Search Results (351)

The primary objective is to determine predictors of pulmonary hypertension (PH) development in patients with centromere antibody (ACA) positive systemic sclerosis (SSc) and to assess survival in patients with and without PH. This was a retrospective cohort study that included both prevalent and incident SSc patients with ACA. Clinical characteristics, mortality and immunomodulatory use were compared between SSc-ACA+ patients with and without PH. Univariable and multivariable logistic regression models, along with a univariable Cox proportional hazards model, were used to assess predictors and survival of PH, respectively. Of 146 SSc-ACA+ patients, 25 (17.1%) developed PH. Patients with PH had more frequent obstructive sleep apnea (36% vs. 12%), heart failure (44% vs. 7.4%), arrhythmias (32% vs. 12%), valvular heart disease (VHD) (32% vs. 8.3%), and chronic kidney disease (36% vs. 12%) than those without PH. In the multivariable logistic regression analysis, VHD was associated with an increased risk of PH development (OR = 7.79), while immunomodulatory use before PH was associated with a reduced risk of PH (OR = 0.34). Patients with PH who received immunomodulatory therapy had a better survival than those with PH without immunomodulatory treatment (p = 0.0008). PH is associated with high mortality in patients with SSc-ACA+. Immunomodulatory use may lower the incidence and mortality of PH in patients with SSc-ACA+ disease. Further randomized studies are needed to confirm this assumption. Full article

Triple-negative breast cancer (TNBC), particularly the androgen receptor-low (AR-low) subtype, is one of the most aggressive and hard-to-treat forms of BC, characterized by a high index of proliferation, chromosomal instability (CIN), and high prevalence of TP53 mutations. These features fuel therapy resistance, metastases, and poor clinical outcomes. An integrated framework describing the dysregulated molecular networks that support the pathobiology of AR-low TNBC is lacking. Multiple published studies in breast cancer have previously proposed mechanistic links between TP53 loss, AR-low states, and heightened FOXM1-driven G2/M transcriptional programs, potentially via deregulation of E2F activity, chromatin-associated co-regulators (e.g., ATAD2), and disruption of repressive networks involving p53–p21–DREAM and SPDEF. Additional reports suggest that FOXM1-associated circuitry may be reinforced by chromatin regulators such as WDR5 and by mitotic/spindle factors such as ASPM, including through feedback interactions and condensate-associated transcriptional organization. We previously showed that FOXM1, a master regulator transcription factor, is upregulated and is a biomarker of poor prognosis in AR-low TNBC. In this study, we filtered a set of “TNBC core genes” known to promote transcriptional chaos downstream of FoxM1. We identified a set of 15 cell cycle regulators—including mitotic kinesin motors (KIF14, KIF11, KIF4A, KIF2C, and KIF20A), centromeric proteins (CENPA, CENPO, CENPL, CENPF, and OIP5), and regulators of proteolysis (UBE2C, UBE2S, UBE2T, PSMD14, and TUBA1B). These 15 genes, which were ranked highly among genes overexpressed in TNBC featured prominently in gene signatures of chromosomal instability and were also overexpressed among AR-low TNBCs and TP53-mutant breast tumors. We show that expression of each of these 15 genes correlates positively with proliferation markers (Ki67, PCNA, and MCM2) in TNBC, and that the overexpression of this gene set is associated with shorter relapse-free survival and distinct immune/stromal infiltration patterns. In light of prior work, our findings point to a FOXM1-associated 15-gene signature enriched in AR-low TNBC and associated with the high-proliferation and high-CIN phenotypes of this clinically challenging tumor type. This 15-gene set represents an actionable vulnerability with therapeutic potential for AR-low TNBC and provides a framework for rethinking how to manage highly proliferative, genomically unstable BCs. Full article

This study systematically investigated the genomic alterations in Saccharomyces cerevisiae driven by Replication Factor A (RFA) dosage insufficiency using a promoter-replacement strategy combined with mutation accumulation and whole-genome sequencing. Our findings reveal that transcriptional suppression of RFA2 or RFA3 leads to severe growth inhibition. RFA deficiency induces a distinct mutational spectrum characterized by a high frequency of monosomy and terminal deletions, indicative of severe replication stress. Furthermore, loss of heterozygosity is significantly enriched at centromeres and high-GC regions, underscoring the role of RFA in stabilizing intrinsic genomic barriers. Utilizing an APOBEC3B-induced mutagenesis assay, we demonstrate that RFA insufficiency leads to the extensive accumulation of exposed ssDNA with a distinct bias towards the lagging strand template. Notably, we observed that cells spontaneously inactivate Mismatch Repair (MMR) genes, such as MSH2 and PMS1, to survive RFA-induced stress. This hypermutant phenotype grants a certain degree of growth recovery on Low Galactose (LG) medium. Overall, these findings demonstrate that RFA dosage is a key determinant of genomic integrity and elucidate how repair pathway modulation drives adaptive evolution under replication stress. Full article

Aleppo oak (Quercus infectoria) is among the most industrially and ecologically significant oak species, valued for its medicinal properties and considerable genetic importance. Cytogenetic analysis provides critical insight into evolutionary history, interspecific relationships, and karyotypic differentiation. This study investigated the chromosomal architecture and karyotypic diversity of five natural populations of this species in western Iran (Sardasht, Oramanat, Baneh, Paveh, and Marivan) using actively dividing root meristems and a high-resolution image-based cytogenetic system. All examined cells displayed a basic chromosome number of x = 12 and a diploid condition, and chromosome lengths ranged from 0.90 to 2.12 µm. ANOVA and mean comparisons of five chromosomal parameters (Long Arm, Short Arm and Total Length, Arm Ratio, and Centromeric Index) revealed significant interpopulation differences in chromosome length and arm dimensions. All populations shared the karyotype formula 12 m and were classified into Stebbins’ Category B, indicating a moderately symmetrical, relatively primitive cytogenetic structure. Principal component analysis reduced the dataset to two major axes explaining 99.93% of the total variance, predominantly influenced by SA and TL on PC1 and by LA, AR, and CI on PC2. Hierarchical clustering grouped the populations into three distinct lineages, with Sardasht–Oramanat–Baneh showing the greatest divergence. Biplot vector patterns further clarified trait correlations, highlighting genomic structuring and potential breeding utility. Full article

Background: Intrachromosomal rearrangements in birds play a subtle but important role in shaping genomic evolution, phenotypic diversity and speciation. However, the avian sex chromosome system (homogametic ZZ males; heterogametic ZW females) remains relatively understudied, and evolutionary rearrangements of the Z chromosome have not been mapped in most species. To address this, we employed universally hybridizing avian Z chromosome probes to metaphases of 11 avian species from South America. Methods: Chromosome preparations were obtained from fibroblast cell cultures of 11 birds representing nine different orders; four bacterial artificial chromosome (BAC) probes were used in our interspecies fluorescence in situ hybridization (FISH) experiments. We identified chromosomal rearrangements in the species investigated, tracing the evolution of the Z chromosome in these species through comparison with reptiles from Southeast Asia (three snake species used as an outgroup), along with two reference species: chicken (Galliformes) and zebra finch (Passeriformes). Results: We observed high rates of intrachromosomal rearrangements in the avian Z chromosome, with most species showing different patterns from chicken and zebra finch. Nannopterum brasilianum (Suliformes) and Jacana jacana (Charadriiformes) showed the same BAC order as chicken, but centromere repositioning was evident. Apart from Piciformes, all other species exhibited a conserved Z chromosome size. The corresponding Z chromosome sequences were homologous to regions of the long arms of Chromosome 2 and W in snakes but not on the Z chromosomes. Conclusions: Comparative analysis of the Z chromosome across avian orders provides important insights into the dynamics of avian sex chromosomes and the evolution of sex chromosome systems in general. Full article

Chromosome dynamics, recombination, and nucleolar organization intersect during meiotic prophase I, yet how the recombination context influences nucleolar architecture remains unclear. We analyzed the nucleolar pool of Cdc14 in Saccharomyces cerevisiae under matched prophase I gating and a uniform, frame-based operational definition of transient two-focus episodes. In a prophase-arrest reference, Cdc14–mCherry formed a predominant single nucleolar focus with occasional, reversible two-focus episodes that Nop56–GFP placed within the nucleolar compartment (nucleolar splitting). Splitting rose sharply when interhomolog recombination was compromised and remained elevated when Spo11 catalytic activity was abolished, indicating that increased DSB formation is not required and pointing instead to the homolog engagement state as a key variable. Population checkpoint readouts did not map onto the phenotype: Hop1 phosphorylation differed strongly across genotypes, yet splitting remained high in recombination-defective and DSB-free contexts and low in the reference. Timing analyses showed that events concentrated early and declined in the reference, whereas recombination-defective and DSB-free backgrounds retained activity into later windows across thresholds. We propose that nucleolar splitting reflects a rheological response of the nucleolus to chromosome-scale forces that vary with homolog engagement, consistent with contributions from DSB-independent chromosome dynamics such as telomere clustering, telomere-led rapid prophase movements, and centromere coupling/pairing. Together, these data support the nucleolus as a mesoscale, mechanically sensitive readout of meiotic chromosome dynamics. Full article

Platelet-rich fibrin (PRF) is widely used in regenerative dentistry and oral surgery for its ability to promote tissue healing and modulate cellular responses. However, PRF contains not only platelets but also leukocytes and plasma components, complicating efforts to define the specific contribution of platelets to its biological activity. To address this, we used washed, leukocyte-depleted platelets activated with thrombin to generate platelet-released supernatant (PRS), which was applied to gingival fibroblasts. RNA sequencing identified 147 upregulated and 39 downregulated genes (|log₂ fold change| ≥ 2, FDR < 0.001), including cytokines IL11 and CXCL8 previously associated with PRF, as well as mitosis-related genes such as centromere-associated proteins, cell division cycle proteins, kinesin-like proteins, and shugoshins, consistent with gene ontology analyses. Validation by RT-PCR and immunoassays confirmed robust upregulation of IL11 and CXCL8. Functionally, PRS activated TGF-β signaling, indicated by Smad2/3 nuclear translocation, but did not induce NF-κB signaling. These findings demonstrate that platelets are major contributors to PRF’s biological effects, independent of leukocytes and plasma, and elicit a pronounced mitogenic and TGF-β-dominant response in gingival fibroblasts. They also provide insight into the cellular mechanisms underlying PRF-mediated tissue regeneration. Full article

The family Sisyridae, the Spongilla-flies, is notable for its phylogenetic position as a basal group within Neuroptera. Using the improved Schiff-Giemsa method, we analyzed the behavior of the sex chromosomes X and Y during male meiosis in Sisyra nigra (Retzius 1738). The diploid chromosome number in males was 2n = 12 + XY. In pachytene, X and Y chromosomes appeared positively heteropycnotic and loosely paired. In early diakinetic nuclei, autosomal bivalents typically exhibited one distally located chiasma, although bivalents with two chiasmata were occasionally observed. The X and Y univalents were isopycnotic with the autosomes, with the X considerably larger than the Y. During the first meiotic division, metaphase plates were radial, with autosomal bivalents forming a ring and X and Y univalents positioned centrally, well separated from each other. In metaphase cells, X and Y were located at the equator, strongly indicating their amphitelic orientation. However, they later formed a pseudobivalent from which X and Y segregated simultaneously with autosomal half bivalents at anaphase I. This achiasmatic segregation mechanism, touch-and-go pairing, has now been observed for the first time in a species carrying chromosomes with a localized centromere. At the second metaphase, two cell types were observed: one with the X chromosome and the other with the Y chromosome. The behavior of the sex chromosomes in S. nigra is notably different from that in other Neuroptera, where sex chromosomes exhibit syntelic orientation and distance pairing at metaphase I. The unusual mechanism of sex chromosome segregation in the family Sisyridae aligns well with molecular phylogenetic findings concerning the family’s basal position within the order Neuroptera. Full article

Background/Objectives: Systemic sclerosis (SSc) is a rare, complex autoimmune disease characterized by fibrosis of the skin and internal organs. While its pathogenesis is not fully understood, chromosomal instability and telomere attrition have emerged as significant areas of investigation. Methods: This review provides a historical narrative perspective and synthesizes current findings on the role of these genomic anomalies in SSc pathogenesis. We synthesized findings from foundational and recent research articles investigating genotoxic factors, chromosomal aberrations, and telomere biology in SSc. Results: There is a strong historical basis for chromosomal instability in SSc, manifesting as micronuclei, translocations, and breaks. This instability is driven by clastogenic factors and oxidative stress. SSc-specific autoantibodies are implicated; anti-centromere antibodies correlate with aneuploidy and micronuclei, while anti-topoisomerase I may inhibit DNA repair. SSc is also characterized by significant telomere attrition, first reported in 1996 and now confirmed by additional genetic studies. This telomere loss is associated with reduced telomerase activity and the presence of autoantibodies against telomere-associated proteins, including shelterin components. Conclusions: We conclude that inflammation, telomere attrition, and chromosomal instability are linked in a self-perpetuating cycle that drives SSc pathogenesis. We propose that an initial inflammatory stimulus leads to reactive oxygen species production, causing telomere damage and attrition. Critically short telomeres trigger faulty DNA repair mechanisms, such as breakage–fusion–bridge cycles, resulting in chromosomal instability. This genomic damage, in turn, acts as a danger signal, further activating inflammatory pathways and creating a feedback loop that perpetuates fibrosis. Full article

Objectives: Lung transplantation (LT) is a rescue therapy for end-stage pulmonary diseases, including systemic autoimmune diseases. The aim of this study was to analyse the evolution of patients with systemic sclerosis (SSc) who, after undergoing LT, become negative for antinuclear antibodies (ANA) and to assess whether they have different clinical and prognostic characteristics than patients who do not become negative. Material and Methods: A retrospective, descriptive analysis was performed over a cohort of patients with a diagnosis of SSc, who underwent unilateral or bilateral LT between 2006 and 2021 at the Vall d’Hebron University Hospital. Clinical and analytical data were obtained from these patients by reviewing their electronic medical records. Two groups of patients were compared: those who tested negative for ANA after LT and those who did not. Statistical analysis was performed with SPSS Statistics 20.0. Results: Eighteen patients were included. The most frequent indication for LT was interstitial lung disease (ILD) combined with pulmonary hypertension (PH), in 13 (72%) patients. All had ANA before the LT (n = 18), and regarding specific SSc autoantibodies, anti-topoisomerase I was presented in 44% (n = 8), anti-U11/U12RNP in 17% (n = 3), anti-RNA Polymerase III in 11.1% (n = 2), anti-Ro52 in 11% (n = 2) and anti-centromere in 6% of individuals (n = 1). 39% (n = 7) of the patients had negative post-LT ANA, 44% (n = 8) had declining titres, and 17% (n = 3) had stable ANA titres. Titres did not increase in any case after LT. Those patients who became ANA-negative after LT were those who had significantly lower titres before LT. No statistically significant differences between groups were found related to pre-LT clinical characteristics, immunosuppressive regimen applied after LT, or in post-LT outcomes. A non-significant trend towards better survival was observed in patients who became ANA negative, with a cumulative survival at 5 years of 85.7% compared to 72.7% among those who remained ANA-positive. Conclusions: Most patients with SSc clear ANA or reduce their levels after LT. A trend towards better survival was observed in this group, compared to the group of transplanted patients who remained positive. Full article

Artificially induced gynogenesis, a technique that utilizes UV-irradiated sperm to activate eggs while excluding paternal genetic contribution, has been instrumental in the genetic improvement of aquaculture species. Although the allo-sperm effect has been observed in some freshwater fish and suggests the integration of paternal DNA, its occurrence and mechanisms in marine fish remain unclear. In this study, a 795.23 Mb chromosome-level genome assembly for red sea bream (Pagrus major) was presented, with a scaffold N50 of 32.03 Mb, encompassing 29,083 protein-coding genes. Furthermore, the allo-sperm effect was investigated on the artificial gynogenesis of Japanese flounder (Paralichthys olivaceus) induced by UV-irradiated P. major sperm. Whole-genome sequencing of gynogenetic and normal fertilized offspring revealed eight representative genomic sequences with >96.88% nucleotide identity to P. major, including six Sparidae-specific centromeric satellite DNA sequences. PCR validation and Sanger sequencing confirmed that these sequences were present exclusively in gynogenetic groups and absent in normally fertilized offspring, providing direct evidence of the allo-sperm effect. Our findings extend the allo-sperm effect to marine fish and demonstrate its potential across taxonomically distant taxa, P. olivaceus (Pleuronectiformes) × P. major (Spariformes). These results offer valuable genomic information for P. major, and provide important insights for future genetic breeding programs in aquaculture. Full article

Satellite DNAs are highly abundant sequences that build functional centromeres and pericentromeric heterochromatin in many eukaryotes. Apart from this structural role, their involvement in gene expression modulation has been demonstrated, although a detailed understanding of the molecular mechanisms is still lacking. Here, using the major human alpha satellite as a model system, we investigate the role of satellite transcripts in gene expression regulation. We generated cell lines with forced, exogenous overexpression of alpha satellite RNA and followed the expression levels of genes containing alpha satellite repeats within introns. Our results reveal a positive correlation between exogenous alpha satellite expression and the downregulation of alpha-associated genes, strongly suggesting that alpha satellite RNA affects their transcription. Notably, the elevated levels of exogenous alpha satellite RNA did not affect histone modifications characteristic of pericentromeric heterochromatin (e.g., H3K9me3 or H3K18Ac) or euchromatin (e.g., H3K4me2) at intronic alpha satellite loci. We propose that alpha satellite RNA directly interacts with homologous DNA at dispersed intronic satellite loci by forming RNA-DNA hybrid structures, which may affect chromatin structure and transcriptional activity. The results demonstrate that alpha satellite RNA is not only involved in centromere and heterochromatin assembly but, as shown here for the first time, also plays a role in modulating the expression of alpha-associated genes. Full article

Stream-dwelling fishes face diverse hydrological pressures, making the broadly distributed Opsariichthys bidens an ideal model for analyzing adaptive evolution. To elucidate its adaptation to a high-dissolved-oxygen and high-flow-velocity stream environment, a high-quality genome with comprehensive annotation is essential. In this study, we present the first telomere-to-telomere (T2T) reference genome for O. bidens, constructed using PacBio HiFi, Oxford Nanopore Ultra-long, and Hi-C technologies. The assembled genome spans 841.96 Mb, comprising 38 chromosomes, each in a single contig (contig N50 = 22.42 Mb, 2.5-fold higher than the previous version), achieving a gap-free standard with 99.34% BUSCO completeness. Additionally, 38 centromeric sequences, 37 double-telomeric sequences, and 1 single-telomeric sequence were successfully identified, providing essential molecular markers. Phylogenetic analysis revealed a divergence time of 13.5 million years between O. bidens and its closely related species Z. platypus, with collinearity analysis confirming their high genomic conservation. Gene family analysis revealed 350 expanded families enriched in pathways associated with adaptation to high-dissolved-oxygen environments (e.g., antioxidant defense, oxidative phosphorylation, mitochondrial electron transport chain) and high-flow-velocity environments (e.g., exercise endurance, myocardial contraction, actin binding). Positive selection analysis further identified multiple pathways and key genes involved in mitochondrial optimization, oxygen utilization, and metabolic regulation. The T2T assembly greatly improves assembly continuity and enabling precise identification of centromeres and telomeres for O. bidens. These results provide a robust foundation for studying its adaptive evolution to stream environment. Full article

Background/Objectives: Satellite DNAs (satDNAs) are tandemly repeated sequences that play essential roles in chromosome structure, genome organization, and evolution. Despite their importance, the satellitome (the complete collection of satDNAs) of most avian lineages remains unexplored. We sought to describe the repeatome of three trogonid species, Trogon surrucura, T. melanurus, and Apaloderma vittatum with a focus on the satellitome to evaluate the general features of this lineage. Methods: Herein, we provide the first comparative characterization of the repeatome, with a particular focus on the comparative characterization of satDNAs in three trogonid species: T. surrucura, T. melanurus, and A. vittatum. Using a combination of bioinformatic pipelines and cytogenetic approaches. Results: We identified 16 satDNA families in T. surrucura, 15 in T. melanurus, and only 3 in A. vittatum. Sequence comparisons revealed that five families are shared between the two Trogon species, consistent with the library hypothesis, whereas no satDNAs were shared with A. vittatum. While both Trogon species exhibited a predominance of GC-rich repeats, A. vittatum represents the first bird described with a satellitome dominated by AT-rich satDNAs. In situ mapping in T. surrucura revealed chromosome-specific satDNAs restricted to pairs 1 and 2 and a Z-specific repeat that was strongly accumulated on its long arms, an atypical feature among birds. Conversely, the W chromosome showed a surprisingly low number of satDNAs, limited to centromeric signals. Conclusions: Our results reveal highly divergent satellitome landscapes among trogonids, characterized by lineage-specific differences in repeat composition, abundance, and chromosomal distribution. These findings support the view that satDNAs are dynamic genomic elements, whose amplification, loss, and chromosomal redistribution can influence genome architecture and play a role in avian speciation. Full article

Background: As a key contributor to metabolic disorders, obesity is recognized as a critical global health challenge. Adipocyte differentiation depends on the mitotic clonal expansion (MCE) phase, which is controlled by oxidative balance and transcription factors like C/EBPβ. Sesaminol, a lignan derived from Sesamum indicum, has potent antioxidant properties. This study aimed to investigate whether sesaminol suppresses adipogenesis by modulating ROS signaling, MCE, and the Nrf2-ARE pathway. Methods: In the early period of adipogenic induction, 3T3-L1 preadipocytes received treatment with sesaminol. Adipogenic development was evaluated through Oil Red O staining together with the assay of GPDH activity. Assays of cell proliferation and expression of cell cycle-related proteins, along with ROS measurement, qRT-PCR, Western blotting, and immunofluorescence, were performed to evaluate the effects on oxidative stress, transcriptional regulation, and AMPK-Nrf2 signaling. Results: Sesaminol significantly inhibited lipid accumulation and GPDH activity without cytotoxicity. It suppressed MCE by inhibiting DNA synthesis and reducing the expression of cyclin E1/E2 and CDK2. Sesaminol decreased C/EBPβ expression and its nuclear localization, resulting in lower levels of C/EBPα and PPARγ. It also reduced intracellular ROS, promoted nuclear translocation of Nrf2, and upregulated antioxidant genes HO-1 and GCLC. AMPK phosphorylation was concurrently enhanced. Conclusions: Sesaminol inhibits early adipogenesis by suppressing ROS-mediated MCE and activating the AMPK-Nrf2-ARE signaling pathway, leading to downregulation of key adipogenic transcription factors. The present study supports the potential of sesaminol as an effective strategy for obesity prevention. Full article