Rapid Synthesis of 2-Substituted-2,3-dihydro-4(1H)-quinazolinones using Boric Acid or Sodium Dihydrogen Phosphate under Solvent-Free Conditions

Two efficient and convenient methods have been described for synthesis of 2-substituted-2,3-dihydro-4(1H)-quinazolinone derivatives by one-pot condensation of 2-anthranilamide with aldehydes or ketones in the presence of a catalytic amount of boric acid or sodium dihydrogen phosphate under solvent-free conditions. The attractive features of these processes are short reaction times, easy isolation of products, excellent yields and an environmental friendly procedure.Keywords: Dihydroquinazolinones, boric acid, sodium dihydrogen phosphate, 2-anthranilamide, solvent-free synthesi

Genetic analysis of field and physiological indicators of drought tolerance in bread wheat (Triticum aestivum L.) using diallel mating design

In order to study the inheritance of field, physiological and metabolite indicators of drought tolerance in wheat, an eight-parental diallel cross, excluding reciprocals, was grown in a randomized complete block design (RCBD) with three replications under two different water regimes (irrigated and rainfed). Significant differences were found for yield potential (Yp), stress yield (Ys), stress tolerance index (STI), leaf water potential (LWP), relative water content (RWC), water use efficiency (WUE) and evapotranspiration efficiency (ETE). Yp, RWC and evapotranspiration efficiency (ETE) showed highly significant differences for both general combining ability (GCA) and specific combining ability (SCA), indicating the involvement of both additive and non-additive gene action in their inheritance. Ys, STI and WUE revealed highly significant differences for SCA, hence non-additive gene action was predominant for these traits. The best general combiners with positive effects, for improvement of Yp, Ys, STI, LWP, RWC, WUE and ETE under drought conditions were parents 5, 1, 6, 2, 7, 1 and 2, respectively. The best specific combination with heterobeltiosis over the best parents for improvement of Yp, Ys, STI, LWP, RWC, WUE and ETE were crosses 3 × 6, 2 × 4, 2 × 6, 5 × 8, 2 × 6, 2 × 4 and 1 × 7, respectively indicating that parents of these crosses are genetically diverse. High broad-sense heritability observed for all the traits confirmed that all the traits are more genetic, but because of low narrow-sense heritability the rule of additive part was low.Key words: Drought tolerance, physiological indicators, diallel mating design, genetic analysis

Análisis del genoma ovino para la identificación de QTL con influencia sobre caracteres de morfología mamaria: resultados preliminares

Ponencia publicada en ITEA, vol.104El objetivo del presente estudio es la localización de regiones genómicas con influencia sobre caracteres de morfología mamaria en ganado ovino, utilizando la metodología de genome scan, o barrido genómico. Con este fin, se ha analizado una población comercial de ganado ovino de raza Churra, organizada en un diseño hija compuesto por 8 familias de medio-hermanas. Un total de 182 marcadores genéticos, distribuidos uniformemente a lo largo del genoma ovino autosómico, fueron genotipados en la población objeto de estudio. Como medidas cuantitativas se utilizaron las desviaciones calculadas para los caracteres de morfología mamaria considerados en el programa de mejora genética de la raza ovina Churra: inserción de la ubre, posición de los pezones, tamaño de los pezones, profundidad y forma global de la ubre. Para la identificación de los QTL se realizó un análisis de regresión de los fenotipos con marcadores flanqueantes. El análisis del genoma para el conjunto de la población permitió la identificación de 11 regiones asociadas con estos caracteres, al nivel chromosome-wise, en los siguientes cromosomas: 4, 6, 7, 8, 10, 14, 15, 20, 22, 23 y 26. Para las asociaciones significativas se debe realizar una verificación previamente al abordaje del mapeo fino.Analysing the ovine genome to detect QTL for mammary morphology: preliminary results The objective of this work was the identification of chromosomal regions influencing udder morphology traits in dairy sheep by using the genome scan approach. For this purpose, we have analyzed a commercial population of Spanish Churra sheep organized according a daughter design, which included 8 half-sib families. A total of 182 genetic markers, evenly distributed along the ovine autosome, were genotyped in the studied population. As quantitative measurements for the analysis, we used the yield deviations calculated for each of the udder traits considered in the breeding program of Churra sheep: udder attachment, teat position and teat size, udder depth and udder shape. A multimarker regression analysis was used to detect QTL. The whole genome analysis allowed the identification of 11 chromosome-wide significant regions associated with the traits analyzed in the following chromosomes: 4, 6, 7, 8, 10, 14, 15, 20, 22, 23 y 26. Confirmation of the detected effects is required before attempting future fine mapping studies on these regions

An application of analytic network process model in supporting decision making to address pharmaceutical shortage

Background: The present study aimed to develop an Analytic Network Process (ANP) model to assist policymakers in identifying and prioritizing allocation indicators, which are being used or should be used to distribute drugs in short supply among different provinces. Methods: The model encompasses the interactions between various indicators and efficiency, equity, and effectiveness paradigms. Accordingly, a set of clusters and elements, which were associated with the allocation of drugs in short supply in Iran's pharmaceutical system, were detected to develop the model and were then compared in pairs in terms of a specified factor to show the priorities. Results: Equity had the highest priority (0.459) following by Efficiency (0.37), and Effectiveness (0.171). The 4 most important allocation indicator were "number of prescriptions"(0.26) and "total bed occupancy rate"(0.19) related to equity, "total population"(0.21) in efficiency and "the burden of rare and incurable disease"(0.07) in effectiveness paradigm. Conclusions: The capability to overcome inefficient resource allocation patterns caused by both oversupply and undersupply derived from historic resource allocation may be highly limited in the absence of the need indicators. The quality of the decision is related to a careful balancing act of the three paradigms which represents roughly the triple aim of public healthcare systems: clinical improvement (effectiveness), population health improvement (equity and access), and reducing cost (economic aspects -efficiency). © 2020 The Author(s)

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C \u3e 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer

Aharonov-Casher effect for spin one particles in a noncommutative space

In this work the Aharonov-Casher (AC) phase is calculated for spin one particles in a noncommutative space. The AC phase has previously been calculated from the Dirac equation in a noncommutative space using a gauge-like technique [17]. In the spin-one, we use kemmer equation to calculate the phase in a similar manner. It is shown that the holonomy receives non-trivial kinematical corrections. By comparing the new result with the already known spin 1/2 case, one may conjecture a generalized formula for the corrections to holonomy for higher spins.Comment: 9 page

Willingness to pay for one quality-adjusted life year in Iran 14 Economics 1402 Applied Economics 11 Medical and Health Sciences 1117 Public Health and Health Services

Background: Recent years have witnessed a strong tendency to apply economic evidence as a guide for making health resource allocation decisions, especially those related to reimbursement policies. One such measure is the use of the cost-effectiveness threshold as a benchmark. This study explored the threshold for use in the health system of Iran by determining society's preferences. Methods: A cross-sectional household survey based on the contingent valuation method was administered to a representative general population of 1002 in Tehran, Iran from April to June 2015. The survey was intended to estimate the respondents' willingness-to-pay (WTP) preferences for one quality-adjusted life year (QALY) gained. The valuation scenarios featured 12 vignettes on mild to severe diseases that can change people's quality of life. The mean of WTP for QALY was estimated using different health instruments, and the determinants of such willingness were analyzed using the Heckman selection model. Results: WTP for QALY varied depending on the severity of a disease and the instrument used to determine health preferences. Mean low health state value were associated with high valuation. The best estimated WTP values ranged from US1032 to US2666 and 0.22-0.56 of Iran's local gross domestic product (GDP) per capita in 2014. Except for educational level, significant variables differed across different disease scenarios. Generally, a high health state valuation for target diseases, high income, high educational level, and being married were associated with high WTP for QALY. Conclusion: From the general public's perspective, the monetary value of QALY for mild to severe diseases with no risk of death was less than one GDP per capita. Therefore, the obtained valuation range is recommended as reference only for the adoption of interventions designed to improve quality of life. Future studies should estimate the threshold of interventions for life-threatening diseases or formulate transparent policies in such contexts. © 2019 The Author(s)

Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers

Background: The mechanisms by which genetic variants, such as single nucleotide polymorphisms (SNPs), identified in genome-wide association studies act to influence body mass remain unknown for most of these SNPs, which continue to puzzle the scientific community. Recent evidence points to the epigenetic and chromatin states of the genome as having important roles. Methods: We genotyped 355 healthy young individuals for 52 known obesity-associated SNPs and obtained DNA methylation levels in their blood using the Illumina 450 K BeadChip. Associations between alleles and methylation at proximal cytosine residues were tested using a linear model adjusted for age, sex, weight category, and a proxy for blood cell type counts. For replication in other tissues, we used two open-access datasets (skin fibroblasts, n = 62; four brain regions, n = 121-133) and an additional dataset in subcutaneous and visceral fat (n = 149). Results: We found that alleles at 28 of these obesity-associated SNPs associate with methylation levels at 107 proximal CpG sites. Out of 107 CpG sites, 38 are located in gene promoters, including genes strongly implicated in obesity (MIR148A, BDNF, PTPMT1, NR1H3, MGAT1, SCGB3A1, HOXC12, PMAIP1, PSIP1, RPS10-NUDT3, RPS10, SKOR1, MAP2K5, SIX5, AGRN, IMMP1L, ELP4, ITIH4, SEMA3G, POMC, ADCY3, SSPN, LGR4, TUFM, MIR4721, SULT1A1, SULT1A2, APOBR, CLN3, SPNS1, SH2B1, ATXN2L, and IL27). Interestingly, the associated SNPs are in known eQTLs for some of these genes. We also found that the 107 CpGs are enriched in enhancers in peripheral blood mononuclear cells. Finally, our results indicate that some of these associations are not blood-specific as we successfully replicated four associations in skin fibroblasts. Conclusions: Our results strongly suggest that many obesity-associated SNPs are associated with proximal gene regulation, which was reflected by association of obesity risk allele genotypes with differential DNA methylation. This study highlights the importance of DNA methylation and other chromatin marks as a way to understand the molecular basis of genetic variants associated with human diseases and traits

Affordability assessment from a static to dynamic concept: A scenario�based assessment of cardiovascular medicines

The out�of�pocket payments for prescription medications can impose a financial burden on patients from low� and middle� incomes and who suffer from chronic diseases. The present study aims at evaluating the affordability of cardiovascular disease (CVD) medication in Iran. This includes measuring affordability through World Health Organization/Health Action International (WHO/HAI) methodology. In this method, affordability is characterized as the number of daysʹ wages of the lowest�paid unskilled government worker. The different medication therapy scenarios are defined in mono�and combination therapy approaches. This method adds on to WHO/HAI methodology to discover new approaches to affordability assessments. The results show the differences in the medicines affordability when different approaches are used in mono�and combination therapy between 6 main sub�therapeutic groups of CVD. It indicates the medicine affordability is not a static concept and it changes dynamically between CVD therapeutic subgroups when it used alone or in combination with other medicines regarding patients� characteristics and medical conditions. Hypertension and anti�arrhythmia therapeutic groups had the most non-affordability and hyperlipidemia had the most affordable medicines. Therefore, affordability can be considered as a dynamic concept, which not only affected by the medicine price but significantly affected by a patient�s characteristics, the number of medical conditions, and insurance coverage. © 2020 by the authors. Licensee MDPI, Basel, Switzerland