Search Results (8,617)

Whole-genome sequencing has revealed that TP53, NOTCH1, ATM, SF3B1, BIRC3, ABL, NXF1, BCR, and ZAP70 are often mutated in CLL, but not consistently across all CLL patients. This paper employs a statistical thermodynamics approach in combination with the systems biology of the CLL protein–protein interaction networks to identify the most significant participant proteins in the cancerous transformation. Betti number (a topology of complexity) estimates highlight a protein hierarchy, primarily in the Wnt pathway known for aberrant CLL activation. These individually identified proteins suggest a network-targeted strategy over single-target drug development. The findings advocate for a multi-target inhibition approach, limited to several key proteins to minimize side effects, thereby providing a foundation for designing therapies. This study emphasizes a shift towards a comprehensive, multi-scale analysis to enhance personalized treatment strategies for CLL, which could be experimentally validated using siRNA or small-molecule inhibitors. The result is not just the identification of these proteins but their rank-order, offering a potent signal amplification in the context of the 20,000 proteins produced by the human body, thus providing a strategic basis for therapeutic intervention in CLL, underscoring the necessity for a more holistic, cellular, chromosomal, and genome-wide study to develop tailored treatments for CLL patients. Full article

Limited or absent activity of the enzyme α-galactosidase A (α-Gal A), due to mutation in the related gene on the X chromosome, leads to the development of a rare hereditary and genetic disease known as Fabry disease (FD). This pathology involves a progressive accumulation in various organs of the substrates of the enzyme e.g., globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (Lyso-Gb3), suggesting these molecules as biomarkers of Fabry disease. The present paper describes the development of an analytical strategy for the identification and quantification of Gb3 and Lyso-Gb3, in serum and blood samples by using liquid chromatography (LC) coupled to mass spectrometry in multiple reaction monitoring (MRM/MS) ion mode. The best experimental conditions were obtained by extracting the glycolipids with chloroform/methanol/H₂O (2/1/0.3) and by separating them on a C4 column with a linear gradient (A: H₂O with 2 mM ammonium formate. B: methanol with 1 mM ammonium formate, both acidified with 0.2% formic acid). The best transitions (a combination of precursor and fragment ions—m/z) were 786.8 m/z > 268.3 m/z for Lyso-GB3, 1137.3 m/z > 264.3 m/z for Gb3, 1039.3 m/z > 264.4 m/z for N-heptadecanoyl-ceramide trihexoside, and 843.5 m/z > 264.3 m/z for N-glycinated lyso-ceramide trihexoside, the latter being used as an internal standard. The developed method provided a reliable, fast, and effective procedure for direct measurements of GB3 and Lyso-GB3 in serum and blood for diagnosis of Fabry disease, suggesting this method as a complementary assay to the current enzymatic test. Therefore, this approach could open new insights into the clinical diagnostics of lysosomal storage disorders. Full article

Uveal melanomas (UMs) represent rare malignant tumors associated with grim prognosis for the majority of patients. DAXX (Death Domain-Associated Protein), HJURP (Holliday Junction Recognition Protein) and CENPA (Centromere Protein A) proteins are implicated in epigenetic mechanisms, now in the spotlight of cancer research to better understand the molecular background of tumorigenesis. Herein, we investigated their expression in UM tissues using immunohistochemistry and explored possible correlations with a multitude of clinicopathological and survival parameters. The Cancer Genome Atlas Program (TCGA) was used for the investigation of their mRNA levels in UM cases. Nuclear DAXX expression correlated with an advanced T-stage (p = 0.004), while cytoplasmic expression marginally with decreased disease-free survival (DFS) (p = 0.084). HJURP nuclear positivity also correlated with advanced T-status (p = 0.054), chromosome 3 loss (p = 0.042) and increased tumor size (p = 0.03). More importantly, both nuclear and cytoplasmic HJURP immunopositivity correlated with decreased overall survival (OS) (p = 0.011 and 0.072, respectively) and worse DFS (p = 0.071 and 0.019, respectively). Lastly, nuclear CENPA overexpression was correlated with presence of irido-corneal angle involvement (p = 0.015) and loss of chromosome 3 (p = 0.041). Nuclear and cytoplasmic CENPA immunopositivity associated with decreased OS (p = 0.028) and DFS (p = 0.018), respectively. HJURP and CENPA mRNA overexpression exhibited strong association with tumor epithelioid histology and was linked to worse prognosis. Our results show the compounding role of DAXX, HJURP and CENPA in UM carcinogenesis, designating them as potential biomarkers for assessing prognosis and possible targets for novel therapeutic interventions. Full article

Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation. More recently, with the use of next-generation sequencing and access to molecular information, targeted molecular approaches to the treatment of AML have been adopted. Molecular targeting is gaining prominence, as AML mostly afflicts the elderly population, who often cannot tolerate traditional chemotherapy. Understanding molecular changes at the gene level is also important for accurate disease classification, risk stratification, and prognosis, allowing for more personalized medicine. Some mutations are well studied and have an established gene-specific therapy, including FLT3 and IDH1/2, while others are being investigated in clinical trials. However, data on most known mutations in AML are still minimal and therapeutic studies are in pre-clinical stages, highlighting the importance of further research and elucidation of the pathophysiology involving these genes. In this review, we aim to highlight the key molecular alterations and chromosomal changes that characterize AML, with a focus on pathophysiology, presently available treatment approaches, and future therapeutic options. Full article

Understanding the complex dynamics of telomere biology is important in the strong link between aging and cancer. Telomeres, the protective caps at the end of chromosomes, are central players in this connection. While their gradual shortening due to replication limits tumors expansion by triggering DNA repair mechanisms, it also promotes oncogenic changes within chromosomes, thus sustaining tumorigenesis. The enzyme telomerase, responsible for maintaining telomere length, emerges as a central player in this context. Its expression in cancer cells facilitates the preservation of telomeres, allowing them to circumvent the growth-limiting effects of short telomeres. Interestingly, the influence of telomerase extends beyond telomere maintenance, as evidenced by its involvement in promoting cell growth through alternative pathways. In this context, inflammation accelerates telomere shortening, resulting in telomere dysfunction, while telomere elements also play a role in modulating the inflammatory response. The recognition of this interplay has promoted the development of novel therapeutic approaches centered around telomerase inhibition. This review provides a comprehensive overview of the field, emphasizing recent progress in knowledge and the implications in understanding of cancer biology. Full article

RNase Y is a key endoribonuclease that regulates global mRNA turnover and processing in Bacillus subtilis and likely many other bacteria. This enzyme is anchored to the cell membrane, creating a pseudo-compartmentalization that aligns with its role in initiating the decay of mRNAs primarily translated at the cell periphery. However, the reasons behind and the consequences of RNase Y’s membrane attachment remain largely unknown. In our study, we examined a strain expressing wild-type levels of a cytoplasmic form of RNase Y from its chromosomal locus. This strain exhibits a slow-growth phenotype, similar to that of an RNase Y null mutant. Genome-wide data reveal a significant impact on the expression of hundreds of genes. While certain RNA substrates clearly depend on RNase Y’s membrane attachment, others do not. We observed no correlation between mRNA stabilization in the mutant strains and the cellular location or function of the encoded proteins. Interestingly, the Y-complex, a specificity factor for RNase Y, also appears also recognize the cytoplasmic form of the enzyme, restoring wild-type levels of the corresponding transcripts. We propose that membrane attachment of RNase Y is crucial for its functional interaction with many coding and non-coding RNAs, limiting the cleavage of specific substrates, and potentially avoiding unfavorable competition with other ribonucleases like RNase J, which shares a similar evolutionarily conserved cleavage specificity. Full article

Fluorescence in situ hybridization (FISH) with two different probes, the canonical insect telomeric sequence (TTAGG)_n and the sequence (TTAGGGATGG)_n, was performed on meiotic chromosomes of two members of the true bug family Cimicidae (Cimicomorpha), the common bed bug Cimex lectularius Linnaeus, 1758 and the tropical bed bug C. hemipterus (Fabricius, 1803), whose telomeric motifs were not known. In both species, there were no hybridization signals with the first probe, but strong signals at chromosomal ends were observed with the second probe, indicating the presence of a telomeric motif (TTAGGGATGG)_n. This study represents the first FISH confirmation of the presence of a non-canonical telomeric motif not only for the infraorder Cimicomorpha but also for the suborder Heteroptera (Hemiptera) as a whole. The present finding is of key significance for unraveling the evolutionary shifts in the telomeric sequences in this suborder. Full article

Hemerocallis citrina Baroni (H. citrina) is an important specialty vegetable that is not only edible and medicinal but also has ornamental value. However, much remains unknown about the regulatory mechanisms associated with the growth, development, and flowering rhythm of this plant. CO, as a core regulatory factor in the photoperiod pathway, coordinates light and circadian clock inputs to transmit flowering signals. We identified 18 COL genes (HcCOL1-HcCOL18) in the H. citrina cultivar ‘Mengzihua’ and studied their chromosomal distribution, phylogenetic relationships, gene and protein structures, collinearity, and expression levels in the floral organs at four developmental stages. The results indicate that these genes can be classified into three groups based on phylogenetic analysis. The major expansion of the HcCOL gene family occurred via segmental duplication, and the Ka/Ks ratio indicated that the COL genes of Arabidopsis thaliana, Oryza sativa, Phalaenopsis equestris, and H. citrina were under purifying selection. Many cis-elements, including light response elements, abiotic stress elements, and plant hormone-inducible elements, were distributed in the promoter sequences of the HcCOL genes. Expression analysis of HcCOL genes at four floral developmental stages revealed that most of the HcCOL genes were expressed in floral organs and might be involved in the growth, development, and senescence of the floral organs of H. citrina. This study lays a foundation for the further elucidation of the function of the HcCOL gene in H. citrina and provides a theoretical basis for the molecular design breeding of H. citrina. Full article

Superior fiber quality is one of the most important objectives in cotton breeding. To detect the genetic basis underlying fiber quality, an F2 population containing 413 plants was constructed by crossing Jifeng 914 and Jifeng 173, both of which have superior fiber quality, with Jifeng 173 being better. Five fiber quality traits were investigated in the F2, F2:3, F2:4, and F2:5 populations. Quantitative trait loci (QTL) mapping was conducted based on a high-density genetic map containing 11,488 single nucleotide polymorphisms (SNPs) and spanning 4202.12 cM in length. Transgressive segregation patterns and complex correlations in the five tested traits were observed. A total of 108 QTLs were found, including 13 major effect QTLs that contributed more than 10% toward phenotypic variation (PV) and 9 stable QTLs that could be repeatedly mapped in different generations. Chromosome A7 contained 12 QTL, ranking the first. No QTL was found on chromosomes D1 and D11. Two QTLs could be repeatedly detected in three populations, including qFL-D3-2 in F2, F2:4, and F2:5 with 9.18–21.45% of PV and qFS-A11-1 in F2:3, F2:4, and F2:5 with 6.05–10.41% of PV. Another seven stable QTLs could be detected in two populations, including four major effect QTLs: qFL-A12-3, qFS-D10-2, qMC-D6-2, and qMC-D8-1. Fourteen QTL-overlapping regions were found, which might explain the complex correlations among the five phenotypic traits. Four regions on chromosome A11, D3, D6, and D10 covered by both stable and major effect QTLs are promising for further fine mapping. The genomic regions of the two QTLs detected in three populations and the four major effect QTLs contain 810 genes. Gene functional analysis revealed that the annotated genes are mainly involved in protein binding and metabolic pathways. Fifteen candidate genes in the qFL-D3-2 region are highly expressed in fiber or ovules during fiber initiation, elongation, secondary cell wall thickening, or maturation stages. qRT-PCR revealed that Ghir_D03G005440.1 and Ghir_D03G011310.1 may play a role in promoting fiber initiation, while Ghir_D03G006470.1 may be beneficial for promoting fiber elongation. This study provides more information for revealing the molecular genetic basis underlying cotton fiber quality. Full article

Species of the Rhodnius genus have a complex taxonomy because the events of phenotypic plasticity and cryptic speciation make it difficult to correctly classify these vectors. During the taxonomic history of the genus, five synonymization events occurred. Additionally, some authors suggest that R. milesi possibly represent only phenotypic polymorphisms of R. neglectus. Thus, we analyzed the specific status of R. milesi in relation to R. neglectus using phylogenetic studies with the mitochondrial gene cytochrome B and the study of reproductive barriers. The phylogenetic reconstruction grouped R. milesi together with R. neglectus from different localities, demonstrating that these taxa represent the same species based on the phylogenetic species concept. Experimental crosses demonstrate the absence of pre- and postzygotic barriers under laboratory conditions. Additionally, when the hatch rates of crosses are compared to intraspecific crosses, it can be noted that they are high and very similar. Finally, the mortality rate of the hybrids does not indicate hybrid inviability, the absence of chromosome pairing errors does not indicate hybrid sterility, and the proportion between male and female hybrids demonstrates that Haldane’s rule was not acting. Therefore, we perform the formal synonymization of R. milesi with R. neglectus. Full article

Currently, clusters of 45S and 5S ribosomal DNA (rDNA) have been studied in about 1000 and 100 species of the class Insecta, respectively. Although the number of insect species with known 45S rDNA clusters (also referred to as nucleolus-organizing regions, or NORs) constitutes less than 0.1 percent of the described members of this enormous group, certain conclusions can already be drawn. Since haploid karyotypes with single 45S and 5S rDNA clusters predominate in both basal and derived insect groups, this character state is apparently ancestral for the class Insecta in general. Nevertheless, the number, chromosomal location, and other characteristics of both 45S and 5S rDNA sites substantially vary across different species, and sometimes even within the same species. There are several main factors and molecular mechanisms that either maintain these parameters or alter them on the short-term and/or long-term scale. Chromosome structure (i.e., monocentric vs. holokinetic chromosomes), excessive numbers of rRNA gene copies per cluster, interactions with transposable elements, pseudogenization, and meiotic recombination are perhaps the most important among them. Full article

Disrupted in Schizophrenia 1 (DISC1) is a scaffold protein implicated in major mental illnesses including schizophrenia, with a significant negative impact on social life. To investigate if DISC1 affects social interactions in Drosophila melanogaster, we created transgenic flies with second or third chromosome insertions of the human full-length DISC1 (hflDISC1) gene fused to a UAS promotor (UAS-hflDISC1). Initial characterization of the insertion lines showed unexpected endogenous expression of the DISC1 protein that led to various behavioral and neurochemical phenotypes. Social interaction network (SIN) analysis showed altered social dynamics and organizational structures. This was in agreement with the altered levels of the locomotor activity of individual flies monitored for 24 h. Together with a decreased ability to climb vertical surfaces, the observed phenotypes indicate altered motor functions that could be due to a change in the function of the motor neurons and/or central brain. The changes in social behavior and motor function suggest that the inserted hflDISC1 gene influences nervous system functioning that parallels symptoms of DISC1-related mental diseases in humans. Furthermore, neurochemical analyses of transgenic lines revealed increased levels of hydrogen peroxide and decreased levels of glutathione, indicating an impact of DISC1 on the dynamics of redox regulation, similar to that reported in transgenic mammals. Future studies are needed to address the localization of DISC1 expression and to address how the redox parameter changes correlate with the observed behavioral changes. Full article

The genus Hedysarum L. (Fabaceae) includes about 200 species of annual and perennial herbs distributed in Asia, Europe, North Africa, and North America. Many species of this genus are valuable medicinal, melliferous, and forage resources. In this review, we consider the taxonomic history of the genus Hedysarum, the chromosomal organization of the species from the sections Hedysarum and Multicaulia, as well as phylogenetic relationships between these sections. According to morphological, genetic, and phylogenetic data, the genus Hedysarum is divided into three main sections: Hedysarum (= syn. Gamotion), Multicaulia, and Stracheya. In species of this genus, two basic chromosome numbers, x = 7 (section Hedysarum) and x = 8 (sections Multicaulia and Stracheya), were determined. The systematic positions of some species within the sections are still uncertain due to their morphological similarities. The patterns of distribution of molecular chromosomal markers (45S rDNA, 5S rDNA, and different satellite DNAs) in karyotypes of various Hedysarum species made it possible to determine their ploidy status and also specify genomic relationships within the sections Hedysarum and Multicaulia. Recent molecular phylogenetic studies clarified significantly the taxonomy and evolutionary development of the genus Hedysarum. Full article

Fruit size is a crucial agronomic trait in bottle gourd, impacting both yield and utility. Despite its significance, the regulatory mechanism governing fruit size in bottle gourd remains largely unknown. In this study, we used bottle gourd (small-fruited H28 and large-fruited H17) parent plants to measure the width and length of fruits at various developmental stages, revealing a single ‘S’ growth curve for fruit expansion. Paraffin section observations indicated that both cell number and size significantly influence bottle gourd fruit size. Through bulked segregant analysis and combined genotype–phenotype analysis, the candidate interval regulating fruit size was pinpointed to 17,747,353 bp–18,185,825 bp on chromosome 9, encompassing 0.44 Mb and including 44 genes. Parental fruits in the rapid expansion stage were subjected to RNA-seq, highlighting that differentially expressed genes were mainly enriched in pathways related to cell wall biosynthesis, sugar metabolism, and hormone signaling. Transcriptome and resequencing analysis, combined with gene function annotation, identified six genes within the localized region as potential regulators of fruit size. This study not only maps the candidate interval of genes influencing fruit size in bottle gourd through forward genetics, but also offers new insights into the potential molecular mechanisms underlying this trait through transcriptome analysis. Full article

Developmental delays (DD) and congenital anomalies (CA) are prevalent yet often remain undiagnosed despite comprehensive genetic testing. This study aims to investigate the diagnostic yield of trio whole-genome sequencing (WGS) in children presenting with DD or CA who remained undiagnosed after previous genetic testing. A prospective cohort study was conducted on children with undiagnosed DD or CA at a single tertiary hospital. All participants suspected of genetic conditions had undergone chromosome analysis, chromosome microarray analysis (CMA), and clinical exome sequencing (CES); however, a subset remained undiagnosed. The WGS test was administered to both the affected children and their parents. A total of 52 children were included, and 10 (19.2%) had undergone a genetic diagnosis through WGS. Eight of these cases were associated with autosomal dominant and de novo variants. WGS led to successful diagnosis due to several factors, including small structural variants, genes not covered in the CES panel, the discovery of newly implicated genes, issues related to coverage depth, low variant allele frequency, challenges in variant interpretation, and differences in the interpretation of variants of unknown significance among clinicians. This study highlights the clinical value of trio WGS testing in undiagnosed children with DD or CA. Notably, an additional 19.2% of affected children were diagnosed through this method. Full article