Genes最新文献

The notion of RNA-based therapeutics has gained wide attractions in both academic and commercial institutions. RNA is a polymer of nucleic acids that has been proven to be impressively versatile, dating to its hypothesized RNA World origins, evidenced by its enzymatic roles in facilitating DNA replication, mRNA decay, and protein synthesis. This is underscored through the activities of riboswitches, spliceosomes, ribosomes, and telomerases. Given its broad range of interactions within the cell, RNA can be targeted by a therapeutic or modified as a pharmacologic scaffold for diseases such as nucleotide repeat disorders, infectious diseases, and cancer. RNA therapeutic techniques that have been researched include, but are not limited to, CRISPR/Cas gene editing, anti-sense oligonucleotides (ASOs), siRNA, small molecule treatments, and RNA aptamers. The knowledge gleaned from studying RNA-centric mechanisms will inevitably improve the design of RNA-based therapeutics. Building on this understanding, we explore the physiological diversity of RNA functions, examine specific dysfunctions, such as splicing errors and viral interactions, and discuss their therapeutic implications.

Background: This study aimed to describe Sickle Cell Disease (SCD) phenotypes, sociodemographic characteristics, healthcare, and clinical outcomes of patients with SCD attending Mnazi Mmoja Hospital (MMH) in Zanzibar.

Methods: Individuals who visited MMH between September 2021 and December 2022 and were known or suspected to have SCD were enrolled in the clinic. Sociodemographic characteristics and clinical features were documented, and laboratory tests were performed. A two-sample test of proportions was used to ascertain the significance of differences in the distribution of clinical outcomes between the follow-up visits.

Results: A total of 724 patients with SCD were enrolled: 367 (50.7%) were male, and 357 (49.3%) were female. Most patients-713 (98.5%) in total-were homozygous (Hb SS), 9 (1.2%) had the Hb SC phenotype, and 2 (0.3%) had HbS β+ thalassemia. The majority of patients were aged 13 years and below-520 (71.8%) in total-and most did not have health insurance-582 (80.4%) in total. While all patients received folic acid, only a quarter received pneumococcal prophylaxis and hydroxyurea. Attendance at the third visit was associated with a reduced frequency of self-reported episodes of pain (24 patients [4.3%] vs. 11 patients [1.9%]).

Conclusion: The population of patients with SCD in Zanzibar mostly comprised children who were Hb SS. Basic care services are still suboptimal, although they are associated with better outcomes when present. Thorough evaluation of SCD prevalence in Zanzibar through newborn screening programs is warranted.

A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer's disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer's research field. The present Perspective challenges this assumption. It analyses the relevant empirical data and reaches an unexpected conclusion, namely that in AD-afflicted neurons, the production of AβPP-derived Aβ is either discontinued or severely suppressed, a concept that, if proven, would fundamentally change our understanding of the disease. This suppression, effectively self-suppression, occurs in the context of the global inhibition of the cellular cap-dependent protein synthesis as a consequence of the neuronal integrated stress response (ISR) elicited by AβPP-derived intraneuronal Aβ (iAβ; hence self-suppression) upon reaching certain levels. Concurrently with the suppression of the AβPP proteolytic pathway, the neuronal ISR activates in human neurons, but not in mouse neurons, the powerful AD-driving pathway generating the C99 fragment of AβPP independently of AβPP. The present study describes molecular mechanisms potentially involved in these phenomena, propounds novel approaches to generate transgenic animal models of AD, advocates for the utilization of human neuronal cells-based models of the disease, makes verifiable predictions, suggests experiments designed to validate the proposed concept, and considers its potential research and therapeutic implications. Remarkably, it opens up the possibility that the conventional production of AβPP, BACE enzymes, and γ-secretase components is also suppressed under the neuronal ISR conditions in AD-affected neurons, resulting in the dyshomeostasis of AβPP. It follows that whereas conventional AD is triggered by AβPP-derived iAβ accumulated to the ISR-eliciting levels, the disease, in its both conventional and unconventional (triggered by the neuronal ISR-eliciting stressors distinct from iAβ) forms, is driven not (or not only) by iAβ produced in the AβPP-independent pathway, as we proposed previously, but mainly, possibly exclusively, by the C99 fragment generated independently of AβPP and not cleaved at the γ-site due to the neuronal ISR-caused deficiency of γ-secretase (apparently, the AD-driving "substance X" predicted in our previous study), a paradigm consistent with a dictum by George Perry that Aβ is "central but not causative" in AD. The proposed therapeutic strategies would not only deplete the driver of the disease and abrogate the AβPP-independent production of C99 but also reverse the neuronal ISR and ameliorate the AβPP dyshomeostasis, a potentially significant contributor to AD pathology.

Background/objectives: The interphotoreceptor matrix proteoglycans 1 and 2 (IMPG1 and IMPG2) are two interdependent proteoglycans of the interphotoreceptor matrix (IPM). Mutations in IMPG1 or IMPG2 are linked to retinal diseases such as retinitis pigmentosa (RP) and vitelliform macular dystrophy (VMD), yet the specific mutations responsible for each condition remain undefined. This study identifies mutations in IMPG1 and IMPG2 linked to either RP or VMD. It also provides an in-depth in silico analysis of these mutations' structural and functional impact on protein domains, alongside a detailed examination of the corresponding disease phenotypes.

Methods: From a cohort of 480 patients with inherited retinal diseases (IRDs), we identified seven patients with mutations in IMPG1 or IMPG2. Multimodal imaging was performed to assess the clinical phenotypes, including fundus photography, fundus autofluorescence, fluorescein angiography, and spectral domain optical coherence tomography (SD-OCT). We provide structure modeling and analysis of each variant.

Results: Our findings indicate a prevalence of 1.45% of IRD patients being affected by IMPG mutations; two were diagnosed with RP and five with VMD. One VMD patient carried a novel IMPG1 p.Asp423Glu mutation. Most patients exhibited heterozygous mutations, and one RP patient presented a compound heterozygous mutation in IMPG2.

Conclusions: This work describes a novel mutation and expands our understanding of the specific IMPG protein domains implicated in RP and VMD. Furthermore, it establishes, for the first time, the prevalence of IMPG mutations in an IRD population.

Background/objectives: All 11 metallothionein protein-coding genes are located on human chromosome 16q13. It is unique among human genetics to have an entire pathway's genes clustered in a short chromosomal region. Since solid tumors, particularly high-grade serous ovarian cancer (HGSC), exhibit high rates of monoallelic aneuploidy, this region is commonly lost. Studies have not yet been performed to determine what vulnerability may be created in cancer cells with low metallothionein expression. Here, a screen of FDA-approved cancer small molecule drugs for those best targeting low metallothionein ovarian cancer was completed.

Methods: Screening methods were tested and compared using vehicle-treated negative controls and cadmium chloride, a positive control for cell loss selective for low metallothionein cells. CAOV3 cells, which are unique in their expression of only two metallothionein isoforms, were used, with or without shRNA knockdown of the predominantly expressed MT2A gene. A library of FDA-approved molecules was then screened.

Results: The optimal assay utilized Hoechst 33342 nuclear staining and mechanized fluorescent microscope counting of cell content. Encorafenib, an RAF inhibitor, was identified as the most selective for enhanced cytotoxicity in MT2A knockdown cells compared to scrambled controls.

Conclusions: The nuclear stain Hoechst 33342, assessed by fluorescence microscopy, provides a low variance, moderate throughput platform for cancer cell loss screens. Low metallothionein ovarian cancer cells exhibit a vulnerability to the RAF inhibitor encorafenib.

This short review bridges two biological fields: ribosomes and nucleosomes-two nucleoprotein assemblies that, along with many viruses, share proteins featuring long filamentous segments at their N- or C-termini. A central hypothesis is that these extensions and tails perform analogous functions in both systems. The evolution of these structures appears closely tied to the emergence of regulatory networks and signaling pathways, facilitating increasingly complex roles for ribosomes and nucleosome alike. This review begins by summarizing the structures and functions of ribosomes and nucleosomes, followed by a detailed comparison highlighting their similarities and differences, particularly in light of recent findings on the roles of ribosomal proteins in signaling and ribosome dynamics. The analysis seeks to uncover whether these systems operate based on shared principles and mechanisms. The nucleosome-ribosome analogy may offer valuable insights into unresolved questions in both fields. For instance, new structural insights from ribosomes might shed light on potential motifs formed by histone tails. From an evolutionary perspective, this study revisits the origins of signaling and regulation in ancient nucleoprotein assemblies, suggesting that tails and extensions may represent remnants of the earliest network systems governing signaling and dynamic control.

Background/Objectives:Auxin response factors (ARFs) are important in plant growth and development, especially flower development. However, there is limited research on the comprehensive identification and characterization of ARF genes in roses. Methods: We employed bioinformatics tools to identify the ARF genes of roses. These genes were characterized for their phylogenetic relationships, chromosomal positions, conserved motifs, gene structures, and expression patterns. Results: In this study, a total of 17 ARF genes were identified in the genomes of Rosa chinensis 'OB', R. chinensis 'CH', R. rugosa, and R. wichurana. Based on RNA-seq analyses, we found that the ARF genes had diverse transcript patterns in various tissues and cultivars. In 'CH', the expression levels of RcCH_ARFs during different flower-development stages were classified into four clusters. In cluster 3 and cluster 4, RcCH_ARFs were specifically high and low in different stages of floral evocation. Gene expression and phylogenetic analyses showed that RcCH_ARF3, RcCH_ARF4, and RcCH_ARF18 were likely to be the key genes for rose flower development. Conclusions: The identification and characterization of ARF genes in Rosa were investigated. The results presented here provide a theoretical basis for the molecular mechanisms of ARF genes in plant development and flowering for roses, with a broader application for other species in the rose family and for the development of novel cultivars.

Background: The quality of soybeans is reflected in the seed coat color, which indicates soybean quality and commercial value. Researchers have identified genes related to seed coat color in various plants. However, research on the regulation of genes related to seed coat color in soybeans is rare.

Methods: In this study, four lines of seed coats with different colors (medium yellow 14, black, green, and brown) were selected from the F_2:5 population, with Beinong 108 as the female parent and green bean as the male parent, and the dynamic changes in the anthocyanins in the seed coat were stained with 4-dimethylaminocinnamaldehyde (DMACA) during the grain maturation process (20 days from grain drum to seed harvest). Through RNA-seq of soybean lines with four different colored seed coats at 30 and 50 days after seeding, we can further understand the key pathways and gene regulation modules between soybean seed coats of different colors.

Results: DMACA revealed that black seed coat soybeans produce anthocyanins first and have the deepest staining. Clustering and principal component analysis (PCA) of the RNA-seq data divided the eight samples into two groups, resulting in 16,456 DEGs, including 5359 TFs. GO and KEGG enrichment analyses revealed that the flavonoid biosynthesis, starch and sucrose metabolism, carotenoid biosynthesis, and circadian rhythm pathways were significantly enriched. We also conducted statistical and expression pattern analyses on the differentially expressed transcription factors. Based on weighted gene coexpression network analysis (WGCNA), we identified seven specific modules that were significantly related to the four soybean lines with different seed coat colors. The connectivity and functional annotation of genes within the modules were calculated, and 21 candidate genes related to soybean seed coat color were identified, including six transcription factor (TF) genes and three flavonoid pathway genes.

Conclusions: These findings provide a theoretical basis for an in-depth understanding of the molecular mechanisms underlying differences in soybean seed coat color and provide new genetic resources.

Background/Objectives: Chronic venous insufficiency (CVI), a chronic vascular dysfunction, is a common health problem that causes serious complications such as painful varicose veins and even skin ulcers. Identifying the underlying genetic and epigenetic factors is important for improving the quality of life of individuals with CVI. In the literature, many genes, variants, and miRNAs associated with CVI have been identified through genomic and transcriptomic studies. Despite molecular pathogenesis studies, how the genes associated with CVI are regulated by miRNAs and the effect of variants in binding regions on expression levels are still not fully understood. In this study, previously identified genes, variants, and miRNAs associated with CVI, common variants in the mRNA-miRNA binding regions, were investigated using in silico analyses. Methods: For this purpose, miRNA research tools, MBS (miRNA binding site) database, genome browsers, and the eQTL Calculator in the GTEx portal were used. Results: We identified SNVs associated with CVI that may play a direct role in the miRNA-mediated regulation of the ZNF664, COL1A2, HFE, MDN, MTHFR, SRPX, TDRD5, TSPYL4, VEGFA, and APOE genes. In addition, when the common SNVs in the mRNA binding region of 75 unique CVI related-miRNAs in five candidate genes associated with CVI were examined, seven miRNAs associated with the expression profiles of ABCA1, PIEZO1, and CASZ1 genes were identified. Conclusions: In conclusion, the relationship between genetic markers identified in the literature that play a role in the pathogenesis of the CVI and the expression profiles was evaluated for the first time in the mRNA-miRNA interaction axis.