Dengue virus (DENV) is a danger to more than 400 million people in the world, and there is no specific treatment. Thus, there is an urgent need to develop an effective method to combat this ...pathology. NS2B/NS3 protease is an important biological target due it being necessary for viral replication and the fact that it promotes the spread of the infection. Thus, this study aimed to design DENV NS2B/NS3pro allosteric inhibitors from a matrix compound. The search was conducted using the Swiss Similarity tool. The compounds were subjected to molecular docking calculations, molecular dynamics simulations (MD) and free energy calculations. The molecular docking results showed that two compounds, ZINC000001680989 and ZINC000001679427, were promising and performed important hydrogen interactions with the Asn152, Leu149 and Ala164 residues, showing the same interactions obtained in the literature. In the MD, the results indicated that five residues, Lys74, Leu76, Asn152, Leu149 and Ala166, contribute to the stability of the ligand at the allosteric site for all of the simulated systems. Hydrophobic, electrostatic and van der Waals interactions had significant effects on binding affinity. Physicochemical properties, lipophilicity, water solubility, pharmacokinetics, druglikeness and medicinal chemistry were evaluated for four compounds that were more promising, showed negative indices for the potential penetration of the Blood Brain Barrier and expressed high human intestinal absorption, indicating a low risk of central nervous system depression or drowsiness as the the side effects. The compound ZINC000006694490 exhibited an alert with a plausible level of toxicity for the purine base chemical moiety, indicating hepatotoxicity and chromosome damage in vivo in mouse, rat and human organisms. All of the compounds selected in this study showed a synthetic accessibility (SA) score lower than 4, suggesting the ease of new syntheses. The results corroborate with other studies in the literature, and the computational approach used here can contribute to the discovery of new and potent anti-dengue agents.
High-resolution satellite images, digital elevation models, bathymetric and sedimentological surveys coupled with statistical analysis were used to understand the physical environment and discuss ...their influence on water quality of the five upland lakes of Serra Sul dos Carajás, southeast Amazonia. The lakes have mid-altitude ranges (elevation), very small (catchment) and shallow to very shallow (central basins). Based on the length, area and volume, Violão and TI (Três Irmãs)-3 lakes may present large vertical movements of the water due to wind action and weakly stratified waters. Trophic conditions based on depth and shore development (Ld) parameters must be used with caution, since Amendoim Lake is relatively deep, but it is oligotrophic to ultra-oligotrophic. Ld values suggest that the lakes are circular to subcircular and are likely formed by solution process, as also suggested by volume development. TI-2 Lake is only presenting convex central basin and has highest dynamic ratio (DR), thus it may have high sedimentation and erosion rates. Based on the relationship between studied parameters, morphometric index and DR likely influence temperature and dissolved oxygen of waters of TI-2 Lake due to its depth profile and wind-induced surface mixing. Nevertheless, water quality parameters are controlled by catchment characteristics of the lakes.
Limnological characteristics of the Violão and Amendoim lakes, in the Serra dos Carajás, Amazon, were studied interannually (2013-2014). Climate data indicate anomalous conditions during the 2013 ...rainy period with higher rainfall and lower temperature in the beginning (November). Lake levels were influenced after the first and second hour of each rainfall, which showed a strong synchronization between seasonal fluctuation of lake levels and local weather patterns. Based on the water quality, both lakes are classified as classes "1" and "2" in the CONAMA (Conselho Nacional do Meio Ambiente) scheme and as "excellent" to "good" in the WQI (Water Quality Index) categories. However, the limnology is distinctly different between the lakes and seasons. Higher trophic state and phytoplankton productivity were observed mainly during the rainy period in Violão Lake compared to Amendoim Lake. This may be due to deposition of leached nutrients in the former, mainly total phosphorus (TP), which was probably derived from mafic soils and guano. This is consistent with the significant positive correlation between Chlorophyll-a and TP at the end of the rainy period (March-April), whereas this was not observed in the beginning (November). This could possibly be a consequence of the more intense cloud cover, and unusual high rainfall that limits nutrient availability.
This study aimed to evaluate the frequency of Neospora caninum antibodies in rodents from the Island of Fernando de Noronha, Brazil, and to contribute to epidemiological data on neosporosis in this ...region. Blood samples were collected from 154 black-rats (Rattus rattus) and 12 rock-cavies (Kerodon rupestris). The search for anti-N. caninum antibodies was made using the NAT technique, with a cut-off of 1:20. The frequency of positive mice was 5.19% (8/154 - 1:20 titer) and all rock-cavies were negative. The low frequency of antibodies against N. caninum in rodents found in the Island shows the low contamination of the environment where these animals live.
Although dengue is a disease that affects more than 100 countries and puts almost 400 million lives at risk each year, there is no approved antiviral in the treatment of this pathology. In this ...context, proteases are potential biological targets since they are essential in the replication process of this virus. In this study, a library of more than 3,000 structures was used to explore the allosteric inhibition of the NS2B/NS3 protease complex using consensual docking techniques. The results show four best ranked structures that were selected for molecular dynamics and free energy simulations. The present analysis corroborates with other studies (experimental and theoretical) presented in the literature. Thus, the computational approach used here proved to be useful for planning new inhibitors in the combat against Dengue disease.
Abstract The economic losses caused by parasite infections, aggravated by resistance to anthelmintics, have generated demand for alternatives involving non-chemical control, such as the selection of ...resistant animals. The objective of this study was to identify which characteristics best describe animals that are resistant, resilient or susceptible to Haemonchus contortus and estimate the percent number in each category. Sixty-one Morada Nova ewes were evaluated in an extensive system. The performance variables (weight, body condition score), hematological variables (packed cell volume, hemoglobin, white blood cells, segmented neutrophils, lymphocytes, eosinophils, monocytes) and fecal egg counts were measured individually every 14 days during 6 months. The variables were transformed, and analysis of variance was carried out, with construction of a correlation network. Characteristics linked to parasite infection showed variations among the categories, which helped to identify sheep resistant, resilient or susceptible to H. contortus. Based on the analyses performed, 88.3% of the animals were resistant or resilient and only 11.7% were susceptible. Presence of Trichostrongylidae eggs, body condition score, packed cell volume (PCV) and eosinophil counts were found to be good indicators of naturally infected ewes, and there were significant differences between the categories and correlations between the traits.
The involvement of cranial nerves is rare in ATTR amyloidosis. However, involvement has occasionally been reported in the p.Val50Met variant, the most commonly studied worldwide. On the other hand, ...in ATTR p.Ile127Val, an uncommon variant, the cranial nerves IX, X, and XII, are frequently involved.
Here, we present a series of cases of ATTR Ile107Val amyloidosis, in which the involvement of multiple cranial nerves V, VII, IX, X, XI, and XII seems to be routinely included in phenotypic manifestations in different phases of clinical evolution, contributing significantly to the resulting disabilities caused by this variant. The recognition of these manifestations enables earlier diagnoses and reduces complications from the involvement of cranial nerves, such as dysphagia and respiratory impairment, which greatly increase the burden caused by the disease and significantly limit the quality of life.
The phylogenetic position of Triatoma sherlocki within triatomines group was inferred by analyzing mtDNA fragments of Cyt B and 16S ribosomal RNA by using maximum parsimony and Bayesian analysis. ...Despite being differentiated from members of the T. brasiliensis complex on morphologic grounds, molecular phylogenetic analysis suggests T. sherlocki is a member of this complex; moreover, it was placed as a sister species of T. melanica. These suggestions were supported by robust credibility rates. Hence, we show evidence for the paraphyletic group of the "Triatoma brasiliensis complex," which should be composed of T. brasiliensis brasiliensis, T. brasiliensis macromelasoma, T. juazeirensis, T. melanica, and T. sherlocki.
This study outlines a methodology to refine Delphi results as part of the process to design a technology roadmap. The objectives of this paper are: (a) present a methodology to design a TRM using ...Delphi associated with other techniques (morphological analysis, decision matrix, interviews, and prioritization analysis), and (b) demonstrate and discuss the application of proposed TRM methodology to define alternative materials aiming to reduce the weight of structural shock absorbers. The field research consisted of a case study approach in the Brazilian subsidiary of an Italian auto parts MNC combined with action research methodology. The main contributions of this paper are: a) The proposition of a methodology to refine Delphi results as part of the process to design a technology roadmap (TRM), including a decision matrix, interviews with external experts, and a prioritization analysis and b) The action research provided good quality results as well as an opportunity to test the methodology in a company environment during eight months; this is not common to find in the literature.
•We propose management techniques to refine Delphi results of a Technology Roadmap.•Action research provided high quality data during eight months of a TRM project.•We discuss lessons learned of proposed methodology applied to Magneti Marelli COFAP.•Visual graphic triangulation of Delphi and decision matrix was key to TRM design.•The decision matrix can contribute to integrate technical and business views in TRM.
The efficacy of Licochalcone A (LicoA) and its two analogs were reported against
and
, and in experimental model of
. Initially, LicoA and its analogs were screened against promastigote forms of
. ...LicoA was the most active compound, with IC
values of 20.26 and 3.88 μM at 24 and 48 h, respectively. Against amastigote forms, the IC
value of LicoA was 36.84 μM at 48 h. In the next step, the effectivity of LicoA was evaluated
against promastigote and amastigote forms of
. Results demonstrated that LicoA exhibited leishmanicidal activity
against promastigote forms with IC
values of 41.10 and 12.47 μM at 24 and 48 h, respectively; against amastigote forms the IC
value was 29.58 μM at 48 h. Assessment of cytotoxicity demonstrated that LicoA exhibited moderate mammalian cytotoxicity against peritoneal murine macrophages; the CC
value was 123.21 μM at 48 h and showed about 30% of hemolytic activity at concentration of 400 μM.
infected hamsters and treated with LicoA at 50 mg/kg for eight consecutive days was able to significantly reduce the parasite burden in both liver and spleen in 43.67 and 39.81%, respectively, when compared with negative control group. These findings suggest that chalcone-type flavonoids can be a promising class of natural products to be considered in the search of new, safe, and effective compounds capable to treat canine visceral leishmaniosis (CVL).
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