CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. CONCLUSIONS: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl

Special Issue on “fruit metabolism and metabolomics”

Over the past 10 years, knowledge about several aspects of fruit metabolism has been greatly improved. Notably, high-throughput metabolomic technologies have allowed quantifying metabolite levels across various biological processes, and identifying the genes that underly fruit development and ripening. This Special Issue is designed to exemplify the current use of metabolomics studies of temperate and tropical fruit for basic research as well as practical applications. It includes articles about different aspects of fruit biochemical phenotyping, fruit metabolism before and after harvest, including primary and specialized metabolisms, and bioactive compounds involved in growth and environmental responses. The effect of genotype, stages of development or fruit tissue on metabolomic profiles and corresponding metabolism regulations are addressed, as well as the combination of other omics with metabolomics for fruit metabolism studies. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.partly funded by MetaboHUB (ANR‐11‐INBS‐0010) and PHENOME (ANR‐11‐ INBS‐0012) French Agence Nationale de la Recherche projects. S.O. was parcially supported by grants RTI2018‐ 099797‐B‐100 (Ministerio de ciencia, Innovación y Universidades, Spain) and UMA18‐DEDERJA‐179 (Consejería de Economía, Conocimiento, Empresas y Universidades, Junta de Andalucía, Spain).Peer reviewe

Modeling the vacuolar storage of malate shed lights on pre- and post-harvest fruit acidity

Background: Malate is one of the most important organic acids in many fruits and its concentration plays a critical role in organoleptic properties. Several studies suggest that malate accumulation in fruit cells is controlled at the level of vacuolar storage. However, the regulation of vacuolar malate storage throughout fruit development, and the origins of the phenotypic variability of the malate concentration within fruit species remain to be clarified. In the present study, we adapted the mechanistic model of vacuolar storage proposed by Lobit et al. in order to study the accumulation of malate in pre and postharvest fruits. The main adaptation concerned the variation of the free energy of ATP hydrolysis during fruit development. Banana fruit was taken as a reference because it has the particularity of having separate growth and post-harvest ripening stages, during which malate concentration undergoes substantial changes. Moreover, the concentration of malate in banana pulp varies greatly among cultivars which make possible to use the model as a tool to analyze the genotypic variability. The model was calibrated and validated using data sets from three cultivars with contrasting malate accumulation, grown under different fruit loads and potassium supplies, and harvested at different stages. Results: The model predicted the pre and post-harvest dynamics of malate concentration with fairly good accuracy for the three cultivars (mean RRMSE = 0.25-0.42). The sensitivity of the model to parameters and input variables was analyzed. According to the model, vacuolar composition, in particular potassium and organic acid concentrations, had an important effect on malate accumulation. The model suggested that rising temperatures depressed malate accumulation. The model also helped distinguish differences in malate concentration among the three cultivars and between the pre and post-harvest stages by highlighting the probable importance of proton pump activity and particularly of the free energy of ATP hydrolysis and vacuolar pH. Conclusions: This model appears to be an interesting tool to study malate accumulation in pre and postharvest fruits and to get insights into the ecophysiological determinants of fruit acidity, and thus may be useful for fruit quality improvement. (Résumé d'auteur

Correlation Network Analysis reveals a sequential reorganization of metabolic and transcriptional states during germination and gene-metabolite relationships in developing seedlings of Arabidopsis

<p>Abstract</p> <p>Background</p> <p>Holistic profiling and systems biology studies of nutrient availability are providing more and more insight into the mechanisms by which gene expression responds to diverse nutrients and metabolites. Less is known about the mechanisms by which gene expression is affected by endogenous metabolites, which can change dramatically during development. Multivariate statistics and correlation network analysis approaches were applied to non-targeted profiling data to investigate transcriptional and metabolic states and to identify metabolites potentially influencing gene expression during the heterotrophic to autotrophic transition of seedling establishment.</p> <p>Results</p> <p>Microarray-based transcript profiles were obtained from extracts of Arabidopsis seeds or seedlings harvested from imbibition to eight days-old. ¹H-NMR metabolite profiles were obtained for corresponding samples. Analysis of transcript data revealed high differential gene expression through seedling emergence followed by a period of less change. Differential gene expression increased gradually to day 8, and showed two days, 5 and 7, with a very high proportion of up-regulated genes, including transcription factor/signaling genes. Network cartography using spring embedding revealed two primary clusters of highly correlated metabolites, which appear to reflect temporally distinct metabolic states. Principle Component Analyses of both sets of profiling data produced a chronological spread of time points, which would be expected of a developmental series. The network cartography of the transcript data produced two distinct clusters comprising days 0 to 2 and days 3 to 8, whereas the corresponding analysis of metabolite data revealed a shift of day 2 into the day 3 to 8 group. A metabolite and transcript pair-wise correlation analysis encompassing all time points gave a set of 237 highly significant correlations. Of 129 genes correlated to sucrose, 44 of them were known to be sucrose responsive including a number of transcription factors.</p> <p>Conclusions</p> <p>Microarray analysis during germination and establishment revealed major transitions in transcriptional activity at time points potentially associated with developmental transitions. Network cartography using spring-embedding indicate that a shift in the state of nutritionally important metabolites precedes a major shift in the transcriptional state going from germination to seedling emergence. Pair-wise linear correlations of transcript and metabolite levels identified many genes known to be influenced by metabolites, and provided other targets to investigate metabolite regulation of gene expression during seedling establishment.</p

Communication of pharmacogenetic research results to HIV-infected treated patients: standpoints of professionals and patients.

International audienceThe aim of pharmacogenetic studies is to adapt therapeutic strategies to individual genetic profiles, thus maximising their efficacy and minimising the likelihood of adverse side effects. Since the advent of personalised medicine, the issue of communicating research results to participants has become increasingly important. We addressed this question in the context of HIV infection, as patients and associations are particularly concerned by research and therapeutic advances. We explored the standpoints of both research professionals and participants involved in a pharmacogenetic study conducted in a cohort of HIV-infected patients. The setting of the research protocol was followed over a 2-year period. Participants' standpoints were collected through a questionnaire and interviews were conducted with research professionals. Of 125 participants, 76% wished to receive individual results and 71% wished to receive collective results; 39% did not know when results might be expected. Communication of global research results is a principle that is generally accepted by professionals. Concerning individual feedback, the professionals felt that it was necessary if it could be of direct benefit to the participant, but they expressed doubts for situations with no recognised benefit. Our results highlight the necessity to consider this issue in greater detail. We suggest the need to anticipate the debates concerning individual feedback, to differentiate between situations and the importance of further investigations on the opportunities and modalities of communication. Finally, our work emphasised the opposite pressures between the pursuit of scientific knowledge and the therapeutic orientation of clinical trials

Metabolite modifications in Solanum lycopersicum roots and leaves under cadmium stress

The effects of cadmium (Cd) were investigated on growth and metabolite profiling in roots and leaves of tomato (Solanum lycopersicum L., Var. Ibiza F1) plants exposed for 3 and 10 days to various CdCl2 concentrations (0 - 300 ìM). The aim of this study was to describe metabolite modifications in response to Cd stress and to identify Cd stress markers in the roots and leaves of tomato plants. During the treatment, Cd accumulated  significantly in the roots compared to stems and leaves. Plant growth (root, stem and leaf) decreased when Cd concentration increased. The analysis of 1H-NMR spectra of polar extracts showed clear differences between metabolites amounts (soluble sugars, organic and amino acids) in 30 and 300 ìM Cd-treated plants versus control ones. Among soluble sugars and organic acids, glucose, fructose and citrate contents significantly increased, by a factor 2 to 5 in both leaves and roots of Cd treated plants during the first three days of the treatment and then only in roots. In addition, Cd induced qualitative and quantitative changes in amino acid contents in the roots. Asparagine, glutamine and branched chain amino acids (valine, isoleucine, phenylalanine and tryptophane) significantly accumulated after 10 days of Cd exposure. Asparagine content which increased by 26 fold in the roots of 300 ìM Cd treated plants when compared with control ones, was found to be a good marker for Cd stress. In contrast, few modifications occurred in the leaves in response to Cd, except for tyrosine which content was highly increased (by 10 fold) after three days of treatment with 30 ìM. Taken together, our results show that, the exposure of tomato plants to various Cd concentrations results in significant changes in primary metabolism compounds, especially in the accumulation of some amino and organic acids involved in cellular compartmentation and detoxification of Cd.Key words: Cadmium, sugars, organic acids, amino acids, tomato (Solanum lycopersicum)

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human

Integrating Technical Standards into ET Curricula to Meet ABET Standards and Industry Needs

With technical standards affecting nearly every aspect of our daily lives, from computers to the components and materials used in car engines, it is critical that undergraduate students are educated on the importance of standards and provided with opportunities to locate and apply relevant technical standards to real world situations. In addition, with ABET accreditation requiring students to have a “basic understanding and familiarity with,” and experience “using” codes and standards, faculty need to consider how such material can be naturally integrated into the curriculum. At Purdue University, education about codes and standards has been integrated into the mechanical engineering technology (MET) curriculum for decades with significant success. This paper discusses how standards are incorporated into mechanical design and quality control courses, as well as strategies for integrating standards into more courses in an MET curriculum. In addition, a discussion of standards resources that are freely available is included. Finally, a call to action for industry is presented, explaining the need and potential areas where industry can increase involvement in teaching students about technical standards