Phenotypic Scores Research Articles

P0065 Circulating cell-free DNA and mitochondrial DNA differentiate disease activity in paediatric-onset inflammatory bowel disease: Interim analysis from Scotland-wide Mini-MUSIC study (2020-26)

Abstract Background Mitochondrial dysfunction has been implicated in the pathogenesis of inflammatory bowel disease (IBD) particularly paediatric-onset IBD (PIBD).1,2 Circulating cell-free DNA (cfDNA) and mitochondrial DNA (mtDNA) are damage-associated molecular patterns (DAMPS) released into the bloodstream during tissue damage and cell death and can be detected in peripheral blood samples.3 Recent studies have suggested that levels of cfDNA and mtDNA may correlate with disease activity in adult IBD4 but their utility in paediatric populations remains unexplored. This study aims to present initial data on the potential use of cfDNA and mtDNA as biomarkers in PIBD. Methods Mini-MUSIC and GI-DAMPS are ongoing longitudinal and cross-sectional multi-centre translational research studies in Scotland (2020 – 2026) with a primary aim of investigating the inflammatory mechanisms of IBD with a focus on multi-omics, immune- and microbiome-profiling aligned to prospective clinical follow-up. We measured circulating cfDNA (GAPDH) and mtDNA (ND2), using digital droplet PCR, in the peripheral blood of patients diagnosed under 17 years of age (A1 phenotype) and correlated this with phenotypic data and disease activity scores. Results Sixty-five A1 patients were included (39/65 (60%) male; 51 Crohn’s disease (CD), 6 ulcerative colitis (UC), 1 inflammatory bowel disease unclassified (IBDU) and 7 symptomatic non-IBD controls) with a median (IQR) age at diagnosis of 13 (10.0-15.0) years. mtDNA levels were significantly higher in those with highly active disease compared to those in remission (median [IQR] 145.1 (89.5-673.7 ng/μl) vs 64.4 (24.3-167.5 ng/μl), p=0.008) and compared to non-IBD symptomatic controls (median [IQR] 145.1 (89.5-673.7 ng/μl) vs 28.8 (12.6 – 138.7 ng/μl), p=0.036). Circulating cell-free DNA levels were significantly higher in those with highly active disease than non-IBD controls (4.94 (1.1-9.9 ng/ul) vs median [IQR] 0.53 (0.0-1.4 ng/ul), p=0.017). mtDNA levels were positively correlated with endoscopic disease activity (SES-CD) in Crohn’s disease (Pearson r=0.7619, p=0.004). Conclusion Our initial data from ongoing work, demonstrate that the levels of cfDNA and mtDNA in the blood are potentially valuable biomarkers for differentiating disease activity in PIBD and to identify PIBD-patients where mitochondrial dysfunction is dominant and thereby with the potential to stratify future human mechanistic studies and mitochondrial-targeted therapies.

Role of high-intensity exercise interventions in the management of frailty: a short systematic review

ABSTRACT This study aimed to summarize the current evidence on the impact of high-intensity exercise training interventions on frailty and physical function in older adults. A systematic review of controlled trials involving frail and prefrail older adults was conducted, examining resistance, power, and aerobic training, as well as combinations of these methods using loads greater than 70% of maximum capacity or maximal intended movement velocity. The review included eight studies with 437 participants, averaging 78.2 yr old. Results showed that high-intensity exercise significantly improved frailty phenotype scores by 0.3 to 3.0 criteria and enhanced physical function metrics, including the Short Physical Performance Battery (SPPB), usual gait speed, and the five-repetition sit-to-stand test. Concurrent supervised training programs involving power-oriented and aerobic exercises yielded the most substantial benefits, particularly in frailty and SPPB scores. In conclusion, high-intensity exercise, especially concurrent training, effectively improved frailty and physical function in older adults. These programs should be incorporated into routine care to reduce frailty and improve the quality of life in this population. Further research should focus on standardizing protocols and evaluating long-term benefits.

Frailty and the risk of age-related macular degeneration: a prospective cohort and Mendelian randomization study.

Both frailty and age-related macular degeneration (AMD) are related to aging and may share some common mechanisms. We aimed to examine the observational and causal association between frailty and the risk of age-related macular degeneration (AMD). We included 320,810 participants free of AMD at baseline from the UK Biobank. Frailty phenotypes were defined according to 5 components: weight loss, exhaustion, slow gait speed, low grip strength, and low physical activity. Cox proportional hazard models were used to evaluate the association between frailty phenotype and the risk of AMD. Causal relationship between frailty phenotype and AMD was examined using two-sample Mendelian randomization (MR) analysis. During a median follow-up of 12.81 years, 7,222 AMD cases were documented. After adjusting for confounding factors, compared with non-frail participants, both pre-frail and frail participants were significantly associated with an increased risk of AMD (HR 1.17, 95% CI: [1.11, 1.23] for pre-frailty and HR 1.55 [95% CI: 1.40, 1.73] for frailty). With each one-point increase in frailty phenotype score, the risk of AMD increased by 14%. Results from the two-sample MR analysis supported the potential causal effect of frailty phenotype on AMD. Our findings suggested that frailty assessment may help identify at-risk populations and serve as a potential strategy for early prevention and management of AMD.

Toward generalizable phenotype prediction from single-cell morphology representations

BackgroundFunctional cell processes (e.g., molecular signaling, response to stimuli, mitosis, etc.) impact cell phenotypes, which scientists can measure with cell morphology. However, linking these measurements with phenotypes remains challenging because it requires manually annotated labels. We propose that nuclear morphology can be a predictive marker for cell phenotypes that are generalizable across contexts.MethodsWe reanalyzed a pre-labeled, publicly-available nucleus microscopy dataset from the MitoCheck consortium. We extracted single-cell morphology features using CellProfiler and DeepProfiler, which provide robust processing pipelines. We trained multinomial, multi-class elastic-net logistic regression models to classify nuclei into one of 15 phenotypes such as ‘Anaphase,’ ‘Apoptosis’, and ‘Binuclear’. We rigorously assessed performance using F1 scores, precision-recall curves, and a leave-one-image-out (LOIO) cross-validation analysis. In LOIO, we retrained models using cells from every image except one and predicted phenotype in the held-out image, repeating this procedure for all images. We evaluated each morphology feature space, a concatenated feature space, and several feature space subsets (e.g., nuclei AreaShape features only). We applied models to the Joint Undertaking in Morphological Profiling (JUMP) data to assess performance using a different dataset.ResultsIn a held-out test set, we observed an overall F1 score of 0.84. Individual phenotype scores ranged from 0.64 (moderate performance) to 0.99 (high performance). Phenotypes such as ‘Elongated’, ‘Metaphase’, and ‘Apoptosis’ showed high performance. While CellProfiler and DeepProfiler features were generally equally effective, concatenation yielded the best results for 9/15 phenotypes. LOIO showed a performance decline, indicating our model could not reliably predict phenotypes in new images. Poor performance was unrelated to illumination correction or model selection. Applied to the JUMP data, models trained using nuclear AreaShape features only increased alignment with the annotated MitoCheck data (based on UMAP space). This approach implicated many chemical and genetic perturbations known to be associated with specific phenotypes.DiscussionPoor LOIO performance demonstrates challenges of single-cell phenotype prediction in new datasets. We propose several strategies that could pave the way for more generalizable methods in single-cell phenotype prediction, which is a step toward morphology representation ontologies that would aid in cross-dataset interpretability.

Unveiling the role of TGF-β signaling pathway in breast cancer prognosis and immunotherapy.

The TGF-β signaling pathway (TSP) is pivotal in tumor progression. Nonetheless, the connection between genes associated with the TSP and the clinical outcomes of breast cancer, as well as their impact on the tumor microenvironment and immunotherapeutic responses, remains elusive. Breast cancer transcriptomic and single-cell sequencing data were obtained from the The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We identified 54 genes associated with the TSP from the Molecular Signatures Database (MSigDB) and analyzed both data types to evaluate TSP activity. Using weighted gene co-expression network analysis (WGCNA), we identified modules linked to TSP activity. To assess patient risk, we used 101 machine learning algorithms to develop an optimal TGF-β pathway-related prognostic signature (TSPRS). We then examined immune activity and response to immune checkpoint inhibitors and chemotherapy in these groups. Finally, we validated ZMAT3 expression levels clinically and confirmed its relevance in breast cancer using CCK-8 and migration assays. At the single-cell level, TSP activity was most notable in endothelial cells, with higher activity in normal tissues compared to tumors. TSPRS was developed. This signature's accuracy was confirmed through internal and external validations. A nomogram incorporating the TSPRS was created to improve prediction accuracy. Further studies showed that breast cancer patients categorized as low-risk by the TSPRS had higher immune phenotype scores and more immune cell infiltration, leading to better prognosis and enhanced immunotherapy response. Additionally, a strong link was found between the TSPRS risk score and the effectiveness of anti-tumor agents. Silencing the ZMAT3 gene in the TSPRS significantly reduced the proliferation and invasiveness of breast cancer cells. Our study developed a TSPRS, which emerges as a potent predictive instrument for the prognosis of breast cancer, offering novel perspectives on the immunotherapeutic approach to the disease.

Two-dimensional Health State Map to define metabolic health using separated static and dynamic homeostasis features: a proof-of-concept study.

Defining metabolic health is critical for the earlier reversing of metabolic dysfunction and disease, and fasting-based diagnosis may not adequately assess an individual's metabolic adaptivity under stress. We constructed a novel Health State Map (HSM) comprising a Health Phenotype Score (HPS) with fasting features alone and a Homeostatic Resilience Score (HRS) with five time-point features only (t=30, 60, 90, 180, 240min) following a standardized mixed macronutrient tolerance test (MMTT). Among 111 Chinese adults, when the same set of fasting and post-MMTT data as for the HSM was used, the mixed-score was highly correlated with the HPS. The HRS was significantly associated with metabolic syndrome prevalence, independently of the HPS (OR [95% CI]: 0.41 [0.18, 0.92]) and the mixed-score (0.34 [0.15, 0.69]). Moreover, the HRS could discriminate metabolic characteristics unseparated by the HPS and the mixed-score. Participants with higher HRSs had better metabolic traits than those with lower HRSs. Large interpersonal variations were also evidenced by evaluating postprandial homeostatic resiliencies for glucose, lipids and amino acids when participants had similar overall HRSs. Additionally, the HRS was positively associated with physical activity level and specific gut microbiome structure. Collectively, our HSM model might offer a novel approach to precisely define an individual's metabolic health and nutritional capacity.

Post-symptomatic administration of hMSCs exerts therapeutic effects in SCA2 mice

BackgroundDefects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2.MethodsHuman bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis.ResultsSignificant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death.ConclusionIn conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice.

Clinical decision-making in bone cancer care management and forecast of ICU needs based on computed tomography

ObjectiveThis study aimed to evaluate the role of computed tomography (CT) imaging in the diagnosis and management of bone cancer during periods of limited access to histopathological testing. We aimed to determine the correlation between CT severity levels and subsequent patient management and care decisions, adhering to established oncological CT reporting guidelines. MethodologyA retrospective analysis was conducted on 60 symptomatic patients from January 2021 to January 2024. The cohort included patients aged between 50 and 86 years, with a mean age of 68 years, and 75 % were male. All patients had their bone cancer diagnosis confirmed through histopathological examination, and CT imaging was used as the reference method. The analysis involved assessing the correlation between CT severity scores and patient management, including ICU admissions. ResultsThe study found that CT imaging demonstrated a sensitivity of 92.6% in diagnosing bone cancer, with accuracy increasing to 97.6% in cases with high-probability CT characteristics. CT specificity also showed a consistent rise. Osteolytic lesions were the predominant finding, detected in 85.9% of cases. Among these, 88% exhibited engagement across multiple skeletal regions, 92.8% showed bilateral distribution, and 92.8% presented with peripheral involvement. In ICU patients, bone consolidation was observed in 81.5% of cases and was predominant in 66.7% of the ICU cohort. Additionally, ICU patients had significantly higher CT severity scores, with scores exceeding 14 being notably prevalent. ConclusionsDuring the management period of bone cancer at our hospital, characteristic features on CT imaging facilitated swift and sensitive investigation. Two distinct CT phenotypes, associated with the primary osteolytic phenotype and severity score, emerged as valuable indicators for assessing the severity of the disease, particularly during ICU care. These findings highlight the diverse manifestations and severity levels encountered in bone cancer patients and underscore the importance of CT imaging in their diagnosis and management.

Phenotype Scoring of Population Scale Single-Cell Data Dissects Alzheimer's Disease Complexity.

The complexity of Alzheimer's disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms (NPSs). However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-nucleus RNA-seq dataset comprising over 6 million nuclei from the prefrontal cortex of 1,494 individual brains, covering a variety of AD-related phenotypes that capture cognitive impairment, severity of pathological lesions, and the presence of NPSs. Leveraging this dataset, we developed a deep learning framework, called Phenotype Associated Single Cell encoder (PASCode), to score single-cell phenotype associations, and identified ∼1.5 million phenotype associate cells (PACs). We compared PACs within 27 distinct brain cell subclasses and prioritized cell subpopulations and their expressed genes across various AD phenotypes, including the upregulation of a reactive astrocyte subtype with neuroprotective function in AD resilient donors. Additionally, we identified PACs that link multiple phenotypes, including a subpopulation of protoplasmic astrocytes that alter their gene expression and regulation in AD donors with depression. Uncovering the cellular and molecular mechanisms underlying diverse AD phenotypes has the potential to provide valuable insights towards the identification of novel diagnostic markers and therapeutic targets. All identified PACs, along with cell type and gene expression information, are summarized into an AD-phenotypic single-cell atlas for the research community.

Circadian rhythm genes contribute to the prognosis prediction and potential therapeutic target in gastric cancer

The role of circadian rhythm genes (CRGs) in gastric cancer (GC) is poorly understood. This study aimed to develop a CRG signature to improve understanding of prognosis and immunotherapy responses in GC patients. We integrated the The Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD) dataset with CRGs to develop a prognostic signature for GC. The signature’s predictive ability was validated using Kaplan-Meier and ROC curves. The CIBERSORT algorithm evaluated immune cell proportions, and tumor immune dysfunction and exclusion score, as well as immune phenotype score, determined the response to immunotherapy for STAD patients. Finally, we assessed signature genes expression using real-time quantitative polymerase chain reaction. We developed a 4-CRG signature for STAD, demonstrating accurate prognostic ability. The low-risk group showed increased B cell memory and CD8 + T cells, and decreased M2 Macrophages compared to the high-risk group. Patients in the low-risk group had a higher likelihood of benefiting from immunotherapy. Additionally, gastric cancer tissues exhibited elevated expression of OPN3 and decreased expression of TP53 compared to adjacent tissue. This study successfully established a prognostic signature for CRGs, accurately predicting prognosis and immunotherapeutic response among STAD patients, providing insights for the development of personalized therapeutic strategies for these patients.

Intestinal barrier damage contributes to a higher prevalence of frailty in aging people living with HIV: a retrospective case control study in a Chinese cohort.

It has been previously demonstrated that intestinal barrier damage is one of the underlying mechanisms leading to frailty in non-HIV-infected aging populations. However, there is a paucity of direct evidence which demonstrates the association between intestinal barrier damage and frailty in people living with HIV (PLWH). The present study is a retrospective case control study. Participants older than 50 years old were stratified into a frail/pre-frail group (case group) and non-frail group (control group) according to the Fried frailty phenotype. We collected and curated data concerning socio-demographic variables, psychological states and social functioning, and clinical information associated with the identification of biomarkers of intestinal barrier damage, microbial translocation, and levels of inflammatory cytokines of participants. The case group had significantly higher levels of Reg-3α (p=0.042) and I-FABP (p=0.045) compared to the control group. We further observed, after adjusting for confounding factors by logistic regression analysis, that I-FABP levels remained significantly higher in the case group compared to the control group (p=0.033). Also, Fried Phenotype scores positively correlated with I-FABP levels (rs=0.21, p=0.01), LPS levels (rs=0.20, p=0.02), and sCD14 levels (rs=0.18, p=0.04). Moreover, the study confirmed both the positive correlation between inflammatory cytokines (IL-6 and IP-10) with frailty in aging PLWH, and between inflammatory cytokines (IL-6, IL-8 and IP-10) with biomarkers of intestinal barrier dysfunction in older PLWH. The present study indicates that the inflammation induced by intestinal barrier damage/dysfunction is likely to contribute to frailty in aging PLWH.

Characterizing alcohol-related and metabolic dysfunction-associated steatotic liver disease cirrhosis via fibrotic pattern analysis

This study aimed to address the diagnostic challenges in distinguishing between alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We utilized whole-slide imaging technology to conduct a comprehensive digital analysis of liver specimens collected from patients undergoing transplantation. This study included 36 and 17 patients with ALD and MASLD cirrhosis, respectively, who underwent transplantation at our institution. Digital slides were analyzed for fibrosis patterns using FibroNest™. Patient background characteristics were comparable between ALD (n = 36) and MASLD (n = 17) groups, except for sex. The ALD group exhibited thicker collagen per strand, longer and more flexural fibrosis, and a more heterogeneous distribution than the MASLD group. In patients with ALD and concomitant metabolic dysfunction, fiber distribution became relatively uniform, resembling MASLD. Application of the phenotypic fibrosis composite score achieved 100% sensitivity and specificity for ALD/MASLD diagnosis. Digital pathological analysis of the fibrosis patterns showed morphological differences between ALD and MASLD. This approach holds promise for histological differentiation, providing valuable insights beyond the current definitions based solely on alcohol intake. This study emphasizes the potential of digital pathology in refining the diagnostic criteria for hepatic disorders.

Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism

BackgroundWhole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex.MethodsTo address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family.ResultsWe observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females.ConclusionsOur findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism’s genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism.

Clinical-grade intranasal NGF fuels neurological and metabolic functions of Mecp2-deficient mice

Abstract MECP2 deficiency causes a broad spectrum of neuropsychiatric disorders that can affect both genders. Rett syndrome is the most common and is characterized by an apparently normal growth period followed by a regression phase in which patients lose most of their previously acquired skills. After this dramatic period, various symptoms progressively appear, including severe intellectual disability, epilepsy, apraxia, breathing abnormalities and motor deterioration. MECP2 encodes for an epigenetic transcription factor that is particularly abundant in the brain; consequently, several transcriptional defects characterize the Rett syndrome brain. The well-known deficiency of several neurotrophins and growth factors, together with the positive effects exerted by trofinetide, a synthetic analogue of insulin-like growth factor 1, in Rett patients and in mouse models of Mecp2 deficiency, prompted us to investigate the therapeutic potential of nerve growth factor. Initial in vitro studies demonstrated a healing effect of recombinant human GMP-grade NGF (rhNGF) on neuronal maturation and activity in cultured Mecp2-null neurons. Subsequently, we designed in vivo studies with clear translational potential using intranasally administered rhNGF already used in the clinic. The efficacy of rhNGF in vivo in Mecp2-null hemizygous male mice and heterozygous female mice was assessed. General well-being was evaluated by a conventional phenotypic score and motor performance through the Pole and Beam Walking tests, while cognitive function and interaction with the environment were measured by the Novel Object Recognition test and the Marble Burying test, respectively. At the end of the treatment, mouse cortices were dissected and bulk RNA sequencing was performed to identify the molecular pathways involved in the protective effects of rhNGF. In both male and female mouse models of Rett syndrome, rhNGF exerted positive effects on cognitive and motor functions. In male hemizygous mice, which suffer from significantly more severe and rapidly advancing symptoms, the drug’s ability to slow the disease’s progression was more pronounced. The unbiased research for the molecular mechanisms triggering the observed benefits revealed a strong positive effect on gene sets related to oxidative phosphorylation, mitochondrial structure and function. These results were validated by demonstrating the drug’s ability to improve mitochondrial structure and respiration in Mecp2-null cerebral cortices. Furthermore, Gene Ontology analyses indicated that NGF exerted the expected improvement in neuronal maturation. We conclude that intranasal administration of rhNGF is a non-invasive and effective route of administration for the treatment of Rett syndrome and possibly for other neurometabolic disorders with overt mitochondrial dysfunction.

Evaluation Tolerant of Four Melon Genotypes in Early Growth Stage under Normal and Drought Stress Conditions

Plant breeding initiative in semi-arid and arid area are primarily focused on developing genotypes at early growth stage under normal conditions and keeping them steady during drought stress conditions. Therefore, four melon genotypes responses to drought stress were evaluated in this study during early growth stage. Two treatments for irrigation rates (Full Irrigation= 100%) and (Deficit Irrigation= 50%) were carried out in randomized complete block design (RCBD) with three biological replications in vermiculite culture in greenhouse in the research farm of faculty of agriculture at Sohag university in Egypt during season 2023. Young plants (45 days old plants) were utilized, and phenotypic traits 1º Leaf Score Tolerance, 2º Leaf Score Tolerance, Flowers Numbers, Vine Length, Green Leaves and Brown Leaves Numbers per vine were calculated by comparing differences in drought stress compared to control to identify tolerant and susceptible genotypes. The findings demonstrated that, in all estimated traits under drought stress conditions, there was significant variation between the studied four melon genotypes. whereas, the best results for all the studied traits were produced under normal conditions. Additionally, the highest significant positive correlation was found between 1º Leaf Score Tolerance and 2º Leaf Score Tolerance (0.966*) under normal conditions, and between Vine Length and Green Leaves Numbers per vine (0.999**) under drought stress conditions. Furthermore, the highest significant negative correlation was observed between 2º Leaf Score Tolerance and Flowers Numbers (-0.974*) and Flowers Numbers and Green Leaves Numbers per vine (-0.960*) under normal conditions, and between Vine Length and Brown Leaves Numbers per vine (-0.974*) and Green Leaves Numbers per vine and Brown Leaves Numbers per vine (-0.981*) under drought stress conditions. Besides, Euclidean heatmap clustering analysis grouped studied genotypes according to their response to normal and drought stress conditions, indicating that, the studied melon genotypes offer high potential for particular breeding purposes. These results have produced helpful framework for breeding strategies in the future under drought stress conditions. Conversely, detailed studies are crucial to predict drought stress tolerance performance in novel breeding strategies.

Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.

Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function, and a cure for this devastating disease remains elusive. This study aimed to identify pre-disposing genetic, phenotypic, and exposure-related factors for amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential. Utilizing data from the UK (United Kingdom) Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates. Both PRSs modestly predicted ALS diagnosis but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved the prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a fourfold higher ALS risk (95% CI [2.04, 7.73]) versus those in the 40%-60% range. By leveraging UK Biobank data, our study uncovers pre-disposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.

Immune-related gene characteristics: A new chapter in precision treatment of gastric cancer

Gastric cancer ranks as the sixth most prevalent cancer worldwide. In recent research within the realm of gastric cancer treatment, the identification and application of immune-related genetic features have emerged as groundbreaking advancements. The study by Ma et al , which developed a prognostic model based on 10 genes, categorizes patients into high and low-risk groups to predict their responsiveness to immune checkpoint inhibitor therapy. This research underscores the potential of immune-related genes as biomarkers for personalized treatment, offering insights into tumor mutation burden and immune phenotype scores. We advocate for further validation, understanding of biological mechanisms, and integration of diverse datasets to enhance the model's predictive accuracy and clinical application, marking a significant step towards personalized and precise treatment for gastric cancer.

Frailty in Medicare Advantage Beneficiaries and Traditional Medicare Beneficiaries

A growing proportion of the population is enrolling in Medicare Advantage (MA), which typically offers additional benefits compared with traditional Medicare (TM). To determine whether frailty and frailty trajectories differ between MA enrollees and TM enrollees. This retrospective cohort study used data from the National Health and Aging Trends Study (2015-2016). Analyses were conducted from August 2023 to March 2024. Participants were community-dwelling Medicare beneficiaries aged 65 years and older. Enrollment in MA vs TM. Frailty was calculated by a frailty index (FI) (range, 0-1, with higher values indicating greater frailty) and the Fried Frailty Phenotype (FFP) score (range, 0-5, with higher values indicating greater frailty). Physical performance, including Short Physical Performance Battery (SPPB) score (range, 0-12, with higher values indicating better performance), and gait speed (meters per second) were measured. The primary outcome was the difference in FI and FFP scores from the 2015 baseline assessment to the 2016 follow-up assessment. Secondary outcomes include the 1-year changes in SPPB and gait speed. The final cohort consisted of 7063 participants (2775 [23.1%] aged >80 years; 4040 [54.7%] female), representing a sample of the 38.8 million beneficiaries. There were 2583 (35.0%) MA enrollees (13.6 million) and 4480 (65.0%) TM enrollees (25.2 million). At baseline, the FI score was similar between MA and TM enrollees (mean [SD], 0.22 [0.15] vs 0.21 [0.14]), although MA enrollees had worse phenotypic frailty (496 participants [15.2%] vs 811 participants [13.7%] considered frail by FFP score), SPPB scores (mean [SD], 6.91 [3.34] vs 7.21 [3.27]), and gait speed (0.79 [0.24] m/s vs 0.82 [0.23] m/s) than TM enrollees. One year later, there were no differences between MA and TM enrollees in the 1-year change in FI score (mean [SD], 0.016 [0.071] vs 0.014 [0.066]; adjusted mean difference, 0.001 [95% CI, -0.004 to 0.005]), FFP score (mean [SD], 0.017 [1.004] vs 0.007 [0.958]; adjusted mean difference, -0.009 [95% CI, -0.067 to 0.049]), SPPB score (mean [SD], -0.144 [2.064] vs -0.211 [1.968]; adjusted mean difference, 0.068 [95% CI, -0.076 to 0.212]), and gait speed (mean [SD], -0.0160 [0.148] m/s vs -0.007 [0.148] m/s; adjusted mean difference, -0.010 m/s [95% CI, -0.067 to 0.049 m/s]). In this cohort study of Medicare beneficiaries from 2015, MA enrollees experienced similar declines in frailty over 1 year compared with TM enrollees. Future work should examine whether the specific types of services covered by health insurance can impact frailty and health trajectories for older adults.

Breathlessness, Frailty, and Sarcopenia in Older Adults

BackgroundBreathlessness shares aging mechanisms of frailty and sarcopenia. Research questionAre frailty and sarcopenia associated with breathlessness itself? Study design and MethodsWe analyzed data from a population-based, prospective cohort study of 780 community-dwelling older adults. Breathlessness was defined using the modified Medical Research Council Dyspnea Scale (≥2 points) and the Chronic Obstructive Pulmonary Disease Assessment Test (≥10 points). Frailty was defined by frailty index (FI), frailty phenotype, and FRAIL questionnaire. Sarcopenia was defined by the Asian Working Group for Sarcopenia 2019. Sarcopenia phenotype score quantifies the number of criteria met. The associations of frailty and sarcopenia with breathlessness was evaluated by logistic regression analyses. Adjusted odds ratio (aOR) were calculated, accounting for age, sex, chronic airway disease, smoking status, body mass index, lung functions, socioeconomic status (living alone, income, education), comorbid conditions (hypertension, diabetes, malignancy, myocardial infarction, heart failure), and other geriatric contributors (cognitive dysfunction, depression, malnutrition, polypharmacy, fall history in the past year). Institutionalization-free survival was compared by log-rank test. ResultsThe prevalence of frailty is higher in the breathlessness group compared to non-breathlessness group (42.6% vs. 10.5% by FI, 26.1% vs. 8.9% by frailty phenotype, and 23.0% vs. 4.2% by FRAIL) and sarcopenia (38.3% vs. 26.9%), with P < 0.01 for all comparisons. The multivariable logistic regression analyses showed that frailty (FI [aOR: 9.29], FRAIL questionnaire [aOR: 5.21], and frailty phenotype [aOR: 3.09]) and sarcopenia phenotype score (score 2 [aOR: 2.00] and score 3 [aOR: 2.04] compared to score 0) were associated with breathlessness. The cumulative incidence of institutionalization-free survival was higher in the breathlessness group than counterparts (P = 0.02). InterpretationThe findings suggest that frailty and sarcopenia strongly contribute to breathlessness in community-dwelling older adults. Measuring sarcopenia and frailty in older adults may offer opportunities to prevent age-related breathlessness.

Genome-wide association study for morphological and hunting-behavior traits in Braque Français Type Pyrénées dogs: A preliminary study

High-throughput genotyping offers great potential to increase our understanding of the genomic basis of canid variation. Braque Français Type Pyrénées (BRA) are smart, agile, and friendly dogs originally developed for tracking, hunting, and retrieving feathered game. On a population of 44 unrelated BRA dogs, single nucleotide polymorphism (SNP) genotype data from the CanineHD Whole-Genome Genotyping BeadChip and evaluation scores for 12 traits related to morphology and hunting performance were available. After quality filtering, 95,859 SNPs on the 38 dog autosomes (CFA) were retained. Phenotypic scores were expressed on a scale from 1 (worst) to 6 (best) and were mostly poorly to moderately correlated except for some morphological traits (e.g. r = 0.81 between the conformation of the head and that of the eye). From GWAS, a total of 378 SNP-phenotype associations with posterior odds of association > 1 have been detected. The strongest associations were found for the eye conformation, for the skull/muzzle ratio, and for connection to the hunter. These included both new and previously identified markers and genes potentially involved with type and behavior traits in BRA. Six of the significant markers mapped within SETDB2, a gene known to be related to pointing behavior in dogs. These results advance our understanding of the genetic basis for morphology and hunting behavior in dogs and identify new variants which are potential targets for further research.