Electrostatic Steering Accelerates C3d:CR2 Association.

Electrostatic effects are ubiquitous in protein interactions and are found to be pervasive in the complement system as well. The interaction between complement fragment C3d and complement receptor 2 (CR2) has evolved to become a link between innate and adaptive immunity. Electrostatic interactions have been suggested to be the driving factor for the association of the C3d:CR2 complex. In this study, we investigate the effects of ionic strength and mutagenesis on the association of C3d:CR2 through Brownian dynamics simulations. We demonstrate that the formation of the C3d:CR2 complex is ionic strength-dependent, suggesting the presence of long-range electrostatic steering that accelerates the complex formation. Electrostatic steering occurs through the interaction of an acidic surface patch in C3d and the positively charged CR2 and is supported by the effects of mutations within the acidic patch of C3d that slow or diminish association. Our data are in agreement with previous experimental mutagenesis and binding studies and computational studies. Although the C3d acidic patch may be locally destabilizing because of unfavorable Coulombic interactions of like charges, it contributes to the acceleration of association. Therefore, acceleration of function through electrostatic steering takes precedence to stability. The site of interaction between C3d and CR2 has been the target for delivery of CR2-bound nanoparticle, antibody, and small molecule biomarkers, as well as potential therapeutics. A detailed knowledge of the physicochemical basis of C3d:CR2 association may be necessary to accelerate biomarker and drug discovery efforts

Structure based de novo design of IspD inhibitors as anti-tubercular agents

Tuberculosis is one of the leading contagious diseases, caused by Mycobacterium tuberculosis. Despite improvements in anti-tubercular agents, it remains one of the most prevalent infectious diseases worldwide, responsible for a total of 1.6 million deaths annually. The emergence of multidrug resistant strains highlighted the need of discovering novel drug targets for the development of anti-tubercular agents. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD) is an enzyme involved in MEP pathway for isoprenoid biosynthesis, which is considered an attractive target for the discovery of novel antibiotics for its essentiality in bacteria and absence in mammals. In the present study, we have employed structure based drug design approach to develop novel and potent inhibitors for IspD receptor. To explore binding affinity and hydrogen bond interaction between the ligand and active site of IspD receptor, docking studies were performed. ADMET and synthetic accessibility filters were used to screen designed molecules. Finally, ten compounds were selected and subsequently submitted for the synthesis and in vitro studies as IspD inhibitors

Effect of shape on mechanical properties and deformation behavior of Cu nanowires: An atomistic simulations study

We study the effect of nanowire shape on mechanical properties and deformation behaviour of Cu nanowires using atomistic simulations. Simulations were carried out on $[100]$ nanowires with different shapes such as triangular, square, pentagon, hexagon and circular.Results indicate yield strength is different for different shapes. In both cases, triangular nanowire exhibit the lowest yield strength, while circular nanowire is the strongest. Deformation in all the nanowires is dominated by partials slip and twinning. Due to twinning, different shapes expose different surfaces at the twinned region. All nanowires show ductile failure and square nanowire exhibits the highest failure strain, while it is lowest for triangular nanowire.Comment: 14 pages, 10 Figure

Peptide redesign for inhibition of the complement system: Targeting age-related macular degeneration.

PurposeTo redesign a complement-inhibiting peptide with the potential to become a therapeutic for dry and wet age-related macular degeneration (AMD).MethodsWe present a new potent peptide (Peptide 2) of the compstatin family. The peptide is developed by rational design, based on a mechanistic binding hypothesis, and structural and physicochemical properties derived from molecular dynamics (MD) simulation. The inhibitory activity, efficacy, and solubility of Peptide 2 are evaluated using a hemolytic assay, a human RPE cell-based assay, and ultraviolet (UV) absorption properties, respectively, and compared to the respective properties of its parent peptide (Peptide 1).ResultsThe sequence of Peptide 2 contains an arginine-serine N-terminal extension (a characteristic of parent Peptide 1) and a novel 8-polyethylene glycol (PEG) block C-terminal extension. Peptide 2 has significantly improved aqueous solubility compared to Peptide 1 and comparable complement inhibitory activity. In addition, Peptide 2 is more efficacious in inhibiting complement activation in a cell-based model that mimics the pathobiology of dry AMD.ConclusionsWe have designed a new peptide analog of compstatin that combines N-terminal polar amino acid extensions and C-terminal PEGylation extensions. This peptide demonstrates significantly improved aqueous solubility and complement inhibitory efficacy, compared to the parent peptide. The new peptide overcomes the aggregation limitation for clinical translation of previous compstatin analogs and is a candidate to become a therapeutic for the treatment of AMD

SURVEY, ISOLATION, BIOCHEMICAL CHARACTERIZATION, AND IDENTIFICATION OF HELICOBACTER PYLORI FROM GASTRIC PATIENT BIOPSY

Objective: This study was to isolate and identify the Helicobacter pylori from the biopsy samples of the gastric patient.Methods: Gastric biopsies were collected from the antral region of the gastric patient. Out of 96 patients, 59 males and 37 females in the age group between 11 and 70 years old were selected. A serial dilution of the sample was made. The bacterial colonies were examined on the basis of Gram staining, colony morphology, and biochemical reactions such as catalase, urease, oxidase, nitrate reduction, glycine utilization, growth (different media, different temperature, and salt tolerance), and antibiotic sensitivityResult: From the findings, it was found that 75% (65% of male and 35% of female) have H. pylori infection remaining 25% were not infected. The rate of infection was found to be more in age group 55-65 and less in age group below 25. Among 75% of H. pylori infected patients, 72% are affected with ulcer, 19% with gastric cancer, and 8.3% found to be non-gastric inflammated. Gram staining result declared that the isolated bacteria from the biopsy sample observed to be Gram-negative, spiral shaped rod. Biochemical reports produced positive indication to all the tests.Conclusion: Based on the morphological, staining and biochemical test result, it was confirmed that the isolated bacteria was found to be H. pylori.Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related to death worldwide. In 1994, the international agencyfor research on cancer classified H. pylori as a Class I (definite) carcinogen, as H. pylori infection is considered as an important trigger in the processof carcinogenesis of both types of distal gastric cancer.Â

Radio frequency electromagnetic radiation (RF-EMR) from GSM (0.9/1.8GHz) mobile phones induces oxidative stress and reduces sperm motility in rats

INTRODUCTION: Mobile phones have become indispensable in the daily lives of men and women around the globe. As cell phone use has become more widespread, concerns have mounted regarding the potentially harmful effects of RF-EMR from these devices. OBJECTIVE: The present study was designed to evaluate the effects of RF-EMR from mobile phones on free radical metabolism and sperm quality. MATERIALS AND METHODS: Male albino Wistar rats (10-12 weeks old) were exposed to RF-EMR from an active GSM (0.9/1.8 GHz) mobile phone for 1 hour continuously per day for 28 days. Controls were exposed to a mobile phone without a battery for the same period. The phone was kept in a cage with a wooden bottom in order to address concerns that the effects of exposure to the phone could be due to heat emitted by the phone rather than to RF-EMR alone. Animals were sacrificed 24 hours after the last exposure and tissues of interest were harvested. RESULTS: One hour of exposure to the phone did not significantly change facial temperature in either group of rats. No significant difference was observed in total sperm count between controls and RF-EMR exposed groups. However, rats exposed to RF-EMR exhibited a significantly reduced percentage of motile sperm. Moreover, RF-EMR exposure resulted in a significant increase in lipid peroxidation and low GSH content in the testis and epididymis. CONCLUSION: Given the results of the present study, we speculate that RF-EMR from mobile phones negatively affects semen quality and may impair male fertility

DEVELOPMENT AND VALIDATION OF UV SPECTROPHOTOMETRIC AND REVERSED PHASE‑HIGH PERFORMANCE LIQUID CHROMATOGRAPHY ‑ PDA METHODS FOR THE ESTIMATION OF ALOGLIPTIN BENZOATE

Objective: To develop and validate simple, rapid, precise, accurate, and economical UV spectrophotometric and reverse phase high performanceliquid chromatographic methods for the estimation of alogliptin benzoate (AGP).Methods: UV spectrophotometric method was performed using UV/Vis double beam spectrophotometer with a spectral bandwidth of 1 nm and1.0 cm matched quartz cells. The maximum absorbance of AGP was observed at 276 nm using methanol as solvent. Reversed phase-high performanceliquid chromatography (RP-HPLC) method was carried out on a Unisol reverse phase C18 column (150 mm × 4.6 mm, 3 μm) with a mobile phasecomposed of methanol and 10 mM ammonium acetate buffer (adjusted to pH 5.0 with glacial acetic acid) in the ratio of 80:20 v/v with a flow rate of0.8 ml/minutes.Results: The linearity of methods was found to be in the range of 5-35 µg/ml (UV) and 20-100 µg/ml (RP-HPLC) and the correlation coefficient was0.999 for both the methods. The regression equations were y = 0.028x + 0.023 (UV) and y = 28,58,942x - 4,33,647 (HPLC). The retention time of AGPwas 2.37 minutes.Conclusion: The proposed methods were validated in terms of linearity, precision, accuracy, specificity, robustness, limit of detection, and limit ofquantitation as per International Conference on Harmonization Q2 R1 guidelines. Thus, the proposed methods are novel, sensitive, and reliable andcan be successfully used for the quantitation of AGP.Keywords: Alogliptin benzoate, UV-visible spectrophotometer, Reversed phase-high performance liquid chromatography, International Conferenceon Harmonization guidelines

Transfer Learning based Automated Essay Summarization

The human evaluation of essays has become a very time-consuming process as the number of schools and universities has grown. The available software entities are unable to assess the sentiment associated with essays. Thus, we propose a model using Natural Language Processing to assess the essay based on both grammar and sentiment associated with the essay by using linear regression and ULMFiT (Universal Language Model Fine-tuning for Text Classification) models.  Evaluation of essay is done in two parts. Part one is on essay grading with respect to grammar with maximum 12 and minimum 0 grade points and in part two score of 0/1 for sentiment analysis with 0 being negative and 1 being positive. The model can be used to score the essay and discard any essay with a score less than a specified value or specified sentiment score