Interactive effects of long-term management of crop residue and phosphorus fertilization on wheat productivity and soil health in the rice-wheat.

In the context of degradation of soil health, environmental pollution, and yield stagnation in the rice-wheat system in the Indo-Gangetic Plains of South Asia, an experiment was established in split plot design to assess the long-term effect of crop residue management on productivity and phosphorus requirement of wheat in rice-wheat system. The experiment comprised of six crop residue management practices as the main treatment factor with three levels (0, 30 and 60 kg P2O5 ha-1) of phosphorus fertilizer as sub-treatments. Significant improvement in soil aggregation, bulk density, and infiltration rate was observed under residue management (retention/incorporation) treatments compared to residue removal or residue burning. Soil organic carbon (SOC), available nutrient content (N, P, and K), microbial count, and enzyme activities were also significantly higher in conservation tillage and residue-treated plots than without residue/burning treatments. The residue derived from both crops when was either retained/incorporated improved the soil organic carbon (0.80%) and resulted in a significant increase in SOC (73.9%) in the topsoil layer as compared to the conventional practice. The mean effect studies revealed that crop residue management practices and phosphorus levels significantly influenced wheat yield attributes and productivity. The higher grain yield of wheat was recorded in two treatments, i.e. the basal application of 60 kg P2O5 ha-1 without residue incorporation and the other with half the P-fertilizer (30 kg P2O5 ha-1) with rice residue only. The grain yield of wheat where the rice and wheat residue were either retained/incorporated without phosphorus application was at par with 30 and 60 kg P2O5ha-1. Phosphorus levels also significantly affected wheat productivity and available P content in the soil. Therefore, results suggested that crop residue retention following the conservation tillage approach improved the yield of wheat cultivated in the rice-wheat cropping system.

Dermaplaning for Transdermal Drug Permeation Enhancement: A Qualitative and Quantitative Assessment.

In this study, we sought to investigate the effect of dermaplaning, a popular cosmeceutical skin rejuvenation technique on the permeation of drugs. Baclofen and diclofenac were used as hydrophilic and hydrophobic model drugs, respectively. A specific area of skin was treated with 4 strokes of a dermaplane device. Interindividual variability was assessed by having multiple users operate the device for the study. Dermaplaned skin was histologically evaluated and characterized for resistance drop and the depletion of the stratum corneum (SC). The effect of dermaplaning on drug permeation was investigated via in vitro permeation studies. Histology studies depicted the removal of SC and some parts of viable epidermis by dermaplaning. A significant drop in electrical resistance post skin dermaplaning was observed for all treatment groups, signifying the depletion of barrier properties of SC (p < 0.05). Consequently, significant drug flux and permeation were observed over 24 h for the model drugs across dermaplaned skin. However, varied absorption profile was observed in vitro for both drugs across dermaplaned skin. Dermaplaning displayed a better suitability for significantly enhancing the permeation of the hydrophilic drug, baclofen. Evidence of variation in results post dermaplaning was observed amidst multiple users as well (p < 0.05).

Sustained drug delivery strategies for treatment of common substance use disorders: Promises and challenges.

Substance use disorders (SUDs) are a leading cause of death and other ill health effects in the United States and other countries in the world. Several approaches ranging from detoxification, behavioral therapy, and the use of antagonists or drugs with counter effects are currently being applied for its management. Amongst these, drug therapy is the mainstay for some drug abuse incidences, as is in place specifically for opioid abuse or alcohol dependence. The severity of the havocs observed with the SUDs has triggered constant interest in the discovery and development of novel medications as well as suitable or most appropriate methods for the delivery of these agents. The chronic need of such drugs in users warrants the need for their prolonged or sustained systemic availability. Further, the need to improve patient tolerance to medication, limit invasive drug use and overall treatment outcome are pertinent considerations for embracing sustained release designs for medications used in managing SUDs. This review aims to provide an overview on up-to-date advances made with regards to sustained delivery systems for the drugs for treatment of different types of SUDs such as opioid, alcohol, tobacco, cocaine, and cannabis use disorders. The clinical relevance, promises and the limitations of deployed sustained release approaches along with future opportunities are discussed.

Pressure-tensor method evaluation of the interfacial tension between Gay-Berne isotropic fluid and a smooth repulsive wall.

The interfacial properties of a confined thermotropic liquid crystalline material are investigated using a molecular dynamics simulation technique. The pairwise interaction among the soft ellipsoidal particles is modeled by the Gay-Berne (GB) potential. The GB ellipsoids are confined by two soft, smooth, repulsive walls defined by the Weeks-Chandler-Andersen (WCA) potential. The aperiodic confinement due to walls makes the system mechanically anisotropic. Hence using the pressure-tensor method, the interfacial tension of an interface between the bulk isotropic (I) phase and WCA wall at various number densities (ρ) is calculated. From the pressure tensor and orientational order profiles, the arrangement of ellipsoids in the bulk and the vicinity of the wall is determined. The effect of system size and the wall-particle interaction strength (εW) on is also analyzed by varying the system size and εW.

Interfacial stiffness of nematic-smectic B interface in Gay-Berne liquid crystals using capillary wave theory.

The interfacial stiffness for nematic-smectic B (nm-smB) interface in a liquid crystalline (LC) material is calculated using Capillary Wave Theory (CWT) and molecular dynamics simulations. The Gay-Berne (GB) pair potential with parameters κ, κ', µ, and ν equal to 3, 5, 2, and 1 is used to model the LC material. Using a smart three-step recipe, we have obtained an nm-smB phase coexistence in our simulations where the nm and smB directors are nearly parallel to each other and perpendicular to the interface normal. The density profiles are used to compute the nm-smB coexisting density range, the interfacial width, and its position. The smectic phase is differentiated from the nematic phase by using the local bond order parameter (q6q6), which has helped us to demonstrate that the interface is indeed rough. Finally, the interfacial stiffness of the nm-smB interface is computed by following the CWT analysis and is found to be γ̃nm-smB=0.39861kBT/σee 2=0.04429/σss 2, where σee and σss are the length and diameter of the GB LC particles.

Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme.

While designing the anti-inflammatory agents targeting cyclooxygenase-2 (COX-2), we first identified a water loop around the heme playing critical role in the enzyme catalysis. The results of molecular dynamic studies supported by the strong hydrogen-bonding equilibria of the participating atoms, radical stabilization energies, the pKa of the H-donor/acceptor sites and the cyclooxygenase activity of pertinent muCOX-2 ravelled the working of the water-peptide channel for coordinating the flow of H·/electron between the heme and Y385. Based on the working of H·/electron transfer channel between the 12.5 Å distant radical generation and the radical disposal sites, a series of molecules was designed and synthesized. Among this category of compounds, an appreciably potent anti-inflammatory agent exhibiting IC50 0.06 µM against COX-2 and reversing the formalin induced analgesia and carageenan induced inflammation in mice by 90% was identified. Further it was revealed that, justifying its bidentate design, the compound targets water loop (heme bound site) and the arachidonic acid binding pockets of COX-2.

Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor.

The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a with IC50 value and the selectivity for COX-2 0.6 nM and 1666, respectively. The MTD of (S)-3a was 2000 mg kg-1 and its pharmacokinetic studies in rat showed t1/2 7.5 h. This compound reversed acetic acid induced analgesia and carragennan induced inflammation by 50% and 25% in rat when used at a dose 10 mg kg-1. Mechanistically, it was found that compound (S)-3a inhibits COX-2. Overall, the combination of physico-chemical and biological experiments facilitated the development of a new lead molecule to anti-inflammatory drug.

Rational modification of semaxanib and sunitinib for developing a tumor growth inhibitor targeting ATP binding site of tyrosine kinase.

Analysis of the crystal structure of tyrosine kinase in complexation with an ATP analogue, supplemented with the molecular docking studies of semaxanib and sunitinib in the ATP binding site of the enzyme enabled us to make design of a series of tyrosine kinase inhibitors. The combination of pyrrole and indolinone in one molecule and placement of appropriate substituent thereof made the molecule compatible for the hydrophobic sub-pocket of the enzyme. Screening of the compounds over 60 cell line panel of human tumor cell lines identified compound 3a that exhibited GI50 35 nM and 63 nM against MCF7 and MDA-MB-468 cell lines of breast cancer.

Rational modification of the lead molecule: Enhancement in the anticancer and dihydrofolate reductase inhibitory activity.

By using molecular docking studies, the practice of fragment based drug discovery is conceptualized by introducing oxindole and iso-propanol moieties in our previous lead molecule 1. The resulting compound 2 exhibited competitive inhibition and favorable Ka and Ki for hDHFR. The screening of compound 2 at 60 cell line panel of human tumor cell lines showed its considerably better efficacy than compound 1 and hence put the candidature of 2 on stronghold for further studies.

Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent.

Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg(-1) dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 10(4) M(-1) and ΔG of -100.3 kJ mol(-1) in comparison to a Ka 0.41 × 10(3) ± 0.09 M(-1) and ΔG of -19.2 ± 0.06 kJ mol(-1) for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg(-1) dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.

The bioinspired design of a reagent allows the functionalization of Cα-H of α,ß-unsaturated carbonyl compounds via the Baylis-Hillman chemistry under ambient conditions.

A rationally designed reagent capable of affecting alkylation at Cα of α,ß-unsaturated carbonyl compounds is reported. The reaction proceeded at room temperature without any additives. The pH and H-bond formation during the reaction play a key role in the working of the reagent.

Triblock Conjugates: Identification of a Highly Potent Antiinflammatory Agent.

Rationally designed conjugates of chrysin, indole, and barbituric acid were synthesized and screened for their antiinflammatory activities through in vitro and in vivo experiments. Improved over the previously reported chrysin-indole-pyrazole conjugates and also in comparison to the chrysin, indole, and barbituric acid based COX-2 inhibitors, the new compounds have displayed significantly better IC50 for COX-2 and some of them also exhibited inhibition of 5-LOX enzyme. For one of the test compounds, IC50 for COX-2 and 5-LOX was 1 and 1.5 nM, respectively. Investigations of Swiss Albino mice through capsaicin induced paw lickings and dextran induced inflammation showed that these compounds possess appreciable analgesic and antiinflammatory activities. Ki, Ka, and ΔG for the enzyme-compound interaction were calculated and found to be in agreement with the biological data. The experimental results were supported by the molecular docking studies of the compounds in the active site of COX-2 and 5-LOX. Overall, a highly promising antiinflammatory agent was identified.

Transformation of gas-phase amino acid clusters to dipeptides: a nice approach to demonstrate the formation of prebiotic peptides.

RATIONALE: Exploring prebiotic developments is a fascinating area of research which is continually drawing the attention of the scientific community. It is probable that first the biomolecules were formed and then they became aggregated to generate life. Formation of one such biomolecules (peptide ions) is shown in the present experiments. METHODS: All amino acid solutions for recording mass spectra were prepared in 3:6.9:0.1 (v/v/v) acetonitrile/water/formic acid at a concentration of 50 µM. The studies were performed using a Bruker MicroTOF QII mass spectrometer. Before carrying out experiments in the collision cell, atmospheric pressure in-source fragmentations were also performed. The formation of different chemical species was detected with high-resolution mass spectrometry. RESULTS: Here, we show experimentally the formation of amino acid cluster ions of varied populations, when a solution of an amino acid was injected into an electrospray ionization quadrupole time-of-flight (ESI-QTOF) mass spectrometer. During in-source fragmentation/collision cell fragmentation, the non-covalent interaction between two identical amino acids forms either the [M2 + H](+) dimer cluster ion and/or the [M2 + K](+) adduct ion which, by elimination of one molecule of water, form the covalent linked dipeptide. CONCLUSIONS: After the formation of the amino acid cluster, it was established that the creation of the dipeptides, by a covalent bond resulting from the loss of a water molecule, was the initial step towards the formation of the primordial peptides.