The ubiquitin-proteasome system is a key component of the SUMO-2/3 cycle

Many proteins are regulated by a variety of post-translational modifications, and orchestration of these modifications is frequently required for full control of activity. Currently little is known about the combinatorial activity of different post-translational modifications. Here we show that extensive cross-talk exists between sumoylation and ubiquitination. We found that a subset of SUMO-2-conjugated proteins is subsequently ubiquitinated and degraded by the proteasome. In a screen for preferential SUMO-1 or SUMO-2 target proteins, we found that ubiquitin accumulated in purified SUMO-2 conjugates but not in SUMO-1 conjugates. Upon inhibition of the proteasome, the amount of ubiquitin in purified SUMO-2 conjugates increased. In addition, we found that endogenous SUMO-2/3 conjugates, but not endogenous SUMO-1 conjugates, accumulated in response to proteasome inhibitors. Quantitative proteomics experiments enabled the identification of 73 SUMO-2-conjugated proteins that accumulated in cells treated with proteasome inhibitors. Cross-talk between SUMO-2/3 and the ubiquitin-proteasome system controls many target proteins that regulate all aspects of nucleic acid metabolism. Surprisingly the relative abundance of 40 SUMO-2-conjugated proteins was reduced by proteasome inhibitors possibly because of a lack of recycled SUMO-2. We conclude that SUMO-2/3 conjugation and the ubiquitin-proteasome system are tightly integrated and act in a cooperative manner.     

Inflammatory and coagulation biomarkers and mortality in patients with HIV infection

Background

In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.

Methods and Findings

Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.

Conclusions

IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. Trial Registration: ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00027352","term_id":"NCT00027352"}}NCT00027352).     

A new family of H3 receptor antagonists based on the natural product Conessine

A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model.     

Modelling the recent and potential future spatial distribution of the Ring Ouzel (Turdus torquatus) and Blackbird (T. merula) in Switzerland

We present here a multiscale modelling approach to predict the current and future spatial distribution of Ring Ouzel (Turdus torquatus) and Blackbird (T. merula) in Switzerland. Species distribution models (SDMs) are applied on three different scales in order to analyse the scale-dependency of predictors that describe the species’ realised niche. While the models on the macro- and mesoscales (grid of 100 and 1 km², respectively) cover the entire country, our small-scale models are based on a small set of territories. Ring Ouzels occur at altitudes above 1000 m a.s.l. only, while Blackbirds occur from the lowlands up to the timberline. Although both species coexist on the macro- and mesoscales, a direct niche overlap on territory scale is rare. Small-scale differences in vegetation cover and structure seem to play a dominant role in habitat selection. On the macroscale, however, we observed a high dependency on bioclimatic variables that mainly represent the altitudinal range and the related forest structure preferred by both species. Applying the models to climate change scenarios, we predict a decline of suitable habitat for the Ring Ouzel with a simultaneous median altitudinal shift of 440 m until 2070. In contrast, the Blackbird is predicted to benefit from higher temperatures and expand its range to higher elevations. Based on the species distribution models we (1) demonstrate the scale-dependency of environmental predictors, (2) quantify the scale-dependent habitat requirements of Blackbird and Ring Ouzel and (3) predict the altitudinal range shift of both species as related to climate change scenarios.