Lipopeptides as dimerization inhibitors of HIV-1 protease

In AIDS therapy, attempts have been made to inhibit the virus-encoded enzymes, e.g, HIV-1 protease, using active site-directed inhibitors. This approach is questionable, however, due to virus mutations and the high toxicity of the drugs, An alternative method to inhibit the dimeric HIV protease is the targeting of the interface region of the protease subunits in order to prevent subunit dimerization and enzyme activity, This approach should be less prone to inactivation by mutation, A list of improved 'dimerization inhibitors' of HIV-1 protease is presented. The main structural features are a short `interface' peptide segment, including non-natural amino acids, and an aliphatic N-terminal blocking group. The high inhibitory power of some of the lipopeptides {[}e.g, palmitoyl-Tyr-Glu-Leu-OH, palmitoyl-Tyr-Glu-(L-thyronine)-OH, palmitoyl-Tyr-Glu-(L-biphenyl-alanine)-OH] with low nanomolar K-i values in the enzyme test suggests that mimetics with good bio-availability can be derived for AIDS therapy

Surface decoration of catanionic vesicles with superparamagnetic iron oxide nanoparticles: a model system for triggered release under moderate temperature conditions

International audienceWe report the design of new catanionic vesicles decorated with iron oxide nanoparticles, which could be used as a model system to illustrate controlled delivery of small solutes under mild hyperthermia. Efficient release of fluorescent dye rhodamine 6G was observed when samples were exposed to an oscillating magnetic field. Our system provides direct evidence for reversible permeability upon magnetic stimulation

The potential for climate-driven bathymetric range shifts: sustained temperature and pressure exposures on a marine ectotherm, Palaemonetes varians

Range shifts are of great importance as a response for species facing climate change. In the light of current ocean-surface warming, many studies have focused on the capacity of marine ectotherms to shift their ranges latitudinally. Bathymetric range shifts offer an important alternative, and may be the sole option for species already at high latitudes or those within enclosed seas; yet relevant data are scant. Hydrostatic pressure (HP) and temperature have wide ranging effects on physiology, importantly acting in synergy thermodynamically, and therefore represent key environmental constraints to bathymetric migration. We present data on transcriptional regulation in a shallow-water marine crustacean (Palaemonetes varians) at atmospheric and high HP following 168-h exposures at three temperatures across the organisms' thermal scope, to establish the potential physiological limit to bathymetric migration by neritic fauna. We observe changes in gene expression indicative of cellular macromolecular damage, disturbances in metabolic pathways and a lack of acclimation after prolonged exposure to high HP. Importantly, these effects are ameliorated (less deleterious) at higher temperatures, and exacerbated at lower temperatures. These data, alongside previously published behavioural and heat-shock analyses, have important implications for our understanding of the potential for climate-driven bathymetric range shift

Surgical repair of post-infarction ventricular free-wall rupture in the Netherlands: data from a nationwide registry

Background: Ventricular free-wall rupture (VFWR) is an infrequent but catastrophic complication of acute myocardial infarction (AMI). Most reports about outcome after surgical treatment are single-center experiences. We examined the early and mid-term outcomes after surgical repair of post-AMI VFWR using the Netherlands Heart Registration (NHR) database. Methods: We included data from NHR patients (>18 years old) who underwent surgery for post-AMI VFWR between 2014 and 2019. The primary end-point was in-hospital mortality. Secondary outcomes included postoperative complications and mid-term survival. Results: The study included 148 patients (54.7% male, mean age 66.5±11.1 years). Critical preoperative status was found in 62.6% of subjects. In-hospital mortality was 31.1% (46 of 148). Multivariable analysis identified female sex [odds ratio (OR), 5.49; 95% confidence interval (CI): 2.24–13.46] and critical preoperative status (OR, 4.06; 95% CI: 1.36–12.13) as independent predictors of in-hospital mortality. The overall median postoperative follow-up was 2.2 (interquartile range, 0.7–3.8) years. Overall survival rates at three and five years were 58.9% and 55.7%, respectively. Among hospital survivors, only 15 (14.7%) patients died during follow-up, with a five-year survival rate of 80.8%. Conclusions: In-hospital mortality after surgical repair of post-AMI VFWR is considerable. Female sex and preoperative critical status are independent predictors of early postoperative (in-hospital) death. Logistic EuroSCORE I can reliably predict in-hospital mortality (optimal cut-off >33%). Mid-term follow-up of patients surviving in-hospital course shows excellent results

3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo

In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate, Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT 1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents

Bacterial communities associated with the wood-feeding gastropod <i>Pectinodonta</i> sp. (Patellogastropoda, Mollusca)

Even though their occurrence was reported a long time ago, sunken wood ecosystems at the deep-sea floor have only recently received specific attention. Accumulations of wood fragments in the deep sea create niches for a diverse fauna, but the significance of the wood itself as a food source remains to be evaluated. Pectinodonta sp. is a patellogastropod that exclusively occurs on woody substrates, where individuals excavate deep depressions, and is thus a potential candidate for a wood-eating lifestyle. Several approaches were used on Pectinodonta sampled close to Tongoa island (Vanuatu) to investigate its dietary habits. Host carbon is most likely derived from the wood material based on stable isotopes analyses, and high cellulase activity was measured in the digestive mass. Electron microscopy and FISH revealed the occurrence of two distinct and dense bacterial communities, in the digestive gland and on the gill. Gland-associated 16S rRNA gene bacterial phylotypes, confirmed by in situ hybridization, included members of three divisions (Alpha- and Gammaproteobacteria, Bacteroidetes), and were moderately related (90–96% sequence identity) to polymer-degrading and denitrifying bacteria. Gill-associated phylotypes included representatives of the Delta- and Epsilonproteobacteria. The possible involvement of these two bacterial communities in wood utilization by Pectinodonta sp. is discussed

Are shallow-water shrimps proxies for hydrothermal-vent shrimps to assess the impact of deep-sea mining?

Polymetallic seafloor massive sulphide deposits are potential targets for deep-sea mining, but high concentrations of metals (including copper - Cu) may be released during exploitation activities, potentially inducing harmful impact. To determine whether shallow-water shrimp are suitable ecotoxicological proxies for deep-sea hydrothermal vent shrimp the effects of waterborne Cu exposure (3 and 10 days at 0.4 and 4 μM concentrations) in Palaemon elegans, Palaemon serratus, and Palaemon varians were compared with Mirocaris fortunata. Accumulation of Cu and a set of biomarkers were analysed. Results show different responses among congeneric species indicating that it is not appropriate to use shallow-water shrimps as ecotoxicological proxies for deep-water shrimps. During the evolutionary history of these species they were likely subject to different chemical environments which may have induced different molecular/biochemical adaptations/tolerances. Results highlight the importance of analysing effects of deep-sea mining in situ and in local species to adequately assess ecotoxicological effects under natural environmental conditions.This work was developed under the MIDAS project (Managing im-pacts of deep-sea resource exploitation), funded by the EuropeanCommission, European Union, 7th Framework Programme under thetheme“Sustainable management of Europe's deep sea and sub-seafloorresources”(Grant Agreement 603418). This work was also supported bythe Fundação para a Ciência e Tecnologia I.P. Portugal (FCT) and theDireção-Geral de Política do Mar (DGPM), Portugal through the projectMining2/2017/001–MiningImpact 2 (JPI Oceans), and FCT furtherfunded the grants CEECIND005262017 and UID/MAR/00350/2013.We acknowledge the captains and crews of the oceanographic ship“Pourquoi Pas?”, and the pilots of Victor 6000 Remotely OperatedVehicle, for their dedicated assistance during sampling of vent shrimps.We are also grateful to F. Lallier, chief scientist of the Biobaz cruise. Wewould like to warmly thank Océanopolis staffmembers, J-M Carré, SDelaporte and O Gouello, for their important contributions to shrimpmaintenance.info:eu-repo/semantics/publishedVersio

HIV-1 Protease and Reverse Transcriptase Control the Architecture of Their Nucleocapsid Partner

The HIV-1 nucleocapsid is formed during protease (PR)-directed viral maturation, and is transformed into pre-integration complexes following reverse transcription in the cytoplasm of the infected cell. Here, we report a detailed transmission electron microscopy analysis of the impact of HIV-1 PR and reverse transcriptase (RT) on nucleocapsid plasticity, using in vitro reconstitutions. After binding to nucleic acids, NCp15, a proteolytic intermediate of nucleocapsid protein (NC), was processed at its C-terminus by PR, yielding premature NC (NCp9) followed by mature NC (NCp7), through the consecutive removal of p6 and p1. This allowed NC co-aggregation with its single-stranded nucleic-acid substrate. Examination of these co-aggregates for the ability of RT to catalyse reverse transcription showed an effective synthesis of double-stranded DNA that, remarkably, escaped from the aggregates more efficiently with NCp7 than with NCp9. These data offer a compelling explanation for results from previous virological studies that focused on i) Gag processing leading to nucleocapsid condensation, and ii) the disappearance of NCp7 from the HIV-1 pre-integration complexes. We propose that HIV-1 PR and RT, by controlling the nucleocapsid architecture during the steps of condensation and dismantling, engage in a successive nucleoprotein-remodelling process that spatiotemporally coordinates the pre-integration steps of HIV-1. Finally we suggest that nucleoprotein remodelling mechanisms are common features developed by mobile genetic elements to ensure successful replication

Discontinuation of Pneumocystis jirovecii Pneumonia Prophylaxis with CD4 Count <200 Cells/µL and Virologic Suppression: A Systematic Review

HIV viral load (VL) is currently not part of the criteria for Pneumocystis jirovecii pneumonia (PCP) prophylaxis discontinuation, but suppression of plasma viremia with antiretroviral therapy may allow for discontinuation of PCP prophylaxis even with CD4 count <200 cells/µL.A systematic review was performed to determine the incidence of PCP in HIV-infected individuals with CD4 count <200 cells/µL and fully suppressed VL on antiretroviral therapy but not receiving PCP prophylaxis.Four articles examined individuals who discontinued PCP prophylaxis with CD4 count <200 cells/µL in the context of fully suppressed VL on antiretroviral therapy. The overall incidence of PCP was 0.48 cases per 100 person-years (PY) (95% confidence interval (CI) (0.06-0.89). This was lower than the incidence of PCP in untreated HIV infection (5.30 cases/100 PY, 95% CI 4.1-6.8) and lower than the incidence in persons with CD4 count <200 cells/µL, before the availability of highly active antiretroviral therapy (HAART), who continued prophylaxis (4.85/100 PY, 95% CI 0.92-8.78). In one study in which individuals were stratified according to CD4 count <200 cells/µL, there was a greater risk of PCP with CD4 count ≤100 cells/µL compared to 101-200 cells/µL.Primary PCP prophylaxis may be safely discontinued in HIV-infected individuals with CD4 count between 101-200 cells/µL provided the VL is fully suppressed on antiretroviral therapy. However, there are inadequate data available to make this recommendation when the CD4 count is ≤100 cells/µL. A revision of guidelines on primary PCP prophylaxis to include consideration of the VL is merited