Reverse Docking on Five Original PPO Structures: Plant, Bacterial, and Human

Protoporphyrinogen oxidase has known remarkable interest in biochemical studies, it is considered a perfect target for the development of new herbicides. PPO herbicides have been developed for more than forty years, and research on this enzyme remains until today, to find new more effective herbicides. In this work, we investigated the inhibitory activity of a compound derived from N-phenylphthalimide with the highest inhibitory activity among a series of 29 molecules, on five PPO structures from various origins, including Plant origin, bacterial, and human, we have based on Reverse Docking, to know the affinity between the inhibitor and the five targets, and the different ligand-receptor interactions. As well as Molecular Dynamics. Interesting results have been obtained, which may help us to discover new targets concerning herbicides

Evolución de parámetros bíométricos y composición química de aceitunas de la variedad Picholine marroquí durante la maduración del fruto

The evolution of the maturity index during the ripeness of olives from the Moroccan Picholine variety did not show any significant variation before the middle of September. After this date it began the growing and reached the maximum value (4.7) at the middle of January. The weight of olives increased continuously from June to November, and remained constant over two months beyond the maximal value of 3.95g (November and December). The weight of the olive kernels was constant during all the sampling period. The olive dimensions (length and width) showed similar trend as the olive weight. The polar lipid fraction of the oil predominated over the neutral one during June and July and after this date, the neutral fraction prevailed. The maximum value was reached in December. The protein content decreased from 4.6 to 2.3%. Ash content grow from 2.72 to 5.57%. The chlorophyll content in the oils decrease progressively and showed an inverse correlation with the maturity index. The phosphorus content diminished until September and then continued to be constant.La evolución del índice de madurez durante la maduración de aceitunas de la variedad Picholine marroquí no mostró variación significativa antes de mediados de septiembre. Después de esta fecha comenzó el crecimiento y alcanzó su valor máximo (4.7) a mediados de enero. El peso de las aceitunas aumentó continuamente desde junio hasta noviembre y se estabilizó durante dos meses más allá del valor máximo de 3.95g (noviembre y diciembre). El peso del hueso de las aceitunas permaneció constante durante todo el período de muestreo. Las dimensiones de las aceitunas (longitud y anchura) tuvieron tendencias similares a las del peso de la aceituna. La fracción lipídica polar del aceite predominó sobre la neutra durante los meses de junio y julio, para después de esta fecha prevalecer la fracción neutra alcanzando su valor máximo en el mes de diciembre. El contenido en proteína disminuyó de 4.6 a 2.3%. El contenido en ceniza aumentó de 2.72 a 5.57%. El contenido en clorofila en los aceites disminuyó progresivamente y mostró una correlación inversa con el índice de madurez. El contenido en fósforo disminuyó hasta septiembre y luego se conservó constante

3D-QSAR, molecular docking, molecular dynamic simulation, and ADMET study of bioactive compounds against candida albicans

Candida albicans has developed significant levels of resistance to traditional antifungals, posing a danger to world health. In this research, the potential inhibitory of a class of twenty-five triazole molecules revealed an activity against candida albicans was addressed by using the three dimensional quantitative structure-activity relationship approach. The reliable models developed by CoMFA and CoMSIA/SEA exhibited high values of Q2 (0.620 and 0.733) respectively, and notable values of R2 (0.840 and 0.890) respectively. CoMFA and CoMSIA/SEA contour maps bring a set of information that may be invested to identify the key sites that have an important influence on the candida albicans activity. These findings lead us to design four new triazole compounds with good predicted activity. The new triazole molecules were undergone to in-depth study by assessing their oral bioavailability and toxicity using in silico ADMET prediction. The new molecules T1, T2 and T3 exhibited good properties in terms of numerous pharmacokinetics parameters as absorption, BBB penetration and toxicity. In addition, molecular docking was conducted to identify the types and mode of interactions between triazole ligands and the receptors. The reached findings appeared the high stability of the new triazole scaffolds at the active site of the receptor (PDB code: 2Y7L). The molecule T1 which is exhibited good stability in the active pocket of the receptor was further subjected to a molecular dynamics (MD) simulation using 20 ns in order to scrutinize the protein's comparative conformational dynamics following ligand binding. MD simulation for 20 ns reveals promising results for the molecule T1

in silico studies of 1,4-disubstituted 1,2,3-triazole with amide functionality antimicrobial evaluation against Escherichia coli using 3D-QSAR, molecular docking, and ADMET properties

E. coli are microbes responsible for the development of urinary tract cancer in women, therefore, the discovery of new antimicrobial agents by computer chemistry allows to improve and provide the new compounds with antimicrobial activity, it is necessary to carry out a 3D-QSAR (quantitative three-dimensional structure-activity) study of antimicrobial analogues to study the validity of this study by statistical parameters. We established the 3D-QSAR model from the comparative analysis of the molecular field (CoMFA)and the comparative analysis of molecular similarity indices (CoMSIA), The most tabular modulus of which is obtained by the CoMFA model (Q2=0,71; R2=0.98; R=0.97) and the best comparative model of acceptor and hydrophobic molecular similarity indices (CoMSIA /AH) (Q2=0.69; R2 = 0.96; R =0.94). To test the validity of the two models, we need to compute the SEE, t-F and their y-randomization for the training set, and the parameters of k. Roy de A. Golbraikh, A. Tropsha for the test set. The CoMFA model analysis shows that the activity of the antimicrobial molecules in our study is influenced by the steric effect and by the acceptor effect of hydrogen for the CoMSIA/AH model, in particular the molecular docking results we show that the interest of amino acids has a direct influence on antimicrobial activity, based on this result we have proposed 4 molecules with antimicrobial activity. These molecules are tested by analyzing their ADMET properties and their drug similarity

Incentivizing the Use of Quantified Self Devices: The Cases of Digital Occupational Health Programs and Data-Driven Health Insurance Plans

Initially designed for a use in private settings, smartwatches, activity trackers and other quantified self devices are receiving a growing attention from the organizational environment. Firms and health insurance companies, in particular, are developing digital occupational health programs and data-driven health insurance plans centered around these systems, in the hope of exploiting their potential to improve individual health management, but also to gather large quantities of data. As individual participation in such organizational programs is voluntary, organizations often rely on motivational incentives to prompt engagement. Yet, little is known about the mechanisms employed in organizational settings to incentivize the use of quantified self devices. We therefore seek, in this exploratory paper, to offer a first structured overview of this topic and identify the main motivational incentives in two emblematical cases: digital occupational health programs and data-driven health insurance plans. By doing so, we aim to specify the nature of this new dynamic around the use of quantified self devices and define some of the key lines for further investigation

Dynamics of Genome Rearrangement in Bacterial Populations

Genome structure variation has profound impacts on phenotype in organisms ranging from microbes to humans, yet little is known about how natural selection acts on genome arrangement. Pathogenic bacteria such as Yersinia pestis, which causes bubonic and pneumonic plague, often exhibit a high degree of genomic rearrangement. The recent availability of several Yersinia genomes offers an unprecedented opportunity to study the evolution of genome structure and arrangement. We introduce a set of statistical methods to study patterns of rearrangement in circular chromosomes and apply them to the Yersinia. We constructed a multiple alignment of eight Yersinia genomes using Mauve software to identify 78 conserved segments that are internally free from genome rearrangement. Based on the alignment, we applied Bayesian statistical methods to infer the phylogenetic inversion history of Yersinia. The sampling of genome arrangement reconstructions contains seven parsimonious tree topologies, each having different histories of 79 inversions. Topologies with a greater number of inversions also exist, but were sampled less frequently. The inversion phylogenies agree with results suggested by SNP patterns. We then analyzed reconstructed inversion histories to identify patterns of rearrangement. We confirm an over-representation of “symmetric inversions”—inversions with endpoints that are equally distant from the origin of chromosomal replication. Ancestral genome arrangements demonstrate moderate preference for replichore balance in Yersinia. We found that all inversions are shorter than expected under a neutral model, whereas inversions acting within a single replichore are much shorter than expected. We also found evidence for a canonical configuration of the origin and terminus of replication. Finally, breakpoint reuse analysis reveals that inversions with endpoints proximal to the origin of DNA replication are nearly three times more frequent. Our findings represent the first characterization of genome arrangement evolution in a bacterial population evolving outside laboratory conditions. Insight into the process of genomic rearrangement may further the understanding of pathogen population dynamics and selection on the architecture of circular bacterial chromosomes

Week 48 resistance analyses of the once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) >= 400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL = 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response

Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1

Altres ajuts: This study was sponsored by Janssen.Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52-96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe