Development of a conserved chimeric vaccine based on helper T-cell and CTL epitopes for induction of strong immune response against Schistosoma mansoni using immunoinformatics approaches.

Currently, three recombinant antigens based vaccines are under clinical trials against Schistosomiasis, but there is no vaccine available for prophylaxis or therapeutic. This study was conducted to construct a multi-epitope based vaccine against Schistosoma mansoni via utilizing Sm14, Sm21.7, Sm23, Sm29, Smp80, Sm-CB and SM-TSP-2 antigens. Helper T lymphocyte (HTL), cytotoxic T lymphocyte (CTL) and IFN-γ epitopes were predicted. Furthermore, Pan HLA DR-binding epitope was added to the vaccine. Moreover, 50S ribosomal protein L7/L12 of Mycobacterium tuberculosis as a novel TLR4 agonist was applied. The TAT peptide was added to the vaccine to augment intracellular delivery. The selected epitopes were linked together through appropriate linkers and chimeric vaccine was constructed with 617 amino acids with molecular weight of 65.43 kDa. Physico-chemical properties revealed a soluble protein with antigenic and non-allergic properties. Further analyses validated the stability of the construct that was able to interact with TLR4. Immunoinformatics analysis demonstrated the strong potential of constructed vaccine to stimulate T and B-cell mediated immune responses. In summary, obtained data indicated that the proposed vaccine can properly induce both T and B cells immune responses and could possibly be utilized for prophylactic or therapeutic aims in response to infection caused by S. mansoni.

Human Immunodeficiency Virus and risk of pre-eclampsia and eclampsia in pregnant women: A meta-analysis on cohort studies.

Maternal HIV infection is related to several perinatal adverse outcomes. This study is aimed at establishing whether maternal HIV infection is associated with the development of pre-eclampsia (PE) and eclampsia. We comprehensively searched MEDLINE/PubMed, Web of Science, SCOPUS and Embase databases for relevant studies published up to 20 November 2018, without time and language restrictions. We have limited our literature searches to observational studies in humans. We applied a random-effects model to calculate the relative risks (RR) and 95% confidence intervals (CI) for the meta-analyses. We also systematically reviewed eligible studies to determine the effects of HIV infection on imbalance of angiogenic and anti-angiogenic factors, which are effective in increased risk of PE or eclampsia. We identified a total of 11,186 publications, out of which 22 eligible studies (11 prospective and 11 retrospective cohort studies) comprising 90,514 HIV-positive and 66,085,278 HIV-negative pregnant women were included in meta-analysis. Results of the meta-analyses suggested that maternal HIV infection is not significantly associated with the development of PE (RR, 1.04; 95%CI, 0.89-1.21) and eclampsia (RR, 1.05; 95%CI, 0.63-1.75). Six studies were included to understand the effects of HIV infection on imbalance of angiogenic and anti-angiogenic factors. All six studies demonstrated that HIV infection had no significant effect on expression levels of these factors in pre-eclamptic and normotensive pregnant women. Our study showed that maternal HIV infection was not significantly associated with increased or reduced risks of pre-eclampsia and eclampsia. More well-designed studies with large sample size and well defined outcomes are recommended to confirm or refute the present findings.

Wnt inhibitor screen reveals iron dependence of ß-catenin signaling in cancers.

Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/ß-catenin signaling, we identified a series of acyl hydrazones that act downstream of the ß-catenin destruction complex to inhibit both Wnt-induced and cancer-associated constitutive Wnt signaling via destabilization of ß-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans.

The genetic landscape of a cell.

A genome-scale genetic interaction map was constructed by examining 5.4 million gene-gene pairs for synthetic genetic interactions, generating quantitative genetic interaction profiles for approximately 75% of all genes in the budding yeast, Saccharomyces cerevisiae. A network based on genetic interaction profiles reveals a functional map of the cell in which genes of similar biological processes cluster together in coherent subsets, and highly correlated profiles delineate specific pathways to define gene function. The global network identifies functional cross-connections between all bioprocesses, mapping a cellular wiring diagram of pleiotropy. Genetic interaction degree correlated with a number of different gene attributes, which may be informative about genetic network hubs in other organisms. We also demonstrate that extensive and unbiased mapping of the genetic landscape provides a key for interpretation of chemical-genetic interactions and drug target identification.

Assessing the metabolic and toxic effects of anticonvulsant doses of polyunsaturated fatty acids on the liver in rats.

Polyunsaturated fatty acids (PUFA), at high doses, have been demonstrated to possess anticonvulsant properties in animal seizure models. Little is known, however, about the possible metabolic or adverse effects of PUFA at these high, anticonvulsant doses. The goal of the present study was to assess the metabolic and potential adverse effects of high-dose PUFA administration to rats. Adult male rats received a fatty acid mixture containing alpha-linolenic and linoleic acid in a 1 to 4 ratio, intraperitoneally, for 3 wk. After sacrifice, livers were isolated and analyzed for fatty acid composition and for mRNA expression of HMG-CoA lyase, catalase, and glutathione S-transferases A1 and A4, markers for ketosis, antioxidant defense, and phase II xenobiotic metabolism, respectively. Chronic administration of the PUFA mixture decreased hepatic levels of total lipids--and several fatty acids within total lipids--without altering mRNA expression of HMG-CoA lyase, a metabolic marker of ketosis. The PUFA mixture did not affect mRNA expression of catalase or glutathione S-transferases A1 and A4, which are involved in antioxidant defense and phase II xenobiotic metabolism. These findings suggest that PUFA, given for 3 wk at anticonvulsant doses, result in significant changes in liver lipid metabolism, but do not alter measured genetic markers of liver toxicity.