Synthesis of AG10 analogs and optimization of TTR ligands for Half-life enhancement (TLHE) of Peptides

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidosis, which is most commonly, caused by aggregation of Immunoglobulin (Ig) light chains or transthyretin (TTR) in the cardiac muscle, represent an important and often underdiagnosed cause of heart failure. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. AG10 is a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of TTR in serum samples obtained from patients with amyloid cardiomyopathy. The oral bioavailability and selectivity of AG10, makes it a very promising candidate to treat TTR amyloid cardiomyopathy. Understanding the reason behind the potency of AG10 would be beneficial for designing stabilizers for other amyloid diseases. This would be possible by designing and synthesizing structural analogues of AG10. Here we report the synthesis, characterization and analysis of AG10 analogs and the comparison of the in vitro activities of the synthesized analogs. The tremendous therapeutic potential of peptides has not been fulfilled and potential peptide therapies that have failed far outnumber the successes so far. A major challenge impeding the more widespread use of peptides as therapeutics is their poor pharmacokinetic profile, due to short In vivo half-life resulting from inactivation by serum proteases and rapid elimination by kidneys. Extending the In vivo half-life of peptides is clearly desirable in order for their therapeutic potential to be realized, without the need for high doses and/or frequent administration. Covalent conjugation of peptides to macromolecules (e.g. polyethylene glycol or serum proteins such albumin) has been the mainstay approach for enhancing the In vivo half-life of peptides. However, the steric hindrance and immunogenicity of these large macromolecules often compromises the In vivo efficacy of the peptides. Recently, our laboratory established the first successful reversible method of extending the half-life of peptides using serum protein TTR. The approach involved the use of a TTR Ligand for Half-life Extension (TLHE-1) which binds to TTR with high specificity and affinity. We have shown that our technology extends the half-life of multiple peptides without seriously affecting their activity. Our main objective here is to modify the structure of TLHE1 using linkers with different length and composition to optimize its affinity and selectivity for TTR in human serum

Master of Science

thesisKneeling is a daily activity for some occupations like carpet layers, miners, tile layers, floor layers, electricians, shipbuilders and many others. Several studies have shown that there is an association between kneeling or squatting and development of osteoarthritis of the knee joint. Even though this relationship has been established, few research studies have been conducted to estimate actual knee stresses and the role of kneepads in reducing these stresses while kneeling. Hence, this study looks at estimating the stress on the knees during simulated kneeling work while wearing six different types of kneepads. Custom force sensors were fabricated using FlexiForce™ Sensors and were placed on both knees over anatomically defined landmarks on the patella and tibial tubercle. Ten participants were recruited and consented to perform a series of kneeling tasks. Five wooden platforms were placed in five different locations surrounding two force plates and custom made three-axis load cells where the participants knelt. A set of five lettered, ceramic tiles were given to each participant and randomly placed on each platform with a corresponding letter. Estimated kneeling reaction forces derived from sensor values were used to quantify the effectiveness of each design in reducing the applied forces on the knee joint. Also these forces were used to verify the significance of location on force. The data from both the sensors and the force plates and load cells were analyzed for results. Two-way analysis of variance (ANOVA) with repeated measures, where kneepad and location were the independent variables and calculated applied force was the independent variable was used to analyze the results. There was a significant relationship between force and kneepad and also between force and location. The placement of the sensor on the knee was found to be a major factor for the estimation of the force on the knees. It is apparent that proper kneepad design and selection can be an effective abatement to reduce the stress accumulated on the knee during kneeling work

The Feministic Vision for Reconstruction of Social Equality

In the history of human race, the role of woman has been wider and her contribution very significant. The Anthropological evidences show that the work of the early woman was tedious. It was only woman‟s food gathering but not man‟s hunting that sustained the humanity. All the tribal societies were centred around and organized through the mothers. But over a period of time the physical strength of males gained importance with the cultivation of land and planned husbandry, and women have been defined as economically dependent, as homemakers and consumers, but not as producers. The failure of societies to acknowledge women‟s contributions has not only undermined women‟s status, but denied their necessary resources. The present paper will discuss the position of woman, origin of feminism, and the feministic vision for reconstruction of social equality

TOPICAL DRUG DELIVERY OF GOSSYPIN FROM PRONIOSOMAL GEL FORMULATIONS: IN VITRO EFFICACY AGAINST HUMAN MELANOMA CELLS

Objective: This work aimed to establish and formulate the gossypinproniosomal gel drug delivery system. Methods: Gossypin-loaded proniosomal gels (GPG) was prepared using specific non-ionic surfactants (Spans), followed by particle size (PS), entrapment efficiency (percent EE), in vitro, ex-vivo drug release, and in vitro efficacy of Gossypin against human melanoma cells (A-375). Results: The results showed that the percentage EE for the GPG is appropriate (81.3 %–95.5 %) and they are Nano-sized (189.3–912.0 nm) and the gels diffusion provided the desired sustaining effect for GPG-F7 formulation (75.5 percent). The GPG reported cell viability of 14.9±2.3 percent compared with 16.1±1.1 percent for free Gossypin at the maximum dose of 100 μg/ml for A-375 human melanoma cells after 24 hr incubation time. No major changes were seen in the percentage EE, PS of GPG after storage for 90d, in the physical stability report. Conclusion: The results obtained suggest that the proniosomal drug delivery system can enhance the flux to the skin and achieve the ideal Gossypin sustainability effect. Consequently, the use of proniosomal gel may be advantageous with regard to the topical delivery of Gossypin for melanoma treatment management

Power quality enhancement using power balance theory based DSTATCOM

The DSTATCOM (Distributed Static Compensator) is used for current harmonic mitigation, Power Factor Correction (PFC), reactive power compensation, load balancing and neutral current compensation in the Power Distribution System (PDS). In this paper, the power balance theory based DSTATCOM is used for power quality enhancement like current harmonic mitigation, power factor correction (PFC), reactive power compensation, load balancing and neural current compensation and load balancing. A non-isolated star/delta transformer is to reduce dc-link voltage v_(dc) of Voltage Source Converter (VSC) and neutral current compensation. The reference source currents can be extracted quickly by using proposed power balance theory. The proposed power balance theory based DSTATCOM is modeled and simulated using MATLAB/SIMULINK under PFC and ZVR (Zero Voltage Regulation) operations

A study on maternal and perinatal out comes in cases of eclampsia admitting to government medical college and general hospital, Anantapuramu, Andhra Pradesh, India

Background: Eclampsia is a life threatening emergency that continues to be a major risk factor dictating the outcome of pregnancy and is still the leading etiological factor of maternal mortality worldwide. The aim was to study the incidence of eclampsia at Government General Hospital, Anantapuramu, Andhra Pradesh, India, to evaluate the clinical course and complications and to study the maternal and perinatal outcome in eclamptic patients.Methods: Current study is a retrospective study carried out based on the data acquired from the case records of all eclampsia patients who admitted in the department of obstetrics and gynecology, government general hospital, Anantapuramu, Andhra Pradesh, India from February 2015 to February 2016. Data was recorded in a pretested proforma and was analyzed using appropriate statistical methods.Results: Out of a total of 8595 deliveries conducted during the study period, 50 cases of eclampsia were recorded making the incidence of eclampsia to be 0.58% in the hospital. There were no maternal deaths occurred during the study period. Total numbers of perinatal deaths due to eclampsia were 14, hence the perinatal mortality rate for eclampsia was 280/1000. Majority of the patients were unbooked (90%). 78% of patients were primigravidas and 80% of patients were less than 25 years of age. Antepartum eclampsia was seen in 72% of the cases, intrapartum eclampsia in 4% patients and postpartum eclampsia was found in 24% of the patients. Vaginal delivery was a common mode of delivery conducted in 56% of patients while 44% of the patients required caesarean section.Conclusions: Eclampsia continues to be an important etiological factor for maternal/perinatal morbidity and mortality. The contributory factors for this being lack of proper antenatal care, low socio economic status and lack of education. There is an urgent need for proper antenatal care, proper medication (magnesium sulfate), intensive monitoring of women with eclampsia and timely hospitalization to improve both the maternal and perinatal outcome. Early presentation and timely decision to terminate pregnancy will improve the maternal and perinatal outcome

Designer Sorghum Combining the High Digestibility and Waxy Grain Traits of Sorghum for Improved Nutrition Bioethanol Beer Feed and Food Products

Sorghum (Sorghum bicolor (L). Moench) is used for human consumption in parts of Africa and Asia and as an animal feed mainly in the U.S. Though sorghum grain contains higher amounts of protein than other cereal grains such as wheat and corn, it is not as readily available for enzyme degradation in humans and animals. Protein body matrices called kafirins surround the starch granules in sorghum. Because the protein is less digestible, the starch is also less digestible for biofuel production. However variation for this trait exists and the line P850029 has a higher protein digestibility compared to other normal grain sorghum lines. This increase in digestibility of protein is due to the rearrangement of the kafirins in the prolamin protein bodies where, the γ-kafirins are rearranged in the seed endosperm and the amount of γ-kafirin in the grain is also reduced. The assay to phenotype the HD trait is time consuming and unpredictable. So identifying a quantitative trait loci (QTL) controlling the protein digestibility trait in sorghum would be beneficial in breeding. A recombinant inbred lines (RILs) population derived from P850029 x ‘Sureno’, were developed and used to map QTL regulating the protein digestibility trait. A single QTL was identified on chromosome 1 between Xtxp43 and Xtxp329. Validation of the identified QTL was done on heterogenous inbred families (HIFs). The results validate the same QTL identified on the RIL population on chromosome 1. Later the high digestibility trait (HD) was integrated with the Waxy trait in sorghum. The Waxy (WX) sorghums have starch completely in the form of amylopectin. The effect of endosperm type on ethanol yield and fermentation efficiencies was studied among HD, WX and HD-WX lines. The HD-WX lines fermented in a shorter time i.e. completed fermentation in 48 h and their fermentation efficiencies were also higher around 90%. The DDGS of the HD-WX lines also had lower residual starch content and 50% higher amino acid lysine content when compared to wildtype sorghum. Moreover, the relation between endosperm traits and grain yield in sorghum has not been fully explored. In this study, we compared the yield and yield components of four unique endosperm phenotypes, HD, WX, HD-WX and wildtype lines. A total of 100 F2:4 derived recombinant inbred lines population from a cross between Tx2907/P850029 were selected with 25 lines from each HD, WX, HD-WX and wild-type line were included in the study. These lines were grown in three replications in College Station and Halfway, Texas in a randomized complete block design. The results show that there are no significant differences in the grain yield

RECENT UPDATE ON PRONIOSOMAL GEL AS TOPICAL DRUG DELIVERY SYSTEM

An existence of transdermal delivery tool, proniosomal gel, has established to showed remarkable development for lipophilic/hydrophilic drugs over additional formulations. Newer drugs of lipophilic nature emerge poor bioavailability, irregular absorption, and pharmacokinetic changes. Therefore, this novel drug delivery system has been proved advantageous over other oral and topical delivery of drug candidates to bypass such disruption. This proniosomal gel basically is a compact semi-solid liquid crystalline (gel) composed of non-ionic surfactants easily formed on dissolving the surfactant in a minimal amount of acceptable solvent and the least amount of aqueous phase and phosphate buffer. Topical application of gel under occlusive condition during which they are converted into nisomes due to hydration by water in the skin present itself. Proniosomal gels are typically present in transparent, translucent, or white semisolid gel texture, which makes them physically stable throughout storage and transport. This review provides an important overview of the preparation, formulation, evaluation, and application of proniosome gel as a drug delivery carrier

Twenty-four-hour QT interval variability: Increased QT variability during sleep in patients with panic disorder

Recent studies on beat-to-beat QT interval variability (QTV) have shown that it can be used as a noninvasive measure of cardiac repolarization lability. It is also a predictor of sudden cardiac death and is higher in patients with anxiety and depression. This study examined the diurnal measures in QTV in 32 normal adults and 22 patients using 24-hour electrocardiogram records. We obtained 8 5-min segments of ECG sampled at 1,000 Hz from the 24-hour records. Our results show that QTV measures at nighttime are significantly higher in patients with panic disorder compared with controls. These findings demonstrate blunted diurnal changes in ventricular repolarization lability in patients resulting in a higher QT variability index during sleep. We speculate that these effects may relate to a relative increase in cardiac sympathetic activity in patients with panic disorder, and may contribute to the increased risk for cardiac mortality in patients with anxiety. Copyright (C) 2002 S. Karger AG, Basel