Search Results (191)

Aggressiveness in dogs is a complex behavioral trait with implications for animal welfare and public safety. Despite domestication, dogs retain aggressive tendencies shaped by both genetic and environmental factors. This systematic review synthesizes the literature from 2000 to 2024 on the genetic and environmental bases of canine aggression. Using PRISMA 2020 guidelines, 144 articles were retrieved from Scopus and PubMed and screened in two phases, resulting in 33 studies selected for analysis. These were evaluated using a 20-question grid across seven categories, including phenotyping, genetic analysis, population structure, and future directions. The studies support a polygenic model of aggressiveness, with associations reported for genes involved in neurotransmission, hormone signaling, and brain function. However, inconsistencies in phenotyping, small sample sizes, and a limited consideration of environmental factors hinder robust conclusions. Most studies focused on popular companion breeds, while those commonly labeled as aggressive were underrepresented. The findings highlight the relevance of gene–environment interactions but underscore that aggression is often poorly defined and measured across studies. Future research should prioritize standardized phenotyping tools, broader breed inclusion, and the functional validation of genetic findings. These efforts will improve the understanding of dog aggression and inform breeding, behavioral assessment, and public policy. Full article

Background and Objectives: Toe walking (TW) is frequently observed in children with Autism Spectrum Disorder (ASD), yet its clinical significance and association with comorbid conditions remain poorly understood. This study aimed to examine the prevalence of TW in a large Italian cohort of children with ASD and to explore its association with ASD severity, sleep disturbances, feeding behaviors, and gastrointestinal symptoms. Materials and Methods: A total of 289 children with ASD and 289 typically developing controls (TDC), matched for age and sex, were evaluated in a multicentric observational study. TW was assessed during neurodevelopmental evaluations. Sleep quality was assessed using the Sleep Disturbance Scale for Children (SDSC), feeding behaviors via the Brief Autism Mealtime Behavior Inventory (BAMBI), and gastrointestinal symptoms through clinical reporting. Statistical analyses included Chi-square tests, Mann–Whitney U tests, Spearman correlations, and logistic regressions. Results: TW was significantly more prevalent in the ASD group (27.3%) than in TDC (5.5%, p < 0.0001). Within the ASD group, TW occurred in 50.5% of children with Level 3 severity but was absent in Levels 1 and 2 (p < 0.0001). Males exhibited TW more frequently than females. Children with TW had higher SDSC scores (ρ = 0.33, p < 0.0001), though no subscale independently predicted TW. Constipation was reported in 100% of children with Level 3 ASD and was strongly correlated with SDSC total scores (ρ = 0.58, p < 0.0001). The Disorders of Arousal (DA) subscale emerged as an independent predictor of constipation (β = 0.184, p = 0.019). Conclusions: TW in ASD appears to be a marker of greater neurodevelopmental severity and is associated with sleep disturbances and gastrointestinal dysfunction. These findings support the hypothesis that TW may reflect broader dysfunctions involving the gut–brain axis, sensory processing, and motor control. The routine clinical assessment of TW should include the evaluation of sleep and somatic symptoms to better understand the multisystemic nature of ASD phenotypes. Full article

Obstructive sleep apnea (OSA) is a prevalent and heterogeneous sleep disorder associated with significant health and societal burdens. While continuous positive airway pressure (CPAP) remains the gold standard treatment, its limitations in adherence and patient tolerance have highlighted the need for alternative therapies. Positional therapy (PT), which targets apneas that occur predominantly in the supine position, has emerged as a promising option for individuals with positional OSA (POSA). This narrative review synthesizes the current literature on PT, examining its clinical indications, typologies, comparative efficacy with CPAP, oral appliances, and hypoglossal nerve stimulation, as well as data on adherence and barriers to long-term use. Traditional methods such as the tennis ball technique have largely been replaced by modern vibrotactile devices, which demonstrate improved comfort, adherence, and comparable short-term outcomes in selected POSA subjects. While PT remains inferior to CPAP in reducing overall AHI and oxygen desaturation, it performs favorably in terms of mean disease alleviation (MDA) and sleep continuity. Importantly, treatment effectiveness is influenced by both anatomical and non-anatomical traits, underscoring the need for accurate phenotyping and individualized care. PT should be considered within a broader patient-centered model that incorporates preferences, lifestyle, and motivational factors. Further research is needed to validate long-term efficacy, optimize selection criteria, and integrate PT into personalized OSA management strategies. Full article

Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, we profiled LGD and HGD adenomas using EM-seq, and identified a consensus differential methylation signature (DMS) of 626 regions through two independent bioinformatics pipelines. This signature effectively distinguished LGD from HGD in both tissue and plasma-derived cell-free DNA (cfDNA), highlighting specific methylation patterns. Functional annotation indicated enrichment for regulatory elements associated with transcription factor activity and cell signaling. Applying the DMS to the TCGA CRC dataset revealed three tumor subtypes with increasing hypermethylation and one normal cluster. The most hypermethylated subtype exhibited poor survival, high mutation burden, and disrupted transcriptional networks. While overlapping with classical CpG Island Methylator Phenotype (CIMP) categories, the DMS captured a broader spectrum of methylation alterations. These findings suggest that the DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression, enabling the robust stratification of dysplasia severity and tumor subtypes. This signature holds promise for enhancing preclinical detection and molecular classification, and warrants further evaluation in larger prospective cohorts. Full article

Background: The management of end-stage renal disease (ESRD) is undergoing a paradigm shift, with increasing emphasis on kidney transplantation as a preferred treatment modality for elderly patients (≥65 years), who constitute a substantial portion of new ESRD cases. Transplantation offers markedly superior survival and quality of life (QoL) advantages compared to dialysis for this demographic. Nevertheless, key determinants such as frailty, physical functionality, and cognitive function have emerged as critical predictors of post-transplant success. Despite their relevance, standardized methodologies for evaluating these parameters in transplantation candidacy remain absent. This systematic review examines the influence of frailty, physical functionality, and cognitive function on outcomes in elderly kidney transplant recipients. Methods: Adhering to PRISMA guidelines, a rigorous literature search was conducted across PubMed, CINAHL, Embase, PsycINFO, and the Web of Science for studies published up to October 31, 2024. Relevant studies focused on elderly transplant candidates and examined correlations between frailty, physical functionality, or cognitive function and post-transplant outcomes. The Newcastle–Ottawa Scale was employed to evaluate studies quality. Results: Seven studies met the inclusion criteria. Five explored physical functionality, demonstrating that better pre-transplant physical performance predicts enhanced survival. Two studies addressed frailty, utilizing the Fried frailty phenotype, and linked frailty to elevated mortality and diminished QoL recovery. Notably, no studies explored cognitive function in elderly kidney transplant candidates or recipients and its association with post-transplant outcomes, exposing a salient gap in the literature. The included studies’ varied methodologies, reliance on single time-point assessments, and exclusive focus on kidney transplant recipients restrict both comparability among studies and the generalizability of findings to the broader end-stage renal disease (ESRD) population. Conclusions: These findings underscore the profound impact of physical functionality and frailty on transplant outcomes in the growing elderly kidney transplant population, illuminating the necessity for standardized assessment protocols and targeted pre-transplant interventions. The critical gap in cognitive function research underscores a vital direction for future investigation. This research received no external funding. This review is registered with PROSPERO under registration ID CRD42025645838. Full article

Cardiomyopathies represent a heterogeneous group of myocardial disorders, traditionally classified by phenotype into hypertrophic, dilated, and arrhythmogenic. Historically, these conditions have been attributed to high-penetrance rare variants in key structural genes, consistent with a classical Mendelian pattern of inheritance. However, emerging evidence suggests that this model does not fully capture the full spectrum and complexity of disease expression. Many patients do not harbor identifiable pathogenic variants, while others carrying well-known disease-causing variants remain unaffected. This highlights the role of incomplete penetrance, likely modulated by additional genetic modifiers. Recent advances in genomics have revealed a broader view of the genetic basis of cardiomyopathies, introducing new players such as common genetic variants identified as risk alleles, as well as intermediate-effect variants. This continuum of genetic risk, reflecting an overall genetic influence, interacts further with environmental and lifestyle factors, likely contributing together to the observed variability in clinical presentation. This model offers a more realistic framework for understanding genetic inheritance and helps provide a clearer picture of disease expression and penetrance. This review explores the evolving genetic architecture of cardiomyopathies, spanning from a monogenic foundation to intermediate-risk variants and complex polygenic contribution. Recognizing this continuum is essential for enhancing diagnostic accuracy, guiding family screening strategies, and enabling personalized patient management. Full article

The excessive use of antimicrobials drives the emergence of multidrug resistance (MDR) in bacterial strains, which harbor resistance genes to survive under diverse drug pressures. Such resistance can result in life-threatening infections. The predominance of MDR Pseudomonas spp. poses significant challenges to public health and environmental sustainability, particularly in ecosystems affected by human activities. Characterizing MDR Pseudomonas spp. is crucial for developing effective diagnostic tools and biosecurity protocols, with broader implications for managing other pathogenic bacteria. Strains were diagnosed through 16S rRNA PCR and sequencing, complemented by phylogenetic analysis to evaluate local and global evolutionary connections. Antibiotic susceptibility tests revealed extensive resistance across multiple classes, with MIC values surpassing clinical breakpoints. This study examined the genetic diversity, resistance potential, and phylogenetic relationships among Pseudomonas aeruginosa strain DG2 and Pseudomonas fluorescens strain FM3, which were isolated from solid waste dump sites (n = 30) and dairy farms (n = 22) in West Bengal, India. Phylogenetic analysis reveals distinct clusters that highlight significant geographic linkages and genetic variability among the strains. Significant biofilm production under antibiotic exposure markedly increased resistance levels. RAPD-PCR profiling revealed substantial genetic diversity among the isolates, indicating variations in their genetic makeup. In contrast, SDS-PAGE analysis provided insights into the protein expression patterns that are activated by stress, which are closely linked to MDR. This dual approach offers a clearer perspective on their adaptive responses to environmental stressors. This study underscores the need for vigilant monitoring of MDR Pseudomonas spp. in anthropogenically impacted environments to mitigate risks to human and animal health. Surveillance strategies combining phenotypic and molecular approaches are essential to assess the risks posed by resilient pathogens. Solid waste and dairy farm ecosystems emerge as critical reservoirs for the evolution and dissemination of MDR Pseudomonas spp. Full article

The mitochondrial regulator MNRR1 is reduced in several pathologies, including the mitochondrial heteroplasmic disease MELAS, and genetic restoration of its level normalizes the pathological phenotype. Here, we investigate the upstream mechanism that reduces MNRR1 levels. We have identified the hypoxic regulator HIF2α to bind the MNRR1 promoter and inhibit transcription by competing with RBPJκ. In MELAS cells, there is a pseudohypoxic state that transcriptionally induces HIF2α and stabilizes HIF2α protein. MELAS cybrids harboring the m.3243A > G mutation display reduced levels of prolyl hydroxylase 3 (PHD3), which contributes to the HIF2α stabilization. These results prompted a search for compounds that could increase MNRR1 levels pharmacologically. The screening of a 2400-compound library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as enhancers of MNRR1 transcription. We show that treating MELAS cybrids with tizoxanide restores cellular respiration, enhances mitophagy, and, importantly, shifts heteroplasmy toward wild-type mtDNA. Furthermore, in fibroblasts from MELAS patients, the compound improves mitochondrial biogenesis, enhances autophagy, and protects from LPS-induced inflammation. Mechanistically, nitazoxanide reduces HIF2α levels by increasing PHD3. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Finally, our data suggests a broader physiological pathway wherein two proteins, induced under severe (1% O2; HIF2α) and moderate (4% O2; MNRR1) hypoxic conditions, regulate each other inversely. Full article

Background/Objectives: Wolf–Hirschhorn syndrome (WHS; OMIM #194190) is a rare neurodevelopmental disorder, caused by deletions in the distal short arm of chromosome 4. It is characterized by developmental delay, epilepsy, intellectual disability, and distinctive facial dysmorphism. Clinical presentation varies widely, complicating prognosis and individualized care. Methods: We assembled a cohort of 140 individuals with genetically confirmed WHS from Spain and Latin-America, and developed and validated a multidimensional, Clinician-Reported Outcome Assessment (ClinRO) based on the Global Functional Assessment of the Patient (GFAP), derived from standardized clinical questionnaires and weighted by HPO (Human Phenotype Ontology) term frequencies. The GFAP score quantitatively captures key functional domains in WHS, including neurodevelopment, epilepsy, comorbidities, and age-corrected developmental milestones (selected based on clinical experience and disease burden). Results: Higher GFAP scores are associated with worse clinical outcomes. GFAP showed strong correlations with deletion size, presence of additional genomic rearrangements, sex, and epilepsy severity. Ward’s clustering and discriminant analyses confirmed GFAP’s discriminative power, classifying over 90% of patients into clinically meaningful groups with different prognoses. Conclusions: Our findings support GFAP as a robust, WHS-specific ClinRO that may aid in stratification, prognosis, and clinical management. This tool may also serve future interventional studies as a standardized outcome measure. Beyond its clinical utility, GFAP also revealed substantial social implications. This underscores the broader socioeconomic burden of WHS and the potential value of GFAP in identifying high-support families that may benefit from targeted resources and services. Full article

Heart failure (HF) treatment evolved in the last 5 years with the introduction of new agents capable of reducing HF hospitalization and HF-related mortality. However, some categories such as patients with renal dysfunction tend to be excluded from larger randomized clinical trials. Additionally, most patients with HF experienced unavoidable glomerular filtration rate (GFR) deterioration during the clinical course. This is related to both cardio–renal interaction pathways and common cardiovascular risk factors that affect HF and chronic kidney disease (CKD). However, mineralocorticoid antagonists (MRAs) remain a cornerstone of HF therapy regardless of left ventricular ejection fraction (LVEF) values; some concerns remain about their utilization in CKD. Nevertheless, three studies (FIDELIO, FIGARO, and FINEARTS) have recently showed beneficial effects in both patients with HF and CKD associated with diabetes. Notably, finerenone a new non-steroidal MRA represents a significant step forward in cardiovascular therapy; its application spans a wide spectrum of HF phenotypes and CKD stages, and ongoing investigations will further elucidate its role in combination regimens and in broader patient populations. Further study may investigate the role of the drug in patients with heart failure with reduced ejection fraction (HFrEF) and in the severe CKD stage of non-diabetic etiology. In the current review paper, we provide a chronological overview of major trials evaluating the renal outcomes of MRAs, culminating in the emergence of finerenone as a novel therapeutic option for high-risk CKD populations, particularly those with type 2 diabetes mellitus (T2DM). Full article

Body stalk anomaly (BSA) is a rare and usually fatal congenital disorder involving severe malformations of the body wall, limbs, spine, and internal organs. This study presents the first documented cases of BSA in seven dogs, offering new insights into how the disorder manifests in animals. The affected fetuses consistently exhibited major anomalies, including large abdominal wall defects, structural spinal abnormalities, and a variety of limb malformations ranging from partial agenesis and meromelia to phocomelia and complete amelia. Structural urogenital anomalies and orofacial clefts were also observed, aligning with similar findings in BSA cases reported in pigs and cats. These findings support the hypothesis of a multifactorial etiology involving early embryonic disruptions, such as abnormal folding of the embryo, rupture of the amniotic membrane, and vascular compromise. The frequent occurrence of abdominal wall defects alongside umbilical cord abnormalities further suggests a shared developmental pathway. This study also highlights the value of veterinary cases in comparative embryology and the need to assess congenital anomalies as part of a broader malformation complex. By expanding the phenotypic spectrum of BSA in domestic animals, this work contributes to a deeper understanding of its pathogenesis and emphasizes the importance of further research into the genetic and environmental factors involved. Such efforts could lead to improved classification and diagnosis of complex congenital malformations, as well as facilitate cross-species comparisons. Full article

Background/Objectives: The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations. Methods: We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS. Results: We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10⁻⁷) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels. Conclusions: This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome. Full article

Background: The Actinidia deliciosa cultivar ‘Guichang’ is a remarkable kiwifruit variety. The phenotypic traits of this variety are influenced by the climatic conditions in Guizhou. The flowering time, which is shaped by multiple environmental factors, has a substantial impact on both the fruit yield and quality. Objectives and Methods: This study was designed to explore the molecular mechanisms underlying the transition from bud to flowering in ‘Guichang’ through transcriptomic and proteomic analyses. Results: The transcriptomic results revealed that 6201 genes were up-regulated, while 5849 genes were down-regulated during this transition. Key genes related to hormone signaling, such as AdPIF4, AdBSK, AdBRI1, and AdCYCD3, were recognized as crucial regulators. The proteomic analysis detected a total of 10,488 proteins. Among them, AdBSK1 was regulated, while AdPIF4, AdBRI1, and AdCYCD3 showed stable expressions. A moderate positive correlation (with a Pearson correlation coefficient of 0.445) was found between the expression levels of transcriptomics and proteomics. When AdBSK1 was over-expressed in Arabidopsis, it promoted earlier flowering. This was achieved by down-regulating FLC and up-regulating FT and SOC1. Conclusions: This study clarifies the molecular mechanisms involved in the bud-to-flowering transition in ‘Guichang’. It emphasizes the intricate interactions among hormonal pathways, key genes, and proteins, which are consistent with the broader understanding of plant flowering regulation in recent research. These findings are significant for deepening our understanding of, and potentially controlling, the flowering mechanisms. Full article

Network-based GWAS (NetWAS) has advanced brain imaging research by identifying genetic modules associated with brain alterations. However, how imaging risk genes exert functions in brain diseases, particularly their mediation through imaging quantitative traits (iQTs), remains underexplored. We propose a module-level polygenic risk score (MPRS)-based NetWAS framework to uncover genetic modules associated with Alzheimer’s disease (AD) through the mediation of an iQT, using amygdala density as a case study. Our framework integrates genotype data, brain imaging phenotypes, clinical diagnosis of AD, and protein–protein interaction (PPI) networks to identify AD-relevant modules (ADMs) influenced by iQT-associated genetic variants. Specifically, we conducted a genome-wide association study (GWAS) of amygdala density ($N=1515$) to identify variants associated with iQT. These variants were mapped onto a PPI network and network propagation was performed to prompt amygdala modules. The meta-GWAS of AD ($N_1=63,926$; $N_2=455,267$) was used to calculate MPRS to further identify AD-relevant modules (ADMs). Four modules that showed significant differences in MPRS between AD and controls were identified as ADM. Post-hoc analyses revealed that these ADMs demonstrated strong modularity, showed increased sensitivity to early stages of AD, and significantly mediated the link between ADMs and AD progression through the amygdala. Furthermore, these modules exhibited high tissue specificity within the amygdala and were enriched in AD-related biological pathways. Our MPRS-based framework bridges genetics, intermediate traits, and clinical outcomes and can be adapted for broader biomedical applications. Full article

Background: The hypoxia-inducible factor 1α (HIF-1α) pathway plays a key role in promoting glycolysis and tumor progression under hypoxic conditions in cancer cells. Purple potato (PP) extract, which is a polyphenol-rich natural product, has previously been shown to enhance mitochondrial function and suppress tumor growth in several cancer models. We hypothesized that PP extract could counteract hypoxia-induced glycolysis by targeting the HIF-1α pathway. Methods: Human colonic epithelial Caco-2 cells were treated with PP extract under hypoxic conditions, and its effects on glycolysis, oxidative phosphorylation, and HIF-1α signaling were evaluated. Results: Under hypoxia PP extract suppressed glycolysis, as evidenced by reduced lactate production and lower phosphorylated pyruvate dehydrogenase levels. In parallel, genes associated with oxidative phosphorylation were upregulated by PP extract, suggesting a metabolic shift under hypoxia. Additionally, PP extract reduced the protein accumulation of HIF-1α and its transcriptional activator XBP1 induced by hypoxia. Correspondingly, the expression of several HIF-1α downstream target genes, including Vegfa, Pdk1, Ldha, Hk1, and Glut1, was markedly reduced. Functionally, PP extract inhibited cell proliferation, migration, and drug resistance under hypoxic stress, indicating a broader inhibitory effect on hypoxia-driven malignant phenotypes. Conclusion: These findings suggest that PP extract disrupts cancer cell adaptation to hypoxia and supports its potential as a dietary approach against hypoxia-driven colorectal cancer, through further preclinical studies are warranted. Full article