Evaluation of antiplasmodial activity in silico and in vitro of N-acylhydrazone derivatives.

N-acylhydrazones are considered privileged structures in medicinal chemistry, being part of antimicrobial compounds (for example). In this study we show the activity of N-acylhydrazone compounds, namely AH1, AH2, AH4, AH5 in in vitro tests against the chloroquine-resistant strain of Plasmodium falciparum (W2) and against WI26 VA-4 human cell lines. All compounds showed low cytotoxicity (LC50 > 100 µM). The AH5 compound was the most active against Plasmodium falciparum, with an IC50 value of 0.07 µM. AH4 and AH5 were selected among the tested compounds for molecular docking calculations to elucidate possible targets involved in their mechanism of action and the SwissADME analysis to predict their pharmacokinetic profile. The AH5 compound showed affinity for 12 targets with low selectivity, while the AH4 compound had greater affinity for only one target (3PHC). These compounds met Lipinski's standards in the ADME in silico tests, indicating good bioavailability results. These results demonstrate that these N-acylhydrazone compounds are good candidates for future preclinical studies against malaria.

Effect of Adding Bevacizumab to Chemotherapy on Pathologic Response to Preoperative Systemic Therapy for Resectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Liver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR in preoperative systemic therapy for CLM. METHODS: We systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase, and LILACS for studies published between January 2004 and August 2019 that compared the pR of CT plus bevacizumab to CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor (pMiR) response. Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. RESULTS: Of the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab and 686 CT alone). The addition of bevacizumab to CT increased the pCR rate without reaching statistical significance (OR: 1.24, 95% CI 0.81 to 1.92, P = .32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 to 3.25, P < .001), and pMiR was significantly lower (OR: 0.41, 95% CI 0.31 to 0.54, P < .001), in the bevacizumab group. The analyses showed a low level of heterogeneity (I2 = 0% to 6%). Publication bias was not found. CONCLUSIONS: This meta-analysis demonstrates that bevacizumab plus preoperative CT is associated with higher rates of pR in CLM. Antiangiogenics might improve the OS of CLM patients and should be evaluated in randomized clinical trials. MICROABSTRACT: The benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR of bevacizumab plus chemotherapy to chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.

Active tuberculosis in inflammatory bowel disease patients under treatment from an endemic area in Latin America.

BACKGROUND: There has been an increase in cases of inflammatory bowel disease (IBD) in recent years. There is also greater access and availability of immunosuppressive and biological agents, which increase the risk of opportunistic infection despite improving the quality of life and promoting mucosal healing. Tuberculosis (TB) remains a public health problem, and it has a high incidence in several countries. Therefore, knowledge of the risk of developing TB in patients with IBD is important. AIM: To evaluate the risk of active TB in patients with IBD under treatment from an endemic area in Latin America. METHODS: A standard questionnaire included demographic variables, clinical aspects of IBD disease, history of active TB during treatment, active TB characteristics and evolution, initial screening and results and time from the start of anti-tumor necrosis factor alpha (TNFα) to TB development. RESULTS: Azathioprine, anti-TNFα and the combination of these two drugs were associated with a higher risk of active TB incidence. The TNFα blockers increased the relative risk of developing active TB compared to other treatments. All four multivariable models showed that the use of TNFα blockers alone or in combination with azathioprine was an important risk factor for the incidence of active TB. After adjustment for sex, age, type of IBD and latent TB, anti-TNFα with azathioprine increased the relative risk to 17.8 times more than conventional treatment. Late TB, which was diagnosed 3 mo after the start of anti-TNFα, was the most frequent. CONCLUSION: Treatment with anti-TNFα increased the risk of active TB in IBD patients from an endemic area in Latin America. This risk was increased when anti-TNFα was combined with azathioprine. The time from the beginning of the treatment to the active TB diagnosis suggests a new TB infection.

Adherence to Medical Treatment in Inflammatory Bowel Disease Patients from a Referral Center in Bahia-Brazil.

METHODS: Observational, analytical, and cross-sectional studies carried out from June/2017 to July/2018, with questionnaire application and medical record review at a referral center in inflammatory bowel diseases in Salvador, Bahia. The Morisky Green Levine Scale was applied to assess adherence. Mean, standard deviation, and frequency analyses were performed using the statistical package SPSS, and chi-square was used to evaluate the association between categorical variables and adherence degree to treatment. Significant associations were considered with p < 0.05. RESULTS: 302 patients with inflammatory bowel diseases were included. Nonadherence was highlighted in the sample. Most part of the study population was female, declared themselves to be mixed race, claimed to be from urban areas, and married. Nonadherence was more frequent than adherence in most sociodemographic variables of the present study. Nonadherence also stood out among the clinical variables, such as disease activity, drug side effect, and use of more than two additional medications. The association between all studied variables and adherence degree to treatment, considering the general sample, did not show statistical significance. When Crohn's disease and ulcerative colitis patients were evaluated separately, a statistically significant association between nonadherence and female patients with ulcerative colitis was observed. CONCLUSIONS: The high frequency of nonadherence was observed in the studied sample. Female gender was associated to nonadherence in the subpopulation with ulcerative colitis.

High-Resolution Linkage Map With Allele Dosage Allows the Identification of Regions Governing Complex Traits and Apospory in Guinea Grass (Megathyrsus maximus).

Forage grasses are mainly used in animal feed to fatten cattle and dairy herds, and guinea grass (Megathyrsus maximus) is considered one of the most productive of the tropical forage crops that reproduce by seeds. Due to the recent process of domestication, this species has several genomic complexities, such as autotetraploidy and aposporous apomixis. Consequently, approaches that relate phenotypic and genotypic data are incipient. In this context, we built a linkage map with allele dosage and generated novel information of the genetic architecture of traits that are important for the breeding of M. maximus. From a full-sib progeny, a linkage map containing 858 single nucleotide polymorphism (SNP) markers with allele dosage information expected for an autotetraploid was obtained. The high genetic variability of the progeny allowed us to map 10 quantitative trait loci (QTLs) related to agronomic traits, such as regrowth capacity and total dry matter, and 36 QTLs related to nutritional quality, which were distributed among all homology groups (HGs). Various overlapping regions associated with the quantitative traits suggested QTL hotspots. In addition, we were able to map one locus that controls apospory (apo-locus) in HG II. A total of 55 different gene families involved in cellular metabolism and plant growth were identified from markers adjacent to the QTLs and APOSPORY locus using the Panicum virgatum genome as a reference in comparisons with the genomes of Arabidopsis thaliana and Oryza sativa. Our results provide a better understanding of the genetic basis of reproduction by apomixis and traits important for breeding programs that considerably influence animal productivity as well as the quality of meat and milk.

Coexpression and Transcriptome analyses identify active Apomixis-related genes in Paspalum notatum leaves.

BACKGROUND: Paspalum notatum exhibits both sexual and apomictic cytotypes and, thus, is considered a good model for studies of apomixis because it facilitates comparative approaches. In this work, transcriptome sequencing was used to compare contrasting P. notatum cytotypes to identify differential expression patterns and candidate genes involved in the regulation of expression of this trait. RESULTS: We built a comprehensive transcriptome using leaf and inflorescence from apomictic tetraploids and sexual diploids/tetraploids and a coexpression network based on pairwise correlations between transcript expression profiles. We identified genes exclusively expressed in each cytotype and genes differentially expressed between pairs of cytotypes. Gene Ontology enrichment analyses were performed to better interpret the data. We de novo assembled 114,306 reference transcripts. In total, 536 candidate genes possibly associated with apomixis were detected through statistical analyses of the differential expression data, and several interacting genes potentially linked to the apomixis-controlling region, genes that have already been reported in the literature, and their neighbors were transcriptionally related in the coexpression network. CONCLUSIONS: Apomixis is a highly desirable trait in modern agriculture due to the maintenance of the characteristics of the mother plant in the progeny. The reference transcriptome, candidate genes and their coexpression network identified in this work represent rich resources for future grass breeding programs.

First microsatellite markers for Paspalum plicatulum (Poaceae) characterization and cross-amplification in different Paspalum species of the Plicatula group.

BACKGROUND: Paspalum plicatulum is a perennial rhizomatous grass with natural diploid and polyploid cytotypes. It is a member of Plicatula, which has historically been recognized as a highly complex group containing species of ecological, ornamental and forage importance. The complex nature of the P. plicatulum genome makes it a challenging species for genetic research. This study aimed to develop and characterize microsatellite molecular markers in P. plicatulum and to evaluate their transferability to other Plicatula group species. FINDINGS: Microsatellite sequences were identified from three enriched libraries from P. plicatulum. Specific primers were designed, and 25 displayed polymorphism when screened across 48 polyploid Paspalum spp. genotypes. The number of bands per locus ranged from 2 to 17, with a mean of 8.65. Private bands for each species were identified; the highest number of private bands was observed for P. plicatulum in 52% of the loci analyzed. The mean polymorphism information content of all loci was 0.69, and the mean discriminatory power was 0.82. Microsatellite markers were satisfactorily cross-amplified for the eight tested Plicatula-group Paspalum species, with P. atratum exhibiting the highest transferability rate (89.86%). STRUCTURE and Discriminant Analysis of Principal Components separated accessions into three groups but did not reveal separation of the accessions according to species. CONCLUSIONS: This study describes the first microsatellite markers in P. plicatulum, which are polymorphic, efficient for the detection and quantification of genetic variation, and show high transferability into other species of the Plicatula group. This set of markers can be used in future genetic and molecular studies necessary for the proper development of conservation and breeding programs. Private bands within the markers can be used to assist in species identification.

Microsatellite markers for studies with the carnivorous plant Philcoxia minensis (Plantaginaceae).

PREMISE OF THE STUDY: Microsatellite markers were developed for the critically endangered carnivorous species Philcoxia minensis (Plantaginaceae) for further population genetic studies aiming at its conservation. METHODS AND RESULTS: We identified 29 clones containing 40 microsatellites from a genomic enriched library. A total of 27 primer pairs were developed and evaluated in 30 individuals of a natural P. minensis population. Seventeen markers successfully presented amplification products within the expected size range, of which 12 were polymorphic. The expected and observed heterozygosities ranged from 0.03 to 0.65 and from 0.00 to 0.77, respectively. Positive transferability with the related species P. bahiensis was observed for the same 17 markers. CONCLUSIONS: The 12 polymorphic microsatellite markers are suitable for studies in genetic diversity and structure, mating system, and gene flow in P. minensis and also may be useful for similar issues regarding the related species P. bahiensis.

Microsatellite markers for Urochloa humidicola (Poaceae) and their transferability to other Urochloa species.

BACKGROUND: Urochloa humidicola is a warm-season grass commonly used as forage in the tropics and is recognized for its tolerance to seasonal flooding. This grass is an important forage species for the Cerrado and Amazon regions of Brazil. U. humidicola is a polyploid species with variable ploidy (6X-9X) and facultative apomixis with high phenotypic plasticity. However, this apomixis and ploidy, as well as the limited knowledge of the genetic basis of the germplasm collection, have constrained genetic breeding activities, yet microsatellite markers may enable a better understanding of the species' genetic composition. This study aimed to develop and characterize new polymorphic microsatellite molecular markers in U. humidicola and to evaluate their transferability to other Urochloa species. FINDINGS: A set of microsatellite markers for U. humidicola was identified from two new enriched genomic DNA libraries: the first library was constructed from a single sexual genotype and the second from a pool of eight apomictic genotypes selected on the basis of previous results. Of the 114 loci developed, 72 primer pairs presented a good amplification product, and 64 were polymorphic among the 34 genotypes tested. The number of bands per simple sequence repeat (SSR) locus ranged from 1 to 29, with a mean of 9.6 bands per locus. The mean polymorphism information content (PIC) of all loci was 0.77, and the mean discrimination power (DP) was 0.87. STRUCTURE analysis revealed differences among U. humidicola accessions, hybrids, and other Urochloa accessions. The transferability of these microsatellites was evaluated in four species of the genus, U. brizantha, U. decumbens, U. ruziziensis, and U. dictyoneura, and the percentage of transferability ranged from 58.33% to 69.44% depending on the species. CONCLUSIONS: This work reports new polymorphic microsatellite markers for U. humidicola that can be used for breeding programs of this and other Urochloa species, including genetic linkage mapping, quantitative trait loci identification, and marker-assisted selection.

Microsatellite markers for an endemic Atlantic Forest tree, Manilkara multifida (Sapotaceae).

Manilkara multifida is a tropical tree that is endemic to the Atlantic forests of southern Bahia, Brazil. Currently, populations of this species are restricted to fragmented landscapes that are susceptible to anthropogenic disturbances. Considering this issue, and that there is no genetic information available for this endangered species, we developed microsatellite markers for M. multifida to provide resources for future conservation genetics studies. Using an enriched genomic library, we isolated eight polymorphic microsatellite loci and optimized the amplification conditions for M. multifida. For each locus, we estimated the number of alleles, H E and H O, paternity exclusion Q, individual identity I and fixation index F, and examined the presence of null alleles. The mean number of alleles was 11.9, and the heterozygosity was high at all loci (average H E = 0.809 and H O = 0.777). The combined values for both paternity exclusion and individual identity were Q = 0.9959 and I = 5.45 × 10(-11), respectively. No evidence of null alleles was detected. The results of our analysis indicated that all eight microsatellites are promising for assessing questions involving inbreeding, gene flow, co-ancestry and mating patterns in M. multifida.

Microsatellite markers for Plathymenia reticulata (Leguminosae)1.

PREMISE OF THE STUDY: Microsatellite markers were developed and characterized to investigate genetic diversity and gene flow and to help in conservation efforts for the endangered timber species Plathymenia reticulata. • METHODS AND RESULTS: Eleven microsatellite loci were characterized using 60 adult trees of two populations of P. reticulata from the Atlantic Forest of southern Bahia, Brazil. Of these, nine loci were polymorphic, with an average of 4.39 alleles per locus. The average expected heterozygosity per population ranged from 0.47 to 0.55. The combined exclusion probability was 0.99996. • CONCLUSIONS: Our results reveal that the microsatellite markers developed in this study are an effective tool for paternity and genetic structure analysis that may be useful for conservation strategies.

A critical survey of predictive mathematical models for migration from packaging.

The migration of chemicals from food contact materials into foods is an important issue in food safety. The assessment of materials compliance with regulations includes migration monitoring for many monomers and additives. However, it is recognized that predictive mathematical modelling can be used in many cases, to avoid or to reduce the effort on migration experiments. This article reviews the approaches followed to apply mathematical models to migration, particularly the models used, the approaches to estimate model parameters, and the systems used to experimentally validate the models. Conclusions on the issues requiring further research are drawn.

Serological characterization and prevalence of spvR genes in Salmonella isolated from foods involved in outbreaks in Brazil.

Salmonella strains (n = 75) isolated from foods involved in foodborne outbreaks occurred in Rio Grande do Sul State, Brazil, during 1999 and 2000 were studied. Strains were serotyped and submitted to PCR analysis to verify the prevalence of Salmonella plasmid virulence (spvR) regulatory gene. Among the 75 isolates, 73 (97%) were classified as Salmonella enterica serovar Enteritidis. All of the Salmonella strains isolated in 1999 were classified as serotype Enteritidis, whereas in 2000 two isolates were serotyped as Salmonella Derby and Salmonella Typhimurium. Regarding the prevalence of spvR gene, 62 strains (82.7%) were PCR positive, and a positive correlation (P < 0.05) between the strains of Salmonella Enteritidis and the presence of spvR gene was demonstrated, which suggests that this gene is a characteristic of the Salmonella Enteritidis analyzed.