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Intracerebral hemorrhage (ICH) is a devastating form of stroke associated with significant morbidity and mortality. Microglia are intracranial innate immune cell that play critical roles in Intracerebral hemorrhage through direct or indirect means. Vesicle transport is a fundamental mechanism of intercellular communication. Recent studies have identified microglia in specific polarized states correlate with pathogenesis, material and signal transmission in ICH through derived extracellular vesicles. Diverse polarization states trigger distinct functions, however, the exosome proteomes across these states remain poorly characterized. Here, we hypothesized that microglia exosomal profiles vary with polarization states, impacting their functional repertoire and influencing outcomes in cerebral hemorrhage. In vitro model of cerebral hemorrhage, administration of 20 μg/ml LPS-induced M1 microglia derived exosomes (M1-Exo) with HT22 enhanced hemin-induced neuronal death, while IL-4-induced M2 microglia derived exosomes (M2-Exo) significantly reduced hemin-induced cell apoptosis and inflammation. Then we identified novel state-specific proteomic profiles of microglia-derived exosomes under these polarization conditions through label-free quantitative mass spectrometry (LFQ-MS). Analysis of protein content identified several exosomal signature proteins and hundreds of differentially expressed proteins across polarization states. Specifically, proteins including UMOD, NLRP3, ACOD1, IL1RN, heme oxygenase 1 (HMOX1), CCL4, and TNFRSF1B in M1-Exo were enriched in inflammatory pathways, while those in M2-Exo exhibited enrichment in autophagy, ubiquitination, and mitochondrial respiration. The analysis of those diverse exosomal proteins suggested unique proteomic profiles and possible intracellular signal transmission and regulation mechanisms. Together, these findings offer new insights and resources for studying microglia-derived exosome and pave the way for the development of novel therapeutic strategies targeting microglial exosome-mediated pathways.

Oculocutaneous albinism type 1 is caused by variants in the TYR (tyrosinase) gene. We describe a family with two affected sibs who inherited the pathogenic missense TYR variant c.1146C > A;p.(Asn382Lys) from their mother and a deletion encompassing 65 kilobase pairs of the upstream region of the gene between hg38 coordinates chr11:89110944 and chr11:89175770, from their father. The deletion likely arose by non-homologous recombination since the regions including the two deletion breakpoints share no sequence homology. The deletion contains a single enhancer element that is homologous to a 5' Tyr core regulatory element in the mouse. A luciferase reporter assay showed that this element had a positive regulatory activity. This represents to our knowledge the first deletion solely restricted to non-coding upstream sequences of the TYR gene. It is assumed that the deletion down-regulates expression of the TYR gene and is therefore pathogenic, allowing to establish the diagnosis of OCA 1 in the patients. This study underscores the need to extend the search for pathogenic variants to regulatory regions either by whole genome sequencing or by targeted next generation sequencing of a panel including entire genes (exons, introns, flanking sequences) in order to improve the diagnostic rate in patients with albinism.

E3 ligases are essential for ubiquitination and play a role in regulating various aspects of eukaryotic life. Ariadne (ARI) proteins, a subfamily of RBR (RING-between-RING) proteins, have been recognized as a new class of RING-finger E3 ligases. Recent research has shed light on their potential involvement in plants' responses to abiotic stress. However, comprehensive studies on ARI genes in apple (Malus domestica) are still lacking. This study identified ten MdARI genes in the apple genome, and examined intraspecific and interspecific collinearity to explore the evolutionary relationships of ARI family members. Phylogenetic analyses classified MdARIs into two subfamilies (A and B), and by integrating gene structure, conserved motifs, and sequence comparison results, subfamily B was further divided into two subgroups (I and II). Tissue expression analyses revealed varied expression patterns of MdARI genes in different tissues, and subcellular localization showed that MdARI1-1, MdARI1-2, and MdARI9-1 were located in the nucleus, while the other seven MdARIs were distributed throughout the cell. Analyses of promoter cis-elements and expression patterns under cold, salt, and drought treatments indicated the involvement of MdARIs in abiotic stress responses. Several proteins crucial to the plant stress response were predicted to be potential MdARIs-interacting proteins based on the protein interaction network. Additionally, the interaction between UBC11 (E2) and MdARI7-2 was confirmed by a yeast two-hybrid (Y2H) experiment, suggesting that MdARI7-2 may function as an E3. These findings will greatly benefit future research on the role and mechanisms of ARI proteins in apple stress response.

Background: Oxidative stress is a cellular characteristic that might induce the proliferation and differentiation of tumor cells and promote tumor progression in diffuse large B-cell lymphoma (DLBCL).

Methods: The DLBCL gene sequencing dataset, tumor mutation burden data, copy number variation data of Somatic cell mutation data in TCGA were downloaded for data training analysis, along with four DLBCL datasets in GEO for validation analysis. The known oxidative stress related genes (OSRGs) were collected from websites. The weighted gene co-expression network analysis (WGCNA) was conducted on the TCGA DLBCL dataset to obtain gene modules related to oxidative stress and intersected with the known OSRGs to obtain the hub genes, which were used to perform consensus clustering on the samples to obtain new phenotypes. Next, the prognosis related OSRGs were selected through regression analysis algorithms and key genes were identified. These genes were used to establish the prognostic risk model and predictive model, and to compare functional and pathway differences among different risk groups.

Results: Through website search, we obtained 297 known OSRGs, and after intersecting with WGCNA results, we obtained 26 OSRGs. The TCGA-DLBC samples were clustered into 2 subtypes with these genes and there were significant differences in immune infiltration between subtypes. After regression analysis, we obtained a total of four key genes, BMI1, CDKN1A, NOX1, and SESN1. The risk prediction model established with these four genes as variables has accurate prognostic prediction ability. The key genes interact with 65 miRNAs, 57 TFs, 47 RBPs, and 62 drugs, respectively, and are closely related to immune infiltration of the disease. Among them, CDKN1A and SESN1 had the highest variability.

Conclusions: The key genes involved in oxidative stress could predict the prognosis of DLBCL and potentially become therapeutic targets.

This paper reports a case of a WDR45 variant inherited from an asymptomatic low-percentage mosaic mother. The proband boy was found to have significant psychomotor developmental delay, epilepsy, and abnormal liver function at four months of age, and a hemizygous variant WDR45 c.867_869dupGTA (p.Y290*) was detected by high throughput sequencing, which has an ACMG rating of likely pathogenic variant. The same variant was detected by high-throughput sequencing of the amniotic fluid of the fetus at his mother's next pregnancy. Eventually, the same variant was detected in mosaic status in the unaffected mother by target capture-based deep sequencing of the asymptomatic mother, with a mutation load of 4.06 %.

Genomic instability is regardedas a hallmark of cancer cells. It can be presented in many ways, among which chromosome instability has received attention. Ultrafine anaphase bridges are a typeof chromatin bridges, the untimely resolution of which can also lead to chromosome instability. PICH can play a role in maintaining chromosome stability by regulating chromosome morphologyand resolving ultrafine anaphase bridges. Recently, PICH has been found to be overexpressed in various cancers. Overexpression of PICH is related to the proliferation of tumors and poor prognosis. In this article, we consider that PICH can maintain genomic stability by regulating appropriate chromosome structure, ensuring proper chromosome segregation, and facilitating replication fork reversal. We summarize how PICH regulates chromosome stability, how PICH resolves Ultrafine anaphase bridges with other proteins, and how PICH promotes tumor progression.

Background: This study aimed to investigate the key molecular mechanisms underlying keloid pathogenesis by integrating oxidative stress, mitochondria, and immune cells.

Methods: Transcriptome sequencing (mRNA, lncRNA, and circRNA expression data), proteomic sequencing, and small RNA sequencing analyses of lesional and non-lesional skin of patients with keloids and healthy control (normal) skin were conducted. By integrating mRNA and publicly available gene expression data (GSE158395), differentially expressed genes related to oxidative stress and mitochondrial function in keloids were identified. Hub genes were identified using various bioinformatics analyses such as immune infiltration analysis, weighted gene co-expression network analysis, machine learning, and expression validation using proteomics sequencing data. Moreover, a competing endogenous RNA (ceRNA) network of hub genes was constructed by combining miRNA, lncRNA, and circRNA expression data. Five hub genes were identified: MGST1, DHCR24, ALDH3A2, ADH1B, and FKBP5.

Results: These hub genes had a high diagnostic value for keloids, with an AUC value > 0.8 each. In addition, five hub genes were associated with the infiltration of multiple immune cells. The immune cells with the strongest positive and negative correlations with hub genes were M0 and M1 macrophages. A ceRNA network was constructed, and several ceRNAs, such as AC005062.1/miR-134-5p/FKBP5 and BASP1-AS1/miR-503-5p/ADH1B, were identified. These five hub genes may contribute to keloid pathogenesis.

Conclusion: These genes and their related ceRNAs may serve as diagnostic biomarkers and therapeutic targets for keloids.