The NS2B-NS3 protease has been identified as an attractive target for drug development against Zika virus (ZIKV) and combined drug repurposing and structure-based virtual screening has improved the ...development of antiviral drugs. In this study, we performed a structure-based virtual screening of 1861 Food and Administration (FDA) approved drugs available in DrugBank by the selection and docking validation of crystal structure of ZIKV NS2B-NS3 protease (PDB ID 5H4I) using Glide and DOCK 6 software. The antihistaminic chlorcyclizine (Grid score −24.8 kcal/mol) exhibited the most promising interaction with NS2B-NS3 protease in comparison to crystallography ligand (Grid score −15.6 kcal/mol) by interaction to Tyr161 by hydrophobic interactions in the binding site of NS2B-NS3 which is recognized as an important amino acid in substrate molecular recognition. Cytotoxicity and global antiviral activity assay in Vero cells by MTT method showed that chlorcyclizine reduced the ZIKV induced cytopathic effect (EC50 of 69.0 ± 7.3 μM and SI = 1.9), and explicit molecular dynamics simulations implemented on a NAMD program indicated great stability of chlorcyclizine in protease binding site, suggesting the repurposing of chlorcyclizine as a promising finding in anti-ZIKV drug development.
1. Agricultural expansion and intensification are major threats to tropical biodiversity. In addition to the direct removal of native vegetation, agricultural expansion often elicits other ...human-induced disturbances, many of which are poorly addressed by existing environmental legislation and conservation programmes. This is particularly true for tropical freshwater systems, where there is considerable uncertainty about whether a legislative focus on protecting riparian vegetation is sufficient to conserve stream fauna. 2. To assess the extent to which stream fish are being effectively conserved in agricultural landscapes, we examined the spatial distribution of assemblages in river basins to identify the relative importance of human impacts at instream, riparian and catchment scales, in shaping observed patterns. We used an extensive dataset on the ecological condition of 83 low-order streams distributed in three river basins in the eastern Brazilian Amazon. 3. We collected and identified 24,420 individual fish from 134 species. Multiplicative diversity partitioning revealed high levels of compositional dissimilarity (DS) among stream sites (DS = 0.74 to 0.83) and river basins (DS = 0.82), due mainly to turnover (77.8% to 81.8%) rather than nestedness. The highly heterogeneous fish faunas in small Amazonian streams underscore the vital importance of enacting measures to protect forests on private lands outside of public protected areas. 4. Instream habitat features explained more variability in fish assemblages (15%-19%) than riparian (2%-12%), catchment (4%-13%) or natural covariates (4%-11%). Although grouping species into functional guilds allowed us to explain up to 31% of their abundance (i.e. for nektonic herbivores), individual riparian - and catchment - scale predictor variables that are commonly a focus of environmental legislation explained very little of the observed variation (partial R² values mostly <5%). 5. Policy implications. Current rates of agricultural intensification and mechanization tropical landscapes are unprecedented, yet the existing legislative frameworks focusing on protecting riparian vegetation seem insufficient to conserve stream environments and their fish assemblages. To safeguard the species-rich freshwater biota of small Amazonian streams, conservation actions must shift towards managing whole basins and drainage networks, as well as agricultural practices in already-cleared land.
The NS5 methyltransferase (MTase) has been reported as an attractive molecular target for antivirals discovery against the Zika virus (ZIKV). Here, we report structure-based virtual screening of ...42 390 structures from the Development Therapeutics Program (DTP) AIDS Antiviral Screen Database. Among the docked compounds, ZINC1652386 stood out due to its high affinity for MTase in comparison to the cocrystallized ligand MS2042, which interacts with the Asp146 residue in the MTase binding site by hydrogen bonding. Subsequent molecular dynamics simulations predicted that this compound forms a stable complex with MTase within 50 ns. Thus, ZINC1652386 may represent a promising ZIKV methyltransferase inhibitor.
Context
Land use change and forest degradation have myriad effects on tropical ecosystems. Yet their consequences for low-order streams remain very poorly understood, including in the world´s largest ...freshwater basin, the Amazon.
Objectives
Determine the degree to which physical and chemical characteristics of the instream habitat of low-order Amazonian streams change in response to past local- and catchment-level anthropogenic disturbances.
Methods
To do so, we collected field instream habitat (i.e., physical habitat and water quality) and landscape data from 99 stream sites in two eastern Brazilian Amazon regions. We used random forest regression trees to assess the relative importance of different predictor variables in determining changes in instream habitat response variables.
Results
Multiple drivers, operating at multiple spatial scales, were important in determining changes in the physical habitat and water quality of the sites. Although we found few similarities in modelled relationships between the two regions, we observed non-linear responses of specific instream characteristics to landscape change; for example 20 % of catchment deforestation resulted in consistently warmer streams.
Conclusions
Our results highlight the importance of local riparian and catchment-scale forest cover in shaping instream physical environments, but also underscore the importance of other land use changes and activities, such as road crossings and upstream agriculture intensification. In contrast to the property-scale focus of the Brazilian Forest code, which governs environmental regulations on private land, our results reinforce the importance of catchment-wide management strategies to protect stream ecosystem integrity.
Genetic resistance is the main strategy to control Fusarium wilt in common bean. Despite this, few studies have focused on defense mechanisms involved in bean resistance to
Fusarium oxysporum
f. sp.
...phaseoli
(
Fop
). Thus, the present study aimed to investigate the changes in xylem morphology and involvement of phenylpropanoid compounds and their biosynthetic enzymes in bean resistance against
Fop
. Uirapuru and UFSC-01 genotypes characterized, respectively, as susceptible and resistant were used. In roots and hypocotyls, guaiacol peroxidase (GPX), phenylalanine ammonia-lyase (PAL), and polyphenol oxidase (PPO) activities were determined at 0, 1, 2, 3, 4, 5, and 6 days after inoculation (dai), and flavonoids, total phenolics, and lignin content were quantified at 0, 3, and 6 dai. Cross sections of taproots and hypocotyls were examined under epifluorescence (at 1, 3, and 6 dai) and transmission electron (at 6 dai) microscopic to analyze the morphology of xylem cell walls. Overall, there was an increase in the activity of all studied enzymes in resistant bean plants, mainly during advanced colonization stages. Modifications in xylem morphology were more intense in roots of resistant genotype resulting in an increase of occluded cells, organelles, and cell wall strengthening. This study provides evidence that bean resistance is associated with increased phenylpropanoid enzymatic activity and cell wall reinforcement of some xylem cells.
In this paper, a series of new ruthenium complexes of the general formula Ru(NS)(dpphpy)(dppb)PF
(
-
), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt,
), ...2-mercaptopyrimidine (pySm,
), and 4,6-diamino-2-mercaptopyrimidine (damp,
), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by
H-
P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with
showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex
was able to diminish the proteasomal chymotrypsin-like activity to a greater extent.
Gender-affirming surgeries expand the options for physical transition among transgender patients, those whose gender identity is incongruent with the sex assigned to them at birth. Growing medical ...insight, increasing public acceptance, and expanding insurance coverage have improved the access to and increased the demand for gender-affirming surgeries in the United States. Procedures for transgender women, those patients with feminine gender identity, include breast augmentation using implants and genital reconstruction with vaginoplasty. Some transgender women receive medically unapproved silicone injections for breast augmentation or other soft-tissue contouring procedures that can lead to disfigurement, silicone pulmonary embolism, systemic reactions, and even death. MRI is preferred over CT for postvaginoplasty evaluation given its superior tissue contrast resolution. Procedures for transgender men, patients with a masculine gender identity, include chest masculinization (mastectomy) and genital reconstruction (phalloplasty or metoidioplasty, scrotoplasty, and erectile device implantation). Urethrography is the standard imaging modality performed to evaluate neourethral patency and other complications, such as leaks and fistulas. Despite a sizeable growth in the surgical literature about gender-affirming surgeries and their outcomes, detailed descriptions of the imaging features following these surgeries remain sparse. Radiologists must be aware of the wide variety of anatomic and pathologic changes unique to patients who undergo gender-affirming surgeries to ensure accurate imaging interpretation.
RSNA, 2019.
Cutaneous secretions of toad species are an important source of bufadienolides, compounds that exhibit interesting structural features and biopharmacological properties. Here we describe the ...isolation of bufadienolides from the Brazilian toad
Rhinella schneideri parotoid glands secretion, including: marinobufagin (
1), bufalin (
2), telocinobufagin (
3), hellebrigenin (
4), and the atypical 20
S,21
R-epoxymarinobufagin (
5) besides the widespread
β-sitosterol (
6). Starting from natural bufadienolides four derivatives were prepared: 3
β-acetoxy-marinobufagin (
7), 3
β-acetoxy-bufalin (
8), 3
β-acetoxy-telocinobufagin (
9), and 3
β-acetoxy-20
S,21
R-epoxymarinobufagin (
10). The cytotoxic evaluation showed that all natural bufadienolides and their derivatives exhibited moderate to strong activity against human HL-60, SF-295, MDA-MB-435, and HCT-8 cancer cell strains without hemolysis of mouse erythrocytes. The acetylated bufadienolides (
7–9) and the epoxide
10 showed lesser peripheral blood lymphocytes (PBLs) inhibitory activity than their precursors, suggesting that chemical modifications on such compounds can play an important role on the modulation of their cytotoxic profile.
Purpose
We compared the diagnostic accuracy of detecting distant metastases for baseline rectal cancer staging between PET/MRI and conventional staging (CS).
Materials and methods
This prospective ...study from November 2016 to April 2018 included 101 rectal adenocarcinoma patients for primary staging. These patients underwent whole-body PET/MRI in addition to CS (pelvic MRI and thoracic and abdominal contrast-enhanced CT). Different readers analyzed CS and PET/MRI findings for primary tumor, nodal, and metastatic staging. The presence, number, and location of metastases were recorded according to the organ involved (non-regional lymph nodes (LNs), liver, lungs, or others). Lesions were defined as positive, negative, or indeterminate. The number of lesions per organ was limited to 10. The McNemar test was used to compare the accuracies.
Results
PET/MRI exhibited a higher accuracy in detecting metastatic disease than CS in all patients (88.4% vs. 82.6%,
p
= 0.003) and in patients with extramural vascular invasion (EMVI) (88.9% vs. 85.5%,
p
= 0.013). The detection rate of PET/MRI was superior to that of CS for all lesions 84.1% vs. 68.9%,
p
= 0.001, as well as those in the liver (89.2% vs. 84.2%), non-regional LNs (90.0% vs. 36.7%), and lungs (76.4% vs. 66.9%). PET/MRI correctly classified 19/33 (57.5%) patients with indeterminate lesions on CS.
Conclusion
PET/MRI yields higher accuracy than CS for detecting distant synchronous metastases in the baseline staging of patients with rectal cancer and EMVI. PET/MRI exhibited a higher detection rate than CS for identifying non-regional LNs, hepatic lesions, and pulmonary lesions as well as correctly classifying patients with indeterminate lesions.
Trial registration
NCT02537340
Rice (Oryza sativa L.) germplasm represents an extraordinary source of genes that control traits of agronomic importance such as drought tolerance. This diversity is the basis for the development of ...new cultivars better adapted to water restriction conditions, in particular for upland rice, which is grown under rainfall. The analyses of subtractive cDNA libraries and differential protein expression of drought tolerant and susceptible genotypes can contribute to the understanding of the genetic control of water use efficiency in rice.
Two subtractive libraries were constructed using cDNA of drought susceptible and tolerant genotypes submitted to stress against cDNA of well-watered plants. In silico analysis revealed 463 reads, which were grouped into 282 clusters. Several genes expressed exclusively in the tolerant or susceptible genotypes were identified. Additionally, proteome analysis of roots from stressed plants was performed and 22 proteins putatively associated to drought tolerance were identified by mass spectrometry.
Several genes and proteins involved in drought-response, as well as genes with no described homologs were identified. Genes exclusively expressed in the tolerant genotype were, in general, related to maintenance of turgor and cell integrity. In contrast, in the susceptible genotype, expression of genes involved in protection against cell damage was not detected. Several protein families identified in the proteomic analysis were not detected in the cDNA analysis. There is an indication that the mechanisms of susceptibility to drought in upland rice are similar to those of lowland varieties.
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