Human APOBEC3G-mediated hypermutation is associated with antiretroviral therapy failure in HIV-1 subtype C-infected individuals

Introduction

Human APOBEC3G/F (hA3G/F) restricts retroviral replication through G-to-A hypermutations, which can generate drug-resistant progenies in vitro. The clinical relevance is still inconclusive. To bridge this gap, we aim to study the role of these hypermutations in evolution of drug resistance; we characterised hA3G/F-mediated hypermutations in the RT region of the pol gene of patients with or without antiretroviral therapy (ART).

Methods

In 88 HIV-1-positive individuals, drug resistance genotyping was carried out in plasma virus and provirus by population sequencing. Hypermutations were determined by three different approaches using Hypermut 2.0 software, cluster analysis and APOBEC3G-mediated defectives indices. Clinical and demographic characteristics of these individuals were studied in relation to these hypermutations.

Results

hA3G/F-mediated hypermutated sequences in proviral DNA, but not in plasma virus, were identified in 11.4% (10/88) subjects. Proviral hypermutations were observed more frequently in patients with ART failure than in ART-naïve individuals (p=0.03). In therapy failure patients, proviral hypermutation were associated with greater intra-compartmental genetic diversity (p<0.001). In therapy-naïve individuals, hypermutated proviral DNA with M184I and M230I mutations due to the editing of hA3G, had stop codons in the open reading frames and the same mutations were absent in the plasma virus. Only a limited concordance was found between the drug resistance mutations in plasma RNA and proviral DNA.

Conclusions

hA3G lethal hypermutation was significantly associated with ART failure in Indian HIV-1 subtype C patients. It is unlikely that viral variants, which exhibit hypermutated sequences and M184I and/or M230I, will mature and expand in vivo.     

Influence of Temperature on Void Collapse in Single Crystal Nickel under Hydrostatic Compression

Employing atomistic simulations, we investigated the void collapse mechanisms in single crystal Ni during hydrostatic compression and explored how the atomistic mechanisms of void collapse are influenced by temperature. Our results suggest that the emission and associated mutual interactions of dislocation loops around the void is the primary mechanism of void collapse, irrespective of the temperature. The rate of void collapse is almost insensitive to the temperature, and the process is not thermally activated until a high temperature (∼1200–1500 K) is reached. Our simulations reveal that, at elevated temperatures, dislocation motion is assisted by vacancy diffusion and consequently the void is observed to collapse continuously without showing appreciable strain hardening around it. In contrast, at low and ambient temperatures (1 and 300 K), void collapse is delayed after an initial stage of closure due to significant strain hardening around the void. Furthermore, we observe that the dislocation network produced during void collapse remains the sample even after complete void collapse, as was observed in a recent experiment of nickel-base superalloy after hot isostatic pressing.     

Spatial Decomposition of a Broadband Pulse Caused by Strong Frequency Dispersion of Sound in Acoustic Metamaterial Superlattice

An acoustic metamaterial superlattice is used for the spatial and spectral deconvolution of a broadband acoustic pulse into narrowband signals with different central frequencies. The operating frequency range is located on the second transmission band of the superlattice. The decomposition of the broadband pulse was achieved by the frequency-dependent refraction angle in the superlattice. The refracted angle within the acoustic superlattice was larger at higher operating frequency and verified by numerical calculated and experimental mapped sound fields between the layers. The spatial dispersion and the spectral decomposition of a broadband pulse were studied using lateral position-dependent frequency spectra experimentally with and without the superlattice structure along the direction of the propagating acoustic wave. In the absence of the superlattice, the acoustic propagation was influenced by the usual divergence of the beam, and the frequency spectrum was unaffected. The decomposition of the broadband wave in the superlattice’s presence was measured by two-dimensional spatial mapping of the acoustic spectra along the superlattice’s in-plane direction to characterize the propagation of the beam through the crystal. About 80% of the frequency range of the second transmission band showed exceptional performance on decomposition.     

A novel peroxisome proliferator-activated gamma (PPAR gamma) agonist,CLX-0921, has potent antihyperglycemic activity with low adipogenic potential

Agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) are pharmacologically active antihyperglycemic agents that act by increasing peripheral tissue sensitivity to insulin. Many of these agonists have antihyperglycemic activity that is directly proportional to their ability to bind and activate PPAR gamma; however, recent data bring this relationship into question. In this report we describe a new PPAR gamma agonist, CLX-0921, that is derived from a natural product. This thiazolidinedione (TZD) has a spectrum of activity that differs from commercially available TZDs. It is a weak activator of PPAR gamma (EC(50) of 0.284 micromol/L) compared to rosiglitazone (EC(50) 0.009 micromol/L). Despite this difference, the drug maintains potent glucose uptake activity in vitro and glucose-lowering activity in vivo that is equipotent to that of rosiglitazone. Moreover, CLX-0921 showed a 10-fold reduction in in vitro adipogenic potential compared to rosiglitazone. CLX-0921 also increases glycogen synthesis, an activity not typically associated with rosiglitazone or pioglitazone. Thus CLX-0921 appears to have a distinct spectrum of activity relative to other TZDs.     

The Use of Social Networking Sites for Public Health Practice and Research: A Systematic Review

Background

Social networking sites (SNSs) have the potential to increase the reach and efficiency of essential public health services, such as surveillance, research, and communication.

Objective

The objective of this study was to conduct a systematic literature review to identify the use of SNSs for public health research and practice and to identify existing knowledge gaps.

Methods

We performed a systematic literature review of articles related to public health and SNSs using PubMed, EMBASE, and CINAHL to search for peer-reviewed publications describing the use of SNSs for public health research and practice. We also conducted manual searches of relevant publications. Each publication was independently reviewed by 2 researchers for inclusion and extracted relevant study data.

Results

A total of 73 articles met our inclusion criteria. Most articles (n=50) were published in the final 2 years covered by our search. In all, 58 articles were in the domain of public health research and 15 were in public health practice. Only 1 study was conducted in a low-income country. Most articles (63/73, 86%) described observational studies involving users or usages of SNSs; only 5 studies involved randomized controlled trials. A large proportion (43/73, 59%) of the identified studies included populations considered hard to reach, such as young individuals, adolescents, and individuals at risk of sexually transmitted diseases or alcohol and substance abuse. Few articles (2/73, 3%) described using the multidirectional communication potential of SNSs to engage study populations.

Conclusions

The number of publications about public health uses for SNSs has been steadily increasing in the past 5 years. With few exceptions, the literature largely consists of observational studies describing users and usages of SNSs regarding topics of public health interest. More studies that fully exploit the communication tools embedded in SNSs and study their potential to produce significant effects in the overall population’s health are needed.     

Cinnamic acid based thiazolidinediones inhibit human P450c17 and 3beta-hydroxysteroid dehydrogenase and improve insulin sensitivity independent of PPARgamma agonist activity

Thiazolidinediones improve insulin sensitivity in type 2 diabetes mellitus by acting as peroxisome proliferator-associated receptor gamma (PPARgamma) agonists, and decrease circulating androgen concentrations in polycystic ovary syndrome by unknown mechanisms. Some thiazolidinediones directly inhibit the steroidogenic enzymes P450c17 and 3beta-hydroxysteroid dehydrogenase type II (3betaHSDII) by distinct mechanisms. We synthesized five novel thiazolidinediones, CLX-M1 to -M5 by linking a 2,4-thiazolidinedione moiety to a substituted alpha-phenyl cinnamic acid previously shown to have glucose-lowering effects. Using yeast microsomes expressing human P450c17 and 3betaHSDII we found that cinnamic acid methyl esters with a double bond in the thiazolidinedione core structure (M3, M5) were stronger inhibitors of P450c17 than methyl esters with the conventional core (M1, M4). These four compounds inhibited 3betaHSDII equally well, while the free cinnamic acid analog (M2) did not inhibit either enzyme. Thus, the inhibition of P450c17 and 3betaHSDII by these novel thiazolidinediones reveals structure-activity relationships independent of PPARgamma transactivation. PPARgamma transactivation was moderate (M1), weak (M2, M3) or even absent (M4, M5). While the PPARgamma agonist activity of M1 was only 3% of that of rosiglitazone, both increased glucose uptake by 3T3-L1 adipocytes and reduced serum glucose levels in ob/ob and db/db mice to a similar extent. The similar glucose-lowering effects of M1 and rosiglitazone, despite their vast differences in PPARgamma agonist activity, suggests these two actions may occur by separate mechanisms.