Viral protein R (Vpr), an apoptogenic accessory protein encoded by HIV-1, induces mitochondrial membrane permeabilization (MMP) via a specific interaction with the permeability transition pore ...complex, which comprises the voltage-dependent anion channel (VDAC) in the outer membrane (OM) and the adenine nucleotide translocator (ANT) in the inner membrane. Here, we demonstrate that a synthetic Vpr-derived peptide (Vpr52-96) specifically binds to the intermembrane face of the ANT with an affinity in the nanomolar range. Taking advantage of this specific interaction, we determined the role of ANT in the control of MMP. In planar lipid bilayers, Vpr52-96 and purified ANT cooperatively form large conductance channels. This cooperative channel formation relies on a direct protein–protein interaction since it is abolished by the addition of a peptide corresponding to the Vpr binding site of ANT. When added to isolated mitochondria, Vpr52-96 uncouples the respiratory chain and induces a rapid inner MMP to protons and NADH. This inner MMP precedes outer MMP to cytochrome c. Vpr52-96–induced matrix swelling and inner MMP both are prevented by preincubation of purified mitochondria with recombinant Bcl-2 protein. In contrast to König's polyanion (PA10), a specific inhibitor of the VDAC, Bcl-2 fails to prevent Vpr52-96 from crossing the mitochondrial OM. Rather, Bcl-2 reduces the ANT–Vpr interaction, as determined by affinity purification and plasmon resonance studies. Concomitantly, Bcl-2 suppresses channel formation by the ANT–Vpr complex in synthetic membranes. In conclusion, both Vpr and Bcl-2 modulate MMP through a direct interaction with ANT.
Abstract Recombinant modified vaccinia virus Ankara (rMVA) expressing HIV-1 genes are promising vaccine candidates. Toward the goal of conducting clinical trials with one or a cocktail of recombinant ...viruses, four rMVAs expressing env and gag-pol genes from primary HIV-1 isolates representing predominant subtypes from Kenya, Tanzania, Uganda, and Thailand (A, C, D, and CRF01_AE, respectively) were constructed. Efficient expression, processing, and function of Env and Gag were demonstrated. All inserted genes were shown to be genetically stable after repeated passage in cell culture. Strong HIV-specific cellular and humoral immune responses were elicited in mice immunized with each individual vaccine candidate. The MVA/CMDR vaccine candidate expressing CRF01_AE genes has elicited HIV-specific T-cell responses in two independent Phase I clinical trials. Further testing of the other rMVA is warranted.
In this paper, we show performance and reliability improvement of Ag- rm GeS 2 -based conductive bridge RAM (CBRAM) devices by addition of a 2-nm-thick rm HfO 2 layer between the electrolyte and the ...W bottom electrode. Our optimized dual-layer electrolyte stack (2-nm rm HfO 2 hbox - - 30 hbox - rm nm ~ rm GeS 2 ) leads to a resistance ratio ( R rm OFF / R rm ON ) higher than 10 6 and projected 10 years read disturb immunity at 0.04 V. The improved memory resistance ratio is explained by means of physical modeling. Using compact modeling and circuit level simulations, we show that our optimized CBRAM device, integrated in a 1T-2R architecture, fits well with the aggressive requirements of field programmable gate array-type reconfigurable applications. Nonvolatility, back-end-of-line compatibility, and 1.3-nA leakage current during continuous reverse read operation at 1 V are strong benefits demonstrated on our device for such applications.
Background: Aminoglycosides are the most prescribed antibiotics in neonatal intensive care units (NICU). Reducing exposure to antibiotics in the NICU is highly desirable, particularly through ...benchmarking methods. Methods: Description of aminoglycosides prescriptions in 23 French NICU using the same computerized system over a 4-year period (2017–2020). A benchmarking program of antibiotics prescription was associated. Results: The population included 53,818 patients. Exposition rates to gentamicin and amikacin were 31.7% (n = 17,049) and 9.1% (n = 4894), respectively. Among neonates exposed to gentamicin, 90.4% of gentamicin and 77.6% of amikacin treatments were started within the 1st week of life. Among neonates exposed to amikacin, 77.6% started amikacin within the 1st week. The average daily dose of gentamicin at first prescription increased over the study period from 3.9 in 2017 to 4.4 mg/kg/d in 2020 (p < 0.0001). Conversely, the corresponding amikacin daily doses decreased from 13.0 in 2017 to 12.3 mg/kg/d in 2020 (p = 0.001). The time interval between the first 2 doses of gentamicin was mainly distributed in 3 values during the first week of life: 49.4% at 24 h, 26.4% at 36 h, and 22.9% at 48 h. At first amikacin prescription, the time interval was distributed in 4 categories: 48% at 24 h, 4.1% at 30 h, 8.5% at 36 h, and 37.1% at 48 h. As compared to literature guidelines, the rates of overdose and underdose in gentamicin (1.5% and 2.7%) and amikacin (0.3% and 1.0%). They significantly decreased for gentamicin over the study period. In multivariate analysis, the factors significantly associated with GENT overdose were the year of admission, prematurity, length of stay, and duration of the treatment. Conclusion: This prescription strategy ensured a low rate of overdose and underdose, and some benefits of the benchmarking program is suggested.
Archeological studies have demonstrated that many Prehistoric artefacts in obsidian found in the Near East have a chemical affinity with obsidian outcropping in the Nemrut volcano. In the ...archaeological literature, Mount Nemrut is considered as one of the most important obsidian sources used by prehistoric societies. During our two field works in 2013 and 2014, we prospected a wide area on and around Nemrut volcano. Our findings confirm the location of the obsidian outcrops described in the literature. According to our observation, obsidian on Mount Nemrut volcano is generally not exploitable for chopping tools. Most of the studied obsidians we defined on the field, present a facies with numerous phenocrysts and cracks, which is not compatible with a good knapping quality. However, we identified a new outcrop associated with obsidian artefacts such as nuclei and rough flakes. Geological samples of the obsidian from this outcrop present all a very different facies compare to those of others Mount Nemrut obsidians: obsidian from this area does not show any phenocryst or cracks, and they are very homogeneous and uniform. These characteristics are in favor to knapping criteria. Comparatively to the other known obsidian outcrops in the Nemrut volcano, we can assume here that this obsidian outcrop is, to date, the only source one that could have been exploited, by Prehistoric people on the Nemrut volcano. Our work, using chemical analyzes (LA-ICP-MS), petrology and field observation enhances characteristics for workable obsidian that depends on the modality of emplacement. This last one should have been different from the other outcrops to provide a different facies.
Dans de nombreux sites du Proche-Orient, des artefacts archéologiques en obsidienne ont été retrouvés et attribués aux sources géologiques du Nemrut. Les publications sur la géologie du Nemrut montrent que des affleurements d’obsidienne sont présents sur les flancs sud, est, ouest et nord du volcan. Lors de deux missions de terrain (2013, 2014), nous avons prospecté une large partie du volcan et repéré les affleurements décrits dans la littérature ; notre prospection n’a cependant pas été exhaustive. La grande majorité des obsidiennes étudiées présente en effet un faciès à phénocristaux et craquelures marquant une piètre qualité pour la taille. De plus, une grande partie de ces obsidiennes affleure sous forme de lits de faible épaisseur, ne permettant pas leur exploitation. Nous avons localisé un seul affleurement d’obsidienne taillable. Associé à un atelier de taille, son faciès, très différent de celui rencontré ailleurs dans le volcan, est uni et homogène, sans phénocristaux ni craquelures. Ces caractéristiques sont compatibles avec la taille pour la confection d’objets. Cet affleurement n’a jamais été décrit dans la littérature. Comparativement aux autres affleurements d’obsidienne connus aujourd’hui, nous pouvons affirmer que cet affleurement d’obsidienne homogène est le seul taillable connu sur le volcan Nemrut. À partir des données de terrain, de l’étude des faciès, d’analyses chimiques en LA-ICP-MS et d’une étude pétrologique, nous pouvons émettre deux hypothèses concernant les modalités de mise en place d’un affleurement exploitable repéré. Ces modalités en effet ont un rapport étroit avec l’accessibilité de la ressource et de ces espaces pour l’homme de la Préhistoire (du Paléolithique au Chalcolithique).
Importance
Compared with term-born peers, children born very preterm generally perform poorly in executive functions, particularly in working memory and inhibition. By taking advantage of ...neuroplasticity, computerized cognitive training of working memory in those children could improve visuospatial processing by boosting visual inhibition via working memory.
Objective
To evaluate the long-term effect of cognitive working memory training on visuospatial processing in children aged 5½ to 6 years born very preterm who have working memory impairment.
Design, Setting, and Participants
This multicenter (18 French university hospitals), open-label randomized clinical trial with 2 parallel groups (EPIREMED) was conducted from November 2016 to April 2018, with the last follow-up during August 2019. Eligible children from the EPIPAGE 2 cohort were aged 5½ to 6 years, were born between 24 and 34 weeks’ gestation, and had a global intelligence quotient greater than 70 and a working memory index less than 85. Data were analyzed from February to December 2020.
Intervention
Children were randomized 1:1 to standard care management and a working memory cognitive training program (Cogmed software) for 8 weeks (25 sessions) (intervention) or to standard management (control).
Main Outcomes and Measures
The primary outcome was the visuospatial index score from the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition. Secondary outcomes were working memory, intellectual functioning, executive and attention processes, language skills, behavior, quality of life, and schooling. Neurobehavioral assessments were performed at inclusion and after finishing training at 6 months (intermeditate assessment; secondary outcomes) and at 16 months (final assessment; primary outcome).
Results
There were 169 children randomized, with a mean (SD) age of 5 years 11 months (2 months); 91 (54%) were female. Of the participants, 84 were in the intervention group (57 of whom 68% completed at least 15 cognitive training sessions) and 85 were in the control group. The posttraining visuospatial index score was not different between groups at a mean (SD) of 3.0 (1.8) months (difference, −0.6 points; 95% CI, −4.7 to 3.5 points) or 12.9 (2.6) months (difference, 0.1 points; 95% CI, −5.4 to 5.1 points). The working memory index score in the intervention group significantly improved from baseline at the intermediate time point (difference, 4.7 points; 95% CI, 1.2-8.1 points), but this improvement was not maintained at the final assessment.
Conclusions and Relevance
This randomized clinical trial found no lasting effect of a cognitive training program on visuospatial processing in children aged 5½ to 6 years with working memory disorders who were born very preterm. The findings suggest that this training has limited long-term benefits for improving executive function. Transient benefits seemed to be associated with the developmental state of executive functions.
Trial Registration
ClinicalTrials.gov Identifier:
NCT02757794
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