In Silico Screening and Molecular Dynamics Simulations against Tyrosine-protein Kinase Fyn Reveal Potential Novel Therapeutic Candidates for Bovine Papillomatosis.

BACKGROUND: Decreased beef productivity due to papillomatosis has led to the development and identification of novel targets and molecules to treat the disease. Protein kinases are promising targets for the design of numerous chemotherapy drugs. OBJECTIVE: This study aimed to screen and design new inhibitors of bovine Fyn, a protein kinase, using structure-based computational methods, such as molecular docking and molecular dynamics simulation (MDS). METHODS: To carry out the molecular docking analysis, five ligands obtained through structural similarity between active compounds along with the cross-inhibition function between the ChEMBL and Drugbank databases were used. Molecular modeling was performed, and the generated models were validated using PROCHECK and Verify 3D. Molecular docking was performed using Autodock Vina. The complexes formed between Fyn and the three best ligands had their stability assessed by MDS. In these simulations, the complexes were stabilized for 100 ns in relation to a pressure of 1 atm, with an average temperature of 300 k and a potential energy of 1,145,336 kJ/m converged in 997 steps. RESULTS: Docking analyses showed that all selected ligands had a high binding affinity with Fyn and presented hydrogen bonds at important active sites. MDS results support the docking results, as the ligand showed similar and stable interactions with amino acids present at the binding site of the protein. In all simulations, sorafenib obtained the best results of interaction with the bovine Fyn. CONCLUSION: The results highlight the identification of possible bovine Fyn inhibitors; however, further studies are important to confirm these results experimentally.

d-Limonene complexed with cyclodextrin attenuates cardiac arrhythmias in an experimental model of doxorubicin-induced cardiotoxicity: Possible involvement of calcium/calmodulin-dependent protein kinase type II.

BACKGROUND: Arrhythmias are one manifestation of the cardiotoxicity that results from doxorubicin (Doxo) administration. Although cardiotoxicity is an anticipated outcome in anticancer therapies, there is still a lack of treatment options available for its effective management. This study sought to evaluate the possible cardioprotective effect of complex d-limonene (DL) plus hydroxypropyl-ß-cyclodextrin (HßDL) during treatment with Doxo, focusing on the arrhythmic feature. METHODS: Cardiotoxicity was induced in Swiss mice with Doxo 20 mg/kg, with 10 mg/kg of HßDL being administered 30 min before the Doxo. Plasma CK-MB and LDH levels were analyzed. Cellular excitability and susceptibility to cardiac and cardiomyocyte arrhythmias were evaluated using in vivo (pharmacological cardiac stress) and in vitro (burst pacing) ECG protocols. Ca2+ dynamics were also investigated. The expression of CaMKII and its activation by phosphorylation and oxidation were evaluated by western blot, and molecular docking was used to analyze the possible interaction between DL and CaMKII. RESULTS: Electrocardiograms showed that administration of 10 mg/kg of HßDL prevented Doxo-induced widening of the QRS complex and QT interval. HßDL also prevented cardiomyocyte electrophysiological changes that trigger cellular arrhythmias, such as increases in action potential duration and variability; decreased the occurrence of delayed afterdepolarizations (DADs) and triggered activities (TAs), and reduced the incidence of arrhythmia in vivo. Ca2+ waves and CaMKII overactivation caused by phosphorylation and oxidation were also decreased. In the in silico study, DL showed potential inhibitory interaction with CaMKII. CONCLUSION: Our results show that 10 mg/kg of ßDL protects the heart against Doxo-induced cardiotoxicity arrhythmias, and that this is probably due to its inhibitory effect on CaMKII hyperactivation.

Occurrence, molecular diversity and pathogenicity of Acanthamoeba spp. isolated from aquatic environments of Northeastern Brazil.

Acanthamoeba is a free-living amoeba (FLA) that is ubiquitous in nature and can cause serious pathologies in humans. This protozoan has been detected in several environmental sources, such as soil, water, and swimming pools. The aim of this study was to evaluate the occurrence and molecular diversity of Acanthamoeba spp. in aquatic environments of the state of Sergipe, northeastern Brazil, and to determine the pathogenic potential of the isolated samples. A total of 138 samples were collected from 69 aquatic environments and, after cell culture, 74% of the samples were positive for FLA, 47% belonging to the genus Acanthamoeba. Genotypic analysis was performed using the primers JDP1 and JDP2, confirming distinct Acanthamoeba genotypes: 18 (75%) isolates belonging to genotype T4, two (8%) to T3, and one isolate (4%) to genotype T5. Tests carried out to analyze the pathogenic potential showed that 11 isolates could grow at 0.5 M mannitol concentration and seven isolates supported hyperosmolarity. In the thermotolerance test, two isolates grew at 37°C. These results confirm the presence and the pathogenic potential of FLA of the genus Acanthamoeba in aquatic environments of the municipalities of Sergipe.

The increase in SARS-CoV-2 lineages during 2020-2022 in a state in the Brazilian Northeast is associated with a number of cases.

SARS-CoV-2 has caused a high number of deaths in several countries. In Brazil, there were 37 million confirmed cases of COVID-19 and 700,000 deaths caused by the disease. The population size and heterogeneity of the Brazilian population should be considered in epidemiological surveillance due to the varied tropism of the virus. As such, municipalities and states must be factored in for their unique specificities, such as socioeconomic conditions and population distribution. Here, we investigate the spatiotemporal dispersion of emerging SARS-CoV-2 lineages and their dynamics in each microregion from Sergipe state, northeastern Brazil, in the first 3 years of the pandemic. We analyzed 586 genomes sequenced between March 2020 and November 2022 extracted from the GISAID database. Phylogenetic analyses were carried out for each data set to reconstruct evolutionary history. Finally, the existence of a correlation between the number of lineages and infection cases by SARS-CoV-2 was evaluated. Aracaju, the largest city in northeastern Brazil, had the highest number of samples sequenced. This represented 54.6% (320) of the genomes, and consequently, the largest number of lineages identified. Studies also analyzed the relationship between mean lineage distributions and mean monthly infections, daily cases, daily deaths, and hospitalizations of vaccinated and unvaccinated patients. For this, a correlation matrix was created. Results revealed that the increase in the average number of SARS-CoV-2 variants was related to the average number of SARS-CoV-2 cases in both unvaccinated and vaccinated individuals. Thus, our data indicate that it is necessary to maintain epidemiological surveillance, especially in capital cities, since they have a high rate of circulation of resident and non-resident inhabitants, which contributes to the dynamics of the virus.

Prevalence of human papillomavirus infection in Brazilian women living with HIV: a systematic review and meta-analysis.

OBJECTIVE: We systematically investigated the prevalence of HPV, high-risk HPV and its genotypes in women living with human immunodeficiency virus (WLHIV) in Brazil. METHODS: A systematic search was performed up to 15 December 2020. We included studies that used molecular methods for HPV detection in cervical samples and reported the prevalence of HPV in Brazilian WLHIV. The pooled prevalence of HPV, high-risk HPV (HR HPV) and HPV types and their 95% confidence interval (CI) were estimated. Subgroup analyses and meta-regression were conducted. RESULTS: Thity-seven studies accounting for 8,436 WLHIV were included. The pooled HPV prevalence was 62% (95%CI 55-68%; I2 = 96.98%; P < 0.001). Prevalence of high-risk HPV was 40% (95%CI, 54-68%; I2 = 94.23%; P < 0.001). We found a wide variety of high-risk HPV genotypes. The high-risk HPV types most reported were HPV 16 (16%) and HPV 58 (6%). We found an increasing ratio of positivity from normal cervix to cancer. There were different factors associated with high-risk HPV, with low CD4+ count the most frequent. CONCLUSION: The increase in the ratio of high-risk HPV positivity from normal cervix to carcinogenic lesions highlights the need to implement well-established testing for high-risk HPV in this population.

Detection of Human Papillomavirus DNA in Paired Peripheral Blood and Cervix Samples in Patients with Cervical Lesions and Healthy Individuals.

This study evaluated the presence of Human Papillomavirus (HPV) DNA in the cervix and peripheral blood of women with cervical intraepithelial neoplasia (CIN I, II, and III) and healthy individuals. Overall, 139 paired peripheral blood and cervix samples of healthy women and women with CIN I, II, and III (n = 68) were tested for HPV DNA by using standard procedures. Polymerase chain reaction (PCR) sequencing determined HPV types. Quantification of HPV16 E6 and E2 genes was performed to determine viral load and physical state. HPV DNA was detected in the cervix (21.1% in healthy individuals; 48.8-55.5% in CIN patients), blood (46.4% in healthy individuals; 44.1-77.7% in CIN patients) and paired peripheral blood and cervix samples (24% in healthy individuals; 32.5-44.4% in CIN patients). The most frequent types found in the cervix were HPV16, 18, 31, 33, 58, and 70, while HPV16, 18, 33, 58, and 66 were the most frequent types found in the blood. HPV DNA in the cervix was associated with previous sexually transmitted infections (STIs) (p = 0.023; OR: 2.978; CI:1.34-7.821), HPV DNA in the blood (p = 0.000; OR: 8.283; CI:3.700-18.540), and cervical lesions (CIN I/II or III) (p = 0.007). Binomial logistic regression showed that HPV DNA in the blood (p = 0.000; OR: 9.324; CI:3.612-24.072) and cervical lesions (p = 0.011; OR: 3.622; CI:1.338-9.806) were associated with HPV DNA in the cervix. However, we did not find an association between HPV DNA in the blood and cervical lesions (p = 0.385). Our results showed that only HPV DNA found in the cervix was associated with cervical lesions.

Development of synthetic antigen vaccines for COVID-19.

The current pandemic called COVID-19 caused by the SARS-CoV-2 virus brought the need for the search for fast alternatives to both control and fight the SARS-CoV-2 infection. Therefore, a race for a vaccine against COVID-19 took place, and some vaccines have been approved for emergency use in several countries in a record time. Ongoing prophylactic research has sought faster, safer, and precise alternatives by redirecting knowledge of other vaccines, and/or the development of new strategies using available tools, mainly in the areas of genomics and bioinformatics. The current review highlights the development of synthetic antigen vaccines, focusing on the usage of bioinformatics tools for the selection and construction of antigens on the different vaccine constructions under development, as well as strategies to optimize vaccines for COVID-19.

Prevalence and genotype distribution of human papillomavirus in women living with HIV/AIDS in an area of Northeast Brazil.

Women infected by human immunodeficiency virus (HIV) are more likely to manifest oncogenic viral infections including human papillomavirus (HPV). It was investigated the HPV prevalence, genotype distribution and HPV relationship with cervical lesions among women living with HIV in Sergipe state, Northeast Brazil. A prevalence survey was conducted including 270 HIV-infected women who attended the reference center for HIV in Sergipe from August 2014 to November 2017. Cervical samples were processed by the polymerase chain reaction for HPV-DNA detection. Among the 270 HIV-infected women, 190 (70.4%) were between 26 and 49 years old and 159 (55.6%) were coinfected with HPV. Among the coinfected women, 24 viral types were identified; 113 (72%) subjects had high-risk HPV types, and the most prevalent was HPV 16 (53/35.3%). Positive HPV status was statistically associated with having 0 to 8 years of schooling compared with ≥9 years of schooling; and have been diagnosed with HIV infection less than 5 years ago compared with more than 10 years. Cytological abnormalities were found in 13.4% (31/231) of women, most with high-grade squamous intraepithelial lesions (16/51.6%). However, of women who had no cytological lesions or malignancy (200/86.6%), almost half were HPV DNA-positive (99/49.5%). In conclusion, the prevalence of HPV among women living with HIV in Sergipe was high. There was a high frequency of high-risk HPV infection, and a wide diversity of genotypes were detected, with HPV 16 being the most frequent.

Phenotypic and genotypic variations among three allopatric populations of Lutzomyia umbratilis, main vector of Leishmania guyanensis.

BACKGROUND: In South America, Lutzomyia umbratilis is the main vector of Leishmania guyanensis, one of the species involved in the transmission of American tegumentary leishmaniasis. In Brazil, L. umbratilis has been recorded in the Amazon region, and in the state of Pernambuco, Northeastern region, where an isolated population has been identified. This study assessed the phylogeographic structure and size and shape differences of the wing of three Brazilian populations. METHODS: Samples of L. umbratilis were collected from Rio Preto da Eva (north of the Amazon River, Amazonas), from Manacapuru (south of the Amazon River), and from the isolated population in Recife, Pernambuco state. These samples were processed to obtain sequences of the Cytochrome Oxidase I mitochondrial gene. Geometrics morphometry analysis of the right wing shape of the three populations was made using discriminate canonical analysis. RESULTS: Phylogenetic analysis revealed the presence of two distinct monophyletic clades: one clade comprised of the Recife and Rio Preto da Eva samples, and the other clade comprised of the Manacapuru samples. Comparing the Manacapuru population with the Recife and Rio Preto da Eva populations generated high indices of interpopulational divergence. Geometric morphometry analysis indicated two distinct groups between the studied populations. Canonical variate analysis of wing shape indicated that Rio Preto da Eva population is significantly closer to Recife population, and both populations were genetically distant from Manacapuru. CONCLUSION: The polymorphic sites and geometric morphometry analysis indicate that the distance, lack of continuity and environmental differences have not modified the ancestral relationship between Recife and Rio Preto da Eva populations. The genetic and morphological similarities shared by the Recife and Rio Preto da Eva populations suggest that these populations are more closely related evolutionarily. These results confirm the existence of an L. umbratilis species complex in the North and Northeast regions.