A novel route for the synthesis of polyaniline nanofibers in the presence of varying amounts of zinc oxide has been reported in this paper. The homogeneous PANI nanofibers were prepared through ...template approach, in which the ZnO nanoparticles were used as template. Structural, optical and morphological analysis of synthesized nanofibers was carried out using X-ray diffraction, UV–vis, IR spectroscopy and FESEM techniques. The thick films of the synthesized polyaniline powder were deposited on alumina substrate and their sensing response to ammonia gas was investigated. Optimum sensing response was achieved with PANI nanofibers synthesized in the presence of 30wt% ZnO powder. The sensing response of fabricated sensor was proportional to the ammonia gas concentration and exhibited excellent selectivity toward ammonia gas.
Nitro-substituted 1,3-benzothiazinones (nitro-BTZs) are mechanism-based covalent inhibitors of Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose-2'-oxidase (DprE1) with strong ...antimycobacterial properties. We prepared a number of oxidized and reduced forms of nitro-BTZs to probe the mechanism of inactivation of the enzyme and to identify opportunities for further chemistry. The kinetics of inactivation of DprE1 was examined using an enzymatic assay that monitored reaction progress up to 100 min, permitting compound ranking according to k
/K
values. The side-chain at the 2-position and heteroatom identity at the 1-position of the BTZs were found to be important for inhibitory activity. We obtained crystal structures with several compounds covalently bound. The data suggest that steps upstream from the covalent end-points are likely the key determinants of potency and reactivity. The results of protein mass spectrometry using a 7-chloro-nitro-BTZ suggest that nucleophilic reactions at the 7-position do not operate and support a previously proposed mechanism in which BTZ activation by a reduced flavin intermediate is required. Unexpectedly, a hydroxylamino-BTZ showed time-dependent inhibition and mass spectrometry corroborated that this hydroxylamino-BTZ is a mechanism-based suicide inhibitor of DprE1. With this BTZ derivative, we propose a new covalent mechanism of inhibition of DprE1 that takes advantage of the oxidation cycle of the enzyme.
This study aims to add to a rich scholarship on the presence of a verb second constraint in old (Italo-)Romance that has been argued to cause V-to-C raising of both the finite verb and one or more ...constituents, provided we understand this constraint to be lax in these varieties (cf. Ledgeway 2007, 2008). In particular, it analyses a late 14th century old Venetian text, corroborating the existence of this constraint within the variety. Within this study, it will be shown that the syntax of 14th century Venetian is one in which we find the gradual loss of the V2 constraint. This will be shown through a range of phenomena present within the text, such as a loss of Informational Focus fronting, the weakening of subject pronouns, and the loss of scrambling to vP. All in all, this study aims to shed light on the syntax of 14th century Venetian specifically, adding to a growing scholarship on what the incipient loss of the V2 constraint looks like within respective old Romance varieties.
The lipidic mesophase or in meso method for crystallizing membrane proteins has several high profile targets to its credit and is growing in popularity. Despite its success, the method is in its ...infancy as far as rational crystallogenesis is concerned. Consequently, significant time, effort, and resources are still required to generate structure-grade crystals, especially with a new target type. Therefore, a need exists for crystallogenesis protocols that are effective with a broad range of membrane protein types. Recently, a strategy for crystallizing a prokaryotic α-helical membrane protein, diacylglycerol kinase (DgkA), by the in meso method was reported ( Cryst. Growth. Des. 2013, 13, 2846−2857 ). Here, we describe its application to the human α-helical microsomal prostaglandin E2 synthase 1 (mPGES1). While the DgkA strategy proved useful, significant modifications were needed to generate structure-quality crystals of this important therapeutic target. These included protein engineering, using an additive phospholipid in the hosting mesophase, performing multiple rounds of salt screening, and carrying out trials at 4 °C in the presence of a tight binding ligand. The crystallization strategy detailed here should prove useful for generating structures of other integral membrane proteins by the in meso method.
In this contemporary era, wetlands and the entire aquatic diversity are suffering from major pollution problem. Not only the aggregation of higher population in metropolitan causes the production of ...plenty of solid, liquid and gaseous wastes, but also the high-technological industries contribute to a mammoth of wastes in the ecosystem. During the process of industrial effluent discharge into the water bodies, the toxic substances available in these wastes can affect the aquatic flora and fauna, resultantly disturbing the entire system and constituting human health hazards indirectly or directly. The objective of this study was to estimate the nutritional value of the liver and intestine of fish which is being discarded as waste during fish processing and pollution status by calculated water quality index (WQI) and comparison of both wetlands during diverse seasons. WQI of Harike Wetland was observed to be 56.68 which indicates that water quality in this wetland is “poor”, while at Nangal Wetland WQI was calculated to be 39.54 and comes under “good” water quality and safe for the entire ecosystem. HPI (heavy metal pollution index) for Harike Wetland was observed 144.9 and for Nangal Wetland was 3.12, indicating heavy load of heavy metal pollution at test sample site. MI (metal index) value was also detected higher at test sample site (4.76) as compared to that at control site (0.22). The mean total n-3 and n-6 polyunsaturated fatty acids (PUFAs) declined in the liver of test fish samples (Harike Wetland) as compared to control fish (Nangal Wetland) samples except in winter season. Similarly, mean total saturated fatty acids (SFAs) were also found to decline significantly (
p
<0.05) in the liver of test fish sample as compared to control fish sample during autumn and winter seasons. Significant (
p
<0.05) decline of mean total n-3 PUFAs (except winter) and total n-6 PUFAs (except rainy) in the intestine of test fish sample was observed during all the seasons when compared to control fish samples. However, total SFAs were found to increase in the intestine of test fish samples as compared to control fish samples during all the studied seasons. In the present investigation, fluctuations recorded in the water quality parameters and major groups of FAs in the tissues were due to the geographical location and pollution load in the fish samples taken from Harike Wetland.
Rice (Oryza sativa L.) is a highly drought sensitive crop, and most semi dwarf rice varieties suffer severe yield losses from reproductive stage drought stress. The genetic complexity of drought ...tolerance has deterred the identification of agronomically relevant quantitative trait loci (QTL) that can be deployed to improve rice yield under drought in rice. Convergent evidence from physiological characterization, genetic mapping, and multi-location field evaluation was used to address this challenge.
Two pairs of backcross inbred lines (BILs) from a cross between drought-tolerant donor Aday Sel and high-yielding but drought-susceptible rice variety IR64 were produced. From six BC4F3 mapping populations produced by crossing the +QTL BILs with the -QTL BILs and IR64, four major-effect QTL--one each on chromosomes 2, 4, 9, and 10--were identified. Meta-analysis of transcriptome data from the +QTL/-QTL BILs identified differentially expressed genes (DEGs) significantly associated with QTL on chromosomes 2, 4, 9, and 10. Physiological characterization of BILs showed increased water uptake ability under drought. The enrichment of DEGs associated with root traits points to differential regulation of root development and function as contributing to drought tolerance in these BILs. BC4F3-derived lines with the QTL conferred yield advantages of 528 to 1875 kg ha⁻¹ over IR64 under reproductive-stage drought stress in the targeted ecosystems of South Asia.
Given the importance of rice in daily food consumption and the popularity of IR64, the BC4F3 lines with multiple QTL could provide higher livelihood security to farmers in drought-prone environments. Candidate genes were shortlisted for further characterization to confirm their role in drought tolerance. Differential yield advantages of different combinations of the four QTL reported here indicate that future research should include optimizing QTL combinations in different genetic backgrounds to maximize yield advantage under drought.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug ...resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characterizing resistance pathways for antimalarial agents not yet in clinical use will increase our understanding of the potential for resistance. We identified resistance mechanisms of Plasmodium falciparum (Pf) DHODH inhibitors via in vitro resistance selections. We found 11 point mutations in the PfDHODH target. Target gene amplification and unknown mechanisms also contributed to resistance, albeit to a lesser extent. These mutant parasites were often hypersensitive to other PfDHODH inhibitors, which immediately suggested a novel combination therapy approach to preventing resistance. Indeed, a combination of wild-type and mutant-type selective inhibitors led to resistance far less often than either drug alone. The effects of point mutations in PfDHODH were corroborated with purified recombinant wild-type and mutant-type PfDHODH proteins, which showed the same trends in drug response as the cognate cell lines. Comparative growth assays demonstrated that two mutant parasites grew less robustly than their wild-type parent, and the purified protein of those mutants showed a decrease in catalytic efficiency, thereby suggesting a reason for the diminished growth rate. Co-crystallography of PfDHODH with three inhibitors suggested that hydrophobic interactions are important for drug binding and selectivity.
Background: Inhibiting PfDHODH kills malaria parasites, but the potential for drug resistance is unknown.
Results: Selections gave several categories of resistance mutations. Several mutants were hypersensitive to other drugs.
Conclusion: Resistance to PfDHODH inhibitors is largely though mutations in or amplification of the target gene, PfDHODH.
Significance: Resistance to PfDHODH inhibitors is possible but often increases sensitivity to other compounds.
Abstract
Background
Antimicrobial peptides (AMPs) are oligopeptides that act as crucial components of innate immunity, naturally occur in all multicellular organisms, and are involved in the first ...line of defense function. Recent studies showed that AMPs perpetuate great potential that is not limited to antimicrobial activity. They are also crucial regulators of host immune responses that can modulate a wide range of activities, such as immune regulation, wound healing, and apoptosis. However, a microorganism's ability to adapt and to resist existing antibiotics triggered the scientific community to develop alternatives to conventional antibiotics. Therefore, to address this issue, we proposed Co-AMPpred, an in silico-aided AMP prediction method based on compositional features of amino acid residues to classify AMPs and non-AMPs.
Results
In our study, we developed a prediction method that incorporates composition-based sequence and physicochemical features into various machine-learning algorithms. Then, the boruta feature-selection algorithm was used to identify discriminative biological features. Furthermore, we only used discriminative biological features to develop our model. Additionally, we performed a stratified tenfold cross-validation technique to validate the predictive performance of our AMP prediction model and evaluated on the independent holdout test dataset. A benchmark dataset was collected from previous studies to evaluate the predictive performance of our model.
Conclusions
Experimental results show that combining composition-based and physicochemical features outperformed existing methods on both the benchmark training dataset and a reduced training dataset. Finally, our proposed method achieved 80.8% accuracies and 0.871 area under the receiver operating characteristic curve by evaluating on independent test set. Our code and datasets are available at
https://github.com/onkarS23/CoAMPpred
.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tenofovir alafenamide (TAF) is an effective nucleotide reverse transcriptase inhibitor that is used in the treatment of HIV-1 and HBV. Currently, it is being investigated for HIV prophylaxis. Oral ...TAF regimens require daily intake, which hampers adherence and increases the possibility of viral resistance. Long-acting formulations would significantly reduce this problem. Therefore, the aim of this study was to develop a transdermal patch containing TAF and investigate its performance in vitro through human epidermis. Two types of TAF patches were manufactured. Transparent patches were prepared using acrylate adhesive (DURO-TAK 87-2516), and suspension patches were prepared using silicone (BIO-PSA 7-4301) and polyisobutylene (DURO-TAK 87-6908) adhesives. In vitro permeation studies were performed while using vertical Franz diffusion cells for seven days. An optimized silicone-based patch was characterized for its adhesive properties and tested for skin irritation. The acrylate-based patches, comprising 2% w/w TAF and a combination of chemical enhancers, showed a maximum flux of 0.60 ± 0.09 µg/cm²/h. However, the silicone-based patch comprising of 15% w/w TAF showed the highest permeation (7.24 ± 0.47 μg/cm²/h). This study demonstrates the feasibility of developing silicone-based transdermal patches that can deliver a therapeutically relevant dose of TAF for the control of HIV and HBV infections.
The human immunodeficiency virus type 1 (HIV-1) aspartic protease is an important enzyme owing to its imperative part in viral development and a causative agent of deadliest disease known as acquired ...immune deficiency syndrome (AIDS). Development of HIV-1 protease inhibitors can help understand the specificity of substrates which can restrain the replication of HIV-1, thus antagonize AIDS. However, experimental methods in identification of HIV-1 protease cleavage sites are generally time-consuming and labor-intensive. Therefore, using computational methods to predict cleavage sites has become highly desirable.
In this study, we propose a prediction method in which sequence, structural, and physicochemical features are incorporated in various machine learning algorithms. Then, a bidirectional stepwise selection algorithm is incorporated in feature selection to identify discriminative features. Further, only the selected features are calculated by various encoding schemes and used as input for decision trees, logistic regression, and artificial neural networks. Moreover, a more rigorous three-way data split procedure is applied to evaluate the objective performance of cleavage site prediction. Four benchmark datasets collected from previous studies are used to evaluate the predictive performance.
Experiment results showed that combinations of sequence, structure, and physicochemical features performed better than single feature type for identification of HIV-1 protease cleavage sites. In addition, incorporation of stepwise feature selection is effective to identify interpretable biological features to depict specificity of the substrates. Moreover, artificial neural networks perform significantly better than the other two classifiers. Finally, the proposed method achieved 80.0% ~ 97.4% in accuracy and 0.815 ~ 0.995 evaluated by independent test sets in a three-way data split procedure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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