Synthesis of 9-[1-(substituted)-3-(phosphonomethoxy)propyl]adenine derivatives as possible antiviral agents

Acyclic N9 adenine nucleosides substituted at C-1' position were prepared by the Mitsunobu reaction of 1-tert-butyldimethylsilyl-4-pivaloylbutan-1,2,4-triol (5) with adenine. Pivaloyl hydroxyl was modified to the phosphonomethoxy derivatives, and the tert-butyldimethylsilyl hydroxyl was converted to methoxy, azido, amino, fluoro, and c-hydroxyethyl and was eliminated to give vinyl. The resulting phosphonic acids were converted to prodrugs also.     

Factors affecting the adsorption of buchnericin LB,a bacteriocin produced by Lactobacillus [correction of Lactocobacillus] buchneri

Buchnericin-LB adsorbs to gram-positive but not to gram-negative bacteria. The tested gram-positive bacteria were species of Lactobacillus, Pediococcus, Leuconostoc, Enterococcus, Lactococcus, Listeria, Bacillus, Staphylococcus; gram-negative bacteria belonged to the genera Salmonella, Escherichia, Yersinia and Pseudomonas. Buchnericin-LB adsorption depended on pH but not on time and temperature. Also some anions of salts and lipoteichoic acid reduced or inhibited its adsorption. Treatment of cells and cell walls of sensitive bacteria with detergents, organic solvents or enzymes did not affect subsequent binding of buchnericin-LB. Treatment with buchnericin-LB caused sensitive cells to lose high amounts of intracellular K+ ions and UV-absorbing materials and became more permeable to o-nitrophenol-beta-D-galactopyranoside. Buchnericin-LB (640-2560 AU/ml) decreased the colony forming units (99%) and absorbance values of Listeria monocytogenes and Bacillus cereus. These results indicate that the mode of action of buchnericin-LB is bactericidal and its lethal effect is very rapid.     

Determining the Most Important Physiological and Agronomic Traits Contributing to Maize Grain Yield through Machine Learning Algorithms: A New Avenue in Intelligent Agriculture

Prediction is an attempt to accurately forecast the outcome of a specific situation while using input information obtained from a set of variables that potentially describe the situation. They can be used to project physiological and agronomic processes; regarding this fact, agronomic traits such as yield can be affected by a large number of variables. In this study, we analyzed a large number of physiological and agronomic traits by screening, clustering, and decision tree models to select the most relevant factors for the prospect of accurately increasing maize grain yield. Decision tree models (with nearly the same performance evaluation) were the most useful tools in understanding the underlying relationships in physiological and agronomic features for selecting the most important and relevant traits (sowing date-location, kernel number per ear, maximum water content, kernel weight, and season duration) corresponding to the maize grain yield. In particular, decision tree generated by C&RT algorithm was the best model for yield prediction based on physiological and agronomical traits which can be extensively employed in future breeding programs. No significant differences in the decision tree models were found when feature selection filtering on data were used, but positive feature selection effect observed in clustering models. Finally, the results showed that the proposed model techniques are useful tools for crop physiologists to search through large datasets seeking patterns for the physiological and agronomic factors, and may assist the selection of the most important traits for the individual site and field. In particular, decision tree models are method of choice with the capability of illustrating different pathways of yield increase in breeding programs, governed by their hierarchy structure of feature ranking as well as pattern discovery via various combinations of features.     

Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA

The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT and mTOR protein expression and exhibits robust cytotoxicity towards TNBC cells but not nontumorigenic normal breast epithelial cells. Mechanically, long noncoding RNA (lncRNA) {"type":"entrez-nucleotide","attrs":{"text":"AL354740","term_id":"15020744","term_text":"AL354740"}}AL354740.1-204 (also named as NUDT3-AS4) acts as a microRNA sponge to compete with AKT1/mTOR mRNAs for binding to miR-99s, leading to decrease in degradation of AKT1/mTOR mRNAs and subsequent increase in AKT1/mTOR protein expression. Inhibition of lncRNA-NUDT3-AS4 and suppression of the NUDT3-AS4/miR-99s association contribute to Comp34-affected biologic pathways. In addition, Comp34 alone is effective in cells with secondary resistance to rapamycin, the best-known inhibitor of mTOR, and displays a greater in vivo antitumor efficacy and lower toxicity than rapamycin in TNBC xenografted models. In conclusion, NUDT3-AS4 may play a proproliferative role in TNBC and be considered a relevant therapeutic target, and Comp34 presents promising activity as a single agent to inhibit TNBC through regulation of NUDT3-AS4 and miR-99s.Subject terms: Drug discovery, Diseases     

Regional Differences in Intervention Coverage and Health System Strength in Tanzania

Background

Assessments of subnational progress and performance coverage within countries should be an integral part of health sector reviews, using recent data from multiple sources on health system strength and coverage.

Method

As part of the midterm review of the national health sector strategic plan of Tanzania mainland, summary measures of health system strength and coverage of interventions were developed for all 21 regions, focusing on the priority indicators of the national plan. Household surveys, health facility data and administrative databases were used to compute the regional scores.

Findings

Regional Millennium Development Goal (MDG) intervention coverage, based on 19 indicators, ranged from 47% in Shinyanga in the northwest to 71% in Dar es Salaam region. Regions in the eastern half of the country have higher coverage than in the western half of mainland. The MDG coverage score is strongly positively correlated with health systems strength (r = 0.84). Controlling for socioeconomic status in a multivariate analysis has no impact on the association between the MDG coverage score and health system strength. During 1991–2010 intervention coverage improved considerably in all regions, but the absolute gap between the regions did not change during the past two decades, with a gap of 22% between the top and bottom three regions.

Interpretation

The assessment of regional progress and performance in 21 regions of mainland Tanzania showed considerable inequalities in coverage and health system strength and allowed the identification of high and low-performing regions. Using summary measures derived from administrative, health facility and survey data, a subnational picture of progress and performance can be obtained for use in regular health sector reviews.     

Khat Chewing Habits in the Population of the Jazan Region,Saudi Arabia: Prevalence and Associated Factors

The use of khat (Catha edulis) is a major public health and social problem that is believed to be growing globally. The khat chewing habit is prevalent in all areas of the Jazan region, Kingdom of Saudi Arabia (KSA). However, few studies have been conducted at the community level to investigate the khat chewing habits in this area. This study was conducted with the aim of assessing the prevalence and predictors of khat chewing among the Jazan community population. A cross-sectional study was conducted with a sample (n = 4,500) of the Jizani population who attended primary heath care centers in Jazan region. The participants were selected using a two-stage cluster random sampling. A structured questionnaire was used for data collection. The overall lifetime prevalence of khat chewing was 33.2% (95% CI 31.8–34.7) and was significantly higher for males 42.2% (95% CI 40.4–43.9) than for females 11.3% (95% CI 9.6–13.1) (P < 0.001). Current khat chewers accounted for 28.7% (95% CI 27.4–30.1) of the population sampled; 36.9% (95% CI 35.2–38.6) of whom were males, which is a significantly higher percentage than the 8.7% (95% CI 7.3–10.4) of current khat chewers who were females (P < 0.001). The multivariate logistic regression analysis suggests that the most important independent predictors of khat chewing were having a friend who chewed khat (OR = 20.1, P < 0.001), participant''s smoking status (OR) = 3.9, P < 0.001), friend''s smoking status (OR = 2.2, P < 0.001), gender (OR = 2.2, P < 0.001) and educational level (OR = 1.5, P < 0.05). A large proportion of the Jizani populations chew khat. Government and non-governmental organizations NGOs should design and strengthen community prevention programs to curb the high prevalence of khat use.     

Synthesis,Characterization, and Cytotoxicity Studies of a Novel Palladium(II) Complex and Evaluation of DNA-Binding Aspects

A new water-soluble palladium(II) complex, [Pd(bpy)(pyr-Ac]NO₃ in which bpy = 2,2′-bipyridine and pyr-Ac is 1-pyrrolacetato, has been synthesized and characterized by spectroscopic methods (¹H NMR, FT-IR, and UV-Vis), molar conductivity measurements, and elemental analysis. The results obtained from elemental analysis and conductivity measurements confirmed the stoichiometry of ligand and its complex while the characteristic peaks in UV-Vis and FT-IR and resonance peaks in ¹H NMR spectra confirmed the formation of ligand frameworks around the palladium ion. The 50% cytotoxic concentration (Ic₅₀) of new synthesized Pd(II) complex was determined by using MTT assay against human breast cancer cell line, T47D. The interaction between the Pd(II) complex with calf thymus DNA was studied at different temperatures by using absorption spectroscopy, fluorescence titration spectra, ethidium bromide displacement, and gel chromatography studies. The results obtained by absorption spectroscopy revealed that the Pd(II) complex can bind to DNA cooperatively at low concentrations. Several binding parameters in the above interaction were calculated by the fluorescence quenching method. The quenching mechanism was suggested to be the static quenching. The thermodynamic parameters: enthalpy change (ΔH °), entropy change (ΔS °), and Gibbs free energy (ΔG °), showed that van der Waals and hydrogen binding are predominant intermolecular forces between Pd(II) complex and DNA. These results were also consistent with the results obtained from Scatchard's plots.     

Synthesis of N6-Substituted 9-[3-(Phosphonomethoxy)Propyl]Adenine Derivatives As Possible Antiviral Agents

A number of N ⁶ -substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having hydroxymethyl at C-1′-position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds are also reported. These compounds showed poor activity against HCV in replicon assay.