Background: Natalizumab is a humanized monoclonal antibody directed against very late activation antigen 4 (VLA-4) and has a potent effect on disease activity in multiple sclerosis. Blockade of VLA-4 with natalizumab may not only interfere with autoimmunological mechanisms but also with central nervous system immune surveillance. Methods: Longitudinal ex vivo and in vitro study to determine the effect of natalizumab on the frequency of distinct immune cells and on the frequency and suppressive function of natural CD4+CD25+ regulatory T cells (Tregs). Results: Natalizumab binding to VLA-4 was more marked for B cells than for T cells (49% reduction in VLA-4-expressing B cells compared to 24.5% reduction of T cells). There was an increase in circulating B cells over T cells (2.6 vs. 1.5 fold, p < 0.001). Natural killer cells increased 1.5-fold (p = 0.01). Natalizumab led to a relative decrease in CD4+CD25+ Tregs from 18.9 to 14.1% (p = 0.04). The impaired suppressive capacity of Tregs was not restored. Conclusion: Natalizumab reduces VLA-4 expression on all investigated immune cells, but changes were most marked for B cells. Further differential effects on immune cells may be relevant to opportunistic central nervous system infections during treatment with natalizumab.

SARS-CoV-2 has spread very quickly from its first reported case on 19 January 2020 in the United Stated of America, leading WHO to declare pandemic by 11 March 2020. RNA viruses accumulate mutations following replication and passage in human population, which prompted us to determine the rate and the regions (hotspots) of the viral genome with high rates of mutation. We analyzed the rate of mutation accumulation over a period of 11 weeks (submitted between 19th January to 15 April 2020) in USA SARS-CoV-2 genome. Our analysis identified that majority of the viral genes accumulated mutations, although with varying rates and these included NSP2, NSP3, RdRp, helicase, Spike, ORF3a, ORF8, and Nucleocapsid protein. Sixteen mutations accumulated in Spike protein in which four mutations are located in the receptor binding domain. Intriguingly, we identified a fair number of viral proteins (NSP7, NSP9, NSP10, NSP11, Envelop, ORF6, and ORF7b proteins), which did not accumulate any mutation. Limited changes in these proteins may suggest that they have conserved functions, which are essential for virus propagation. This provides a basis for a better understanding of the genetic variation in SARS-CoV-2 circulating in the US, which could help in identifying potential therapeutic targets for controlling COVID-19.

Altered expression of many genes and proteins is essential for cancer development and progression. Recently, the affected expression of metadherin (MTDH), also known as AEG-1 (Astrocyte Elevated Gene 1) and Lyric, has been implicated in various aspects of cancer progression and metastasis. Elevated expression of MTDH/AEG-1 has been reported in many cancers including breast, prostate, liver, and esophageal cancers, whereas its expression is low or absent in non-malignant tissues. These expression studies suggest that MTDH may represent a potential tumor associated antigen. MTDH also regulates multiple signaling pathways including PI3K/Akt, NF-κB, Wnt/β-catenin, and MAPK which cooperate to promote the tumorigenic and metastatic potential of transformed cells. Several microRNA have also been found to be associated with the increased MTDH expression in different cancers. Increased MTDH levels were linked to the tumor chemoresistance making it an attractive novel therapeutic target. In this review, we summarize data on MTDH function in various cancers.

Context Dunaliella salina Teodoresco (Dunaliellaceae) is one of the promising microalgae consumed as food and medicine for many years. Objective Dunaliella salina was grown under different stress conditions for enhancing carotene production. The carotene enriched extract was evaluated for antioxidant and cytotoxic activity. Materials and methods Carotene content was calculated under salinity, nitrogen and temperature stress conditions. Antioxidant activity was determined through DPPH assay by incubating the samples for 45 min with 250 lg/mL of extract and reducing power assay was performed with 50, 100, 150 and 200 lg/mL of extract. Cytotoxicity was determined by incubating $2 Â 10 4 MCF-7 (breast cancer) cells with 250 lg of extract in each well for 72 h by MTT assay. Result Carotene content was significantly increased to 9.8 (3.5 M NaCl), 13.9 (37 C), 8.2 (250 mM KNO 3 ) and 10.6 lg/mL (nitrogen-depleted medium) as compared with 3.2 lg/mL in normal conditions (1.7 M NaCl, 0.75 mM KNO 3 and 28 C). Free radical scavenging activity increased at 3.0 and 3.5 M NaCl (27.8 and 57.5%, respectively), 37 C (31.4%) and in nitrogen-depleted medium (41.9%) compared with normal (15%) conditions. Carotene content and scavenging activity were positively correlated under salinity (r ¼ 0.97), temperature (r ¼ 0.85) and nitrogen (r ¼ 0.7) stress conditions. Cytotoxicity against MCF-7 cell lines increased due to increase in carotene content suggesting that cytotoxicity may be associated with carotene accumulation. Discussion and conclusions Carotene content enhanced by D. salina under stress conditions increased the antioxidant and cytotoxic activity. ARTICLE HISTORY

Multiple sclerosis (MS) is a neurodegenerative disease characterized by lesions in the central nervous system (CNS). Inflammation and demyelination are the leading causes of neuronal death and brain lesions formation. The immune reactivity is believed to be essential in the neuronal damage in MS. Cytokines play important role in differentiation of Th cells and recruitment of auto-reactive B and T lymphocytes that leads to neuron demyelination and death. Several cytokines have been found to be linked with MS pathogenesis. In the present study, serum level of eight cytokines (IL-1β, IL-2, IL-4, IL-8, IL-10, IL-13, IFN-γ, and TNF-α) was analyzed in USA and Russian MS to identify predictors for the disease. Further, the model was extended to classify MS into remitting and non-remitting by including age, gender, disease duration, Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) into the cytokines datasets in Russian cohorts. The individual serum cytokines data for the USA cohort was generated by Z score percentile method using R studio, while serum cytokines of the Russian cohort were analyzed using multiplex immunoassay. Datasets were divided into training (70%) and testing (30%). These datasets were used as an input into four machine learning models (support vector machine, decision tree, random forest, and neural networks) available in R programming language. Random forest model was identified as the best model for diagnosis of MS as it performed remarkable on all the considered criteria i.e., Gini, accuracy, specificity, AUC, and sensitivity. RF model also performed best in predicting remitting and non-remitting MS. The present study suggests that the concentration of serum cytokines could be used as prognostic markers for the prediction of MS.

Pandemic threats of the H1N1 influenza virus have drawn attention to developing a universal vaccine against circulating and future strains of this virus. An immunoinformatics study was conducted to identify conserved peptides containing CD4+ and CD8+ T-cell epitopes from all the hemagglutinin (HA) and neuraminidase (NA) protein sequences available until February 2013 to cover the seasonal as well as the pandemic strains of the H1N1 virus. In the present study, six different immunoinformatics prediction programs were used in order to define the epitopes. Five conserved peptides of HA and six of NA protein were obtained that contained overlapping CD4+ and CD8+ T-cell epitopes. These identified peptides have a binding affinity for a large number of major histocompatibility complex (MHC) alleles. WHGSNRPWVSF of NA protein is a new peptide whose T-cell response has not been previously reported. Population coverage studies have shown that these peptide fragments have the capacity to induce a potent immune response among individuals from different populations around the world. Hence, these HA and NA peptides may be considered as interesting candidates for vaccine design.

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Immunoinformatics has come by leaps and bounds to finding potent vaccine candidates against various pathogens. In the current study, a combination of different T (CD4 + and CD8 +) and B cell epitope prediction tools was applied to find peptides containing multiple epitopes against Ebola nucleoprotein (NP) and the presentation of peptides to human leukocyte antigen (HLA) molecules was analyzed by prediction, docking and population coverage tools. Further, potential peptides were analyzed by ELISA for peptide induced IFN-γ secretion in peripheral blood mononuclear cells isolated from healthy volunteers. Six peptides were obtained after merging the overlapping multiple HLA I (CD8 +) and II (CD4 +) restricted T cell epitopes as well as B cell epitopes and eliminating the peptides liable to generate autoimmune and allergic response. All peptides displayed 100% conservancy in Zaire ebolavirus. In other Ebola virus species (Sudan, Bundibugyo and Taï forest) and Filoviridae members (Lloviuvirus and Margburgvirus), some peptides were found to be conserved with minor variations. Prediction tools confirmed the ability of predicted peptides to bind with diverse HLA (HLA-A, HLA-B, HLA-DP, HLA-DQ and HLA-DR) alleles. CABS-dock results displayed that the average root mean square deviation (RMSD) value was less than three in majority of cases representing strong binding affinity with HLA alleles. Population coverage analysis predicted high coverage (> 85%) for expected immune response in four continents (Africa, America, Asia and Europe). Nine out of ten blood samples exhibited enhanced IFN-γ secretion for two peptides (P2 and P3). Thus, the identified NP peptides can be considered as potential synthetic vaccine candidates against Ebola virus.