Search Results (40)

F-box-LRR (FBXL) proteins are crucial components of the SCF ubiquitin ligase complex, regulating diverse processes such as development and stress responses in plants. However, the FBXL family in tobacco (Nicotiana tabacum L.) remains poorly characterized. This study performed the first genome-wide analysis of the FBXL gene family in tobacco and identified 47 NtaFBXL genes. Phylogenetic analysis classified them into five clades, among which Clade III exhibited notable expansion. Promoter analysis revealed abundant stress- and hormone-related cis-elements. Expression profiling demonstrated tissue-specific patterns and strong responses to drought, ABA, IAA, and TMV infection. Importantly, six genes exhibited a significant negative correlation with TMV accumulation, suggesting their potential roles in antiviral defense. Moreover, both drought and TMV stress triggered a disturbance of redox homeostasis, a dynamic process that was closely associated with the expression of specific NtaFBXL genes, characterized by upregulated antioxidant enzymes (SOD, POD, CAT) and accumulated oxidative markers (H₂O₂, MDA). Collectively, this study provided a foundational resource for understanding the function of NtaFBXLs and identified key candidate genes for the genetic improvement of stress resistance in tobacco. Full article

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. In Mexico, its higher incidence and lower survival suggest a role for epigenetic factors like DNA methylation (DNAme). We conducted an epigenome-wide association study (EWAS) to define the methylation landscape and identify the profiles associated with ALL and relapse. Bone marrow or peripheral blood samples from pediatric ALL patients at diagnosis and controls without ALL were analyzed using an Infinium MethylationEPIC v2.0 array. Differential methylation was assessed using the ChAMP package. We identified a significant hypermethylated profile in ALL patients compared to controls. Probes in MAD1L1 and RPTOR contained the most differentially methylated CpG sites. Key affected pathways included proliferation, neurotransmission, and neuronal signaling. Survival analysis revealed that hypomethylation of four specific CpGs—cg01052776 (RNH1), cg20747787, cg05001671, and cg01767116 (FBXL22)—was significantly associated with an increased risk of relapse, highlighting their potential as prognostic biomarkers. This study underscores the importance of epigenetic mechanisms in pediatric ALL. Full article

Background: The periosteum and periosteum-derived cells have attracted considerable attention for their potential use in clinical applications for treating bone defects. Bovine periosteum-derived cells have been investigated because of their capability for scaffold-free bone regeneration. Previous mass spectrometry (MS) and immunohistochemistry studies have shown the presence of F-box/leucine-rich repeat protein 14 (FBXL14) in bovine periosteum and periosteum-derived cells. Recently, studies using ESI-Q-Orbitrap MS suggested the presence of type IV collagen in the periosteum. The aim of the present study was to clarify the relationship between type IV collagen and FBXL14 in the formation of periosteum-derived cells. Methods: Bovine periosteum-derived cells were obtained from Japanese Black Cattle’s legs in Medium 199 with ascorbic acid and 10% fetal bovine serum. Immunohistochemistry for type IV collagen and FBXL14 was performed using bovine bone with periosteum and periosteum alone for explant culture. Results: Both type IV collagen and FBXL14 were expressed in Volkmann’s canals and the Haversian canals in bone and periosteum. After 5 weeks, type IV collagen and FBXL14 surrounded crystals containing osteocalcin and had formed periosteum-derived cells. Von Kossa staining and immunostaining of osteocalcin revealed that the crystals contained calcified substances and osteocalcin. Conclusions: Clinically, understanding osteocalcin-interacting proteins will help promote bone regeneration. Interactions between type IV collagen and FBXL14 may contribute to scaffold-free bone regeneration. Full article

Mammalian circadian rhythms, governing ~24 h oscillations in behavior, physiology, and hormone levels, are orchestrated by transcriptional–translational feedback loops centered around the core clock protein cryptochrome 1 (CRY1). While CRY1 ubiquitination is known to regulate clock function, the roles of specific ubiquitination sites remain unclear. Here, we identify lysine 151 (K151) as a critical residue modulating the circadian period through non-canonical mechanisms. Using site-directed mutagenesis, we generated CRY1-K151Q/R mutants mimicking constitutive deubiquitination. Circadian rescue assays in Cry1/2-deficient cells revealed period shortening (K151Q: −2.25 h; K151R: −1.4 h; n = 3, p < 0.01, Student’s t-test), demonstrating K151’s functional importance. Despite normal nuclear localization kinetics, K151Q/R mutants exhibited reduced transcriptional repression in luciferase assays, a weakened interaction with BMAL1 by the luciferase complementation assay, and enhanced binding to E3 ligase FBXL12 (but not FBXL3) while showing more stability than wild-type CRY1. Notably, the absence of ubiquitination-linked degradation or altered FBXL3 engagement suggests a ubiquitination-independent mechanism. We propose that CRY1-K151 serves as a structural hub fine-tuning circadian periodicity by modulating core clock protein interactions rather than through traditional ubiquitin-mediated turnover. These findings redefine the mechanistic landscape of post-translational clock regulation and offer new therapeutic avenues for circadian disorders. Full article

Background: The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Results: Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (cyp3a65, cyp1a) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (myhb/mylz3) enhancing wound repair and tlr5-cdc42 signaling fine-tuning inflammation; (3) proteolytic cascades (c6ast4, prss1) coupled to autophagy (ulk1a, atg2a) and metabolic rewiring (g6pca.1-tg axis); and (4) melanogenesis-circadian networks (pmela/dct-fbxl3l) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP’s unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6–2.1 edges). Hub genes, such as nr1i2 (pxr), ppara, and bcl6aa/b, mediate crosstalk between these systems, while potential risks—including muscle hypercontractility (myhb overexpression) or cardiovascular effects (ace2-ppp3ccb)—underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP’s ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Conclusions: Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics. Full article

The evaluation of external pelvimetry measurements and the genetic factors influencing them is essential for improving morphological characteristics and reproductive performance in cattle. This study represents the first comprehensive analysis of the association between single nucleotide polymorphisms (SNPs) and external pelvimetry traits in Romanian Simmental cattle, a breed recognized for its distinctive pelvic morphology. The relationship between single-nucleotide polymorphisms (SNPs) and external pelvimetry traits—including croup height (CH), buttock height (BH), croup width (CW), rump angle (RA), and croup length (CL)—was examined in Simmental cows. From an initial set of 110 SNPs, 33 markers were retained after applying quality control filters, including a minor allele frequency (MAF) greater than 0.05 and Hardy–Weinberg equilibrium. These SNPs, located on multiple chromosomes, were identified within intronic, exonic, or regulatory regions of relevant genes such as CLSTN2, DPYD, FBXL7, FBXL13, SEMA6A, RUNX2, FSTL4, DST, DCBLD2, FRMD6, CAV2.3, ABL2, SH3BP4, RSBN1L,and SAMD12, suggesting that these genetic variants may influence the development and morphology of the pelvic bones. Statistical analysis revealed significant relationships between certain allele variants and croup measurements, highlighting that the presence of alternative alleles can modify their morphological traits. Notably, the G allele in CLSTN2 reduced croup height by 5.74 cm (p = 0.0227), while the T allele in RUNX2 decreased rump angle by 4.49° (p = 0.0119). Full article

Avian leukosis (AL), a major vertically transmitted infectious disease, poses a significant challenge to the conservation and industrial development of indigenous chicken breeds in China. In this study, Chengkou mountain chickens were used as a model to systematically identify genetic markers associated with resistance to avian leukosis virus subgroup J (ALV-J) through a genome-wide association study (GWAS). Genomic DNA was extracted from 500 hens at 300 days of age, and cloacal swabs, plasma, and egg white samples were collected to assess the ALV-J infection status. A total of 325 ALV-positive (ALV+) and 175 ALV-negative (ALV−) individuals were identified. Based on 10× whole-genome resequencing and stringent quality control, 12,644,463 high-quality SNPs were obtained. GWAS revealed a significant enrichment of SNPs on chromosome 6 (Chr6), from which 218 SNPs significantly associated with ALV-J resistance and 49 candidate genes were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that many of these genes, including PTPN13, TTF2, TIAL1, DLG2, FBXL7, CDH5, and CDH11, are involved in tumorigenesis and immunosuppression through the JAK/STAT signaling pathway and cell adhesion molecule pathways. Additionally, candidate genes, such as ANKH, SLC4A7, and SLC5A1, were found to potentially regulate ALV-J infection by modulating membrane transport and inflammatory responses. This study is the first to identify ALV-J resistance-associated genetic markers in Chengkou mountain chickens, revealing key genes related to immune regulation, membrane function, and tumor development. The findings provide a foundational molecular basis for disease-resistant breeding in poultry. Full article

This study purpose was to determine the gene expression as well as serum profile of acute phase proteins (APPs) and hormonal indicators linked to Barki sheep’s susceptibility to postpartum issues. Three equal-sized groups (each with fifty ewes) were created from the blood of 150 adult Barki ewes: the control group (CG), the inflammatory postpartum disorders group (IPG), and the non-inflammatory postpartum disorders group (NIPG). The expression levels of the oxidative stress (PGC-1α, SIRT1, GCLC, GCLM, and EPAS1) and metabolic (FBXL12, KPNA7, and LRRK1) genes were significantly higher in postpartum disorders sheep than in resistant ones. Ewes with inflammatory postpartum illnesses showed significantly higher levels of the examined markers than did the non-inflammatory and control groups. The serum profile analysis also revealed that the levels of Fb, Cp, Hp, SAA, cortisol, TIBC, UIBC, and ferritin were significantly higher in the IPG than in the NIPG and CG. Serum insulin, iron, transferrin, and Tf Sat.% levels, however, were all markedly lower. On the basis of the variance in the genes being studied and the modulation in the serum indicators being studied, it should be possible to monitor the health status in postpartum problems of sheep. Full article

We investigated the transcription of circadian clock genes in publicly available datasets of gene expression in medulloblastoma (MB) tissues using the R2 Genomics Analysis and Visualization Platform. Differential expression of the core clock genes among the four consensus subgroups of MB (defined in 2012 as Group 3, Group 4, the SHH group, and the WNT group) included the core clock genes (CLOCK, NPAS2, PER1, PER2, CRY1, CRY2, BMAL1, BMAL2, NR1D1, and TIMELESS) and genes which encode proteins that regulate the transcription of clock genes (CIPC, FBXL21, and USP2). The over-expression of several clock genes, including CIPC, was found in individuals with the isochromosome 17q chromosomal aberration in MB Group 3 and Group 4. The most significant biological pathways associated with clock gene expression were ribosome subunits, phototransduction, GABAergic synapse, WNT signaling pathway, and the Fanconi anemia pathway. Survival analysis of clock genes was examined using the Kaplan–Meier method and the Cox proportional hazards regression model through the R2 Genomics Platform. Two clock genes most significantly related to survival were CRY1 and USP2. The data suggest that several clock proteins, including CRY1 and USP2, be investigated as potential therapeutic targets in MB. Full article

This article proposes a methodology for establishing a relationship between the change rate of a given gene (relative to a given taxon) together with the amino acid composition of the proteins encoded by this gene and the traits of the species containing this gene. The methodology is illustrated based on the mammalian genes responsible for regulating the circadian rhythms that underlie a number of human disorders, particularly those associated with aging. The methods used are statistical and bioinformatic ones. A systematic search for orthologues, pseudogenes, and gene losses was performed using our previously developed methods. It is demonstrated that the least conserved Fbxl21 gene in the Euarchontoglires superorder exhibits a statistically significant connection of genomic characteristics (the median of dN/dS for a gene relative to all the other orthologous genes of a taxon, as well as the preference or avoidance of certain amino acids in its protein) with species-specific lifespan and body weight. In contrast, no such connection is observed for Fbxl21 in the Laurasiatheria superorder. This study goes beyond the protein-coding genes, since the accumulation of amino acid substitutions in the course of evolution leads to pseudogenization and even gene loss, although the relationship between the genomic characteristics and the species traits is still preserved. The proposed methodology is illustrated using the examples of circadian rhythm genes and proteins in placental mammals, e.g., longevity is connected with the rate of Fbxl21 gene change, pseudogenization or gene loss, and specific amino acid substitutions (e.g., asparagine at the 19th position of the CRY-binding domain) in the protein encoded by this gene. Full article

Left displaced abomasum (LDA) is a multifactorial disease of cattle that occurs mainly during the transition postpartum period and is characterized by a decrease in milk production and an increased risk of culling. Several studies have been conducted confirming the hereditary nature of predisposition to this disease. The aim of our study is to identify genetic associations characterizing the genomic variability of susceptibility to LDA in Holstein cattle of the Leningrad region of the Russian Federation. The objects of this study were 360 highly productive dairy cows divided into two groups: animals with LDA, and healthy ones (control). Runs of homozygosity analysis revealed one ROH on BTA13 that was found to be significantly more prevalent in the group of animals with LDA than in the healthy group. Fourteen candidate SNPs were found to be nominally associated with left displacement of the abomasum (p-value < 1 × 10⁻⁴). When performing functional annotation of genes containing associated polymorphisms or located close to them, candidate genes presumably associated with the development of LDA were identified: ABCB11, SRP72, RGS18, SOX4, GSG1L, FBXL19, and PNPLA4. Full article

TNF inhibitors (TNFi) have revolutionized the therapeutic management of various chronic immune-mediated inflammatory diseases. Despite their known benefits, these therapies are related to paradoxical adverse effects (PAEs), including paradoxical psoriasis (PP). Although the underlying mechanism remains somewhat unclear, some theories suggest that genetic factors, particularly certain single-nucleotide polymorphisms (SNPs), may play an important role. The present review aimed to research and analyze recent findings regarding the pathomechanisms involved in the appearance of PP and the association between various genetic factors and PP in individuals treated with TNFi. We performed a literature search and found that certain genes (IL23R, TNF, FBXL19, CTLA4, SLC12A8, TAP1) are strongly associated with the occurrence of PP in pediatric and adult patients during therapy with TNFi. The identification of the specific SNPs involved in the appearance of PP and other PAEs in patients treated with TNFi for various diseases and in different populations may later favor the recognition of those patients at a high risk of developing such adverse effects and could guide personalized therapeutic strategies in future years. Full article

In recent years, research has intensified in exploring the genetic basis of psoriasis (PsO) and psoriatic arthritis (PsA). Genome-wide association studies (GWASs), including tools like ImmunoChip, have significantly deepened our understanding of disease mechanisms by pinpointing risk-associated genetic loci. These efforts have elucidated biological pathways involved in PsO pathogenesis, particularly those related to the innate immune system, antigen presentation, and adaptive immune responses. Specific genetic loci, such as TRAF3IP2, REL, and FBXL19, have been identified as having a significant impact on disease development. Interestingly, different genetic variants at the same locus can predispose individuals to either PsO or PsA (e.g., IL23R and deletion of LCE3B and LCE3C), with some variants being uniquely linked to PsA (like HLA B27 on chromosome 6). This article aims to summarize known and new data on the genetics of PsO and PsA, their associated genes, and the involvement of the HLA system and cytokines. Full article

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (DPP10, FBXL7, NDFIP1, TBXT, GLCCI1, HDAC9, TBXAS1, STAT6, GSDMB/ORMDL3, CRHR1, GNGT2, FCER2), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants (p-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (p-value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations. Full article

Background: Although inhaled corticosteroids (ICS) are the first-line therapy for patients with persistent asthma, many patients continue to have exacerbations. We developed machine learning models to predict the ICS response in patients with asthma. Methods: The subjects included asthma patients of European ancestry (n = 1371; 448 children; 916 adults). A genome-wide association study was performed to identify the SNPs associated with ICS response. Using the SNPs identified, two machine learning models were developed to predict ICS response: (1) least absolute shrinkage and selection operator (LASSO) regression and (2) random forest. Results: The LASSO regression model achieved an AUC of 0.71 (95% CI 0.67–0.76; sensitivity: 0.57; specificity: 0.75) in an independent test cohort, and the random forest model achieved an AUC of 0.74 (95% CI 0.70–0.78; sensitivity: 0.70; specificity: 0.68). The genes contributing to the prediction of ICS response included those associated with ICS responses in asthma (TPSAB1, FBXL16), asthma symptoms and severity (ABCA7, CNN2, PTRN3, and BSG/CD147), airway remodeling (ELANE, FSTL3), mucin production (GAL3ST), leukotriene synthesis (GPX4), allergic asthma (ZFPM1, SBNO2), and others. Conclusions: An accurate risk prediction of ICS response can be obtained using machine learning methods, with the potential to inform personalized treatment decisions. Further studies are needed to examine if the integration of richer phenotype data could improve risk prediction. Full article