A Study of the Genomic Variations Associated with Autistic Spectrum Disorders in a Russian Cohort of Patients Using Whole-Exome Sequencing.

This study provides new data on the whole-exome sequencing of a cohort of children with autistic spectrum disorders (ASD) from an underexplored Russian population. Using both a cross-sectional approach involving a control cohort of the same ancestry and an annotation-based approach involving relevant public databases, we explored exonic single nucleotide variants and copy-number variation potentially involved in the manifestation of ASD. The study results reveal new potential ASD candidate-variants found in the studied Russian cohort and show a high prevalence of common ASD-associated genomic variants, especially those in the genes known to be associated with the manifestation of intellectual disabilities. Our screening of an ASD cohort from a previously understudied population allowed us to flag at least a few novel genes (IGLJ2, FAM21A, OR11H12, HIP1, PRAMEF10, and ZNF717) regarding their potential involvement in ASD.

Horses for Courses in the Era of CARs: Advancing CAR T and CAR NK Cell Therapies.

The adoptive transfer of allogeneic CAR NK cells holds great promise as an anticancer modality due to the relative ease of manufacturing and genetic modification of NK cells, which translates into affordable pricing. Compared to the pronounced efficacy of CAR T cell therapy in the treatment of B cell malignancies, rigorous clinical and preclinical assessment of the antitumor properties of CAR NK cells has been lagging behind. In this brief review, we summarize the biological features of NK cells that may help define the therapeutic niche of CAR NK cells as well as create more potent NK cell-based anticancer products. In addition, we compare T cells and NK cells as the carriers of CARs using the data of single-cell transcriptomic analysis.

Genome-wide association study reveals genetic variants associated with HIV-1C infection in a Botswana study population.

Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States-African American or United States-European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population.

p130 And pRb in the Maintenance of Transient Quiescence of Mesenchymal Stem Cells.

An effective regulation of quiescence plays a key role in the differentiation, plasticity, and prevention of stem cells from becoming malignant. The state of quiescence is being controlled by the pRb family proteins which show overlapping functions in cell cycle regulation; however, their roles in controlling the proliferation of mesenchymal stem cells (MSCs) remain to be understood. This study investigated the regulation of transient quiescence using growth curves, proliferation assay, the cytometric evaluation of cell cycle, Western blotting, and the electromobility gel shift assay (EMSA) on synchronized MSCs of the C3H10Т1/2 and control cells with different statuses of pRb proteins. It has been found that functional steady-state level of p130 but not pRb plays a critical role for entering, exiting, and maintenance of transient quiescence in multipotent mesenchymal stem cells.

Genome-wide sequence analyses of ethnic populations across Russia.

The Russian Federation is the largest and one of the most ethnically diverse countries in the world, however no centralized reference database of genetic variation exists to date. Such data are crucial for medical genetics and essential for studying population history. The Genome Russia Project aims at filling this gap by performing whole genome sequencing and analysis of peoples of the Russian Federation. Here we report the characterization of genome-wide variation of 264 healthy adults, including 60 newly sequenced samples. People of Russia carry known and novel genetic variants of adaptive, clinical and functional consequence that in many cases show allele frequency divergence from neighboring populations. Population genetics analyses revealed six phylogeographic partitions among indigenous ethnicities corresponding to their geographic locales. This study presents a characterization of population-specific genomic variation in Russia with results important for medical genetics and for understanding the dynamic population history of the world's largest country.

Analytical "bake-off" of whole genome sequencing quality for the Genome Russia project using a small cohort for autoimmune hepatitis.

A comparative analysis of whole genome sequencing (WGS) and genotype calling was initiated for ten human genome samples sequenced by St. Petersburg State University Peterhof Sequencing Center and by three commercial sequencing centers outside of Russia. The sequence quality, efficiency of DNA variant and genotype calling were compared with each other and with DNA microarrays for each of ten study subjects. We assessed calling of SNPs, indels, copy number variation, and the speed of WGS throughput promised. Twenty separate QC analyses showed high similarities among the sequence quality and called genotypes. The ten genomes tested by the centers included eight American patients afflicted with autoimmune hepatitis (AIH), plus one case's unaffected parents, in a prelude to discovering genetic influences in this rare disease of unknown etiology. The detailed internal replication and parallel analyses allowed the observation of two of eight AIH cases carrying a rare allele genotype for a previously described AIH-associated gene (FTCD), plus multiple occurrences of known HLA-DRB1 alleles associated with AIH (HLA-DRB1-03:01:01, 13:01:01 and 7:01:01). We also list putative SNVs in other genes as suggestive in AIH influence.

Alzheimer's disease: as it was in the beginning.

Since Alzheimer's disease was first described in 1907, many attempts have been made to reveal its main cause. Nowadays, two forms of the disease are known, and while the hereditary form of the disease is clearly caused by mutations in one of several genes, the etiology of the sporadic form remains a mystery. Both forms share similar sets of neuropathological and molecular manifestations, including extracellular deposition of amyloid-beta, intracellular accumulation of hyperphosphorylated tau protein, disturbances in both the structure and functions of mitochondria, oxidative stress, metal ion metabolism disorders, impairment of N-methyl-D-aspartate receptor-related signaling pathways, abnormalities of lipid metabolism, and aberrant cell cycle reentry in some neurons. Such a diversity of symptoms led to proposition of various hypotheses for explaining the development of Alzheimer's disease, the amyloid hypothesis, which postulates the key role of amyloid-beta in Alzheimer's disease development, being the most prominent. However, this hypothesis does not fully explain all of the molecular abnormalities and is therefore heavily criticized. In this review, we propose a hypothetical model of Alzheimer's disease progression, assuming a key role of age-related mitochondrial dysfunction, as was postulated in the mitochondrial cascade hypothesis. Our model explains the connections between all the symptoms of Alzheimer's disease, with particular attention to autophagy, metal metabolism disorders, and aberrant cell cycle re-entry in neurons. Progression of the Alzheimer's disease appears to be a complex process involving aging and too many protective mechanisms affecting one another, thereby leading to even greater deleterious effects.

The Genome-Wide Analysis of Carcinoembryonic Antigen Signaling by Colorectal Cancer Cells Using RNA Sequencing.

Сarcinoembryonic antigen (CEA, CEACAM5, CD66) is a promoter of metastasis in epithelial cancers that is widely used as a prognostic clinical marker of metastasis. The aim of this study is to identify the network of genes that are associated with CEA-induced colorectal cancer liver metastasis. We compared the genome-wide transcriptomic profiles of CEA positive (MIP101 clone 8) and CEA negative (MIP 101) colorectal cancer cell lines with different metastatic potential in vivo. The CEA-producing cells displayed quantitative changes in the level of expression for 100 genes (over-expressed or down-regulated). They were confirmed by quantitative RT-PCR. The KEGG pathway analysis identified 4 significantly enriched pathways: cytokine-cytokine receptor interaction, MAPK signaling pathway, TGF-beta signaling pathway and pyrimidine metabolism. Our results suggest that CEA production by colorectal cancer cells triggers colorectal cancer progression by inducing the epithelial- mesenchymal transition, increasing tumor cell invasiveness into the surrounding tissues and suppressing stress and apoptotic signaling. The novel gene expression distinctions establish the relationships between the existing cancer markers and implicate new potential biomarkers for colorectal cancer hepatic metastasis.