Pharmacogenomics: Applications in Drug Discovery and Pharmacotherapy

Pharmacogenomics is the scientific study which explains individual variability of drug targets and to explore the genetic basis for such changes. With the completion of human genomic study, clear relation could now be established between the drug response in relation to a person’s genome. Pharmacogenomics, also known as personalized medicine, uses the person’s genome to determine the dose and dosage regimen, so that therapy could be optimized. As with the techniques like DNA microarray technologies person’s response to a therapy can be predicted and new therapies could be assigned. In the present review, the current technologies, and past significance has been discussed

NIOSOMES:THE UNIQUE VESICULAR DRUG CARRIERS

Drug targeting is the ability to direct a therapeutic agent specifically to desired site of action with little or no interaction with nontarget tissue. Niosomes are one of the best carriers for drug targeting. Niosomes are self assembled vesicles composed primarily of synthetic surfactants and cholesterol. They are analogous in structure to the more widely studied liposomes formed from biologically derived phospholipids. Niosomes are biodegradable, relatively nontoxic, more stable and inexpensive, an alternative to liposomes. The method of preparation of niosome is based on liposome technology. The basic process of preparation is the same i.e. hydration by aqueous phase of the lipid phase which may be either a pure surfactant or a mixture of surfactant with cholesterol. After preparing niosomal dispersion, unentrapped drug is separated by dialysis centrifugation or gel filtration. Niosomes can be SUV (Small Unilamellar Vesicles), MLV (Multilamellr Vesicles) or LUV (Large Unilamellar Vesicles). Niosomal drug delivery is potentially applicable to many pharmacological agents for their action against various diseases

Polymer-Inorganic Hybrid Materials: Formation, Processing, Characterization And Applications

Polymers are soft macromolecules that can be structured and designed according to the need. The properties of these materials, however, are often limited due to purely organic nature of these macromolecules. Addition of an inorganic material into the polymer, however, results in a hybrid material with improved properties that are a combination of its constituents. In this dissertation, formation, processing, characterization and applications of two different polymer-inorganic hybrid systems are discussed, where order and dynamics of the hybrid material is driven by the polymer thermodynamics. The first system combines the block copolymer selfassembly with functional inorganic nanoparticles to generate nanostructured and nanoporous thin films. The order in the nanoporous thin films is determined by quantitative image analysis. Nanoporous films are used as templates to generate epitaxial and heteroepitaxial single crystalline nanostructures on silicon substrates. The single crystalline nanostructures are characterized through various microscopy and diffraction techniques to determine the lateral order, crystal structure and orientation of the resulting nanostructures on the substrate. The second system combines a thermoresponsive polymer with charged clay nanoparticles to form hybrid hydrogels with improved mechanical properties. Additional porosity is induced into the gels for faster swelling kinetics. The resulting super-porous hybrid gels are used in a device that induces directed motion by inducing the volume phase transition locally and propagating the volume phase transitions through the length of the gel

ABCF1 is a novel E2 ubiquitin-conjugating enzyme that controls Toll-like receptor-mediated innate immune responses and cytokine storm during sepsis

Immune responses are tightly controlled mechanisms that serve as the primary means by which invading pathogens are eradicated. These mechanisms are governed by the action of several proteins that, when activated, regulate a cascade of downstream effectors in immune cells that help control and, often eliminate the infection. We have discovered a protein, ABCF1, which regulates this immune response cascade through Toll-like receptor (TLR) signaling and helps maintain cellular homeostasis. ABCF1 is the only known member of the ATP-Binding Cassette (ABC) superfamily that lacks a trans-membrane domain and thus doesn’t function as a transporter. Previous studies on ABCF1 indicate a role for this protein in DNA sensing mechanisms and in the pathophysiology of rheumatoid arthritis and autoimmune pancreatitis. We have discovered that ABCF1 is the sole member of the ABC superfamily possessing E2 ubiquitin-conjugating enzyme activity and exclusively regulates TLR4 endocytosis in murine macrophages. In our studies, ABCF1 was found to target Spleen Tyrosine Kinase (SYK) and TNF Receptor Associated Factor (TRAF3) proteins for K63-linked polyubiquitination, thereby regulating the shift from MyD88-dependent to TRIF-dependent signaling. We also observed that ABCF1 negatively regulates MyD88-dependent pro-inflammatory cytokine production in TLR2 and TLR9 signaling, thereby controlling macrophage polarization to the M2 phenotype. ABCF1 was also found to control viral immune responses by regulating OAS1a enzyme activity and negatively regulating ABCE1 thereby modulating RNase L activation. ABCF1 also seemed to control FcγR II-mediated phagocytosis through phosphorylation of SRC Family Kinases (SFKs). Our data also revealed that ABCF1 negatively regulates cytokine storm during the inflammatory phase of sepsis. It associates with TRAF3 and targets TRAF3 for K63-linked poly ubiquitination, thereby controlling the shift from inflammatory phase to immune compromised phase during sepsis. ABCF1 haploinsufficiency was found to trigger lethal renal circulatory dysfunction, which drastically reduced survival rates during the inflammatory phase of sepsis. We herein report the discovery of a novel E2 enzyme, ABCF1, whose E2 ubiquitin-conjugating activity controls TLR-mediated inflammation and cytokine storm during sepsis in murine macrophages.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat

Ponseti Technique for the Management of Congenital Talipes Equinovarus in a Rural Set-Up in India: Experience of 356 Patients

Congenital talipes equinovarus (CTEV), also known as clubfoot, is a complex congenital deformity of the foot that, left untreated, can limit a person’s mobility by making it difficult and painful to walk. Worldwide, 80% of children born with clubfoot are in low- and middle-income countries. The management of clubfoot has a long history. Non-operative management did not become popular, as an increasing number of orthopaedists started leaning towards surgical treatment. The late Dr. Ignacio Ponseti developed a method of clubfoot correction that successfully realigns clubfoot in infants without extensive and major surgery. The aim of the study was to assess the functional outcome of CTEV management by the Ponseti technique, to study the severity of CTEV deformity using the Pirani score, and to evaluate the cost-effectiveness of the technique. A total of 356 cases with 402 feet with CTEV were treated by the Ponseti method. The average age of the children and the number of casts applied before full correction were 4.03 months and 6.91, respectively. There was a good functional outcome in 95.45% of cases (score > 30) at the last follow up. The management of CTEV by the Ponseti technique provides a good functional and cosmetic outcome. In a developing country like India, this technique is a safe, easy, economical method of clubfoot management

Efficient Jitter Analysis for a Chain of CMOS Inverters

This paper presents an efficient method to estimate jitter in a chain of CMOS inverters in the presence of multiple noise sources, including the power supply noise, input data noise, and the ground bounce noise. For this purpose, necessary noise transfer functions are derived and the recently developed EMPSIJ method [J. N. Tripathi, R. Achar, and R. Malik, “Efficient modeling of power supply induced jitter in voltage-mode drivers (EMPSIJ),” IEEE Trans. Compon., Packag.Manuf. Technol., vol. 7, no. 10, pp. 1691–1701, Oct. 2017.] is advanced to handle cascaded CMOS inverter stages. Results from the proposed method are compared with the results from a conventional EDA simulator, which demonstrate a significant speed-up using the proposed method for a comparable accuracy