Rational design of thiazolidine-4-one-gallic acid hybrid derivatives as selective partial PPARγ modulators: an in-silico approach for type 2 diabetes treatment.

Type 2 diabetes mellitus is a bipolar metabolic disorder characterized by abnormalities in insulin production from ß-cells and insulin resistance. Thiazolidinediones are potent anti-diabetic agents that act through the modulation of the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor. However, their full agonistic activity leads to severe side effects by stabilizing Helix12 through strong hydrogen bonding with the TYR473 residue. Partial and selective PPARγ modulators (GW0072, GQ16, VSP-51, MRL-20, MBX-213, INT131) have demonstrated superior results compared to full agonists without causing adverse effects, as reported in existing data. To address this uncertainty and advance therapeutic options, we identified and designed a novel class of compounds (A1-A23) based on a hybrid structure combining phenolic and Thiazolidine-4-one's moieties. Our rational drug design strategy incorporated structural-activity relationship principle, and validated the docking studies through calculated the root mean square deviation. Additionally, we conducted molecular docking, binding energy, molecular dynamics simulations, and post-molecular dynamics calculations to evaluate the dynamics behavior between the ligands and protein. The selected ligands demonstrated highly favorable docking scores and binding energies, comparable to the co-crystal (rosiglitazone) such as A12 (-13.9 kcal/mol and -86.2 kcal/mol), A1 (-11.1 kcal/mol and -79.5 kcal/mol), A13 (-11.3 kcal/mol and -91.4 kcal/mol), and the co-crystal itself (-9.8 kcal/mol and -76 kcal/mol), respectively. Finally, the MD revealed that, the selected ligands were equally contributed for stabilization of Helix12 and ß-sheets. It was concluded, the designed ligands (A12, A1, and A13) exhibited weaker hydrogen-bond interactions with specific residue TYR473 which partially modulated the PPARγ protein.Communicated by Ramaswamy H. Sarma.

Tuning the Surface Electronic Structure of Amorphous NiWO4 by Doping Fe as an Electrocatalyst for OER.

Water electrolysis is considered as one of the alternative potential approaches for producing renewable energy. Due to the sluggish kinetic nature of oxygen evolution reaction (OER), it encounters a significant overpotential to achieve water electrolysis. Hence, the advancement of cost-effective transition metal-based catalysts toward water splitting has gained global attention in recent years. In this work, the doping of Fe over amorphous NiWO4 increased the OER activity effectively and achieved stable oxygen evolution in the alkaline medium, which show better electrocatalytic activity as compared to crystalline tungstate. As NiWO4 has poor activity toward OER in the alkaline medium, the doping of Fe3+ will tune the electronic structure of Ni in NiWO4 and boost the OER activity. The as-synthesized Fe-doped amorphous NiWO4 exhibits a low overpotential of 230 mV to achieve a current density of 10 mA cm-2 and a lower Tafel slope value of 48 mV dec-1 toward OER in 1.0 M KOH solution. The catalyst also exhibits long-term static stability of 30 h during chronoamperometric study. The doping of Fe improves the electronic conductivity of Ni-3d states in NiWO4 which play a dominant role for better catalytic activity via synergistic interaction between Fe and active Ni sites. In future, these results offer an alternative route for precious metal-free catalysts in alkaline medium and can be explicitly used in various tungstate-based materials to increase the synergism between the doped atom and metal ions in tungstate-based materials for further improvement in the electrocatalytic performance.

Characterization of Enterocytozoon hepatopenaei causing hepatopancreatic microsporidiosis in L. vannamei and a new molecular method for its detection in shrimps, and other environmental samples.

Hepatopancreatic microsporidiosis (HPM) caused by Enterocytozoon hepatopenaei (EHP) is a disease of utmost concern in almost all shrimp growing countries. The pathogen was characterized by ultramicrography, histopathology and phylogenetic analysis of 18srDNA. A total of 183 biological samples were collected from all major shrimp growing states of the country.The histology technique could be used very well in identifying the site of infection and can aid in diagnosis of EHP. Wet mount and Ultramicrography were employed to observe the structure of spores. A single step PCR based method was developed for detecting the pathogen from variety of DNA samples including shrimp and non-shrimp sources.The developed PCR assay proved to be a robust and reliable technique to detect EHP in shrimps and environmental samples and for assessing the distribution of pathogen within geographical zones, thus aid in mitigating the disease. The PCR primers was also used to generate DIG labelled probe which was successful in binding to the EHP infected cells in HP of shrimp. The presence of pathogen was confirmed from many non-shrimp environmental samples suggests that they could act as reservoirs for recurrent infection in shrimp ponds. Proper control of these reservoirs will be the first step in recovering an EHP affected pond back to normal.

Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.

B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.

Managing Outpatient Cycle Times in Hospitals Using Integrated Closed-Loop Approaches.

Long waiting times in outpatient clinics have multiple adverse effects on patients and their attendants, staff and hospital management. Several approaches practiced to manage the cycle time have been proposed. The purpose of this study was to evaluate the impact of implementing closed-loop based multiple approaches together. This study was conducted in Aravind Eye Hospital (AEH), Madurai, India where several approaches to manage cycle times have been implemented over the years. Scheduling system was introduced to manage COVID-19 specific norms. We compared the cycle times in general outpatient clinics in a regime in which multiple approaches were practiced together before and after introducing scheduling to regimes in which individual approaches were practiced. We analysed how the cycle time varied by patient load. Cycle time for all patient days when the combined approach was used was 19% lower than baseline, and better than under each of the individual approaches. The outcome sustained even during the COVID-19 pandemic that necessitated additional processes and procedures. Therefore, implementing multiple approaches can be more effective to reduce the cycle time than implementing individual approaches.

Modulating the Surface Electronic Structure of Active Ni Sites by Engineering Hierarchical NiFe-LDH/CuS over Cu Foam as an Efficient Electrocatalyst for Water Splitting.

Water electrolysis encounters a challenging problem in designing a highly efficient, long durable, non-noble metal-free electrocatalyst for both oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Here, in our work, a two-step hydrothermal reaction was performed to construct a hierarchal NiFe-layer double hydroxide (LDH)/CuS over copper foam for the overall water splitting reaction. While employed the same as an anode material, the designed heterostructure electrode NiFe-LDH/CuS/Cu exhibits excellent OER performance and it demands 249 mV overpotential to reach a current density of 50 mA cm-2 with a lower Tafel slope value of 81.84 mV dec-1. While as a cathode material, the NiFe-LDH/CuS/Cu shows superior HER performance and it demands just 28 mV of overpotential value to reach a current density of 10 mA cm-2 and a lower Tafel slope value of 95.98 mV dec-1. Hence, the NiFe-LDH/CuS/Cu outperforms the commercial Pt/C and RuO2 in terms of activity in HER and OER, respectively. Moreover, when serving as both the cathode and anode catalysts in an electrolyzer for total water splitting, the synthesized electrode only needs a cell potential of 1.55 V versus RHE to reach a current density of 20 mA cm-2 and long-term durability for 25 h in alkaline media. To study the interfacial electron transfer, Mott-Schottky experiments were performed, representing that the electron is transferred from n-type NiFe-LDH to p-type CuS as a result of creating the p-n junction in NiFe-LDH/CuS/Cu. The formation of this p-n junction allows the LDH layer to be more active toward the OH- adsorption and thereby could allow the OER or HER with a less energy input. This work affords another route to a cost effective, highly efficient catalyst toward producing clean energy across the globe.

Central Retinal Artery: A Human Fetal Cadaveric Study with Histological Correlation.

The optic nerve is the second cranial nerve. It is supplied by the central retinal artery. It is said that this artery starts getting incorporated within the optic nerve at around the sixth week of gestation, and by the ninth week it is entirely inside the optic nerve. However, the point of incorporation lies in the intraorbital course of the optic nerve. The present study aimed at identifying the location of the central retinal artery inside the optic nerve, i.e. the peripheral or central position. Human fetuses of second and third trimester were dissected to expose the optic nerve. Morphometric measurements were taken and sectioned in 3 regions. These transverse sections were subjected to histological procedures. The results showed that the central retinal artery, at its entry into the optic nerve, was peripheral and inferior in 3 of 25 optic nerves and peripheral and lateral in the remaining optic nerves. However, the arteries were all centrally placed, close to the posterior pole of the eyeball. These findings are important for the ophthalmologist in identifying certain congenital anomalies of the eyeball in neonates.

Access to eye care during the COVID-19 pandemic, India.

OBJECTIVE: To study the impact of the coronavirus disease 2019 (COVID-19) pandemic on outpatient visits to eye care facilities in south India. METHODS: We used data on 7.69 million outpatient visits to primary (i.e. vision centres), secondary and tertiary Aravind Eye Care System's centres between January 2019 and June 2021. We compared outpatient numbers and outpatients' age and sex between the pandemic period and the pre-pandemic period in 2019 for all centres, whereas vision and ophthalmic assessments were compared for vision centres only. FINDINGS: During the first wave, the number of outpatient visits at tertiary, secondary and vison centres was 39% (647 968/1 656 296), 60% (170 934/283 176) and 73% (180 502/246 282) respectively, of 2019 levels. During the second wave, outpatient visits at tertiary, secondary and vision centres were 54% (385 092/710 949), 73% (88 383/121 739) and 79% (121 993/154 007), respectively, of 2019 levels. The proportion of outpatients who were female or younger than 20 years or older than 60 years was significantly lower during the first and second waves than in 2019 (P < 0.0001 for all). The proportion of outpatients whose worse eye vision was poorer than 5/60 or who required referral was significantly higher (P < 0.0001 for both). CONCLUSION: Restrictive measurements led to declines in outpatient visits, however the decline was less at secondary and vision centres than at tertiary centres. Easy access to specialized ophthalmic care via telemedicine and the relative proximity of these centres to communities helped reduce barriers to access.

Prevalence of elevated blood lead levels and risk factors among children living in Patna, Bihar, India 2020.

Childhood lead exposure remains a key health concern for officials worldwide, contributing some 600,000 new cases of intellectually disabled children annually. Most children affected by high exposure to lead live in low- and middle-income countries. The leaded gasoline phase out in India was completed in 2000. Yet, in 2020, an estimated 275 million children aged 0 to 9 years had blood lead levels (BLLs) ≥ 5 µg/dL known to adversely affect intelligence and behavior. Lead sources reported in India include spices, cookware, paint, traditional medicines and cosmetics, and lead-acid battery recycling and repair. However, their relative contribution has not been characterized. More than 200 lead pollution sites related to battery recycling and repair activities were identified in Bihar and Jharkhand, India. Ninety percent of the recycling sites had soil lead concentrations exceeding the US Environmental Protection Agency's standards. We compared blood and environmental lead levels in two groups of children in Patna, Bihar. Households in proximity to battery recycling operations (Proximal n = 67) versus households distal to these operations (Distal n = 68). The average age of children was 40 months; 46% were female. Overall, the geometric mean (GM) BLL was 11.6 µg/dL. GM BLLs of children in Proximal and Distal households were not significantly different (10.2 µg/dL vs. 13.1 µg/dL respectively; p≤0.07). About 87% children, 56 Proximal and 62 Distal had BLLs ≥5 µg/dl. Lead concentrations in environmental samples were significantly higher in Proximal households (soil mean 9.8 vs. 1.6 µg/ft2; dust mean 52.9 vs. 29.9 µg/ft2 p<0.001; Proximal vs. Distal respectively) whereas concentrations in all spices were higher in Distal households (mean 46.8 vs 134.5 ppm p<0.001; Proximal vs. Distal respectively), and turmeric (mean 59.4 vs. 216.9 ppm Proximal vs. Distal respectively). In multivariate analyses for all children lead in spices and turmeric and number of rooms in the house were significant while for the Proximal group only lead in spices remained in the model. The predictive value of these models was poor. For the Distal group, a model with lead concentration in spices, turmeric and soil and number of rooms in the house was a much better fit. Of the 34 water samples collected, 7 were above the Indian standard of 10 ppb for lead in drinking water (2 in the Proximal area, 5 in the Distal area). Children in Patna, Bihar, India are exposed to multiple sources of lead, with lead levels in house dust and loose, locally sourced spices the most likely to increase blood lead levels. A holistic approach to blood lead testing and source identification and remediation are necessary to prevent lead exposure.

Novel synthesis of fluorescent carbon dots from bio-based Carica Papaya Leaves: Optical and structural properties with antioxidant and anti-inflammatory activities.

Fluorescent carbon dots (CDs) are prepared from a natural resource Carica Papaya Leaves, by sand bath method. The as-synthesized CDs optical and structural properties were characterized by UltraViolet-Visible, FT- IR, and fluorescence spectroscopy. Also the size, shape, and particle size distribution was studied using Transmission electron microscopy technique. These CDs were examined for biomedical applications like free radical scavenging activity using DPPH assay, antioxidant activity using phosphomolybdate assay, and in vitro anti-inflammatory activity using membrane stabilization protocol. The CDs exhibited excellent biological activities at lower concentrations and showed notable half-maximal effective concentration (EC50). The EC50 of free radical scavenging activity (27.6 µg/mL), antioxidant activity (23.00 µg/mL), and in vitro anti-inflammatory activity (15.52 µg/mL) signifies that CDs can be potential therapeutic agents.

A systematic review on the guidelines for nutritional assessment for head and neck cancer patients managed by surgery.

There are a number of guidelines to assess the nutrition status of cancer cases. None of these guidelines are specifically head and neck cancer related; except for the European guidelines. This article reviews the different guidelines in nutrition for cancer cases and also their drawbacks.

Influence of chitosan thioglycolic acid conjugate in improving bioavailability of an antiparkinson drug; Rasagiline Mesylate from transdermal patch.

OBJECTIVE: Parkinson disease (PD) is a chronic disorder of central nervous system mainly affecting the motor systems. The drug of choice to treat PD is Rasagiline Mesylate (RM) and it belongs to BCS class III drug. The objective of the present study was the preparation of transdermal drug delivery system for RM. Several permeation enhancers were screened to be included in the formulation. To achieve desired flux a new strategy was developed by including in-house prepared CTC to enhance the permeation of RM. METHODS: The CTC was prepared by reaction between chitosan and thioglycolicacid, characterized by determining physical properties and applying analytical tools. Seven permeation enhancers with different mechanisms were screened. The transdermal patches were prepared with chitosan along with permeation enhancer IPM, various proportions of CTC and evaluated for physical and permeation studies. The optimized transdermal patch was obtained by two factors and three responses to obtain the design space and further evaluated for pharmacokinetic studies. RESULTS: The results of the present study confirmed the formation of CTC, IPM was best permeation enhancer among all. The presence of CTC in the formulations significantly improved the permeation of RM to achieve desired steady-state flux. The relative bioavailability of optimized transdermal patch was determined and it was observed that improved bioavailability as compared to marketed conventional tablets. CONCLUSION: The study was concluded that CTC has significant influence on permeation enhancing ability of IPM.

Phenomics, genomics of oil palm (Elaeis guineensis Jacq.): way forward for making sustainable and high yielding quality oil palm.

Oil palm (Elaeis guineensis Jacq.) is a heterogeneous, perennial crop having long breeding cycle with a genome size of 1.8 Gb. The demand for vegetable oil is steadily increasing, and expected that nearly 240-250 million tons of vegetable oil may be required by 2050. Genomics and next generation technologies plays crucial role in achieving the sustainable availability of oil palm with good yield and high quality. A successful breeding programme in oil palm depends on the availability of diverse gene pool, ex-situ conservation and their proper utilization for generating elite planting material. The major breeding methods adopted in oil palm are either modified recurrent selection or the modified reciprocal recurrent selection method. The QTLs of yield and related traits are chiefly located on chromosome 4, 10, 12 and 15 which is discussed in the current review. The probable chromosomal regions influencing the less height increment is observed to be on chromosomes 4, 10, 14 and 15. Advanced genomic approaches together with bioinformatics tools were discussed thoroughly for achieving sustainable oil palm where more efforts are needed. Major emphasis is given on oil palm crop improvement using holistic approaches of various genomic tools. Also a road map given on the milestones in the genomics and way forward for making oil palm to high yielding quality oil palm.

A systematic approach for stability-indicating HPLC method optimization for Nilotinib bulk through design of experiments: Application towards characterization of base degradation products by mass spectrometry.

A novel and reliable stability-indicating high-performance liquid chromatography method was developed using design of experiments. Under forced degradation conditions (hydrolysis, oxidative, photolytic and thermal) Nilotinib produced five major degradation products utilizing sodium hydroxide in base hydrolysis. The degradation products were separated by Hypersil ODS column (150×4.6mm i.d., 5µ) utilizing methanol and 10mM ammonium acetate (pH 3.0, adjusted with acetic acid) as mobile phase in gradient elusion mode at a flow rate of 1.2mL/min column temperature set at 35°C and UV detection at 263nm. Tandem mass spectrometry method was used to characterize the base degradation products by accurate mass measurements. The developed method was found to be linear, accurate, precise and selective for the separation of Nilotinib from its degradation products as per the International Conference on Harmonisation guidelines. The structures of the degradation products have been elucidated, of which three degradation products were reported for the first time.

Seven-year trends in cataract surgery indications and quality of outcomes at Aravind Eye Hospitals, India.

PURPOSE: To report trends in cataract surgery indications, visual acuity outcomes, complication rates and reoperation rates at ten Aravind Eye Hospitals in Tamil Nadu, India. METHODS: In this retrospective database study we analyzed seven years of data of cataract surgeries at Aravind during January 1, 2012 to December 31, 2018. Our main outcome measures were preoperative and 1-month postoperative uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA); and rates of intraoperative complications and reoperations. We performed Cochran-Armitage trend tests. RESULTS: In 1.86 million eyes that underwent cataract surgery, the percentage of eyes undergoing phacoemulsification (PE) showed an increasing trend (p < 0.0001), from 26.8% in 2012 to 33.5% in 2018. The percentage of eyes undergoing manual small incision cataract surgery (SICS) showed a decreasing trend (p < 0.0001), from 70.0% in 2012 to 65.1% in 2018. For SICS, the percentages of eyes with good postoperative UCVA and BCVA showed increasing trends (p < 0.0001 for each), and the percentages of eyes with poor postoperative UCVA and BCVA showed decreasing trends (p < 0.0001 for each). Results for PE surgeries were mixed. For both PE and SICS rates of intraoperative complications showed a declining trend (p < 0.0001 for each) and a slight increasing trend for reoperations (PE p < 0.02; SICS p < 0.0001). CONCLUSIONS: During this seven-year period there were noticeable trends in cataract surgeries performed at Aravind in terms of the mix of surgical procedures, preoperative vision, and cataract surgical outcomes.

Genistein binding protein targets in dental pathogens.

Oral pathogens have created a menace in recent years due to biofilm formation and antimicrobial drug resistance. The current treatment strategy works well with antibiotics. However, constant use of antibiotics creates a selective pressure, which increases adaptability of the pathogens. Therefore, it is of interest to analyze the potential targets of genistein in dental pathogens using computer aided prediction tools.

Development and validation of a sensitive LC-MS/MS method for pioglitazone: application towards pharmacokinetic and tissue distribution study in rats.

In the present study, a sensitive LC-MS/MS method was developed and validated to measure pioglitazone (PGZ) concentrations in rat plasma and tissues. The chromatographic separation was achieved by using a YMC Pro C18 column (100 mm × 4.6 mm, 3µ) with a mobile phase consisting of formic acid (0.1% v/v) and acetonitrile (5 : 95) at a flow rate of 0.7 mL min-1 and injection volume of 10 µL (IS: rosiglitazone). Mass spectrometric detection was done using triple quadrupole mass spectrometry using the ESI interface operating in a positive ionization mode. The developed method was validated over a linearity range of 1-500 ng mL-1 with detection and a lower quantification limit of 0.5 ng mL-1 and 1 ng mL-1. The method accuracy ranged from 95.89-98.78% (inter-day) & 93.39-97.68% (intra-day) with a precision range of 6.09-8.12% for inter-day & 7.55-9.87% for intra-day, respectively. The PGZ shows the highest C max of 495.03 ng mL-1 in plasma and the lowest C max, 24.50 ± 2.71 ng mL-1 in bone. The maximum T max of 5.00 ± 0.49 h was observed in bone and a minimum of 1.01 ± 0.05 h in plasma. The AUC(0-24 h and 0-∞) values are highest in plasma (1056.58 ± 65.78 & 1069.38 ± 77.50 ng h-1 mL-1) and lowest in brain (166.93 ± 15.70 &167.12 ± 16.77 ng h-1 mL-1), and the T 1/2 was highest in plasma (5.62 ± 0.74 h) and lowest in kidney (2.78 ± 0.19). The developed method was successfully used to measure the PGZ pharmacokinetic and tissue distribution. Further, the developed method could be utilized for validating target organ (adipose tissue) specific delivery of PGZ (nano-formulations) in addition to conventional dosage forms.

Genetic characterization of maize doubled haploid lines for Fusarium stalk rot caused by Fusarium verticillioides.

Fusarium stalk rot disease (FSR) of maize caused by Fusarium verticillioides (Sacc.) Nirenberg is becoming an important biotic production constraint in many of the major maize growing areas causing substantial yield losses. Inbreds are preferred as parents in hybrid development owing to homozygous nature and high heterotic ability. Double haploid (DH) technology has emerged as a significant milestone. A total of 339 DH lines were generated from two inbred lines, VL1043 (susceptible) and CM212 (resistant), through in vivo haploid induction method. The 339 DH lines along with parents were phenotyped for their response to the FSR at the College of Agriculture, V. C. Farm, Mandya, India during summer, kharif and rabi seasons of the 2019-2020. Best linear unbiased predictors (BLUPs) were estimated for the FSR disease scores over three seasons. Awide range of BLUP scores of three to nine indicated the presence of higher variation for response of DH lines to FSR disease. The higher estimates of standardized range (1.31) and phenotypic coefficient of variation (19.80) also displayed higher variability. Nine lines were moderately resistant and 188 exhibited moderately susceptible reaction. The distribution of DH lines was positively skewed (1.34) and platykurtic (2.31) which suggested complementary epistasis and involvement of large number of genes in the disease expression.