Biochemical investigation of phosphodiesterase type IV post-translational modification, cellular localisation and interaction with associated binding proteins

cAMP is a secondary messenger that is involved in a variety of signalling pathways through its effectors including EPAC, PKA and ion channels. cAMP signalling regulates processes such as memory, muscle contraction and inflammatory responses. PDE enzymes offer a mechanism to negatively regulate elevated cAMP levels elicited by activators of adenylyl cyclase. Studies have shown that cAMP signalling is compartmentalised through binding of PDEs to A-kinase anchoring proteins (AKAPs) that scaffold PKA regulatory subunits. In this study post-translational-modification of PDE4 isoforms is investigated. SUMOylation is a relatively newly identified post-translational modification that is known to regulate the structure and function of its substrates. PDE4 isoforms of the PDE4A and 4D subfamilies are SUMOylated by an E3 ligase, PIASy. SUMOylation alters the rolipram sensitivity and potentiates the PKA mediated activation of the isoforms whilst it confers protection from ERK-mediated inhibition of PDE4 activity. SUMOylation alters the association of PDE4 isoforms with binding partners like β-Arrestin, AKAP18 δ and UBC9. Rolipram is an archetypal PDE4 specific inhibitor. In this study it is shown that in cells expressing a GFP tagged form of PDE4A4 undergoes redistribution into accretion foci upon chronic treatment with rolipram. Data suggests that foci formation requires protein turnover and is regulated by signalling pathways such as PI3 kinase pathway, p38 MAP kinase pathway and PKC pathways. Further, the Immunomodulatory drug Thalidomide® also inhibits foci formation. PDE4 isoforms have isoforms specific N-terminal regions, which play a crucial role in sub-cellular localisation and protein-protein interactions. It is shown here that PDE4D5 interacts with a novel RhoGAP called ARHGAP21 which has been previously reported to bind β-arrestins. This interaction is independent of GAP activity of ARHGAP as well as PDE4 activity. Previous reports have indicated a role of β-Arrestin, PDE4 and ARHGAP21 in regulation of actin cytoskeleton dynamics. Hence complex β-Arrestin-PDE4-ARHGAP21 may play a crucial role in regulating actin dynamics

Dynamic Evolutionary Optimization with Particle Swarm Optimization

Many real world optimization problems have to be solved in the presence of uncertainties. An optimization algorithm has to perform satisfactorily under the presence of such dynamic changes in the environment. In addition to it, the algorithm also has to justify for the additional computational cost incurred. Multi population approaches are found very effective in tracking and locating dynamic optima. In addition, it is necessary to reuse the information from the past evolutions as it facilitates a faster and effective convergence after the occurrence of the change. This thesis proposes a new dynamic particle swarm optimization technique that uses multiple swarms to locate a set of optimal solutions and effectively exploits the past information and adapts the population to the corresponding new locations using the concept of relocation radius. The proposed algorithm uses an adaptive hierarchical clustering mechanism to form multiple swarms. The relocation radius is determined based on the change in the functional values of the particles due to change in the environment and the average sensitivities of the decision variables to the corresponding change in the objective space. The newly adapted population is fitter compared to the original population or a randomly initialized population. The algorithm is tested on dynamic benchmark functions and compared to some of the state-of-the-art dynamic evolutionary algorithms and the results are found to be promising. The algorithm performs better than most of the existing algorithms proposed in literature.Electrical Engineerin

Pharmacological evaluation and kinetics of in vitro drug release efficacy of biofabricated silver nanoparticles using medicinally important Justicia neesii Ramamoorthy

Green nanotechnology, the science that utilizes various plant resources for the synthesis of nanoparticles without posing any chemical hazard has proved to be highly efficient and environment friendly technique. This opens up options for the synthesis of novel nanoparticles with desirable characteristics required for various application viz., biosensors, biomedicine, cosmetics, nanobiotechnology, as antimicrobials, electronics, sensing etc. In this context, here, we have made an attempt for cost effective and eco-friendly synthesis of silver nanoparticles (AgNPs) using the extract of medicinally important plant Justicia neesii Ramamoorthy. The phytochemical analysis of the extract exhibited the presence of glycosides, flavonoids, lignins, phenols, phytosterols, reducing sugars, saponins, etc. The absorbance peak of the biofabricated nanoparticles at 425 nm as indicated by UV-Vis spectrophotometer broadens with increase in time indicating their poly dispersity nature and particle size analyzer revealed the average size to be in the range of 20-45 nm. The antioxidant and antimicrobial activity of the synthesized AgNPs demonstrated promising results. The kinetics of in vitro drug release profile of the drug loaded AgNPs was carried out and the data obtained was correlated with various mathematical models. The drug release from AgNPs at both the pH’s shows good fit to the First order model which is obvious from the high values of coefficient of correlation which logically means that the release of drug from AgNPs is dependent on the concentration present within the nanoparticles

Kinetics and in vitro release studies of drug loaded silver nanoparticles from Indigofera tinctoria extract

Silver nanoparticles (AgNP’s) have been successfully fabricated via bio-reduction of Indigofera tinctoria plant extract as the reducing and capping agent. The effects of pH and temperature on the formation of the AgNP’s have been studied. The synthesized AgNP’s have been characterized using UV-Visible spectroscopy, Fourier Transform Infrared (FTIR) spectroscopy, Zeta potential analysis, Scanning Electron Microscope (SEM) and Atomic Force Microscopy (AFM). Antimicrobial activities of the synthesized AgNP’s have been tested against both bacterial and fungal strains by agar well diffusion method. The biomass-capped AgNP’s imparted antimicrobial activity by inhibiting the growth of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus cereus, Aspergillus niger and Penicillium chrysogenum. The antioxidant activities of the synthesized AgNP’s exhibit low IC50 value of ~55.72 μg/mL. Studies on drug loading and kinetics of drug release reveal that I. tinctoria AgNP’s follow the zero-order kinetics at pH 4.6 and pH 7.4. The gradient value of 0.568 (pH 4.6) and 0.6 (pH 7.4) falls between 0.42 < n < 0.85 when fitted into Peppa’s plot indicating that the drug release follow an anomalous transport or non-Fickian diffusion transport, indicating that the diffusion is time dependent

Prevalence of Hepatitis B and Hepatitis C Infections in a Tertiary Care Hospital, Telangana, India - Comparison of Pre-Pandemic and COVID-19 Pandemic times

WHO estimates show that 296 million people were living with chronic hepatitis B infection in 2019 with 1.5 million new infections occurring every year and approximately 290 000 people died from hepatitis C, mostly from cirrhosis and hepatocellular carcinoma. The prevalence and trends of Hepatitis B and Hepatitis C infections were affected during the pandemic, hence this study aimed to compare the difference in prevalence rates, trends, demographic data, and outcomes of Hepatitis B and Hepatitis C cases in pre-pandemic and pandemic era. The study was carried out in a 1060 bedded tertiary care teaching hospital located 90 kilometers away from Hyderabad, Telangana catering to a majorly rural population from around 200 villages. This study was a retrospective observational study where data of 4 years (March 2018 to Feb 2022) of patients whose samples were sent to Microbiology laboratory and were found to be positive for Hepatitis B surface antigen (HBsAg) or antibodies to Hepatitis C (Anti-HCV) were included. The medical records of Hepatitis B and Hepatitis C positive cases were analysed for demographic data like age, sex, address, requesting department, and present status retrieved from the hospital information system. The prevalence rates of Hepatitis B and Hepatitis C infections and trends every year were calculated and compared. Out of the total 39,578 samples tested for Hepatitis B surface antigen, 413 were positive with a seroprevalence of 1.04%. Among the 20,394 samples tested for anti-Hepatitis C antibodies, 53 samples were found to be positive showing a seroprevalence of 0.25%. There was a 23.63% decrease in the number of samples received during the pandemic period demonstrating the impact of COVID-19 on various laboratory testing. Male predominance was observed for both Hepatitis B (65.37%) and Hepatitis C (56.60%) positivity in this study. Hepatitis B was highest in the 61-80 years age group before the pandemic but during the pandemic, Hepatitis B positivity was equally distributed in the 41 to 60 years and 61-80 years age groups. Hepatitis C positive cases were equally distributed in the 41 to 60 years and 61-80 years age groups before the pandemic whereas during the pandemic Hepatitis C positivity was highest among the 41 to 60 years age group. Among the 413 positive cases of Hepatitis B, 315 (76.27%) cases belonged to the rural population and among the 53 Hepatitis C positive cases, 37 (69.81%) cases were from rural areas. The seroprevalence for Hepatitis B surface antigen displayed a decreasing trend in the pandemic era when compared to the pre-pandemic era. Seroprevalence for anti-HCV antibodies showed a small increase in the pandemic era when compared to the pre-pandemic era. Male predominance was observed for both Hepatitis B and Hepatitis C positivity in this study. Hepatitis B was highest in the 61-80 years age group before the pandemic but during the pandemic, Hepatitis B positivity was equally distributed in the 41 to 60 years and 61-80 years age groups. Hepatitis C positive cases were equally distributed in the 41 to 60 years and 61-80 years age groups before the pandemic whereas during the pandemic Hepatitis C positivity was highest among the 41 to 60 years age group. Detailed analysis of these variations in the trends during the pandemic will aid in guiding tertiary care hospitals on the way forward in the retrieval of medical services after the pandemic

Mild and Highly Efficient Stereoselective Synthesis of 2,3-Unsaturated Glycopyranosides using La(NO3)3 · 6H2O as a Catalyst: Ferrier Rearrangement

A mild and highly efficient stereoselective reaction of 3,4,6-tri-O-acetyl-D-glucal with a variety of nucleophiles, viz. alcohols, phenols, thiols, thiophenols, and allyl trimethyl silane (TMS), in the presence of 5 mol% of lanthanum(III) nitrate hexahydrate under solvent-free conditions yielded the corresponding 2,3-unsaturated glycopyranosides (pseudoglycals) in excellent yields

2-(Benzo[d]thia­zol-2-ylsulfon­yl)-1-(4-bromo­phen­yl)ethanone

In the title mol­ecule, C15H10BrNO3S2, the dihedral angle between the benzothia­zole ring system and the benzene ring is 67.57 (12)°. The crystal structure is stabilized by weak inter­molecular C—H⋯O inter­actions. In addition, there is an inter­molecular Br⋯C [3.379 (3) Å] contact which is shorter than the sum of the van der Waals radii of these atoms

Design, Synthesis, and Testing of a Molecular Truck for Colonic Delivery of 5-Aminosalicylic Acid

A molecular scaffold bearing eight terminal alkyne groups was synthesized from sucrose. Eight copies of an azide-terminated, azo-linked precursor to 5-aminosalicylic acid were attached to the scaffold via copper(I)-catalyzed azide–alkyne cycloaddition. The resulting compound was evaluated in a DSS model of colitis in BALB/c mice against sulfasalazine as a control. Two independent studies verified that the novel pro-drug, administered in a dose calculated to result in an equimolar 5-ASA yield, outperformed sulfasalazine in terms of protection from mucosal inflammation and T cell activation. A separate study established that 5-ASA appeared in feces produced 24–48 h following administration of the pro-drug. Thus, a new, orally administered pro-drug form of 5-aminosalicylic acid has been developed and successfully demonstrated

Sustained Immunogenicity of 2-dose Human Papillomavirus 16/18 AS04-adjuvanted Vaccine Schedules in Girls Aged 9-14 Years: A Randomized Trial

Background: We previously reported the noninferiority 1 month after the last dose of 2-dose human papillomavirus 16/18 AS04-adjuvanted (AS04-HPV-16/18) vaccine schedules at months 0 and 6 (2D_M0,6) and months 0 and 12 (2D_M0,12) in girls aged 9-14 years compared with a 3-dose schedule at months 0, 1, and 6 (3D_M0,1,6) in women aged 15-25 years. Here, we report the results at study end (month 36 [M36]).Methods: Girls were randomized 1:1 and received 2 vaccine doses either 6 months (2D_M0,6) or 12 months apart (2D_M0,12); women received 3 doses at months 0, 1, and 6 (3D_M0,1,6). Endpoints included noninferiority of HPV-16/18 antibodies for 2D_M0,6 versus 3D_M0,1,6; 2D_M0,12 versus 3D_M0,1,6; and 2D_M0,12 versus 2D_M0,6; and assessment of neutralizing antibodies, T cells, B cells, and safety.Results: At M36, the 2D_M0,6 and 2D_M0,12 schedules remained noninferior to the 3D_M0,1,6 schedule in terms of seroconversion rates and 3D/2D geometric mean titers for anti-HPV-16 and anti-HPV-18. All schedules elicited sustained immune responses up to M36.Conclusions: Both 2-dose schedules in young girls remained noninferior to the 3-dose schedule in women up to study conclusion at M36. The AS04-HPV-16/18 vaccine administered as a 2-dose schedule was immunogenic and well tolerated in young girls

Efficacy, safety and immunogenicity of a human rotavirus vaccine (RIX4414) in Hong Kong children up to three years of age: A randomized, controlled trial

AbstractBackgroundA phase III, double-blind, randomized, controlled trial was conducted in Hong Kong to evaluate the efficacy, safety and immunogenicity of a human rotavirus vaccine, RIX4414 (Rotarix™) against severe rotavirus gastroenteritis in children up to three years of age.MethodsHealthy infants aged 6–12 weeks were enrolled between 08-December-2003 and 31-August-2005 and received two oral doses of either RIX4414 vaccine (N=1513) or placebo (N=1512) given 2 months apart. Vaccine efficacy was assessed from two weeks post-Dose 2 until the children were two and three years of age. Anti-rotavirus IgA seroconversion rate was calculated pre-vaccination and 1–2 months post-Dose 2 using ELISA (cut-off=20U/mL) for 100 infants. Safety was assessed until the children were two years of age; serious adverse events (SAEs) were recorded throughout the study period.ResultsIn children aged two and three years of life, vaccine efficacy against severe rotavirus gastroenteritis was 95.6% (95% CI: 73.1%–99.9%) and 96.1% (95% CI: 76.5%–99.9%), respectively. The seroconversion rate 1–2 months after the second dose of RIX4414 was 97.5% (95% CI: 86.8%–99.9%). At least one SAE was recorded in 439 and 477 infants who were administered RIX4414 and placebo, respectively (p-value=0.130). Six intussusception cases were reported (RIX4414=4; placebo=2) and none was assessed to be vaccine-related.ConclusionRIX4414 was efficacious, immunogenic and safe in the prevention of rotavirus gastroenteritis for at least two years post-vaccination in Hong Kong children