Identification of scaffold/Matrix Attachment (S/MAR) like DNA element from the gastrointestinal protozoan parasite Giardia lamblia

<p>Abstract</p> <p>Background</p> <p>Chromatin in the nucleus of all eukaryotes is organized into a system of loops and domains. These loops remain fastened at their bases to the fundamental framework of the nucleus, the matrix or the scaffold. The DNA sequences which anchor the bases of the chromatin loops to the matrix are known as Scaffold/Matrix Attachment Regions or S/MARs. Though S/MARs have been studied in yeast and higher eukaryotes and they have been found to be associated with gene organization and regulation of gene expression, they have not been reported in protists like <it>Giardia</it>. Several tools have been discovered and formulated to predict S/MARs from a genome of a higher eukaryote which take into account a number of features. However, the lack of a definitive consensus sequence in S/MARs and the randomness of the protozoan genome in general, make it a challenge to predict and identify such sequences from protists.</p> <p>Results</p> <p>Here, we have analysed the <it>Giardia </it>genome for the probable S/MARs predicted by the available computational tools; and then shown these sequences to be physically associated with the nuclear matrix. Our study also reflects that while no single computational tool is competent to predict such complex elements from protist genomes, a combination of tools followed by experimental verification is the only way to confirm the presence of these elements from these organisms.</p> <p>Conclusion</p> <p>This is the first report of S/MAR elements from the protozoan parasite <it>Giardia lamblia</it>. This initial work is expected to lay a framework for future studies relating to genome organization as well as gene regulatory elements in this parasite.</p

Three dimensional quadratic algebras: Some realizations and representations

Four classes of three dimensional quadratic algebras of the type \lsb Q_0 , Q_\pm \rsb $=$ $\pm Q_\pm$, \lsb Q_+ , Q_- \rsb $=$ $aQ_0^2 + bQ_0 + c$, where $(a,b,c)$ are constants or central elements of the algebra, are constructed using a generalization of the well known two-mode bosonic realizations of $su(2)$ and $su(1,1)$. The resulting matrix representations and single variable differential operator realizations are obtained. Some remarks on the mathematical and physical relevance of such algebras are given.Comment: LaTeX2e, 23 pages, to appear in J. Phys. A: Math. Ge

Role of glycans and glycoproteins in disease development by Mycobacterium tuberculosis

Glycoproteins play a critical role in host-pathogen interactions, antigenicity, and virulence determination, and are therefore, considered as potential drug targets. The cell wall of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), dominantly contains sugars and lipids. Despite the efforts taken by the World Health Organization to reduce the incidence rate, the prevalence of TB is increasing in certain regions. This is mainly attributed to the emergence of multidrug-resistant bacteria. Factors that contribute to Mtb virulence and antigenicity remain elusive. However, several studies have shown that sugars and lipids are mainly responsible for Mtb pathogenesis and resistance to numerous drugs. This review gives insight into the role of glycoproteins in mycobacterium pathogenesis, disease development, and its implications in drug development

Systems Biology Genetic Approach Identifies Serotonin Pathway as a Possible Target for Obstructive Sleep Apnea: Results from a Literature Search Review

Rationale. Overall validity of existing genetic biomarkers in the diagnosis of obstructive sleep apnea (OSA) remains unclear. The objective of this systematic genetic study is to identify “novel” biomarkers for OSA using systems biology approach. Methods. Candidate genes for OSA were extracted from PubMed, MEDLINE, and Embase search engines and DisGeNET database. The gene ontology (GO) analyses and candidate genes prioritization were performed using Enrichr tool. Genes pertaining to the top 10 pathways were extracted and used for Ingenuity Pathway Analysis. Results. In total, we have identified 153 genes. The top 10 pathways associated with OSA include (i) serotonin receptor interaction, (ii) pathways in cancer, (iii) AGE-RAGE signaling in diabetes, (iv) infectious diseases, (v) serotonergic synapse, (vi) inflammatory bowel disease, (vii) HIF-1 signaling pathway, (viii) PI3-AKT signaling pathway, (ix) regulation lipolysis in adipocytes, and (x) rheumatoid arthritis. After removing the overlapping genes, we have identified 23 candidate genes, out of which >30% of the genes were related to the genes involved in the serotonin pathway. Among these 4 serotonin receptors SLC6A4, HTR2C, HTR2A, and HTR1B were strongly associated with OSA. Conclusions. This preliminary report identifies several potential candidate genes associated with OSA and also describes the possible regulatory mechanisms

Combined sequence and copy number analysis improves diagnosis of limb girdle and other myopathies

Abstract Objective Clinical and genetic heterogeneities make diagnosis of limb‐girdle muscular dystrophy (LGMD) and other overlapping disorders of muscle weakness complicated and expensive. We aimed to develop a comprehensive next generation sequence‐based multi‐gene panel (“The Lantern Focused Neuromuscular Panel”) to detect both sequence variants and copy number variants in one assay. Methods Patients with clinical diagnosis of LGMD or other overlapping muscular dystrophies in the United States were tested by PerkinElmer Genomics in 2018–2021 via “The Lantern Project,” a sponsored diagnostic testing program. Sixty‐six genes related to LGMD subtypes‐ and other myopathies were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes' prevalence. Results Molecular diagnosis was established in 19.6% (1266) of 6473 cases. Major genes contributing to LGMD were identified including CAPN3 (5.4%, 68), DYSF (4.0%, 51), GAA (3.7%, 47), ANO5 (3.6%, 45), and FKRP (2.7%, 34). Genes of other overlapping MD subtypes identified included PABPN1 (10.5%, 133), VCP (2.2%, 28), MYOT (1.2% 15), LDB3 (1.0%, 13), COL6A1 (1.5%, 19), FLNC (1.1%, 14), and DNAJB6 (0.8%, 10). Different sizes of copy number variants including single exon, multi‐exon, and whole genes were identified in 7.5% (95) cases in genes including DMD, EMD, CAPN3, ANO5, SGCG, COL6A2, DOK7, and LAMA2. Interpretation “The Lantern Focused Neuromuscular Panel” enables identification of LGMD subtypes and other myopathies with overlapping clinical features. Prevalence of some MD subtypes was higher than previously reported. Widespread deployment of this comprehensive NGS panel has the potential to ensure early, accurate diagnosis as well as re‐define MD epidemiology

DrugMechDB: A Curated Database of Drug Mechanisms

Abstract Computational drug repositioning methods have emerged as an attractive and effective solution to find new candidates for existing therapies, reducing the time and cost of drug development. Repositioning methods based on biomedical knowledge graphs typically offer useful supporting biological evidence. This evidence is based on reasoning chains or subgraphs that connect a drug to a disease prediction. However, there are no databases of drug mechanisms that can be used to train and evaluate such methods. Here, we introduce the Drug Mechanism Database (DrugMechDB), a manually curated database that describes drug mechanisms as paths through a knowledge graph. DrugMechDB integrates a diverse range of authoritative free-text resources to describe 4,583 drug indications with 32,249 relationships, representing 14 major biological scales. DrugMechDB can be employed as a benchmark dataset for assessing computational drug repositioning models or as a valuable resource for training such models

A Mycobacterial Phosphoribosyltransferase Promotes Bacillary Survival by Inhibiting Oxidative Stress and Autophagy Pathways in Macrophages and Zebrafish

Mycobacterium tuberculosis employs various strategies to modulate host immune responses to facilitate its persistence in macrophages. The M. tuberculosis cell wall contains numerous glycoproteins with unknown roles in pathogenesis. Here, by using Concanavalin A and LC-MS analysis, we identified a novel mannosylated glycoprotein phosphoribosyltransferase, encoded by Rv3242c from M. tuberculosis cell walls. Homology modeling, bioinformatic analyses, and an assay of phosphoribosyltransferase activity in Mycobacterium smegmatis expressing recombinant Rv3242c (MsmRv3242c) confirmed the mass spectrometry data. Using Mycobacterium marinum-zebrafish and the surrogate MsmRv3242c infection models, we proved that phosphoribosyltransferase is involved in mycobacterial virulence. Histological and infection assays showed that the M. marinum mimG mutant, an Rv3242c orthologue in a pathogenic M. marinum strain, was strongly attenuated in adult zebrafish and also survived less in macrophages. In contrast, infection with wild type and the complemented Delta mimG: Rv3242c M. marinum strains showed prominent pathological features, such as severe emaciation, skin lesions, hemorrhaging, and more zebrafish death. Similarly, recombinant Msm Rv3242c bacteria showed increased invasion in non-phagocytic epithelial cells and longer intracellular survival in macrophages as compared with wild type and vector control M. smegmatis strains. Further mechanistic studies revealed that the Rv3242c- and mimG-mediated enhancement of intramacrophagic survival was due to inhibition of autophagy, reactive oxygen species, and reduced activities of superoxide dismutase and catalase enzymes. Infection with MsmRv3242c also activated the MAPK pathway, NF-kappa B, and inflammatory cytokines. In summary, we show that a novel mycobacterial mannosylated phosphoribosyltransferase acts as a virulence and immunomodulatory factor, suggesting that it may constitute a novel target for antimycobacterial drugs