The ingenol-based protein kinase C agonist GSK445A is a potent inducer of HIV and SIV RNA transcription

Activation of the NF-κB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro. However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/ simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP). CD4+ T cells from people living with HIV and from SIV+ rhesus macaques (RM) on antiretroviral therapy (ART) exposed in vitro to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA/Ionomycin, indicating that GSK445A can potently reverse HIV/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8+ T cells, but instead, increased their numbers and enhanced IFN-γ production in response to HIV peptides. In vivo, GSK445A tolerability was established in SIV-naïve RM at 15 μg/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription in vivo. Collectively, these results indicate that GSK445A is a potent HIV/SIV LRA in vitro and has a tolerable safety profile amenable for further evaluation in vivo in NHP models of HIV cure/remission

Using high performance computing to create and freely distribute the South Asian genomic database, necessary for precision medicine in this population

10.14529/jsfi170201Supercomputing Frontiers and Innovations424-De

Harnessing donor unrestricted T-cells for new vaccines against tuberculosis

Immunogenetics and cellular immunology of bacterial infectious disease

De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes

Item does not contain fulltextCornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for approximately 1%-2% of CdLS-like phenotypes

The Nab experiment: A precision measurement of unpolarized neutron beta decay

Neutron beta decay is one of the most fundamental processes in nuclear physics and provides sensitive means to uncover the details of the weak interaction. Neutron beta decay can evaluate the ratio of axial-vector to vector coupling constants in the standard model, λ = gA/gV, through multiple decay correlations. The Nab experiment will carry out measurements of the electron-neutrino correlation parameter a with a precision of δa/a = 10−3 and the Fierz interference term b to δb = 3 × 10−3 in unpolarized free neutron beta decay. These results, along with a more precise measurement of the neutron lifetime, aim to deliver an independent determination of the ratio λ with a precision of δλ/λ = 0.03% that will allow an evaluation of Vud and sensitively test CKM unitarity, independent of nuclear models. Nab utilizes a novel, long asymmetric spectrometer that guides the decay electron and proton to two large area silicon detectors in order to precisely determine the electron energy and an estimation of the proton momentum from the proton time of flight. The Nab spectrometer is being commissioned at the Fundamental Neutron Physics Beamline at the Spallation Neutron Source at Oak Ridge National Lab. We present an overview of the Nab experiment and recent updates on the spectrometer, analysis, and systematic effects

The Nab experiment: A precision measurement of unpolarized neutron beta decay

Neutron beta decay is one of the most fundamental processes in nuclear physics and provides sensitive means to uncover the details of the weak interaction. Neutron beta decay can evaluate the ratio of axial-vector to vector coupling constants in the standard model, λ = gA/gV, through multiple decay correlations. The Nab experiment will carry out measurements of the electron-neutrino correlation parameter a with a precision of δa/a = 10−3 and the Fierz interference term b to δb = 3 × 10−3 in unpolarized free neutron beta decay. These results, along with a more precise measurement of the neutron lifetime, aim to deliver an independent determination of the ratio λ with a precision of δλ/λ = 0.03% that will allow an evaluation of Vud and sensitively test CKM unitarity, independent of nuclear models. Nab utilizes a novel, long asymmetric spectrometer that guides the decay electron and proton to two large area silicon detectors in order to precisely determine the electron energy and an estimation of the proton momentum from the proton time of flight. The Nab spectrometer is being commissioned at the Fundamental Neutron Physics Beamline at the Spallation Neutron Source at Oak Ridge National Lab. We present an overview of the Nab experiment and recent updates on the spectrometer, analysis, and systematic effects