Validation of a physician global assessment tool for vitiligo extent: Results of an international vitiligo expert meeting

Currently, vitiligo lacks a validated Physician Global Assessment (PGA) for disease extent. This PGA can be used to stratify and interpret the numeric scores obtained by the Vitiligo Extent Score (VES). We investigated the interrater reliability of a 5‐point PGA scale during an international vitiligo workshop. Vitiligo experts from five different continents rated photographs of non‐segmental vitiligo patients with varying degrees of extent with the PGA score. Good interrater agreements (intraclass correlation coefficient >0.6) were observed between the raters overall and within each continent. All hypotheses to evaluate construct validity were confirmed. Median VES values per category were for limited 1.10 [IQR: 0.21–1.67], moderate 3.17 [IQR: 1.75–6.21], extensive 9.58 [IQR: 6.21–13.03] and very extensive 42.67 [IQR: 21.20–42.67]. Defined categories for vitiligo extent can be valuable for inclusion criteria and may impact future reimbursement criteria.     

Sex differences in lizard escape decisions vary with latitude,but not sexual dimorphism

Sexual selection is a powerful evolutionary mechanism that has shaped the physiology, behaviour and morphology of the sexes to the extent that it can reduce viability while promoting traits that enhance reproductive success. Predation is one of the underlying mechanisms accounting for viability costs of sexual displays. Therefore, we should expect that individuals of the two sexes adjust their anti-predator behaviour in response to changes in predation risk. We conducted a meta-analysis of 28 studies (42 species) of sex differences in risk-taking behaviour in lizards and tested whether these differences could be explained by sexual dichromatism, by sexual size dimorphism or by latitude. Latitude was the best predictor of the interspecific heterogeneity in sex-specific behaviour. Males did not change their escape behaviour with latitude, whereas females had increasingly reduced wariness at higher latitudes. We hypothesize that this sex difference in risk-taking behaviour is linked to sex-specific environmental constraints that more strongly affect the reproductive effort of females than males. This novel latitudinal effect on sex-specific anti-predator behaviour has important implications for responses to climate change and for the relative roles of natural and sexual selection in different species.     

Human eukaryotic release factor 3a depletion causes cell cycle arrest at G1 phase through inhibition of the mTOR pathway

Eukaryotic release factor 3 (eRF3) is a GTPase associated with eRF1 in a complex that mediates translation termination in eukaryotes. Studies have related eRF3 with cell cycle regulation, cytoskeleton organization, and tumorigenesis. In mammals, two genes encode two distinct forms of eRF3, eRF3a and eRF3b, which differ in their N-terminal domains. eRF3a is the major factor acting in translation termination, and its expression level controls termination complex formation. Here, we investigate the role of eRF3a in cell cycle progression using short interfering RNAs and flow cytometry. We show that eRF3a depletion induces a G1 arrest and that eRF3a GTP-binding activity, but not the eRF3a N-terminal domain, is required to restore G1-to-S-phase progression. We also show that eRF3a depletion decreases the global translation rate and reduces the polysome charge of mRNA. Finally, we show that two substrates of the mammalian TOR (mTOR) kinase, 4E-BP1 and protein kinase S6K1, are hypophosphorylated in eRF3a-depleted cells. These results strongly suggest that the G1 arrest and the decrease in translation induced by eRF3a depletion are due to the inhibition of mTOR activity and hence that eRF3a belongs to the regulatory pathway of mTOR activity.     

Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1

The rise in multidrug resistant (MDR) cases of tuberculosis (TB) has led to the need for the development of TB drugs with different mechanisms of action. The genome sequence of Mycobacterium tuberculosis (Mtb) revealed twenty different genes coding for cytochrome P450s. CYP121A1 catalyzes a CC crosslinking reaction of dicyclotyrosine (cYY) producing mycocyclosin and current research suggests that either mycocyclosin is essential or the overproduction of cYY is toxic to Mtb. A series of 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives were designed and synthesised as cYY mimics. The derivatives substituted in the 4-position of the phenyl rings with halides or alkyl group showed promising antimycobacterial activity (MIC 6.25?μg/mL), with the more lipophilic branched alkyl derivatives displaying optimal binding affinity with CYP121A1 (ⁱPr K_D?=?1.6?μM; ^tBu K_D?=?1.2?μM). Computational studies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.     

DNAJB3/HSP-40 Cochaperone Is Downregulated in Obese Humans and Is Restored by Physical Exercise

Obesity is a major risk factor for a myriad of disorders such as insulin resistance and diabetes. The mechanisms underlying these chronic conditions are complex but low grade inflammation and alteration of the endogenous stress defense system are well established. Previous studies indicated that impairment of HSP-25 and HSP-72 was linked to obesity, insulin resistance and diabetes in humans and animals while their induction was associated with improved clinical outcomes. In an attempt to identify additional components of the heat shock response that may be dysregulated by obesity, we used the RT²-Profiler PCR heat shock array, complemented with RT-PCR and validated by Western blot and immunohistochemistry. Using adipose tissue biopsies and PBMC of non-diabetic lean and obese subjects, we report the downregulation of DNAJB3 cochaperone mRNA and protein in obese that negatively correlated with percent body fat (P = 0.0001), triglycerides (P = 0.035) and the inflammatory chemokines IP-10 and RANTES (P = 0.036 and P = 0.02, respectively). DNAJB positively correlated with maximum oxygen consumption (P = 0.031). Based on the beneficial effect of physical exercise, we investigated its possible impact on DNAJB3 expression and indeed, we found that exercise restored the expression of DNAJB3 in obese subjects with a concomitant decrease of phosphorylated JNK. Using cell lines, DNAJB3 protein was reduced following treatment with palmitate and tunicamycin which is suggestive of the link between the expression of DNAJB3 and the activation of the endoplasmic reticulum stress. DNAJB3 was also shown to coimmunoprecipiate with JNK and IKKβ stress kinases along with HSP-72 and thus, suggesting its potential role in modulating their activities. Taken together, these data suggest that DNAJB3 can potentially play a protective role against obesity.     

Zamilon,a Novel Virophage with Mimiviridae Host Specificity

Virophages, which are potentially important ecological regulators, have been discovered in association with members of the order Megavirales. Sputnik virophages target the Mimiviridae, Mavirus was identified with the Cafeteria roenbergensis virus, and virophage genomes reconstructed by metagenomic analyses may be associated with the Phycodnaviridae. Despite the fact that the Sputnik virophages were isolated with viruses belonging to group A of the Mimiviridae, they can grow in amoebae infected by Mimiviridae from groups A, B or C. In this study we describe Zamilon, the first virophage isolated with a member of group C of the Mimiviridae family. By co-culturing amoebae with purified Zamilon, we found that the virophage is able to multiply with members of groups B and C of the Mimiviridae family but not with viruses from group A. Zamilon has a 17,276 bp DNA genome that potentially encodes 20 genes. Most of these genes are closely related to genes from the Sputnik virophage, yet two are more related to Megavirus chiliensis genes, a group B Mimiviridae, and one to Moumouvirus monve transpoviron.     

A Linear Epitope in the N-Terminal Domain of CCR5 and Its Interaction with Antibody

The CCR5 receptor plays a role in several key physiological and pathological processes and is an important therapeutic target. Inhibition of the CCR5 axis by passive or active immunisation offers one very selective strategy for intervention. In this study we define a new linear epitope within the extracellular domain of CCR5 recognised by two independently produced monoclonal antibodies. A short peptide encoding the linear epitope can induce antibodies which recognise the intact receptor when administered colinear with a tetanus toxoid helper T cell epitope. The monoclonal antibody RoAb 13 is shown to bind to both cells and peptide with moderate to high affinity (6x10^8 and 1.2x10⁷ M^-1 respectively), and binding to the peptide is enhanced by sulfation of tyrosines at positions 10 and 14. RoAb13, which has previously been shown to block HIV infection, also blocks migration of monocytes in response to CCR5 binding chemokines and to inflammatory macrophage conditioned medium. A Fab fragment of RoAb13 has been crystallised and a structure of the antibody is reported to 2.1 angstrom resolution.