Genetic alterations, RNA expression profiling and DNA methylation of HMGB1 in malignancies.

The high mobility group box 1 (HMGB1) is a potential biomarker and therapeutic target in various human diseases. However, a systematic, comprehensive pan-cancer analysis of HMGB1 in human cancers remains to be reported. This study analysed the genetic alteration, RNA expression profiling and DNA methylation of HMGB1 in more than 30 types of tumours. It is worth noting that HMGB1 is overexpressed in malignant tissues, including lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), pancreatic adenocarcinoma (PAAD) and thymoma (THYM). Interestingly, there is a positive correlation between the high expression of HMGB1 and the high survival prognosis of THYM. Finally, this study comprehensively evaluates the genetic variation of HMGB1 in human malignant tumours. As a prospective biomarker of COVID-19, the role that HMGB1 plays in THYM is highlighted.

Spindle and Kinetochore-Associated Complex Is Associated With Poor Prognosis in Adrenocortical Carcinoma.

INTRODUCTION: The spindle and kinetochore-associated (SKA) complex, composed of three subunits (SKA1, SKA2, and SKA3), stabilizes spindle microtubule attachment to the kinetochore (KT) in the middle stage of mitosis. High expression of this complex is associated with poor prognosis for several tumors. However, the potential role of SKA complex overexpression in rare malignant diseases, such as adrenocortical carcinoma (ACC), has not been well investigated. MATERIALS AND METHODS: In this study, we used several databases to explore the relationship between SKA subunit expression and prognosis in ACC patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) databases were used to analyze enriched pathways in ACC. RESULTS: The results suggest that each of the three SKA subunits are overexpressed in ACC and that high expression is correlated with poor patient prognosis. Overexpression of the SKA complex is associated with the expression of organelle fission, nuclear division, and chromosome segregation pathways. Furthermore, differential expression of hub genes for proteins that interact physically or functionally with the SKA complex (CCNB2, UBE2C, BUB1B, TPX2, CCNA2, CDCA8, CCNB1, MELK, TOP2A, and KIF2C) revealed additional potential biomarkers for ACC. CONCLUSIONS: Our findings provide additional understanding of the mechanisms of ACC and suggest an approach for biomarker discovery using publicly available resources.

The long-range interaction map of ribosomal DNA arrays.

The repeated rDNA array gives rise to the nucleolus, an organelle that is central to cellular processes as varied as stress response, cell cycle regulation, RNA modification, cell metabolism, and genome stability. The rDNA array is also responsible for the production of more than 70% of all cellular RNAs (the ribosomal RNAs). The rRNAs are produced from two sets of loci: the 5S rDNA array resides exclusively on human chromosome 1 while the 45S rDNA arrays reside on the short arm of five human acrocentric chromosomes. These critical genome elements have remained unassembled and have been excluded from all Hi-C analyses to date. Here we built the first high resolution map of 5S and 45S rDNA array contacts with the rest of the genome combining over 15 billion Hi-C reads from several experiments. The data enabled sufficiently high coverage to map rDNA-genome interactions with 1MB resolution and identify rDNA-gene contacts. The map showed that the 5S and 45S arrays display preferential contact at common sites along the genome but are not themselves sufficiently close to yield 5S-45S Hi-C contacts. Ribosomal DNA contacts are enriched in segments of closed, repressed, and late replicating chromatin, as well as CTCF binding sites. Finally, we identified functional categories whose dispersed genes coalesced in proximity to the rDNA arrays or instead avoided proximity with the rDNA arrays. The observations further our understanding of the spatial localization of rDNA arrays and their contribution to the architecture of the cell nucleus.

Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes.

Tandemly repeated ribosomal DNA (rDNA) arrays are among the most evolutionary dynamic loci of eukaryotic genomes. The loci code for essential cellular components, yet exhibit extensive copy number (CN) variation within and between species. CN might be partly determined by the requirement of dosage balance between the 5S and 45S rDNA arrays. The arrays are nonhomologous, physically unlinked in mammals, and encode functionally interdependent RNA components of the ribosome. Here we show that the 5S and 45S rDNA arrays exhibit concerted CN variation (cCNV). Despite 5S and 45S rDNA elements residing on different chromosomes and lacking sequence similarity, cCNV between these loci is strong, evolutionarily conserved in humans and mice, and manifested across individual genotypes in natural populations and pedigrees. Finally, we observe that bisphenol A induces rapid and parallel modulation of 5S and 45S rDNA CN. Our observations reveal a novel mode of genome variation, indicate that natural selection contributed to the evolution and conservation of cCNV, and support the hypothesis that 5S CN is partly determined by the requirement of dosage balance with the 45S rDNA array. We suggest that human disease variation might be traced to disrupted rDNA dosage balance in the genome.

The influence of gender and wealth inequality on Alzheimer's disease among the elderly: A global study.

This study was designed to explore the relationship between Alzheimer's disease (AD) rates and socioeconomic conditions in 120 countries. We used mixed effect models to investigate the relationship between the rates of AD and socioeconomic data. This study is among the first studies to put forward statistical evidence of a significant association between AD and other dementias among the elderly and socioeconomic inequality. These findings could help to inform the policies to be designed to improve the quality of interventions for AD.

Estimating the relative roles of recombination and point mutation in the generation of single locus variants in Campylobacter jejuni and Campylobacter coli.

Single locus variants (SLVs) are bacterial sequence types that differ at only one of the seven canonical multilocus sequence typing (MLST) loci. Estimating the relative roles of recombination and point mutation in the generation of new alleles that lead to SLVs is helpful in understanding how organisms evolve. The relative rates of recombination and mutation for Campylobacter jejuni and Campylobacter coli were estimated at seven different housekeeping loci from publically available MLST data. The probability of recombination generating a new allele that leads to an SLV is estimated to be roughly seven times more than that of mutation for C. jejuni, but for C. coli recombination and mutation were estimated to have a similar contribution to the generation of SLVs. The majority of nucleotide differences (98 % for C. jejuni and 85 % for C. coli) between strains that make up an SLV are attributable to recombination. These estimates are much larger than estimates of the relative rate of recombination to mutation calculated from more distantly related isolates using MLST data. One explanation for this is that purifying selection plays an important role in the evolution of Campylobacter. A simulation study was performed to test the performance of our method under a range of biologically realistic parameters. We found that our method performed well when the recombination tract length was longer than 3 kb. For situations in which recombination may occur with shorter tract lengths, our estimates are likely to be an underestimate of the ratio of recombination to mutation, and of the importance of recombination for creating diversity in closely related isolates. A parametric bootstrap method was applied to calculate the uncertainty of these estimates.

Comprehensive analysis of the expression and prognosis for APOE in malignancies: A pan-cancer analysis.

Apolipoprotein E (APOE), a gene identified as one of the strongest genetic factors contributing to the risk determinant of developing late-onset Alzheimer's disease (AD), may also contribute to the risk of cancer. However, no pan-cancer analysis has been conducted specifically for the APOE gene. In this study, we investigated the oncogenic role of the APOE gene across cancers by GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas). Based on the available data, we found that most cancer types overexpress APOE, and clear associations exist between the expression level of APOE and prognosis in tumor patients. The expression of APOE also correlates with certain gender-associated tumors including, ovarian cancer, uterine carcinosarcoma, and breast cancer. However, there is a significant negative association between cancer-associated fibroblast infiltration levels and the expression level of APOE in testicular germ cell tumors. Moreover, acute inflammatory response and protein-activation cascade-associated functions play an important role in the functional mechanisms of APOE. The present pan-cancer analysis of APOE shows that the protein phosphorylation, DNA methylation, and genetic alterations of APOE have a significant clinical relevance for survival prognosis and immune cell infiltration. This novel pan-cancer study outlines the current understanding of APOE oncogenic roles across thirty-three cancers and highlights the complex association between AD and cancers.

Overexpression of SKA Complex Is Associated With Poor Prognosis in Gliomas.

The spindle and kinetochore-associated complex is composed of three members: SKA1, SKA2, and SKA3. It is necessary for stabilizing spindle microtubules attaching to kinetochore (KT) in the middle stage of mitosis. The SKA complex is associated with poor prognosis in several human cancers. However, the role of SKA complex in rare malignant diseases, such as gliomas, has not been fully investigated. We investigated several databases, including Oncomine, UALCAN, and cBioPortal to explore the expression profile and prognostic significance of SKA complex in patients with gliomas. Gene ontology and Kyoto Encyclopedia of Genes and Genome pathways were used to analyze the potential enriched pathways. The genes co-expressed with SKA complex were identified and used for developing a protein-protein interaction (PPI) network using the STRING database. We found a significant overexpression of the mRNA levels of SKA1, SKA2, and SKA3 in patients with glioma patients. Higher expression of SKA1 and SKA3, but not SKA2, was significantly correlated with shorter overall survival of patients with glioma. In glioma, SKA complex was found to be involved in nuclear division, chromosome segregation, and DNA replication. The results of PPI network identified 10 hub genes (CCNB2, UBE2C, BUB1B, TPX2, CCNA2, CCNB1, MELK, TOP2A, PBK, and KIF11), all of which were overexpressed and negatively associated with prognosis of patients with glioma. In conclusion, our study sheds new insights into the biological role and prognostic significance of SKA complex in glioma.

Environmentally induced ribosomal DNA (rDNA) instability in human cells and populations exposed to hexavalent chromium [Cr (VI)].

Hexavalent Chromium [Cr (VI)] is an established toxicant, carcinogen, and a significant source of public health concern. The multicopy ribosomal DNA (rDNA) array is mechanistically linked to aging and cancer, is the most evolutionarily conserved segment of the human genome, and gives origin to nucleolus, a nuclear organelle where ribosomes are assembled. Here we show that exposure to Cr (VI) induces instability in the rDNA, triggering cycles of rapid, specific, and transient amplification and contraction of the array in human cells. The dynamic of environmentally responsive rDNA copy number (CN) amplification and contraction occurs at doses to which millions of individuals are regularly exposed. Finally, analyses of human populations occupationally exposed to Cr (VI) indicate that environmental exposure history and drinking habits but not age shape extensive naturally occurring rDNA copy number variation. Our observations identify a novel pathway of response to hexavalent chromium exposure and raise the prospect that a suite of environmental determinants of rDNA copy number remain to be discovered.

Uncovering the geographical and host impacts on the classification of Vibrio vulnificus.

Vibrio vulnificus causes human sickness throughout the world via the consumption of undercooked seafood or exposure to contaminated water. Previous attempts at phylogenetic analyses of V. vulnificus have proven unsuccessful, mainly due to the poorly understood impact of factors on its divergence. In this study, we used advanced statistical and phylogenetic methods to strengthen the classification of V. vulnificus. This updated classification included the impact of geographical and host factors. The results demonstrate the existence of hierarchies and multidimensional effects in the classification of V. vulnificus, from the molecular level using biotypes, to the distributional level using geographical location, to the adaptational level through host immune response. These findings have implications for the classification of bacteria, bacterial evolution, and public health.

Uncovering the hidden impacts of inequality on mental health: a global study.

Women are nearly twice as likely as men to suffer from mental illness. This gender disparity in depressive disorders may relate to social inequalities and living standards across nations. Currently, these disparities were not reflected at the level of health policies. This study utilized global data for depressive disorders and socioeconomic data from the United Nations' World Bank databases and Global Burden of Disease database to demonstrate the correlation between social inequality and gender disparities in mental health. This study investigated the association among the ratio of female to male depressive disorder rates, gross domestic product, the GINI Index, and the gender inequality index for 122 countries. The research yielded some major findings. First, there exists a significant correlation between gender inequality and gender disparities in mental health. Second, the GINI index is significantly associated with male-but not female-depressive disorder rates. Third, gender disparities in depressive disorders are associated with a country's wealth. These findings can help to inform society, policy-makers, and clinicians to improve the overall health level globally.

A Portrait of Ribosomal DNA Contacts with Hi-C Reveals 5S and 45S rDNA Anchoring Points in the Folded Human Genome.

Ribosomal RNAs (rRNAs) account for >60% of all RNAs in eukaryotic cells and are encoded in the ribosomal DNA (rDNA) arrays. The rRNAs are produced from two sets of loci: the 5S rDNA array resides exclusively on human chromosome 1, whereas the 45S rDNA array resides on the short arm of five human acrocentric chromosomes. The 45S rDNA gives origin to the nucleolus, the nuclear organelle that is the site of ribosome biogenesis. Intriguingly, 5S and 45S rDNA arrays exhibit correlated copy number variation in lymphoblastoid cells (LCLs). Here we examined the genomic architecture and repeat content of the 5S and 45S rDNA arrays in multiple human genome assemblies (including PacBio MHAP assembly) and ascertained contacts between the rDNA arrays and the rest of the genome using Hi-C datasets from two human cell lines (erythroleukemia K562 and lymphoblastoid cells). Our analyses revealed that 5S and 45S arrays each have thousands of contacts in the folded genome, with rDNA-associated regions and genes dispersed across all chromosomes. The rDNA contact map displayed conserved and disparate features between two cell lines, and pointed to specific chromosomes, genomic regions, and genes with evidence of spatial proximity to the rDNA arrays; the data also showed a lack of direct physical interaction between the 5S and 45S rDNA arrays. Finally, the analysis identified an intriguing organization in the 5S array with Alu and 5S elements adjacent to one another and organized in opposite orientation along the array. Portraits of genome folding centered on the ribosomal DNA array could help understand the emergence of concerted variation, the control of 5S and 45S expression, as well as provide insights into an organelle that contributes to the spatial localization of human chromosomes during interphase.

Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans.

Ribosomes are essential intracellular machines composed of proteins and RNA molecules. The DNA sequences (rDNA) encoding ribosomal RNAs (rRNAs) are tandemly repeated and give origin to the nucleolus. Here we develop a computational method for estimating rDNA dosage (copy number) and mitochondrial DNA abundance using whole-genome short-read DNA sequencing. We estimate these attributes across hundreds of human genomes and their association with global gene expression. The analyses uncover abundant variation in rDNA dosage that is coupled with the expression of hundreds of functionally coherent gene sets. These include associations with genes coding for chromatin components that target the nucleolus, including CTCF and HP1ß. Finally, the data show an inverse association between rDNA dosage and mitochondrial DNA abundance that is manifested across genotypes. Our findings uncover a novel and cryptic source of hypervariable genomic diversity with global regulatory consequences (ribosomal eQTL) in humans. The variation provides a mechanism for cellular homeostasis and for rapid and reversible adaptation.