Genes最新文献

Background/objectives: Next-generation sequencing (NGS) has become the standard of care for identifying actionable genomic alterations in non-small cell lung cancer (NSCLC). This study aims to describe the clinicopathological characteristics and genomic landscape of a non-selected cohort of NSCLC patients from the Canary Islands (Spain), analyzed during the first two years of our Molecular Diagnosis Unit's operation.

Methods: We conducted an observational, retrospective study including 448 tumors from 446 patients diagnosed between March 2023 and March 2025. Genomic profiling was performed using amplicon-based NGS panels (Oncomine™ Focus and Precision Assays) on semiconductor sequencing platforms to detect single-nucleotide variants (SNVs), indels, copy number alterations (CNAs), and gene fusions from DNA and RNA.

Results: Actionable alterations were identified in 55.1% of tumors. The most prevalent alterations were found in TP53 (29.5%), KRAS (27.2%), and EGFR (14.1%), with KRAS G12C being the most frequent variant. Stratified analysis revealed a high prevalence of ALK fusions in patients < 50 years (33.3%). Crucially, and in stark contrast with traditional exclusion criteria, 54.0% of EGFR mutations and 50.0% of ALK fusions were detected in patients with a history of smoking. Concomitant alterations were observed in 34.8% of cases, with TP53 being the most common co-mutation partner.

Conclusions: Our real-world data confirm the feasibility and clinical value of routine NGS testing for NSCLC. The findings highlight specific genomic patterns in this population and demonstrate that smoking status should not preclude comprehensive molecular testing for canonical drivers.

Background: Cholesterol imbalances and elevated blood pressure (BP) are closely interrelated risk factors for cardiovascular disease (CVD) and are subject to genetic influences. We sought to identify novel associations between candidate genetic coding variants and CVD traits in our isolated study cohort and validate them in a general population cohort.

Methods: We leveraged the population genetic features of the Norfolk Island Health Study (NIHS, n = 601), to identify candidate functional variants which were analysed for association with CVD and metabolic syndrome traits. We followed up suggestive variant-trait associations in the 2022 release of UK Biobank whole exome data (n = 200,625).

Results: We identified a novel ten-base-pair in-frame missense multi-nucleotide variant (MNV), tagged by rs35724886, in the lipid metabolism gene ACOT4, which was associated with cholesterol levels and blood pressure. The MNV was associated with a lower incidence of 'elevated BP'-systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg-(OR: 0.70; 95% CI: 0.51, 0.97; p = 0.03), and higher total cholesterol levels (β = 0.08; p = 0.04) in the NIHS. Validation in the UK Biobank revealed consistent associations between the MNV (proxied by rs35725886) and lower incidence of 'elevated BP' (p = 0.0001), higher total cholesterol (p = 0.01), and reduced use of medication for managing blood pressure (p = 1.8 × 10^-6) and cholesterol (p = 0.002). Structural modelling and in-silico predictions suggested that the MNV introduced destabilising changes in the ACOT4 protein, likely influencing peroxisomal lipid metabolism pathways critical to CVD risk.

Conclusions: This study identified a coding MNV with potential implications for understanding the genetic regulation of lipid metabolism and its impact on cardiovascular health.

Background: Formin proteins are crucial regulators of actin filament assembly and elongation in eukaryotic cells, playing important roles in plant development and abiotic stress responses. However, the functional characterization of formins in Brassica rapa L. remains undiscovered.

Methods: A total of 27 formin family members (BrFHs) were identified through genome-wide alignment with Arabidopsis thaliana (L.) Heynh.

Results: Phylogenetic analysis classified BrFH gene family into two distinct clades, designated Group I and Group II, which exhibit divergent protein architectures. Promoter analysis revealed that BrFHs contain multiple cis-regulatory elements related to growth and development, stress responses, and phytohormone signaling. These findings suggest that BrFHs may have diversified functions. Tissue-specific expression analysis revealed that BrFHs exhibit distinct expression patterns across various tissues. Notably, BrFH15 and BrFH18 are highly expressed in flowers, displaying expression profiles similar to those of floral development genes such as AP3, AGL10 and so on. Additionally, many BrFHs show dynamic expression patterns in response to cold stresses. In particular, BrFH2, BrFH19 and BrFH27 were up-regulated, and their co-expression within the gene network suggests potential roles in regulating cold stress.

Conclusions: These results clarify the functional roles of BrFHs and shed light on the molecular mechanisms underlying their regulation of tissue development and responses to cold stress in Brassica rapa.

Background: Anterior cruciate ligament (ACL) rupture, Achilles tendinopathy, and stress fracture are common sports injuries with significant long-term effects on performance and health. Despite similar exposure, injury susceptibility varies among athletes, suggesting a genetic component. Variants in COL1A1, COL5A1, ACTN3, MMP3, and GDF5 genes influence collagen integrity, muscle performance, and extracellular matrix remodelling, making them potential risk factors.

Objective: To systematically review associations between five selected genes and musculoskeletal injury risk.

Methods: Following PRISMA 2020 guidelines, PubMed, EMBASE, SPORTDiscus, and Web of Science were searched for studies examining these genes in relation to sports injuries. Data were extracted using Covidence and assessed for quality via the Newcastle-Ottawa Scale (NOS).

Results: Twenty-six studies (n > 7000) were included. COL1A1 rs1800012 showed a protective effect against ACL rupture; COL5A1 rs1272 and rs13946 increased risk for ACL rupture and Achilles tendinopathy. MMP3 variants (rs679620, 5A/6A) showed variable associations, particularly in combination with COL5A1. ACTN3 R577X was linked to higher muscle and soft tissue injury risk in XX genotype carriers. Evidence for GDF5 rs143383 was limited but suggested a possible association with stress fractures.

Conclusions: Genetic variants in COL1A1, COL5A1, MMP3, ACTN3, and GDF5 may influence susceptibility to ACL rupture, Achilles tendinopathy, and stress fractures. Larger, multi-ethnic studies are needed to validate these findings and inform personalised injury prevention strategies.

Background/objectives: Adeno-associated virus serotype 9 (AAV9) can cross the blood-brain barrier, making it widely used as a gene delivery vector for central nervous system (CNS) applications. Despite extensive use of AAV9 in translational research, variability in study designs makes cross-comparisons difficult to interpret. We designed a study in mice to generate a resource of AAV9 biodistribution across tissues for commonly used routes of administration and treatment ages.

Methods: Lumbar intrathecal, intracerebroventricular, lumbar intrathecal and intracerebroventricular combination, or intravenous injections of vehicle or AAV9/GFP were performed in C57BL/6J male and female mice on postnatal day 1, 5, 10, or 28. Organs were collected at postnatal day 56 and biodistribution of AAV9/GFP was evaluated by quantifying GFP protein expression and vector genome copy number.

Results: Direct cerebrospinal fluid injections led to higher transgene expression levels in the brain and spinal cord compared to intravenous administration but did not de-target transgene expression in peripheral tissues. Lumbar intrathecal and intracerebroventricular combination injections resulted in expression throughout the CNS but did not substantially increase expression in either the spinal cord or brain beyond the levels obtained with the respective single routes. Treatment age had effects on AAV9 biodistribution regardless of the route of administration, especially in the brain, eye, and liver.

Conclusions: Our results provide the necessary biodistribution data to establish a standardized benchmark for comparison of the current gold standard AAV9 to next generation viral vectors. Additionally, this body of work can provide valuable insights for the design of translational gene therapy studies.

Siberian cats are characterized by a high level of genetic variability, which is also reflected in a wide range of colour variations. Knowledge about the genetic background of these coat colour varieties is fragmented and predominantly derived from research on other breeds, with inconsistencies in nomenclature across major feline organizations. This review aims to offer a comprehensive synthesis of the genetic mechanisms underlying coat colour and pattern variation in Siberian cats, while also critically examining how these phenotypes are defined, named, and recognized across key international feline breed registries. In Siberian cats, as in other breeds, the fundamental factor in the development of a phenotype is the interaction of multiple genes involved in the production of various types of melanin, its quantity, and distribution in the skin and coat. An analysis of breed standards revealed inaccuracies in the naming of several traits and differences in the acceptance of certain phenotypes within the breed, most notably concerning basic colours, ticked patterns, colourpoint recognition, silver and golden variants, as well as definitions of white spotting categories. The Siberian cat exhibits complex and partially breed-specific genetic determinants of coat colouration. Unification of nomenclature among feline federations would improve clarity in breeding practice and genetic documentation. Some of the traits still require molecular research into their genetic background, making the breed interesting not only to cat lovers but also to researchers.

Genetic variation underlies the capacity of populations to adapt, yet what drives how this variation is generated and maintained in natural populations remains poorly understood. Fundamental processes such as mutation, ploidy, and recombination are known to shape genetic variation and adaptive potential but are typically studied in isolation and under controlled laboratory conditions. How these processes act together under varying environmental conditions to structure genetic variation across complex natural populations remains unresolved. In yeasts, these processes are dependent on reproductive mode, ploidy shifts, and environmental stressors, which jointly shape genomic stability and adaptive potential. Here, we review our current knowledge on the roles of mutation, ploidy, and recombination in adaptation in the model yeasts Saccharomyces cerevisiae and the human pathogenic Cryptococcus. We highlight heterogeneity in mutation rates, recombination, and ploidy states across strains, environments, and populations, challenging the assumption that these parameters are uniform. We argue that fluctuating environments, increasingly driven by climate change, are likely to intensify interactions among these processes to impact evolution in ways that remain difficult to predict. Integrating population genomics with ecologically realistic frameworks will be essential for understanding natural evolutionary dynamics and anticipating fungal adaptation and disease emergence.

Background/Objectives: Phelan-McDermid syndrome (PMS), caused by either chromosome 22q13.3 deletions or pathogenic/likely pathogenic variants in the SHANK3 gene, is a rare neurodevelopmental disorder. Behavioral issues greatly impair the quality of life for affected individuals and their families. This genotype-phenotype study intended to further characterize key behavioral features and their genetic and metabolic correlates in PMS. Methods: We conducted a cross-sectional analysis of data on 56 individuals with PMS. Autistic and related behaviors were assessed with the Autism Diagnosis Interview-Revised (ADI-R) and adaptive behavior skills were assessed with the Vineland Adaptive Behavior Scales-Third Edition (Vineland-3), both covering multiple aspects of communication, socialization and abnormal behaviors. Genetic diagnostic information on deletions or pathogenic variants was supplemented with the sequencing data of nine candidate genes on 22q13.3. Metabolic data were obtained using the Biolog Phenotype Mammalian MicroArray plates (PM-M). Results. Every subject in the cohort presented either prominent autistic behavior or adaptive behavior impairment, 55.4% of them meeting the ASD cutoff in every ADI-R domain and 92.9% scoring in the lowest level of adaptive behavior (range of 20-70). Individuals with SHANK3 variants had lower adaptive behavioral skills than those with 22q13 deletions regardless of deletion size, while genomic parameters were largely unrelated to ADI-R scores. Metabolic profiling identified unique profiles of individuals with PMS compared with controls, while distinct profiles distinguished those who met or did not meet the ADI-R ASD cutoff. Cluster analyses revealed groups of individuals with ASD and other clinical features. Conclusion. This study highlighted the importance of SHANK3 in adaptive behavioral skills and uncovered potential metabolic biomarkers of therapeutic relevance.

Background/objectives: Grapevine (Vitis vinifera L.) is one of the most economically and culturally important fruit crops worldwide and hosts more than 100 viruses. Viral infections can cause severe yield losses, but plants can adapt to infection through changes in miRNA-mediated regulatory pathways. MicroRNAs are key regulators of plant development and stress responses. Several prediction tools are available for miRNA detection from small RNA sequencing data, each relying on different algorithms. The aim of this study was to compare miRNA predictions generated by three widely used tools (miRador, ShortStack, and miRDeep2) and to evaluate how viral coinfections influence miRNA expression in grapevine.

Methods: Two grapevine cultivars, Refošk ("Terrano") and Zeleni Sauvignon ("Sauvignon Vert"), were analyzed. Small RNA sequencing was performed on virus-free plants and plants coinfected with grapevine Pinot gris virus (GPGV), grapevine rupestris stem pitting-associated virus (GRSPaV), and grapevine rupestris vein feathering virus (GRVFV). Three miRNA prediction tools were used to identify miRNAs annotated in public databases. Differential expression analysis was performed separately for each tool and by using an integrated approach that combined all three datasets. The expression of selected miRNAs was further evaluated using stem-loop RT-qPCR.

Results: The three prediction tools detected markedly different numbers of miRNAs, resulting in largely distinct sets of differentially expressed miRNAs and limited overlap between individual analyses. The integrated approach yielded a separate set of differentially expressed miRNAs, most of which overlapped with at least one individual dataset. Stem-loop RT-qPCR analysis supported the differential expression of several selected miRNAs.

Conclusions: This study provides new insight into miRNA expression in grapevine under mixed-virus infection and demonstrates that miRNA profiling outcomes are strongly influenced by the choice of bioinformatic prediction tool. Our results highlight the importance of integrated analytical strategies combined with experimental validation to obtain robust and biologically meaningful interpretations of miRNA expression in plants.

Background/objectives: A rise in infections associated with carbapenem-resistant Providencia species (CRPS) has been observed worldwide. This study presents a genomic analysis of CRPS isolates from four hospitals in Croatia and the outpatient setting, in order to determine the extent of the spread of CRPS in Croatia. In the present study, we applied a combination of phenotypic characterization and molecular analysis of resistance traits to determine the mechanisms and the routes of spread of CRPS.

Material and methods: The antibiotic susceptibility testing was performed using disk-diffusion and broth dilution methods. The nature of extended-spectrum β-lactamases (ESBLs), carbapenemases, and fluoroquinolone resistance determinants was investigated by polymerase chain reaction (PCR). In order to obtain an insight into the whole resistome, selected isolates were subjected to the Interarray Genotyping Kit CarbaResist and whole genome sequencing (WGS).

Results: In total, 30 isolates were collected from four centers, located in different geographic regions of Croatia. There was uniform resistance to piperacillin-tazobactam, cefuroxime, expanded-spectrum cephalosporins (ESCs), imipenem, ertapenem, meropenem, and ciprofloxacin. Immunochromatographic testing and PCR revealed OXA-48 and NDM carbapenemase in 15 isolates, respectively. Phenotypic tests for ESBLs were positive in all OXA-48 and one NDM-positive organism (16 isolates). The isolates were categorized as extensively drug-resistant (XDR). OXA-48-producing isolates were susceptible only to ceftazidime-avibactam, whereas NDM producers were susceptible to cefiderocol and, in the majority of cases, also to amikacin. WGS identified a plethora of genes encoding resistance to aminoglycosides, such as aadA1 and aadA2, (aph(3″)-Ib and aph(6)-Id, sulfonamides sul1 and sul2, trimethoprim dfrA1, dfrA10, and dfrA12, tetracyclines tet(A) and tet(B), and chloramphenicol catA3 and catA5.

Conclusions: Providencia spp., in spite of being a rare pathogen, should be included in the surveillance studies across the medical centers in Croatia.