Treatment of W. bancrofti (Wb) in HIV/Wb Coinfections in South India

BackgroundThe disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coincident infections.Conclusions/SignificanceWe were unable to find a significant effect of W. bancrofti infection or its treatment on HIV clinical course or surrogate markers of HIV disease progression though we recognized that our study was limited by the smaller than predicted sample size and by the use of ART in half of the patients. Treatment of W. bancrofti coinfection in HIV positive subjects (as is usual in mass drug administration campaigns) did not represent an increased risk to the subjects, and should therefore be considered for PLWHA living in W. bancrofti endemic areas.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00344279","term_id":"NCT00344279"}}NCT00344279     

Hepatitis C virus core protein enhances HIV-1 replication in human macrophages through TLR2, JNK,and MEK1/2-dependent upregulation of TNF-α and IL-6

Despite their differential cell tropisms, HIV-1 and HCV dramatically influence disease progression in coinfected patients. Macrophages are important target cells of HIV-1. We hypothesized that secreted HCV core protein might modulate HIV-1 replication. We demonstrate that HCV core significantly enhances HIV-1 replication in human macrophages by upregulating TNF-α and IL-6 via TLR2-, JNK-, and MEK1/2-dependent pathways. Furthermore, we show that TNF-α and IL-6 secreted from HCV core-treated macrophages reactivates monocytic U1 cells latently infected with HIV-1. Our studies reveal a previously unrecognized role of HCV core by enhancing HIV-1 infection in macrophages.     

Implementing a mathematical model to compare oxygen uptake kinetics between cyclists and noncyclists during steady state

The purpose was to compare a mathematical model of oxygen uptake and bioenergetic systems to an experimental protocol. Twelve (N = 12) noncyclists (NC), age (21.8 ± 1.4 years), and 8 (N = 8) cyclists (C), age (30.5 ± 5.7 years), were subjects. All subjects signed an informed consent. Oxygen consumption (VO2, ml·kg?1·min?1) was measured with steady-state VO2 requirements and responses determined using the mathematical model from the following equation: VO2 (WR) = VO2 (rest) + VO2 (unloading pedaling) + α.WR; ΔVO2(t, WR) = ΔVO2 (WR) = [1-e[-(t-td)/tO2]. Exercise means (SD) included the following: VO2NC(WR) = 48.4 (16.6) ml?1·min?1 for NCs and VO2C(WR) = 56.4 (24.95) ml?1·min?1 for Cs ; ΔVO2C(t, WR) = 6:38 ml?1·min?1 for NCs and ΔVO2C(t, WR) = 7.44 ml?1·min?1 for Cs. The correlation between the mathematical model and actual measure was statistically significant (p < 0.01) with a coefficient of r = 0.947. The experimental protocol was significantly associated with the mathematical model. This allows for a quantitative analysis and safe prediction of steady-state oxygen uptake conditions on populations before exposure to exercising conditions. Through more precise analysis of conditions, greater specificity of training may lead to more predictable adaptation outcomes.     

Synthesis and biological activity of 2H-quinolizin-2-one based p38α MAP kinase inhibitors

The development and synthesis of potent p38α MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed.     

Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway

The ubiquitination of the receptor that mediates signaling induced by the polypeptide pituitary hormone prolactin (PRL) has been shown to lead to the degradation of this receptor and to the ensuing negative regulation of cellular responses to PRL. However, the mechanisms of PRL receptor (PRLr) proteolysis remain largely to be determined. Here we provide evidence that PRLr is internalized and primarily degraded via the lysosomal pathway. Ubiquitination of PRLr is essential for the rapid internalization of PRLr, which proceeds through a pathway dependent on clathrin and the assembly polypeptide 2 (AP2) adaptor complexes. Recruitment of AP2 to PRLr is stimulated by PRLr ubiquitination, which also is required for the targeting of already internalized PRLr to the lysosomal compartment. While mass spectrometry analysis revealed that both monoubiquitination and polyubiquitination (via both K48- and K63-linked chains) occur on PRLr, the results of experiments using forced expression of ubiquitin mutants indicate that PRLr polyubiquitination via K63-linked chains is important for efficient interaction of PRLr with AP2 as well as for efficient internalization, postinternalization sorting, and proteolytic turnover of PRLr. We discuss how specific ubiquitination may regulate early and late stages of endocytosis of PRLr and of related receptors to contribute to the negative regulation of the magnitude and duration of downstream signaling.     

Pigmentation and Vitamin D Metabolism in Caucasians: Low Vitamin D Serum Levels in Fair Skin Types in the UK

Background

Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated.

Methodology/Principal Findings

We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p<0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p<0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001).

Conclusions/Significance

Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in view of their risk of vitamin D deficiency.     

An adenovirus prime/plasmid boost strategy for induction of equipotent immune responses to two dengue virus serotypes

Background  

Dengue is a public health problem of global significance for which there is neither an effective antiviral therapy nor a preventive vaccine. It is a mosquito-borne viral disease, caused by dengue (DEN) viruses, which are members of the Flaviviridae family. There are four closely related serotypes, DEN-1, DEN-2, DEN-3 and DEN-4, each of which is capable of causing disease. As immunity to any one serotype can potentially sensitize an individual to severe disease during exposure to a heterologous serotype, the general consensus is that an effective vaccine should be tetravalent, that is, it must be capable of affording protection against all four serotypes. The current strategy of creating tetravalent vaccine formulations by mixing together four monovalent live attenuated vaccine viruses has revealed the phenomenon of viral interference leading to the manifestation of immune responses biased towards a single serotype.