Search Results (36)

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

I previously reported that F-box/leucine-rich repeat protein 14 (FBXL14) expressed in periosteum-derived cells, and F-box and WD-40 domain-containing protein 2 (FBXW2) in the periosteum form a fiber-like structure. Here, two culture medium conditions, that is, media with and without ascorbic acid, were compared during explant culture. In the absence of ascorbic acid, the expression patterns of osteocalcin, FBXW2, and elastin were compared using fluorescent immunostaining during weeks 3–5. By observing the periosteum, cambium layer and bone, I demonstrated FBXL14 expression in micro-vessels and bone lacuna. Fluorescent immunostaining revealed that, without ascorbic acid, the FBXL14 layer was thin. Conversely, in the presence of ascorbic acid, FBXL14 formed a thick membrane-like structure inside the periosteum, and the multilayer of periosteum-derived cells (PDCs) was strong. The expression patterns of osteocalcin and FBXW2 were similar. Elastin retained its fiber structure for up to five weeks. Although osteocalcin and FBXW2 were expressed in regions similar to elastin, they could not retain their fiber structures. In conclusion, FBXL14 appears to play a role in preparing a native scaffold for forming a multilayered sheet of PDCs inside the periosteum. FBXW2 and osteocalcin appear to separate from elastic fibers during calcification. Full article

The purpose of this investigation was to examine mutations and mRNA levels of potential genes linked to diarrhea susceptibility in order to assess the health status of diarrheic kids of Baladi goats. One hundred female Baladi kids (35 diarrheic and 65 apparently healthy) were used. PCR-DNA sequencing was conducted for TMED1, CALR, FBXW9, HS6ST3, SMURF1, KPNA7, FBXL2, PIN1, S1PR5, ICAM1, EDN1, MAPK11, CSF1R, LRRK1, and CFH markers revealed nucleotide sequence variants in the frequency of distribution of all detected SNPs (p ˂ 0.05) between healthy and affected kids. Chi-square analysis showed a significant difference between resistant and affected animals. Gene expression profile revealed that TMED1, CALR, FBXW9, HS6ST3, SMURF1, KPNA7, FBXL2, PIN1, S1PR5, ICAM1, EDN1, MAPK11, CSF1R and LRRK1 were significantly up-regulated in diarrheic kids than resistant ones. Meanwhile, CFH gene elicited an opposite trend. On the mRNA levels of the examined indicators, there was a substantial interaction between the type of gene and diarrhea resistance/susceptibility. The findings could support the importance of nucleotide variations and the expression pattern of the examined genes as biomarkers for diarrhea resistance/susceptibility and offer a useful management strategy for Baladi goats. Full article

(1) Background: Mounting evidence supports the idea that one of the most critical agents in controlling gene expression could be long non-coding RNAs (lncRNAs). Upregulation of lncRNA is observed in the different processes related to pathologies, such as tumor occurrence and development. Among the crescent number of lncRNAs discovered, FLVCR1-AS1 and FBXL19-AS1 have been identified as oncogenes in many cancer progression and prognosis types, including cholangiocarcinoma, gastric cancer, glioma and glioblastoma, hepatocellular carcinoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, and osteosarcoma. Therefore, abnormal FBXL19-AS1 and FLVCR1-AS1 expression affect a variety of cellular activities, including metastasis, aggressiveness, and proliferation; (2) Methods: This study was searched via PubMed and Google Scholar databases until May 2022; (3) Results: FLVCR1-AS1 and FBXL19-AS1 participate in tumorigenesis and have an active role in impacting several signaling pathways that regulate cell proliferation, migration, invasion, metastasis, and EMT; (4) Conclusions: Our review focuses on the possible molecular mechanisms in a variety of cancers regulated by FLVCR1-AS1 and FBXL19-AS1. It is not surprising that there has been significant interest in the possibility that these lncRNAs might be used as biomarkers for diagnosis or as a target to improve a broader range of cancers in the future. Full article

Epithelial ovarian cancer (EOC) is highly aggressive with poor patient outcomes, and a deeper understanding of ovarian cancer tumorigenesis could help guide future treatment development. We proposed an optimized hit network-target sets model to systematically characterize the underlying pathological mechanisms and intra-tumoral heterogeneity in human ovarian cancer. Using TCGA data, we constructed an epithelial ovarian cancer regulatory network in this study. We use three distinct methods to produce different HNSs for identification of the driver genes/nodes, core modules, and core genes/nodes. Following the creation of the optimized HNS (OHNS) by the integration of DN (driver nodes), CM (core module), and CN (core nodes), the effectiveness of various HNSs was assessed based on the significance of the network topology, control potential, and clinical value. Immunohistochemical (IHC), qRT-PCR, and Western blotting were adopted to measure the expression of hub genes and proteins involved in epithelial ovarian cancer (EOC). We discovered that the OHNS has two key advantages: the network’s central location and controllability. It also plays a significant role in the illness network due to its wide range of capabilities. The OHNS and clinical samples revealed the endometrial cancer signaling, and the PI3K/AKT, NER, and BMP pathways. MUC16, FOXA1, FBXL2, ARID1A, COX15, COX17, SCO1, SCO2, NDUFA4L2, NDUFA, and PTEN hub genes were predicted and may serve as potential candidates for new treatments and biomarkers for EOC. This research can aid in better capturing the disease progression, the creation of potent multi-target medications, and the direction of the therapeutic community in the optimization of effective treatment regimens by various research objectives in cancer treatment. Full article