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"Sharon, David"
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Characterization of immune responses to two and three doses of the adenoviral vectored vaccine ChAdOx1 nCov-19 and the whole virion inactivated vaccine BBV152 in a mix-and-match study in India
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Infections with SARS-CoV-2 variants and declining immunity after primary vaccination, encouraged the use of booster doses. Some countries changed their immunization programmes to boost with vaccines different from the ones in their original schedule, based on results from immunogenicity and effectiveness studies. This study reports immunological analysis of samples collected in a phase 4 randomized trial, where participants who had previously received two primary doses of ChAdOx1 nCov-19 (ChAd) or inactivated BBV152 vaccine were randomized to receive either ChAd or BBV152 booster and further categorized as: Group 1 (two primary doses of ChAd - ChAd booster), Group 2 (two primary doses of ChAd - BBV152 booster), Group 3 (two primary doses of BBV152 - ChAd booster), and Group 4 (two primary doses of BBV152 - BBV152 booster). SARS-CoV-2 specific cellular and humoral responses at day 0 (pre-boost samples 12–36 weeks after the second primary dose), and at day 28 post booster, were measured in a subset of participants (ChAd recipients, n = 37 and BBV152 recipients, n = 36). Additionally, on day180 post-booster humoral responses were assessed for the entire cohort (N = 378). Primary vaccination with 2 doses of BBV152 generated higher memory-B cells (median% 0.41 vs 0.35) and cytokine producing CD8-Tcells (median% 0.09 vs 0.04) while lower anti-spike IgG levels (medianAU/ml: 12,433 vs 27,074) as compared to ChAd. Irrespective of the primary vaccine received, ChAd boosted individuals generated higher memory-B cell frequencies and anti-spike IgG levels as compared to BBV152 booster. The percentage ACE-2 inhibition against Omicron and its sub-variants was higher in Group 3 (median > 60 %) as compared to other groups (median < 25 %). At day180 post booster the hierarchy of the antibody amounts was Group 1 ∼ Group 2 ∼ Group 3 > Group 4.
Sustained humoral and robust cellular immune response to SARS-CoV-2 can be obtained with ChAd booster irrespective of the primary vaccination regimen. The trial is registered with ISRTCN (CTRI/2021/08/035648).
Journal Article
The biopolitics of disability : neoliberalism, ablenationalism, and peripheral embodiment
In the neoliberal era, when human worth is measured by its relative utility within global consumer culture, selected disabled people have been able to gain entrance into late capitalist culture. This title terms this phenomenon 'ablenationalism' and asserts that 'inclusion' becomes meaningful only if disability is recognized as providing modes of living that are alternatives to governing norms of productivity and independence.
Book
An integrative systems biology approach to overcome venetoclax resistance in acute myeloid leukemia
The over-expression of the Bcl-2 protein is a common feature of many solid cancers and hematological malignancies, and it is typically associated with poor prognosis and resistance to chemotherapy. Bcl-2-specific inhibitors, such as venetoclax, have recently been approved for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, and they are showing promise in clinical trials as a targeted therapy for patients with relapsed or refractory acute myeloid leukemia (AML). However, successful treatment of AML with Bcl-2-specific inhibitors is often followed by the rapid development of drug resistance. An emerging paradigm for overcoming drug resistance in cancer treatment is through the targeting of mitochondrial energetics and metabolism. In AML in particular, it was recently observed that inhibition of mitochondrial translation via administration of the antibiotic tedizolid significantly affects mitochondrial bioenergetics, activating the integrated stress response (ISR) and subsequently sensitizing drug-resistant AML cells to venetoclax. Here we develop an integrative systems biology approach to acquire a deeper understanding of the molecular mechanisms behind this process, and in particular, of the specific role of the ISR in the commitment of cells to apoptosis. Our multi-scale mathematical model couples the ISR to the intrinsic apoptosis pathway in venetoclax-resistant AML cells, includes the metabolic effects of treatment, and integrates RNA, protein level, and cellular viability data. Using the mathematical model, we identify the dominant mechanisms by which ISR activation helps to overcome venetoclax resistance, and we study the temporal sequencing of combination treatment to determine the most efficient and robust combination treatment protocol.
Journal Article
A pooled genome-wide screening strategy to identify and rank influenza host restriction factors in cell-based vaccine production platforms
NRC publication: Yes
Journal Article
Defining criteria for broadly neutralizing HIV antibodies
Over the course of a few years, a small percentage of individuals with HIV-1 develop broadly neutralizing antibodies (bnAbs) capable of neutralizing diverse viruses. Although hundreds of antibodies with neutralizing activity against heterologous viruses have been referred to as bnAbs, there is no universally accepted numerical definition of a bnAb. Here, we will review important elements of HIV neutralizing antibodies and proposed definitions of bnAbs, as well as introduce a web-based tool, CAByN (Choose Antibodies by Neutralization), allowing users to identify antibodies meeting their numerical definitions of a bnAb from data in the Los Alamos HIV Databases CATNAP (Compile, Analyze and Tally NAb Panels) antibody neutralization database. Biological findings from use of CAByN are also presented here, including differential neutralizing activity for certain antibodies across viral clades, and identification of antibodies with suspected incomplete neutralization. Website address: http://hiv.lanl.gov/content/sequence/CABYN/CABYN.html .
Journal Article
Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10−/− mouse model of inflammatory bowel disease
Background
Following viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain-specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-10
−/−
) model derived from the SvEv mouse, had evidence of increased Mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wild type. MMTV is endemic in several mouse strains as an endogenously encoded Betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut-associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10
−/−
model.
Results
Viral preparations extracted from IL-10
−/−
weanling stomachs revealed augmented MMTV load compared to the SvEv wild type. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4–97.3% identity with the
mtv-1
endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV
sag
gene cloned from IL-10
−/−
spleen encoded the MTV-9 superantigen that preferentially activates T-cell receptor Vβ-12 subsets, which were expanded in the IL-10
−/−
versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10
−/−
splenocytes with amplified interferon-γ production versus the SvEv wild type. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12-week treatment versus placebo. The combination antiretroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL-10
−/−
mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis.
Conclusions
This study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain-specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis.
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Video Abstract
Journal Article