Target Cell APOBEC3C Can Induce Limited G-to-A Mutation in HIV-1

The evolutionary success of primate lentiviruses reflects their high capacity to mutate and adapt to new host species, immune responses within individual hosts, and, in recent years, antiviral drugs. APOBEC3G (A3G) and APOBEC3F (A3F) are host cell DNA-editing enzymes that induce extensive HIV-1 mutation that severely attenuates viral replication. The HIV-1 virion infectivity factor (Vif), expressed in vivo, counteracts the antiviral activity of A3G and A3F by inducing their degradation. Other APOBECs may contribute more to viral diversity by inducing less extensive mutations allowing viral replication to persist. Here we show that in APOBEC3C (A3C)-expressing cells infected with the patient-derived HIV-1 molecular clones 210WW, 210WM, 210MW, and 210MM, and the lab-adapted molecular clone LAI, viral G-to-A mutations were detected in the presence of Vif expression. Mutations occurred primarily in the GA context and were relatively infrequent, thereby allowing for spreading infection. The mutations were absent in cells lacking A3C but were induced after transient expression of A3C in the infected target cell. Inhibiting endogenous A3C by RNA interference in Magi cells prevented the viral mutations. Thus, A3C is necessary and sufficient for G-to-A mutations in some HIV-1 strains. A3C-induced mutations occur at levels that allow replication to persist and may therefore contribute to viral diversity. Developing drugs that inhibit A3C may be a novel strategy for delaying viral escape from immune or antiretroviral inhibition

Impact of entrepreneurial programs on master’s degree students at ISAAS considering the long-term perspective

The main objective of this research is to analyze the impact and effects of formal teaching of entrepreneurial programs on master’s degree students at the High Institute of Business Administration of Sfax (ISAAS) in Tunisia considering the long-term perspective. The study focused on two main aspects of impact when considering: * Entrepreneurial intention and profile of participants (Krueger et Brazeal, 1994 ; Krueger et al, 2000; Tounés, 2001); * Life career of these participants by examining how they have transferred their knowledge to their professional work (according to literature on learning transfer, Phillips, 1997; Baldwin & Ford, 1988). Empirically, the findings show that programs offered by Entrepreneurship’s Professional Master (EPM) have a positive impact on entrepreneurial intention and profiles of participants. Then, entrepreneurship’s master alumni how have find a job have transferred what they have learned on their works. Therefore, individual factors such as individual motivation and self-efficacy are the most stimulators of learning transfer. Finally, learning transfer has led to individual performance

Pharmacological inhibitors of the cystic fibrosis transmembrane conductance regulator exert off-target effects on epithelial cation channels

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel and the epithelial Na+ channel (ENaC) play essential roles in transepithelial ion and fluid transport in numerous epithelial tissues. Inhibitors of both channels have been important tools for defining their physiological role in vitro. However, two commonly used CFTR inhibitors, CFTRinh-172 and GlyH-101, also inhibit non-CFTR anion channels, indicating they are not CFTR specific. However, the potential off-target effects of these inhibitors on epithelial cation channels has to date not been addressed. Here, we show that both CFTR blockers, at concentrations routinely employed by many researchers, caused a significant inhibition of store-operated calcium entry (SOCE) that was time-dependent, poorly reversible and independent of CFTR. Patch clamp experiments showed that both CFTRinh-172 and GlyH-101 caused a significant block of Orai1-mediated whole cell currents, establishing that they likely reduce SOCE via modulation of this Ca2+ release-activated Ca2+ (CRAC) channel. In addition to off-target effects on calcium channels, both inhibitors significantly reduced human αβγ-ENaC-mediated currents after heterologous expression in Xenopus oocytes, but had differential effects on δβγ-ENaC function. Molecular docking identified two putative binding sites in the extracellular domain of ENaC for both CFTR blockers. Together, our results indicate that caution is needed when using these two CFTR inhibitors to dissect the role of CFTR, and potentially ENaC, in physiological processes

Production of H2 by water radiolysis in cement paste under electron irradiation: A joint experimental and theoretical study

International audienceLong-term confinement of nuclear waste is one of the main challenges faced by the nuclear industry. Fission products such as 90 Sr and 137 Cs, both β − emitters known to induce serious health hazards, represent the largest fraction of nuclear waste. Cement is a good candidate to store them, provided it can resist the effects of irradiation over time. Here, we have investigated the effects of β − decay on cement by performing electron irradiation experiments on different samples. We show that H 2 production in cement, the main effect of water radiolysis, depends strongly on composition and relative humidity. First-principles calculations indicate that the water-rich interlayer regions with Ca 2+ ions act as electron traps that promote the formation of H 2. They also show that holes localize in water-rich regions in low Ca content samples and are then able to participate in H 2 production. This work provides new understanding of radiolysis effects in cements

Text Recognition in Multimedia Documents: A Study of two Neural-based OCRs Using and Avoiding Character Segmentation

International audienceText embedded in multimedia documents represents an important semantic information that helps to automatically access the content. This paper proposes two neural-based OCRs that handle the text recognition problem in different ways. The first approach segments a text image into individual characters before recognizing them, while the second one avoids the segmentation step by integrating a multi-scale scanning scheme that allows to jointly localize and recognize characters at each position and scale. Some linguistic knowledge is also incorporated into the proposed schemes to remove errors due to recognition confusions. Both OCR systems are applied to caption texts embedded in videos and in natural scene images and provide outstanding results showing that the proposed approaches outperform the state-of-the-art methods

N-terminal β-strand underpins biochemical specialization of an ATG8 isoform

Autophagy-related protein 8 (ATG8) is a highly conserved ubiquitin-like protein that modulates autophagy pathways by binding autophagic membranes and a number of proteins, including cargo receptors and core autophagy components. Throughout plant evolution, ATG8 has expanded from a single protein in algae to multiple isoforms in higher plants. However, the degree to which ATG8 isoforms have functionally specialized to bind distinct proteins remains unclear. Here, we describe a comprehensive protein-protein interaction resource, obtained using in planta immunoprecipitation (IP) followed by mass spectrometry (MS), to define the potato ATG8 interactome. We discovered that ATG8 isoforms bind distinct sets of plant proteins with varying degrees of overlap. This prompted us to define the biochemical basis of ATG8 specialization by comparing two potato ATG8 isoforms using both in vivo protein interaction assays and in vitro quantitative binding affinity analyses. These experiments revealed that the N-terminal β-strand-and, in particular, a single amino acid polymorphism-underpins binding specificity to the substrate PexRD54 by shaping the hydrophobic pocket that accommodates this protein's ATG8-interacting motif (AIM). Additional proteomics experiments indicated that the N-terminal β-strand shapes the broader ATG8 interactor profiles, defining interaction specificity with about 80 plant proteins. Our findings are consistent with the view that ATG8 isoforms comprise a layer of specificity in the regulation of selective autophagy pathways in plants

Is there any advantage to combined trastuzumab and chemotherapy in perioperative setting her 2neu positive localized gastric adenocarcinoma?

We report here a 44-year-old Moroccan man with resectable gastric adenocarcinoma with overexpression of human epidermal growth factor receptor 2 (HER2) by immunohistochemistry who was treated with trastuzumab in combination with chemotherapy in perioperative setting. He received 3 cycles of neoadjuvant chemotherapy consisting of trastuzumab, oxaliplatin, and capecitabine. Afterwards, he received total gastrectomy with extended D2 lymphadenectomy without spleno-pancreatectomy. A pathologic complete response was obtained with a combination of trastuzumab and oxaliplatin and capecitabine. He received 3 more cycles of trastuzumab containing regimen postoperatively

Low Levels of Influenza Vaccine Uptake among the Diabetic Population in Spain: A Time Trend Study from 2011 to 2020

Background: In this work, we aim to describe influenza vaccine uptake among the diabetic population in Spain to assess the time trend from 2011 to 2020 and identify predictors of vaccine uptake among diabetes patients. (2) Methods: We conducted a descriptive cross-sectional study using the European Health Interview Survey for Spain (2014 and 2020) and the Spanish National Health Surveys (2011 and 2017). The independent variables analysed included socio-demographic characteristics, health-related variables and lifestyle variables. We matched each participant with diabetes with a non-diabetic participant based on age, sex, place of residence and year of survey. (3) Results: The overall coverage among diabetic adults was 52.1% compared to 40.6% for matched participants without diabetes (p < 0.01). The vaccine uptake among adults with diabetes was 52.6% in 2011, 54.38% in 2014 and 53.4% in 2017. The adjusted OR of having been vaccinated in 2020, with respect to 2011, was not significant at 0.87 (95% CI: 0.72–1.06). Factors such as being male, higher age, being affected by respiratory disease or cancer and being physically active were identified as positive predictors for influenza vaccination uptake, while smoking was a negative predictor. (4) Conclusions: The influenza vaccine uptake is below desirable levels among the adult diabetic population in Spain and has not improved from 2011 to 2020. More efforts should be made to increase influenza vaccine uptake in this high-risk group, especially for women, those aged 18–64 years, without other high-risk conditions and smokers

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

An overview of the approaches for automotive safety integrity levels allocation

YesISO 26262, titled Road Vehicles–Functional Safety, is the new automotive functional safety standard for passenger vehicle industry. In order to accomplish the goal of designing and developing dependable automotive systems, ISO 26262 uses the concept of Automotive Safety Integrity Levels (ASILs), the adaptation of Safety Integrity Levels. ASILs are allocated to the components and subsystems that can cause system failure and malfunctions that lead to hazards. ASILs allocation is a hard problem consists of finding the optimal allocation of safety levels to the system architecture which must guarantee that the highest safety requirements are met while development cost of the automotive system is kept minimum. There were many successful attempts to solve this problem using different techniques. However, it is worth pointing out that there is an absence of a review that provides an in-depth study of all the existing methods and highlights their merits and demerits. This paper presents an overview of different approaches that were used to solve ASILs allocation problem. The review provides an overview of safety requirements including the related standards followed by a study of the resolution methods of the existing approaches. The study of each approach provides a detailed explanation of the used methodology and a discussion of its strength and weaknesses including the main open challenges