained uncut. Injections into theexu-Cas9 drive line had 100% knockout efficiency among surviving offspring at three separate target genes. These results support the development and application of novel genetic pest control technologies aimed at combatingA. aegypti.
Transcription elongation factor ELOF1 is required for efficient somatic hypermutation and class switch recombination
Authors: Wu Lizhen , Yadavalli Anurupa Devi , Matos-Rodrigues Gabriel , Xu Dijin , Pintado-Urbanc Andreas P. , Simon Matthew D. , Wu Wei , Nussenzweig André , Schatz David G.
Published: September 2024

Somatic hypermutation (SHM) and class switch recombination (CSR) diversify immunoglobulin (Ig) genes and are initiated by the activation induced deaminase (AID), a single-stranded DNA cytidine deaminase that is thought to engage its substrate in the context of RNA polymerase II (RNAPII) transcription. Through a loss of function genetic screen, we identified numerous potential factors involved in SHM including ELOF1, a component of the RNAPII elongation complex that has been shown to function in DNA repair and transcription elongation. Loss of ELOF1 strongly compromises SHM, CSR, and AID targeting and alters RNAPII transcription by reducing RNAPII pausing downstream of transcription start sites and levels of serine 5 but not serine 2 phosphorylated RNAPII throughout transcribed genes. ELOF1 must bind to RNAPII to be a proximity partner for AID and to function in SHM and CSR. We propose that ELOF1 helps create the appropriate stalled RNAPII substrate on which AID acts.

Highlights

A CRISPR knockout screen has identified numerous potential SHM factors.

SHM, CSR, and AID targeting are strongly compromised in the absence of ELOF1.

ELOF1 must interact with RNAPII to be an AID proximity partner and support AID targeting.

ELOF1 supports RNAPII pausing and generation of the substrate for AID action.
The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia
Authors: Lam Kentson , Kim Yoon Joon , Ong Carlo M. , Liu Andrea Z. , Zhou Fanny J. , Sunshine Mary Jean , Chua Bernadette A. , Vicenzi Silvia , Ford Pierce W. , Zhou Jie-Hua , Hong Yuning , Bennett Eric J. , Crews Leslie A. , Ball Edward D. , Signer Robert A.J.
Published: September 2024

Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation ofHSF1sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survivalin vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed AML cells, and significantly reduced AML burden and extended survivalin vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
Sanctioning of bacterial cheaters by the host plant in nitrogen-fixing symbiosis betweenMedicago truncatulaandSinorhizobium meliloti
Authors: Chen Min , Raisin Axelle , Judkins Nathalie , Allard Pierre-Marie , Défossez Emmanuel , Stumpe Michael , Yruela Inmaculada , Becana Manuel , Reinhardt Didier
Published: September 2024

In plant-microbe interactions, the host plant invests considerable amounts of resources in the microbial partner until the symbiotic machinery is established. If the microbial partner does not reciprocate with a comparable symbiotic benefit, the interaction represents a parasitic relationship. This is thought to elicit a plant’s response to prevent the selective disadvantage of being parasitized by such microbial cheaters. Indeed, negative feedback against bad mutualists, known as sanctioning, has been observed in interactions such as the arbuscular mycorrhizal and legume-rhizobium symbioses. Here, to study sanctioning by the plant host, we manipulate the exchange of resources between the model legumeMedicago truncatulaand its bacterial partnerSinorhizobium melilotiby three ways: mutating the bacterial nitrogenase enzyme, replacing nitrogen in the atmosphere with argon gas, and supplying high nitrate to the host. Then, we follow the consequences for the interaction by examining the metabolome, proteome, and phosphoproteome of nodules. We find that such cheating conditions result in sanctioning of the bacterial partner, and observe characteristic shifts including induced defense markers, repressed symbiotic markers, and changes in central metabolism that may be relevant for microbial fitness and that could therefore contribute to sanctioning.
Colorectal Cancer Screening in Adults 45-49: Provider Availability, CT Colonography Access, and Screening Rates
Authors: Liu-Galvin Rachel , Xie Zhigang , Hong Young-Rock
Published: September 2024

Background

The US Preventive Services Task Force updated colorectal cancer (CRC) screening guidelines in 2021, recommending screening for adults aged 45-49. This study aimed to evaluate CRC screening prevalence among this newly eligible population and examine associations with healthcare provider supply and CT colonography facility availability in 2022.

Methods

Using 2022 Behavioral Risk Factor Surveillance System data (n=25,592), we estimated CRC screening prevalence among adults aged 45-49. We examined associations between screening rates and state-level healthcare provider supply using 2021-2022 Area Health Resources File data. Spearman rank-order correlations assessed relationships between provider supply, CT colonography facility availability, and screening prevalence.

Results

Overall CRC screening prevalence was 34.5% (95% CI: 33.4%-35.8%). Endoscopic tests were most common (74.9%), followed by stool-based tests (9.3%) and CT colonography (0.5%). Significant variations in screening modalities were observed across sociodemographic factors. Gastroenterology physician supply positively correlated with overall CRC screening prevalence (ρ=0.42, P=.002) and endoscopy screening prevalence (ρ=0.39, P=.005). CT colonography facility availability weakly correlated with CT colonography screening prevalence (ρ=0.18, P=.22).

Conclusions

CRC screening rates among newly eligible adults aged 45-49 appear to be suboptimal in 2022. Disparities in screening methods across sociodemographic factors highlight potential access barriers. The association between gastroenterology physician supply and screening rates emphasizes the importance of addressing projected workforce shortages. Targeted efforts are needed to increase CRC screening uptake in this age group and ensure equitable access to screening services.
An Automation Framework for Clinical Codelist Development Validated with UK Data from Patients with Multiple Long-term Conditions
Authors: Aslam A. , Walker L. , Abaho M. , Cant H. , O’Connell M. , Abuzour A. S. , Hama L. , Schofield P. , Mair F.S. , Ruddle R.A. , Popoola O. , Sperrin M. , Tsang J.Y. , Shantsila E. , Gabbay M. , Clegg A. , Woodall A.A. , Buchan I. , Relton S. D.
Published: September 2024

Background

Codelists play a crucial role in ensuring accurate and standardized communication within healthcare. However, preparation of high-quality codelists is a rigorous and time-consuming process. The literature focuses on transparency of clinical codelists and overlooks the utility of automation.

Method and Automated Framework Design

Here we present a Codelist Generation Framework that can automate generation of codelists with minimal input from clinical experts. We demonstrate the process using a specific project, DynAIRx, producing appropriate codelists and a framework allowing 1future projects to take advantage of automated codelist generation. Both the framework and codelist are publicly available.

Use-case: DynAIRx

DynAIRx is an NIHR-funded project aiming to develop AIs to help optimise prescribing of medicines in patients with multiple long-term conditions. DynAIRx requires complex codelists to describe the trajectory of each patient, and the interaction between their conditions. We promptly generated≈200 codelists for DynAIRx using the proposed framework and validated them with a panel of experts, significantly reducing the amount of time required by making effective use of automation.

Findings and Conclusion

The framework reduced the clinician time required to validate codes, automatically shrunk codelists using trusted sources and added new codes for review against existing codelists. In the DynAIRx case study, a codelist of≈9600 codes required only 7-9 hours of clinician’s time in the end (while existing methods takes months), and application of the automation framework reduced the workload by>80%.
Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19–associated ME/CFS
Authors: Anft Moritz , Wiemers Lea , Rosiewicz Kamil , Doevelaar Adrian , Skrzypczyk Sarah , Kurek Julia , Kaliszczyk Sviatlana , Seidel Maximilian , Stervbo Ulrik , Seibert Felix S. , Westhoff Timm H. , Babel Nina
Published: September 2024

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments. We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients’ blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients. 30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a substantial amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CSF questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.
The family as a health producer: household composition and health behaviours in a Southern Europe population
Authors: Alves Ricardo , Gonçalves Judite , Perelman Julian
Published: September 2024

Objectives

In the context of rapid transformations in family structures, understanding how household composition can affect adults’ health behaviours is crucial, particularly when considering the potential role of such close social relationships in shaping those behaviours. This paper documents how household structure relates to individual health behaviours.

Study design

We pooled cross-sectional data from the Portuguese National Health Interview Surveys of 2014 and 2019, covering 26,000+ households.

Methods

Linear and logistic regression models were used to assess the association between different household compositions (single dwelling adults, single parents, couples with or without children) and adherence to the Mediterranean diet, frequency of physical activity, likelihood of risky alcohol consumption, and smoking, distinguishing between men and women.

Results

People living alone and single parents were significantly less likely to adhere to the Mediterranean diet than individuals living in couple. Single dwellers had significantly higher likelihood of engaging in risky alcohol consumption or being smokers than individuals living in couple and/or with children. Analyses by gender revealed that women in couples with children were less likely to practice physical activity than women in couples without children; this difference was not observed among men.

Conclusions

Overall, family contexts strongly correlate with individual health behaviours, with people living alone or in single-parent households appearing at higher risk of having less healthy diets, risky alcohol consumption, and smoking. This study identifies key target groups for policies aiming to improve population health (behaviours) including, critically, single dwellers and single parent households.

Key massages

What is already known on this topic

Social relationships, particularly within the family, play a significant role in shaping individuals’ health behaviors. With rapid changes in family structures, understanding how household composition influences adult behaviors is crucial.

What this study adds

This study reveals that single dwellers generally exhibit unhealthier behaviors, except in the case of physical activity. Additionally, it highlights that having children tends to promote healthier lifestyles among couples.

How this study might affect research, practice, or policy

The findings underscore the importance of considering household composition in health interventions and policy development. Specifically, attention may need to be directed towards individuals living alone and single-parent households to address potential health disparities and promote healthier behaviors.
Single-cell RNA sequencing reveals immunosuppressive pathways associated with metastatic breast cancer
Authors: Ozmen Furkan , Ozmen Tugba Y. , Ors Aysegul , Janghorban Mahnaz , Rames Matthew J. , Li Xi , Behbod Fariba , Mills Gordon B. , Mohammed Hisham
Published: September 2024

Metastatic breast cancer remains largely incurable, and the mechanisms underlying the transition from primary to metastatic breast cancer remain elusive. We analyzed the complex landscape of primary and metastatic breast cancer using scRNA-seq data from twenty-three female patients with either primary or metastatic disease to elucidate the genetic and molecular mechanisms underlying changes in the metastatic tumor ecosystem. We identify specific subtypes of stromal and immune cells critical to forming a pro-tumor microenvironment in metastatic lesions, including CCL2+ macrophages, cytotoxic T cells with an exhausted gene signature, and FOXP3+ regulatory T cells. Analysis of cell-cell communication highlights a marked decrease in tumor-immune cell interactions in metastatic tissues, likely strengthening the immunosuppressive microenvironment. In contrast, primary breast cancer samples displayed increased activation of the TNF-α signaling pathway via NF-kB, indicating a potential therapeutic target. Our study comprehensively characterizes the transcriptional landscape encompassing primary and metastatic breast cancer.
STRIVE-ON: Safety and ToleRability of GTX-104 (Nimodipine Injection for IV Infusion) ComparEd with Oral Nimodipine in Patients Hospitalized for Aneurysmal Subarachnoid Hemorrhage (aSAH): a Prospective, Randomized Trial (STRIVE-ON)
Authors: Choi A , Chou SH-Y , Ducruet AF , Kimberly WT , Macdonald RL , Rabinstein AA
Published: September 2024

Oral nimodipine is the only drug approved in North America for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is variable and frequently poor, leading to fluctuations in peak plasma concentrations that cause dose-limiting hypotension. Furthermore, administration is problematic in patients who cannot swallow capsules. An oral liquid formulation exists but causes gastrointestinal complications. An intravenous nimodipine formulation (GTX-104) has been developed that has bioavailability approaching 100% and is not affected by feeding or gastointestinal absorption. GTX-104 causes less hypotension and has more consistent peak plasma concentrations than oral nimodipine in healthy human volunteers.

Herein we describe the protocol of a prospective, randomized, open-label safety and tolerability study of GTX-104 compared to oral nimodipine in patients with aSAH (STRIVE-ON,NCT05995405). Inclusion and exclusion criteria match the prescribing information for oral nimodipine and include adult patients with aSAH of all Hunt and Hess grades who can receive investigational product within 96 hours of aSAH. Subjects at imminent risk of death are excluded. Subjects are randomized 1:1 to GTX-104 or oral nimodipine for up to 21 days. The primary endpoint is the proportion of subjects in each group with clinically significant hypotension, defined as hypotension requiring any medical treatment, with a reasonable likelihood of being due to investigational product as determined by an independent, blinded endpoint adjudication committee. No statistical analysis of the endpoint is planned. Secondary endpoints include all episodes of hypotension, all adverse events, delayed cerebral ischemia, rescue therapy and suicidal ideation. Clinical and health economic outcomes include quality of life using the EQ-5D-3L, modified Rankin scale at 30 and 90 days after aSAH and hospital resource use. The planned sample size is 100 subjects across 25 sites in the United States and Canada.

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The source of funding for the study is disclosed. It is Acasti Pharma.
Evolution of the neural sex-determination system in insects: Thedoublesexhomolog in crickets functions as an X-linked masculinizing factor to regulate morphological but not behavioral sexual dimorphism
Authors: Watanabe Takayuki
Published: September 2024

In animals, sex-specific social behaviors, such as courtship and aggression, are controlled by sex-specific neural circuits. To understand the neural mechanisms of sex-specific social behaviors from a comparative perspective, it is necessary to understand the sex determination mechanisms of neural circuits and their evolution across animal lineages. To address this, I have focused on the evolution of the neural sex determination system in insects. In the fruit flyDrosophila melanogaster, a model insect with powerful genetics, the molecular mechanisms underlying neuronal sex determination are well understood, and two transcription factor genes,fruitlessanddoublesex(dsx), have been identified as terminal differentiators. In contrast, those in direct-developing insects, which diverged from the holometabolous lineage, includingDrosophila, about 400 million years ago, remain unclear. My previous studies found that thefruitlesshomolog is unlikely to be integrated into the neuronal sex determination system in direct-developing insects. In this study, I investigated whether thedsxhomolog in direct-developing insects contributes to neuronal sex determination to form neural circuits that regulate adult social behaviors. I identified thedsxhomolog in the two-spotted cricketGryllus bimaculatus(Gryllus dsxgene) and revealed that it has a unique isoform configuration, and its encoded proteins contain a cryptic DNA-binding DM domain with accumulated amino acid substitutions. A knockout study revealed that theGryllus dsxgene functions as an X-linked morphological masculinizing factor but does not determine the sexual orientation or behavioral patterns of adult social behavior in crickets. These results suggest that, at least in crickets, an unknown sex determination factor(s) other thanfruitlessanddsxplays a central role in neuronal sex determination.
The effects of P2Y12 loss on microglial gene expression, dynamics, and injury response in the cerebellum and cerebral cortex
Authors: Stoessel Mark B. , Stowell Rianne D. , Lowery Rebecca L. , Le Linh , Vu Andy N. , Whitelaw Brendan S. , Majewska Ania K.
Published: September 2024

Despite the emerging consensus that microglia are critical to physiological and pathological brain function, it is unclear how microglial roles and their underlying mechanisms differ between brain regions. Microglia throughout the brain express common markers, such as the purinergic receptor P2Y12, that delineate them from peripheral macrophages. P2Y12 is a critical sensor of injury but also contributes to the sensing of neuronal activity and remodeling of synapses, with microglial loss of P2Y12 resulting in behavioral deficits. P2Y12 has largely been studied in cortical microglia, despite the fact that a growing body of evidence suggests that microglia exhibit a high degree of regional specialization. Cerebellar microglia, in particular, exhibit transcriptional, epigenetic, and functional profiles that set them apart from their better studied cortical and hippocampal counterparts. Here, we demonstrate that P2Y12 deficiency does not alter the morphology, distribution, or dynamics of microglia in the cerebellum. In fact, loss of P2Y12 does little to disturb the distinct transcriptomic profiles of cortical and cerebellar microglia. However, unlike in cortex, P2Y12 is not required for a full microglial response to focal injury, suggesting that cerebellar and cortical microglia use different cues to respond to injury. Finally, we show that P2Y12 deficiency impairs cerebellar learning in a delay eyeblink conditioning task, a common test of cerebellar plasticity and circuit function. Our findings suggest not only region-specific roles of microglial P2Y12 signaling in the focal injury response, but also indicate a conserved role for P2Y12 in microglial modulation of plasticity across regions.
Detection of intra-tumoral microbiota from transcriptomic sequencing of Asian breast cancer
Authors: Yeo Li-Fang , Yan Lee Audrey Weng , Ern Tee Phoebe Yon , Fong Chin Joyce Seow , Lee Bernard KB , Lim Joanna , Teo Soo-Hwang , Pan Jia Wern
Published: September 2024

The human microbiome has garnered significant interest in recent years as an important driver of human health and disease. Likewise, it has been suggested that the intra-tumoral microbiome may be associated with specific features of cancer such as tumour progression and metastasis. However, additional research is needed to validate these findings in diverse populations. In this study, we characterized the intra-tumoral microbiota of 883 Malaysian breast cancer patients using transcriptomic data from bulk tumours and investigated their association with clinical variables and immune scores. We found that the tumour microbiome was not associated with breast cancer molecular subtype, cancer stage, tumour grade, or patient age, but was weakly associated with immune scores. We also found that the tumour microbiome was able to predict immune scores in our cohort using random forest models, suggesting the possibility of an interaction between the tumour microbiome and the tumour immune microenvironment in Asian breast cancer.
Heterotrophic diazotrophy along a river–lake continuum: lifestyle and contribution to N2fixation
Authors: Geisler Eyal , Siebner Hagar , Kolton Max , Sisma-Ventura Guy , Rahav Eyal , Arnon Shai , Bar-Zeev Edo
Published: September 2024

Heterotrophic diazotrophs are potentially important agents in freshwater ecosystems, yet they remain poorly understood. This study elucidates the contribution of freshwater heterotrophic diazotrophs as free-living or aggregate-associated cells to total N2fixation along the continuum from the Jordan River to Lake Kinneret, Israel. Heterotrophic diazotrophs accounted for 25%–56% of the total diazotrophs and commonly found as free-living cells or attached to aggregates in the river. N2fixation by heterotrophic diazotrophs associated with aggregates varied along the river, while accounting for ~50% of N2fixation in the lake. Non-cyanobacterial diazotrophs dominated the free-living fraction in the river, and cyanobacteria were mostly identified in the lake. The diversity of free-living diazotrophs was sensitive to environmental changes, as the aggregates have likely provided a protected micro-environment. The results reveal the dynamic lifestyle of heterotrophic diazotrophs along a river–lake continuum and highlight their contribution to total N2fixation and primary production.

Teaser

Freshwater heterotrophic diazotrophs are more ubiquitous than previously thought, can be found as free-living cells or associated with aggregates, and significantly contribute to primary production.