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The placement of elementary school teachers is an NP-complex problem. Teacher placement can be optimized by considering several factors that influence their performance, including the distance of teacher's residence to school, age, and gender of the teacher. This paper discusses the solution model of the problem based on genetic algorithms by finding a chromosome formation that represents the possibility of teachers placement solution, composing a population, and finding the recommended combination of two selected mutations operators and two selected crossover operators to achieve optimal results. The selected mutation operators were Reverse Sequence Mutation (RSM) and Partial Shuffle Mutation (PSM), while the selected crossover-operators were Single Point Crossover (SPX) and Ordered Crossover (OX). The combined performance of these operators is measured based on the fitness value and running time of the program. Based on experiments, it can be concluded that the combination of OX-PSM with mutation probability 1:20 gives the lowest minimum fitness value compared to other combinations of crossover and mutation operators. The running time of the combination of OX-PSM is stable in any mutation probability, ranging from 39,5 - 41 minutes.

This study was conducted to measure the effects of the timing of nitrogen fertilization (NF) on soil N-NH4 + and N-NO3 -, macronutrient contents in the leaves and grains, and the grain yield of super early genotypes (SEG) of common bean. Field experiments were performed for four growing seasons in an Oxisol soil in Santo Antônio de Goiás, Brazil, using a randomized block experimental design in a split plot scheme. The plots were planted with common bean SEG, and the subplots were the NF timings, including a treatment without N fertilization. The available soil N with improved fertility and medium to high levels of organic matter were enough to meet the N demands of the common bean crop in order to achieve yields of up to 3,000 kg ha-1. Fertilization with N, regardless of the time of application, provided no increase in the yield components, grain yield and the N, P and K contents in the leaves and grains of the common bean SEG. The genotypes CNFC 15873 and CNFC 15875 had higher grain yields in the rainfed summer, and the genotype CNFC 15874 had higher grain yields in the irrigated winter growing season. It can be inferred that the use of common bean SEG, with life cycles ranging from 65 to 77 days, can be a promising technology, providing grain yields similar to the control (IPR Colibri).

There is a lack of researches that evaluate the development and nutrient accumulation in super early genotypes of common bean for the elaboration of fertilization programs. This study aimed at characterizing the development; N, P, K, Ca and Mg accumulation by leaves; grain yield; and yield components of super early genotypes of common bean. Field experiments were conducted in a randomized blocks design, with four replications. The treatments consisted of the IPR Colibri (control), CNFC 15873, CNFC 15874 and CNFC 15875 genotypes. Plants were sampled throughout the common bean development, being divided into leaves, stems and pods. After determining the dry matter, the contents of N, P, K, Ca and Mg accumulated in leaves were estimated. At harvesting, the grain yield and yield components were evaluated. The biomass accumulation in stems and leaves occurred until the flowering stage, and then it started in the pods until harvesting. The genotypes that absorbed more nitrogen and phosphorus had a higher grain yield. The average growing season of super early genotypes was 70 days (winter) and 63 days (summer). CNFC 15874 was the most productive genotype in the winter, with grain yield similar to the IPR Colibri cultivar (control). In the summer, CNFC 15873 and CNFC 15875 achieved grain yield similar to the IPR Colibri cultivar.

There is a lack of researches that evaluate the development and nutrient accumulation in super early genotypes of common bean for the elaboration of fertilization programs. This study aimed at characterizing the development; N, P, K, Ca and Mg accumulation by leaves; grain yield; and yield components of super early genotypes of common bean. Field experiments were conducted in a randomized blocks design, with four replications. The treatments consisted of the IPR Colibri (control), CNFC 15873, CNFC 15874 and CNFC 15875 genotypes. Plants were sampled throughout the common bean development, being divided into leaves, stems and pods. After determining the dry matter, the contents of N, P, K, Ca and Mg accumulated in leaves were estimated. At harvesting, the grain yield and yield components were evaluated. The biomass accumulation in stems and leaves occurred until the flowering stage, and then it started in the pods until harvesting. The genotypes that absorbed more nitrogen and phosphorus had a higher grain yield. The average growing season of super early genotypes was 70 days (winter) and 63 days (summer). CNFC 15874 was the most productive genotype in the winter, with grain yield similar to the IPR Colibri cultivar (control). In the summer, CNFC 15873 and CNFC 15875 achieved grain yield similar to the IPR Colibri cultivar.

Collaborative Filtering (CF) is a method that is widely used in recommendation systems. There are two approaches that are often used in CF, namely User-based CF and Item-based CF. The User-based CF approach requires several similar users to predict the rating of a new item. Meanwhile, Item-based CF requires several similar items to predict the rating of a new item. The number of similar users or similar items involved in predicting ratings will affect the computing load. This research aims to see the effect of the number of neighbors (similar user or similar items) used on the level of accuracy of rating predictions for an item. By using different numbers of neighbors for both User-based CF and Item-based CF, the results of the experiment show that the number of neighbors affects the level of accuracy although not too significant.

Understanding the principles of neuronal connectivity requires tools for efficient quantification and visualization of large datasets. The primate cortex is particularly challenging due to its complex mosaic of areas, which in many cases lack clear boundaries. Here, we introduce a resource that allows exploration of results of 143 retrograde tracer injections in the marmoset neocortex. Data obtained in different animals are registered to a common stereotaxic space using an algorithm guided by expert delineation of histological borders, allowing accurate assignment of connections to areas despite interindividual variability. The resource incorporates tools for analyses relative to cytoarchitectural areas, including statistical properties such as the fraction of labeled neurons and the percentage of supragranular neurons. It also provides purely spatial (parcellation-free) data, based on the stereotaxic coordinates of 2 million labeled neurons. This resource helps bridge the gap between high-density cellular connectivity studies in rodents and imaging-based analyses of human brains. Understanding principles of neuronal connectivity requires tools for quantification and visualization of large datasets. Here, the authors introduce an online resource encompassing the coordinates of two million neurons labelled by tracer injections in the marmoset cortex, and analysis tools.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy 1 , 2 . This is mediated in part by a complex tumour microenvironment 3 , low vascularity 4 , and metabolic aberrations 5 , 6 . Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy. A metabolite screen of pancreatic cells shows that pancreatic cancer cells metabolize uridine-derived ribose via UPP1, supporting redox balance, survival and proliferation.

Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough. COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2). From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9–0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1–1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2). Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough. Merck Sharp & Dohme.

Trichothecenes are a family of terpenoid toxins produced by multiple genera of fungi, including plant and insect pathogens. Some trichothecenes produced by the fungus Fusarium are among the mycotoxins of greatest concern to food and feed safety because of their toxicity and frequent occurrence in cereal crops, and trichothecene production contributes to pathogenesis of some Fusarium species on plants. Collectively, fungi produce over 150 trichothecene analogs: i.e., molecules that share the same core structure but differ in patterns of substituents attached to the core structure. Here, we carried out genomic, phylogenetic, gene-function, and analytical chemistry studies of strains from nine fungal genera to identify genetic variation responsible for trichothecene structural diversity and to gain insight into evolutionary processes that have contributed to the variation. The results indicate that structural diversity has resulted from gain, loss, and functional changes of trichothecene biosynthetic (TRI) genes. The results also indicate that the presence of some substituents has arisen independently in different fungi by gain of different genes with the same function. Variation in TRI gene duplication and number of TRI loci was also observed among the fungi examined, but there was no evidence that such genetic differences have contributed to trichothecene structural variation. We also inferred ancestral states of the TRI cluster and trichothecene biosynthetic pathway, and proposed scenarios for changes in trichothecene structures during divergence of TRI cluster homologs. Together, our findings provide insight into evolutionary processes responsible for structural diversification of toxins produced by pathogenic fungi.

Fatty acids are precursors of inflammatory oxylipins. In the context of COVID-19, an excessive production of pro-inflammatory cytokines is associated with disease severity. The objective was to investigate whether the baseline omega 3/omega 6 fatty acids ratio and the oxylipins were associated with inflammation and oxidative stress in unvaccinated patients with COVID-19, classified according to the severity of the disease during hospitalization. This Prospective population-based cohort study included 180 hospitalized patients with COVID-19. The patients were classified into five groups according to the severity of their disease. Group 1 was the least severe and Group 5 was the most severe. Three specific types of fatty acids—eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)—as well as their enzymatic and non-enzymatic oxylipins were determined using chromatography coupled mass spectrometry. There was no difference in the ratio of omega-3 to omega-6 fatty acids between the groups ( p  = 0.276). However, the EPA/AA ratio was lower in Group 4 compared to Group 1 ( p  = 0.015). This finding was associated with an increase in both C-Reactive Protein ( p  < 0.001) and Interleukin-6 ( p  = 0.002). Furthermore, the concentration of F 2 -Isoprostanes was higher in Group 4 than in Group 1 ( p  = 0.009), while no significant changes were observed for other oxylipins among groups. Multivariate analysis did not present any standard of biomarkers, suggesting the high complexity of factors involved in the disease severity. Our hypothesis was confirmed in terms of EPA/AA ratio. A higher EPA/AA ratio upon hospital admission was found to be associated with lower concentration of C-Reactive Protein and Interleukin-6, leading to a better prognosis of hospitalized SARS-CoV-2 patients. Importantly, this beneficial outcome was achieved without any form of supplementation. The trial also provides important information that can be further applied to reduce the severity of infections associated with an uncontrolled synthesis of pro-inflammatory cytokines. Trial registration : https://clinicaltrials.gov/study/NCT04449718 —01/06/2020. ClinicalTrials.gov Identifier: NCT04449718.