Mycobacterium tuberculosis RuvX is a Holliday junction resolvase formed by dimerisation of the monomeric YqgF nuclease domain.

The Mycobacterium tuberculosis genome possesses homologues of the ruvC and yqgF genes that encode putative Holliday junction (HJ) resolvases. However, their gene expression profiles and enzymatic properties have not been experimentally defined. Here we report that expression of ruvC and yqgF is induced in response to DNA damage. Protein-DNA interaction assays with purified M. tuberculosis RuvC (MtRuvC) and YqgF (MtRuvX) revealed that both associate preferentially with HJ DNA, albeit with differing affinities. Although both MtRuvC and MtRuvX cleaved HJ DNA in vitro, the latter displayed robust HJ resolution activity by symmetrically related, paired incisions. MtRuvX showed a higher binding affinity for the HJ structure over other branched recombination and replication intermediates. An MtRuvX(D28N) mutation, eliminating one of the highly conserved catalytic residues in this class of endonucleases, dramatically reduced its ability to cleave HJ DNA. Furthermore, a unique cysteine (C38) fulfils a crucial role in HJ cleavage, consistent with disulfide-bond mediated dimerization being essential for MtRuvX activity. In contrast, E. coli YqgF is monomeric and exhibits no branched DNA binding or cleavage activity. These results fit with a functional modification of YqgF in M. tuberculosis so that it can act as a dimeric HJ resolvase analogous to that of RuvC.

Real-life Safety Profile of ZRC3197 (Adalimumab Biosimilar) in Indian Patients with Common Rheumatic Diseases.

The advent of biologic therapies has brought in significant improvement in the outcome of patients suffering from chronic inflammatory arthritis. High costs and unavailability have however, limited their utility in some parts of the world. These limitations have been overcome to a good extent by the introduction of biosimilar versions of original products, which are gaining momentum, of late. Adalimumab (Humira®), a TNF-α inhibitor has been successfully used in patients with inflammatory arthritis for more than a decade now. ZRC3197 (Adalimumab Biosimilar) was developed in India and approved for use since 2014. Ongoing evaluation of safety in real-world setting outside the context of controlled clinical trials is pivotal in ensuring long-term safety of such biologic therapies. We share the real-life safety profile of biosimilar Adalimumab in patients with chronic inflammatory arthritis and other autoimmune conditions from a tertiary care centre in south India.

Esterase-Responsive Floxuridine-Tethered Multifunctional Nanoparticles for Targeted Cancer Therapy.

Floxuridine is a potential clinical anticancer drug for the treatment of various cancers. However, floxuridine typically causes unfavorable side effects due to its very poor tumor selectivity, and, hence, there is a high demand for the development of novel approaches that permit the targeted delivery of floxuridine into cancerous cells. Herein, the design and synthesis of an esterase-responsive multifunctional nanoformulation for the targeted delivery of floxuridine in esterase-overexpressed cancer cells is reported. Photopolymerization of floxuridine-tethered lipoic acid results in the formation of amphiphilic floxuridine-tethered poly(disulfide). Self-assembly of the amphiphilic polymer results in the formation of nanoparticles with floxuridine decorated on the surfaces of the particles. Integration of aptamer DNA for nucleolin onto the surface of the nanoparticle is demonstrated by exploring the base-pairing interaction of floxuridine with adenine. Targeted internalization of the aptamer-decorated nanoparticle into nucleolin-expressed cancer cells is demonstrated. Esterase triggered cleavage of the ester bond connecting floxuridine with the polymer backbone, and the subsequent targeted delivery of floxuridine into cancer cells is also shown. Excellent therapeutic efficacy is observed both in vitro and also in the 3D tumor spheroid model. This noncovalent strategy provides a simple yet effective strategy for the targeted delivery of floxuridine into cancer cells in a less laborious fashion.

Molecular docking analysis of metformin analogues with GSK-3ß.

We report the molecular docking analysis of four analogues of metformin [1-Carbamimidoyl-1,2-dimethylguanidine hydrochloride, Metformin hydrochloride, N1,N1-Dimethyl-N5-methylbiguanide hydrochloride, and N1,N1,N5,N5-Tetrakis (methyl-biguanide hydrochloride] with GSK3.