Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: A Women\u27s interagency HIV study.

HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear. In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-γ, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI). We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (P \u3c 0.001, coefficient r = −0.463). Immune activation varied by HIV phenotype but was not modified by HCV viremia. HCV viremia was associated with elevated CD8 T-cell Caspase-3 in Elites, ARTuc, and HIV− except ARTc. CD8 T-cell Caspase-3 levels were significantly higher in HCV RNA+ Elites (P = 0.04) and ARTuc (P = 0.001) and HIV− groups (P = 0.02) than ARTc. Importantly, ARTuc HCV RNA+ had significantly higher CD4 T-cell interleukin-17 levels than ARTuc HCV RNA− (P = 0.005). HIV control was associated with lower liver fibrosis in HCV/HIV co-infected women. HCV viremia is associated with an inflammatory CD4 TH-17 phenotype in absence of HIV control and higher frequency of pro-apoptosis CD8 T-cells critical to avert progression of HIV and HCV disease that is attenuated in ART controllers. Elite controllers with HCV viremia are more prone to CD8 T-cell apoptosis than ART controllers, which could have negative consequences over time, highlighting the importance of ART control in HCV/HIV coinfected individuals

Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis

Objectives: Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing. Methods: In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug. Results: Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy. Conclusions: The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed. Trial Registration ClinicalTrials.gov NCT00349622

LISP Machine Progress Report

This informal paper introduces the LISP Machine, describes the goals and current status of the project, and explicates some of the key ideas. It covers the LISP machine implementation, LISP as a system language, input/output, representation of data, representation of programs, control structures, storage organization, garbage collection, the editor, and the current status of the work

Private versus Shared, Automated Electric Vehicles for U.S. Personal Mobility: Energy Use, Greenhouse Gas Emissions, Grid Integration, and Cost Impacts.

Transportation is the fastest-growing source of greenhouse gas (GHG) emissions and energy consumption globally. While the convergence of shared mobility, vehicle automation, and electrification has the potential to drastically reduce transportation impacts, it requires careful integration with rapidly evolving electricity systems. Here, we examine these interactions using a U.S.-wide simulation framework encompassing private electric vehicles (EVs), shared automated EVs (SAEVs), charging infrastructure, controlled EV charging, and a grid economic dispatch model to simulate personal mobility exclusively using EVs. We find that private EVs with uncontrolled charging would reduce GHG emissions by 46% compared to gasoline vehicles. Private EVs with fleetwide controlled charging would achieve a 49% reduction in emissions from baseline and reduce peak charging demand by 53% from the uncontrolled scenario. We also find that an SAEV fleet 9% the size of today's active vehicle fleet can satisfy trip demand with only 2.6 million chargers (0.2 per EV). Such an SAEV fleet would achieve a 70% reduction in GHG emissions at 41% of the lifecycle cost as a private EV fleet with controlled charging. The emissions and cost advantage of SAEVs is primarily due to reduced vehicle manufacturing compared with private EVs

Private versus Shared, Automated Electric Vehicles for U.S. Personal Mobility: Energy Use, Greenhouse Gas Emissions, Grid Integration, and Cost Impacts.

Transportation is the fastest-growing source of greenhouse gas (GHG) emissions and energy consumption globally. While the convergence of shared mobility, vehicle automation, and electrification has the potential to drastically reduce transportation impacts, it requires careful integration with rapidly evolving electricity systems. Here, we examine these interactions using a U.S.-wide simulation framework encompassing private electric vehicles (EVs), shared automated EVs (SAEVs), charging infrastructure, controlled EV charging, and a grid economic dispatch model to simulate personal mobility exclusively using EVs. We find that private EVs with uncontrolled charging would reduce GHG emissions by 46% compared to gasoline vehicles. Private EVs with fleetwide controlled charging would achieve a 49% reduction in emissions from baseline and reduce peak charging demand by 53% from the uncontrolled scenario. We also find that an SAEV fleet 9% the size of today's active vehicle fleet can satisfy trip demand with only 2.6 million chargers (0.2 per EV). Such an SAEV fleet would achieve a 70% reduction in GHG emissions at 41% of the lifecycle cost as a private EV fleet with controlled charging. The emissions and cost advantage of SAEVs is primarily due to reduced vehicle manufacturing compared with private EVs

p53 modulates homologous recombination by transcriptional regulation of the RAD51 gene

DNA repair by homologous recombination is involved in maintaining genome stability. Previous data report that wild-type p53 suppresses homologous recombination and physically interacts with Rad51. Here, we show the in vivo binding of wild-type p53 to a p53 response element in the promoter of Rad51 and the downregulation of Rad51 messenger RNA and protein by wild-type p53, favoured by DNA damage. Moreover, wild-type p53 inhibits Rad51 foci formation in response to double-strand breaks, whereas p53 contact mutant R280K fails to repress Rad51 mRNA and protein expression and Rad51 foci formation. We propose that transcriptional repression of Rad51 by p53 participates in regulating homologous recombination, and impaired Rad51 repression by p53 mutants may contribute to malignant transformation

HIV RNA levels in plasma and cervical-vaginal lavage fluid in elite controllers and HAART recipients

ObjectivesThe introduction of HAART leads to control of HIV replication to less than 50 copies/ml, similar to levels in 'elite controllers'. Low-level viral replication may be one of the contributing factors to persistent immune activation/inflammation in HAART-treated individuals. There are still gaps in our knowledge of whether low-level replication persists in systemic versus mucosal sites.Design and methodsParticipants for this study were recruited from the Women's Interagency HIV Study. We evaluated 33 'elite controllers' who naturally controlled HIV replication and 33 matched HAART-suppressed recipients. This study employed a sensitive target-capture transcription-mediated-amplification assay to compare low-level virus concentrations in plasma and cervical-vaginal lavage (CVL) samples from HIV-positive HAART recipients and 'elite controllers'.ResultsThe median (interquartile range) plasma viral load signal/cut-off (S/Co) for 'elite controllers' was 10.5 (3.9-21.1), which was significantly (P < 0.001) higher than the S/Co for HAART recipients [2.0 (1-4.9)]. The majority of CVL samples from both groups had undetectable HIV RNA and the proportion of CVL samples with a cut-off more than 1.0 was not different between 'elite controllers' and HAART-suppressed recipients.ConclusionThis study demonstrated persistent low-level HIV replication in 'elite controllers', suggesting potential value of HAART treatment for these individuals. Absent or very low levels of HIV RNA in CVL indicate very low risk of secondary sexual transmission for both groups