Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein–protein interactions

Cell Biology and Toxicology - Chronic inflammation (CI) is a primary contributing factor involved in multiple diseases like cancer, stroke, diabetes, Alzheimer’s disease, allergy, asthma,...     

Characteristics of HIV-1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1 prevention

Introduction

Stable heterosexual HIV-1 serodiscordant couples in Africa have high HIV-1 transmission rates and are a critical population for evaluation of new HIV-1 prevention strategies. The Partners PrEP Study is a randomized, double-blind, placebo-controlled trial of tenofovir and emtricitabine-tenofovir pre-exposure prophylaxis to decrease HIV-1 acquisition within heterosexual HIV-1 serodiscordant couples. We describe the trial design and characteristics of the study cohort.

Methods

HIV-1 serodiscordant couples, in which the HIV-1 infected partner did not meet national guidelines for initiation of antiretroviral therapy, were enrolled at 9 research sites in Kenya and Uganda. The HIV-1 susceptible partner was randomized to daily oral tenofovir, emtricitabine-tenofovir, or matching placebo with monthly follow-up for 24–36 months.

Results

From July 2008 to November 2010, 7920 HIV-1 serodiscordant couples were screened and 4758 enrolled. For 62% (2966/4758) of enrolled couples, the HIV-1 susceptible partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28–40) and (26–39) respectively]. Most couples (98%) were married, with a median duration of partnership of 7.0 years (IQR 3.0–14.0) and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1–2.0)]. During the month prior to enrollment, couples reported a median of 4 sex acts (IQR 2–8); 27% reported unprotected sex and 14% of male and 1% of female HIV-1 susceptible partners reported sex with outside partners. Among HIV-1 infected partners, the median plasma HIV-1 level was 3.94 log₁₀ copies/mL (IQR 3.31–4.53) and median CD4 count was 496 cells/µL (IQR 375–662); the majority (64%) had WHO stage 1 HIV-1 disease.

Conclusions

Couples at high risk of HIV-1 transmission were rapidly recruited into the Partners PrEP Study, the largest efficacy trial of oral PrEP. (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00557245","term_id":"NCT00557245"}}NCT00557245)     

Development of eco-friendly process for the production of bioethanol from banana peel using inhouse developed cocktail of thermo-alkali-stable depolymerizing enzymes

Bioprocess and Biosystems Engineering - Conversion of agro-industrial wastes to energy is an innovative approach for waste valorization and management which also mitigates environmental pollution....     

Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2

One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology (IPF/UIP) is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving IL-13 driving CCL2, which in turn drives TGFbeta1 in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human IPF/UIP fibroblasts. IPF/UIP fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to TGFbeta1 but were relatively non-responsive to IL-13 or CCL2, whereas, IPF/UIP cells were hyper-responsive to TGFbeta1, IL-13 and CCL2. Interestingly, TGFbeta1, CCL2 and IL-13 all upregulated TGFbeta receptor and IL-13 receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of CCL2, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between TGFbeta1, IL-13 and CCL2 in IPF/UIP, where these three mediators feedback on each other, promoting the fibrotic response.     

Survival of Infants Born to HIV-Positive Mothers,by Feeding Modality,in Rakai,Uganda

Background

Data comparing survival of formula-fed to breast-fed infants in programmatic settings are limited. We compared mortality and HIV-free of breast and formula-fed infants born to HIV-positive mothers in a program in rural, Rakai District Uganda.

Methodology/Principal Findings

One hundred eighty two infants born to HIV-positive mothers were followed at one, six and twelve months postpartum. Mothers were given infant-feeding counseling and allowed to make informed choices as to whether to formula-feed or breast-feed. Eligible mothers and infants received antiretroviral therapy (ART) if indicated. Mothers and their newborns received prophylaxis for prevention of mother-to-child HIV transmission (pMTCT) if they were not receiving ART. Infant HIV infection was detected by PCR (Roche Amplicor 1.5) during the follow-up visits. Kaplan Meier time-to-event methods were used to compare mortality and HIV-free survival. The adjusted hazard ratio (Adjusted HR) of infant HIV-free survival was estimated by Cox regression. Seventy-five infants (41%) were formula-fed while 107 (59%) were breast-fed. Exclusive breast-feeding was practiced by only 25% of breast-feeding women at one month postpartum. The cumulative 12-month probability of infant mortality was 18% (95% CI = 11%–29%) among the formula-fed compared to 3% (95% CI = 1%–9%) among the breast-fed infants (unadjusted hazard ratio (HR)  = 6.1(95% CI = 1.7–21.4, P-value<0.01). There were no statistically significant differentials in HIV-free survival by feeding choice (86% in the formula-fed compared to 96% in breast-fed group (Adjusted RH = 2.8[95%CI = 0.67–11.7, P-value = 0.16]

Conclusions/Significance

Formula-feeding was associated with a higher risk of infant mortality than breastfeeding in this rural population. Our findings suggest that formula-feeding should be discouraged in similar African settings.     

Down modulation of human TLR3 function by a monoclonal antibody

Toll-like receptors are a family of pattern-recognition receptors that contribute to the innate immune response. Toll-like receptor 3 (TLR3) signals in response to foreign, endogenous and synthetic ligands including viral dsRNA, bacterial RNA, mitochondrial RNA, endogenous necrotic cell mRNA and the synthetic dsRNA analog, poly(I:C). We have generated a monoclonal antibody (mAb CNTO2424) that recognizes the extracellular domain (ECD) of human TLR3 in a conformation-dependent manner. CNTO2424 down-regulates poly(I:C)-induced production of IL-6, IL-8, MCP-1, RANTES, and IP-10 in human lung epithelial cells. In addition, mAb CNTO2424 was able to interfere with the known TLR3-dependent signaling pathways, namely NF-κB, IRF-3/ISRE, and p38 MAPK. The generation of this neutralizing anti-TLR3 mAb provides a unique tool to better understand TLR3 signaling and potential cross-talk between TLR3 and other molecules.     

Quantitative traits for the tail suspension test: automation, optimization, and BXD RI mapping

Immobility in the tail suspension test (TST) is considered a model of despair in a stressful situation, and acute treatment with antidepressants reduces immobility. Inbred strains of mouse exhibit widely differing baseline levels of immobility in the TST and several quantitative trait loci (QTLs) have been nominated. The labor of manual scoring and various scoring criteria make obtaining robust data and comparisons across different laboratories problematic. Several studies have validated strain gauge and video analysis methods by comparison with manual scoring. We set out to find objective criteria for automated scoring parameters that maximize the biological information obtained, using a video tracking system on tapes of tail suspension tests of 24 lines of the BXD recombinant inbred panel and the progenitor strains C57BL/6J and DBA/2J. The maximum genetic effect size is captured using the highest time resolution and a low mobility threshold. Dissecting the trait further by comparing genetic association of multiple measures reveals good evidence for loci involved in immobility on chromosomes 4 and 15. These are best seen when using a high threshold for immobility, despite the overall better heritability at the lower threshold. A second trial of the test has greater duration of immobility and a completely different genetic profile. Frequency of mobility is also an independent phenotype, with a distal chromosome 1 locus. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Catechin as an antioxidant in liver mitochondrial toxicity: Inhibition of tamoxifen-induced protein oxidation and lipid peroxidation

Tamoxifen (TAM) is a nonsteroidal triphenylethylene antiestrogenic drug widely used in the treatment and prevention of breast cancer. TAM brings about a collapse of the mitochondrial membrane potential. It acts both as an uncoupling agent and as a powerful inhibitor of mitochondrial electron transport chain. The effect of catechin pretreatment on the mitochondrial toxicity of TAM was studied in liver mitochondria of Swiss albino mice. TAM treatment caused a significant increase in the mitochondrial lipid peroxidation (LPO) and the protein carbonyls (PCs). It also caused a significant increase in superoxide radical production. Pretreatment of mice with catechin (40 mg/kg) showed significant protection as demonstrated by marked attenuation of increased oxidative stress parameters such LPO, PCs, and superoxide production. It also restored the decreased nonenzymatic and enzymatic antioxidants of mitochondria. The inhibitory effect of catechin on TAM-:induced oxidative damage suggests that it may have potential benefits in prevention of human diseases where reactive oxygen species have some role as causative agents.