Search Results (25)

Background: Obstructive sleep apnea (OSA) is a complex and diverse disorder affecting almost one billion individuals worldwide. Severity of untreated OSA, measured by the apnea–hypopnea index (AHI), is noted to be associated with an increased all-cause and cardiovascular mortality. Although widely used, AHI insufficiently captures disease variability as there is a poor correlation of symptoms with the AHI. There lies individual susceptibility to the effects of OSA and that parameter alone poorly predicts cardiovascular outcomes without considering intermittent hypoxia and the hemodynamic effects of OSA. Recognition of clinical, polysomnographic, and neurophysiological phenotypes offers an opportunity to refine diagnosis, prognosis, and management strategies. Methods: We conducted a narrative synthesis of the literature involving 70 articles, focusing on quantitative and qualitative (Q2) clinical traits, polysomnographic parameters, and mechanistic insights that enable subclassification of OSA beyond AHI. Evidence from large cohorts, animal models, and pathophysiological studies were reviewed. Results: Phenotyping based on a Q2 analysis of polysomnographic respiratory event predominance, event duration, positional and REM dependence, hypoxic burden, and arousal characteristics reveals significant heterogeneity in risk profiles and therapeutic response. Apnea-predominant OSA correlates with a higher oxygen desaturation index and Epworth sleepiness scale. Hypopnea-predominant OSA correlates with a cardiometabolic disease burden and may show a more favorable response to surgical therapies. The duration of respiratory events is related to cardiovascular risk, and REM-predominant OSA independently predicts hypertension and adverse cardiovascular outcomes. Supine-predominant OSA demonstrates treatment responsiveness to auto-positive airway pressure and positional therapy. Respiratory effort–related arousals (RERAs), RERA-predominant OSA and the broader respiratory disturbance index (RDI) provide neurophysiological insight often missed by AHI-based classifications. Hypoxic burden, rather than AHI, emerged as a superior predictor of cardiovascular events and mortality. Finally, arousal frequency and periodic limb movements independently predict cardiovascular morbidity. Conclusions: Employing Q2-based phenotyping that incorporates clinical, polysomnographic, and neurophysiological markers improves risk stratification, prognosis, and individualized management of OSA. Future investigations should prioritize integrating phenotypic subclassification into diagnostic criteria and treatment planning to advance precision medicine in sleep apnea care. Full article

Cities increasingly face the impacts of global change, demanding innovative approaches in species selection and management to create more adapted and resilient urban landscapes. The incorporation of native Mediterranean flora into planting design offers an opportunity for certain Mediterranean cities to achieve this by selecting species according to their ecological feasibility and aesthetic impression throughout the year. This study constitutes a first step towards understanding the germination behaviour of 16 native Iberian plant species, with potential for use in urban planting through direct seeding. Species were selected for their ecological feasibility in Mediterranean urban environments and to maximise functional diversity in growth forms, phenology, and other vegetative and reproductive traits, thereby supporting biodiversity and ecosystem resilience. Controlled germination trials were used to evaluate germination percentage and mean germination time of 16 species under temperature and light conditions that simulated autumn and spring, the main Mediterranean germination seasons, and spring-like conditions following cold stratification. The results revealed variability in seed germination among scenarios and species, indicating diverse and contrasting germination strategies. The majority of species achieved their highest final germination percentage under the autumn scenario. Germination speed was also strongly scenario-dependent, with several species completing germination within 10 days, and cold stratification reducing the mean germination time of the most responsive species. Based on these findings, a functional classification is proposed to guide the optimal sowing season. Although autumn appears to be the most favourable time for seed sowing, species-specific germination patterns must be considered to ensure successful establishment and the effective inclusion of each species in seed mixtures. Full article

Background/Objectives: Factors modulating phenotypic variability in Rett syndrome (RTT, OMIM 312750) include X chromosome inactivation (XCI), type of MECP2 variant, and/or disease modifiers. Emerging evidence also points to multi-locus genetic variants. Understanding the phenotypic variability associated with multi-locus genetic diagnoses in individuals with RTT and MECP2-related disorders would be important not only for accurate diagnosis, risk stratification and clinical management but also to explain symptoms that might not be typically associated with RTT. Methods: We present a case series of five individuals with a diagnosis of RTT or an MECP2-related disorder with co-occurring genetic findings, including pathogenic variants, variants of unknown significance and chromosome duplications. Clinical features such as neurodevelopmental history and comorbid medical conditions were assessed alongside the genetic findings. Results: A review of 200 cases with RTT identified five cases (all females aged 7–27 years) with a co-occurring genetic finding. Each case harboured at least one additional genetic variant that included a beta thalassaemia trait, Calmodulin 3 (CALM3) missense variant, maternally inherited 22q12.3 to q13.1 duplication, 7p14.3 and Dynein Cytoplasmic 1 Heavy Chain 1 (DYNC1H1) variants of uncertain significance and a pathogenic Set Domain-containing protein 5 (SETD5) variant. A rare triple genetic finding was illustrated in a single case, combining MECP2, CALM3, and DYNC1H1 variants. Conclusions: This case series supports the premise that RTT and MECP2-related disorders exist in a more complex neurogenetic spectrum than previously defined. It also emphasises the complexity within MECP2-related disorders. They are not static, and in the context of severe treatment resistant epilepsy, MECP2 disorders can evolve over time, necessitating diagnostic reclassification. Although the co-occurrence of multiple genetic disorders in RTT and MECP2-related disorders is rare, these cases underscore the importance of considering cumulative genetic burden when evaluating individuals with atypical features or evolving neurodevelopmental phenotypes. Full article

Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies, with nearly 80% of patients diagnosed at advanced stages due to the absence of early symptoms and the nonspecific nature of later clinical manifestations. This highlights the urgent need for robust molecular biomarkers that can refine patient stratification and guide personalized therapeutic approaches. A major determinant of OC aggressiveness is the epithelial-to-mesenchymal transition (EMT), a transcriptionally driven program that represses epithelial identity while promoting mesenchymal traits, thereby enhancing invasion, dissemination, recurrence, and resistance to therapy. EMT dysregulation is widespread in OC and fuels tumor heterogeneity, metastatic spread, and chemoresistance. To investigate the contribution of EMT-related genes in OC biology, we analyzed whole-genome sequencing and RNA-seq data from 419 patients in The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas, assessing their genomic and transcriptomic alterations. We integrated these findings with transcriptomic and drug-sensitivity data from the CTRPv2 portal, performing Pearson correlation analyses to identify therapeutic vulnerabilities associated with EMT gene expression. Our analysis identifies recurrent genomic and transcriptomic alterations across several EMT-associated genes. Notably, we identified a four-EMT gene signature (EFNA1, OVOL2, GATA3, and DSG2) whose expression correlates with differential sensitivity to VEGFR and EGFR inhibitors in OC cell lines. Overall, these results suggest that EMT-driven molecular changes contribute to the onset and progression of OC and highlight a subset of EMT genes as promising predictive biomarkers for targeted therapy responses. Full article

The Yan goose (YE, Anser cygnoides) is a valuable indigenous poultry genetic resource, renowned for its superior meat quality and environmental adaptability. Despite its economic importance, the genetic basis underlying these adaptive traits remains unclear. In this study, we employed whole-genome resequencing (WGS) to perform high-throughput sequencing on a conserved population of 15 samples. Bioinformatic analyses were conducted to systematically evaluate the population’s genetic structure, and a genome-wide scan for selection signals related to economically significant traits was performed using the integrated haplotype score (iHS) method. An average of 4.43 million high-quality SNPs were identified, which were predominantly located in intergenic and intronic regions. Population structure analysis revealed a close genetic relationship within the conserved population of YE, with no significant lineage stratification observed. Pairwise sequentially Markovian coalescent (PSMC) analysis indicated that the YE underwent a severe genetic bottleneck during the Last Glacial Maximum (LGM), followed by gradual population recovery in the early Neolithic period. Genome-wide selection signal scanning identified multiple genomic regions under strong selection, annotating key genes associated with growth and development (e.g., GHRL, AKT1, and MAPK3), lipid deposition (e.g., PLPP4, SAMD8, and LPIN1), and disease resistance and stress resilience (e.g., TP53, STAT3). Functional enrichment analysis revealed significant enrichment of these genes in pathways related to glycerophospholipid metabolism (p < 0.01), purine metabolism (p < 0.01), and immune response (p < 0.01). This study not only provides a theoretical foundation for the scientific conservation of the YE germplasm resources but also offers valuable genomic resources for identifying functional genes underlying important economic traits and advancing molecular breeding strategies. Full article

Population stratification based on gut microbiota composition has revealed several enterotypes in humans and animals, providing valuable tools for studying the gut microbiota landscape, which is crucial for animal health and production. However, knowledge about rumen enterotype identification in sheep, its influencing factors, and its association with growth performance and host genetics remains limited. Here, we investigated host genetic effects and phenotypic landscapes of rumen bacterial enterotypes in a large sheep population. Ruminal contents from 1150 healthy sheep were analyzed using 16S rRNA gene sequencing and genus-level clustering, complemented by extensive phenotypic data covering 47 traits spanning growth, feed efficiency, meat yield, and ruminal fermentation, along with whole-genome resequencing data. We identified two distinct enterotypes: Enterotype 1 (E1), a mixture of multiple genera, and Enterotype 2 (E2), dominated by Prevotella. E2 sheep exhibit superior growth and meat production performance, but lower feed efficiency and increased fat deposition. Two-part beta-regression models and co-occurrence network analyses revealed the extensive impact of enterotypes on microbial community structure, with E1 displaying a higher frequency of unique bacterial interactions. The estimated heritability of the enterotype was 0.47, and a GWAS identified five key genetic markers associated with rumen enterotype, localized to two candidate genes: CHODL and ENPP6. These markers significantly influence 58 ruminal bacterial genera, including key taxa and driving genus. Overall, our data provide new insights into sheep rumen-enterotype characteristics, contributing to a better understanding of microbial interactions that are crucial for improving ruminant growth performance. Full article

Background and Clinical Significance: Neural tube defects (NTDs) represent a group of malformations, typically arising from a complex interplay between genetic susceptibility and environmental influences. Increasing evidence points to the contribution of rare pathogenic variants in genes involved in embryonic development in selected cases. To date, two families with NTDs carrying biallelic variants in TRIM36 and NUAK2 have been described. Specifically, germline homozygous pathogenic variants in NUAK2 were identified in three fetuses with anencephaly, thus implicating this gene as a critical regulator of neural tube closure. Case Presentation: We describe a family in which five individuals presented with sacral dimples, a subtle midline defect considered a minor malformation. Exome sequencing revealed a heterozygous missense variant, c.487G>A in NUAK2, segregating with the phenotype. Although sacral dimples are often clinically silent and do not typically cause functional impairment, their presence in multiple relatives highlights a possible shared genetic etiology. Careful phenotypic recognition of such findings can therefore provide valuable insights into underlying molecular mechanisms. Conclusions: This report extends the clinical spectrum of NUAK2-related anomalies by demonstrating a novel genotype–phenotype correlation. Our findings suggest that variants in this gene may follow a semi-dominant inheritance pattern, with heterozygous carriers manifesting milder phenotypes, such as sacral dimples, while biallelic pathogenic variants lead to severe NTDs. This observation reinforces the association between NUAK2 loss-of-function variants and NTDs and emphasizes the importance of genetic investigations in families where such dysmorphic traits recur. Ultimately, these results contribute to clarifying the molecular basis of NTDs and may inform both genetic counseling and risk stratification in affected families. Full article

Background: Rheumatoid arthritis (RA) is an autoimmune disease that remains incurable. An increasing number of proteomic genome-wide association studies (GWASs) are emerging, offering immense potential for identifying novel therapeutic targets for diseases. This study aims to identify potential therapeutic targets for RA based on human plasma proteome. Methods: Protein quantitative trait loci were extracted and integrated from eight large-scale proteomic GWASs. Proteome-wide Mendelian randomization (Pro-MR) was performed to prioritize proteins causally associated with RA. Further validation of the reliability and stratification of prioritized proteins was performed using MR meta-analysis, colocalization, and transcriptome-wide summary-data-based MR. Subsequently, prioritized proteins were characterized through protein–protein interaction and enrichment analyses, pleiotropy assessment, genetically engineered mouse models, cell-type-specific expression analysis, and druggability evaluation. Phenotypic expansion analyses were also conducted to explore the effects of the prioritized proteins on phenotypes such as endocrine disorders, cardiovascular diseases, and other immune-related diseases. Results: Pro-MR prioritized 32 unique proteins associated with RA risk. After validation, prioritized proteins were stratified into four reliability tiers. Prioritized proteins showed interactions with established RA drug targets and were enriched in an immune-related functional profile. Four trans-associated proteins exhibited vertical or horizontal pleiotropy with specific genes or proteins. Genetically engineered mouse models for 18 prioritized protein-coding genes displayed abnormal immune phenotypes. Single-cell RNA sequencing data were used to validate the enriched expression of several prioritized proteins in specific synovial cell types. Nine prioritized proteins were identified as targets of existing drugs in clinical trials or were already approved. Further phenome-wide MR and mediation analyses revealed the effects and potential mediating roles of some prioritized proteins on other phenotypes. Conclusions: This study identified 32 plasma proteins as potential therapeutic targets for RA, expanding the prospects for drug discovery and deepening insights into RA pathogenesis. Full article

Background: The present study aimed to investigate the clinical correlates of treatment response to mood stabilizers in patients with bipolar disorder (BD), with a specific focus on trait-related characteristics such as impulsivity and affective temperaments. Methods: In- and outpatients diagnosed with BD were recruited at the Section of Psychiatry of the General Hospital/University of Perugia. Socio-demographic, clinical, and current psychopathological characteristics were collected. The treatment response was retrospectively assessed using the Alda Scale. Trait characteristics were evaluated through the Barratt Impulsiveness Scale (BIS-11) and the Brief Temperament Evaluation of Memphis, Pisa, and San Diego—Münster version (briefTEMPS-M). Bivariate analyses and a general linear model were employed to analyze the correlates of treatment response to mood stabilizers. Results: Among the investigated variables, trait impulsivity showed a significant negative association with treatment response. A similar effect was observed for depressive temperament, while other affective temperaments were not significantly associated with treatment outcomes. Patients with good treatment responses exhibited higher illness duration and lower severity of BD, higher prevalence of comorbid anxiety disorders, lower diurnal variation in depressive symptoms, and lower functional impairment in autonomy and occupational domains. The main limitations of this study were represented by the small sample size, the retrospective assessment of treatment response, and the inclusion of patients from a single center. Conclusions: The present findings suggest that impulsivity and depressive temperament should be investigated as potential predictors of poor response to mood stabilizers in BD. These trait dimensions, together with other clinical markers, may serve as useful targets for patient stratification and the development of personalized treatment strategies. Full article

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia and abnormal behaviors occurring during REM sleep. Idiopathic RBD (iRBD) is recognized as the strongest prodromal hallmark of α-synucleinopathies, with an established conversion rate to a neurodegenerative condition that reaches up to 96.6% at 15 years of follow-up. Moreover, RBD-converters display a more severe clinical trajectory compared to those that do not present with RBD. However, the extent to which iRBD represents a distinct genetic entity or an early manifestation of neurodegeneration remains unclear. To address this, we applied Genomic Structural Equation Modeling (GenomicSEM) using a GWAS-by-subtraction approach to disentangle the genetic architecture of iRBD from the shared genomic liability across α-synucleinopathies. Our findings highlight the SNCA locus as a key genetic regulator of iRBD susceptibility. While iRBD exhibits a partially distinct genetic signature, residual genomic overlap with neurodegenerative traits suggests that its genetic architecture exists along a continuum of α-synucleinopathy risk. In this scenario, the associations with neuroanatomical correlates may serve as early indicators of a trajectory toward future neurodegeneration. These findings provide a framework for identifying biomarkers that could aid in disease stratification and risk prediction, potentially improving early intervention strategies. Full article

Rhodotypos scandens (Thunb.) Makino is known to have a seed dispersal that is thick and stony (endocarp + seeds) and has potential as a landscaping tree seed. In several Rosaceae species, seeds are covered with a hard endocarp, making the internal seeds water-impermeable and germination difficult. Here, we analyzed the morphoanatomical traits and germination properties of R. scandens seeds. To identify ideal seed propagation conditions, we immersed R. scandens seeds in sulfuric acid for varying durations and subjected them to phytohormone (gibberellic acid A3 and fluridone) and a cold stratification (CS) (5 °C) treatment after endocarp removal (ER). The R. scandens stony seeds did not increase in mass by ≥25.0%. Following ER, the seed mass increased by ≥50.0% with water absorption when compared to the initial dry mass. Seed surfaces showed damage and cracks through scarification after 1 h of immersion in sulfuric acid, failing to germinate. A combination of ER, phytohormone treatment, and CS improved seed germination compared to ER alone (26.0 ± 5.3%). Overall, R. scandens seeds showed a dispersal with a hard endocarp from the parent plant, and a pre-treatment with ER, phytohormones, and CS was required for effective seed propagation. Full article

Introduction: Chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries, is a mature B-cell chronic lymphoproliferative disorder characterized by the accumulation of neoplastic CD5+ B lymphocytes, functionally incompetent and usually monoclonal in origin, in bone marrow, lymph nodes and blood. Diagnosis occurs predominantly in elderly patients, with a median age reported between 67 and 72 years. CLL has a heterogeneous clinical course, which can vary from indolent to, less frequently, aggressive forms. Early-stage asymptomatic CLL patients do not require immediate therapeutic intervention, but only observation; treatment is necessary for patients with advanced disease or when “active disease” is observed. The most frequent autoimmune cytopenia (AIC) is autoimmune haemolytic anaemia (AHIA). The main mechanisms underlying the appearance of AIC in CLL are not fully elucidated, the predisposition of patients with CLL to suffering autoimmune complications is variable and autoimmune cytopenia can precede, be concurrent, or follow the diagnosis of CLL. Case presentation: A 74-year-old man was admitted to the emergency room following the finding of severe macrocytic anaemia during blood tests performed that same day, in particular the patient showed a profound asthenia dating back several months. The anamnesis was silent and the patient was not taking any medications. The blood examination showed an extremely high White Blood Cell count and findings of AIHA in CLL-type mature B-cell lymphoproliferative neoplasia. Genetic investigations: Conventional karyotyping was performed and it obtained a trisomy 8 and an unbalanced translocation between the short arm of chromosome 6 and the long arm of chromosome 11, concurrent with interstitial deletions in chromosomes 6q and 11q that could not be defined in detail. Molecular cytogenetics (FISH) analyses revealed Ataxia Telangiectasia Mutated (ATM) monoallelic deletion (with loss of ATM on derivative chromosome 11) and retained signals for TP53, 13q14 and centromere 12 FISH probes. TP53 and IGHV were not mutated. Array-CGH confirmed trisomy of the entire chromosome 8 and allowed us to resolve in detail the nature of the unbalanced translocation, revealing multiple regions of genomic losses on chromosomes 6 and 11. Discussion: The present case report is an unusual CLL case with complex karyotype and refinement of all breakpoints at the gene level by the genomic array. From a genetic point of view, the case under study presented several peculiarities. Conclusions: We report the genetic findings of a CLL patient with abrupt disease onset, so far responding properly to treatments despite the presence of distinct genetic adverse traits including ATM deletion, complex karyotype and chromosome 6q chromoanagenesis event. Our report confirms that interphase FISH alone is not able to provide an overview of the whole genomic landscape in selected CLL cases and that additional techniques are required to reach an appropriate cytogenetic stratification of patients. Full article

The pig industry is significantly influenced by complex traits such as growth rate and fat deposition, which have substantial implications for economic returns. Over the years, remarkable genetic advancements have been achieved through intense artificial selection to enhance these traits in pigs. In this study, we aimed to investigate the genetic factors that contribute to growth efficiency and lean meat percentages in Large White pigs. Specifically, we focused on analyzing two key traits: age at 100 kg live weight (AGE100) and backfat thickness at 100 kg (BF100), in three distinct Large White pig populations—500 Canadian, 295 Danish, and 1500 American Large White pigs. By employing population genomic techniques, we observed significant population stratification among these pig populations. Utilizing imputed whole-genome sequencing data, we conducted single population genome-wide association studies (GWAS) as well as a combined meta-analysis across the three populations to identify genetic markers associated with the aforementioned traits. Our analyses highlighted several candidate genes, such as CNTN1—which has been linked to weight loss in mice and is potentially influential for AGE100—and MC4R, which is associated with obesity and appetite and may impact both traits. Additionally, we identified other genes—namely, PDZRN4, LIPM, and ANKRD22—which play a partial role in fat growth. Our findings provide valuable insights into the genetic basis of these important traits in Large White pigs, which may inform breeding strategies for improved production efficiency and meat quality. Full article

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition that arises from multiple causes, including sepsis, pneumonia, trauma, and severe coronavirus disease 2019 (COVID-19). Given the heterogeneity of causes and the lack of specific therapeutic options, it is crucial to understand the genetic and molecular mechanisms that underlie this condition. The identification of genetic risks and pharmacogenetic loci, which are involved in determining drug responses, could help enhance early patient diagnosis, assist in risk stratification of patients, and reveal novel targets for pharmacological interventions, including possibilities for drug repositioning. Here, we highlight the basis and importance of the most common genetic approaches to understanding the pathogenesis of ARDS and its critical triggers. We summarize the findings of screening common genetic variation via genome-wide association studies and analyses based on other approaches, such as polygenic risk scores, multi-trait analyses, or Mendelian randomization studies. We also provide an overview of results from rare genetic variation studies using Next-Generation Sequencing techniques and their links with inborn errors of immunity. Lastly, we discuss the genetic overlap between severe COVID-19 and ARDS by other causes. Full article

Background: Pancreatic cancer surgery is related to significant mortality, thus necessitating the accurate assessment of perioperative risk to enhance treatment decision making. A Surgical Outcome Risk Tool (SORT) and SORT v2 have been developed to provide enhanced risk stratification. Our aim was to validate the accuracy of SORT and SORT v2 in pancreatic cancer surgery. Method: Two hundred and twelve patients were included and underwent pancreatic surgery for cancer. The surgeries were performed by a single surgical team in a single tertiary hospital (2016–2022). We assessed a total of four risk models: SORT, SORT v2, POSSUM (Physiology and Operative Severity Score for the enumeration of Mortality and Morbidity), and P-POSSUM (Portsmouth-POSSUM). The accuracy of the model was evaluated using an observed-to-expected (O:E) ratio and the area under the curve (AUC). Results: The 30-day mortality rate was 3.3% (7 patients). Both SORT and SORT v2 demonstrated excellent discrimination traits (AUC: 0.98 and AUC: 0.98, respectively) and provided the best-performing calibration in the total analysis. However, both tools underestimated the 30-day mortality. Furthermore, both reported a high level of calibration and discrimination in the subgroup of patients undergoing pancreaticoduodenectomy, with previous ERCP, and CA19-9 ≥ 500 U/mL. Conclusions: SORT and SORT v2 are efficient risk-assessment tools that should be adopted in the perioperative pathway, shared decision-making (SDM) process, and counseling of patients with pancreatic cancer undergoing surgery. Full article