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Healthy aging is associated with a decline in cognitive function, and is a major risk factor for many neurodegenerative diseases. Although, there are several evidence that brain mitochondrial function is altered with aging its significance at the cellular level is elusive. In this study, we have investigated mitochondrial TCA cycle and neurotransmitter cycle fluxes associated with glutamatergic, GABAergic neurons and astroglia in the cerebral cortex and hippocampus of young (6 months) and aged (24 months) C57BL6 mice by using 1 H-[13 C]-NMR spectroscopy together with timed infusion of 13 C-labeled glucose and acetate. The ratio VCyc /VTCA was determined from a steady-state [2-13 C]acetate experiment. Metabolic fluxes were obtained by fitting a three-compartment metabolic model to 13 C turnover of amino acids from glucose. Levels of glutamate, aspartate and taurine were reduced in the cerebral cortex, while glutamine and choline were elevated in the hippocampus of aged mice. Interestingly, the rate of acetate oxidation increased in the cerebral cortex, while the flux of mitochondrial TCA cycle of glutamatergic neurons decreased in the cerebral cortex (P < .0001) and hippocampus (P = .025) of aged mice. The glutamate-glutamine neurotransmitter cycle flux was reduced in the cerebral cortex (P < .0001). The GABAergic TCA cycle flux was reduced in the cerebral cortex (P = .0008), while GABA-glutamine neurotransmitter cycling flux was also reduced in the cerebral cortex (P = .011) and hippocampus (P = .042) of aged brain. In conclusion, the reduction in excitatory and inhibitory neurotransmitter activity of glutamatergic and GABAergic neurons in the cerebral cortex and hippocampus correlates qualitatively with declined cognitive function in aged mice.

Requirements Change Management (RCM) is one of the challenges faced by Global Software Development (GSD) organisations as requirements evolution is inevitable due to dynamic business and o...

Development and operations (DevOps) practices significantly accelerate and automate the continuous delivery and deployment of software systems. However, adopting DevOps concepts is not a s...

The Indian securities market regulator intervened in June 2010 with a regulatory amendment in the listing requirement that mandated all the listed firms other than PSUs (government‐owned companies) to have a minimum public shareholding of 25%. The affected firms were given a 3‐year window to comply with the regulation. This study examines the impact of the new regulation on the affected firms’ value. We explore the relationship between improvement in firms’ value and stock liquidity. This regulatory intervention offers a natural experiment to examine direct causality between stock liquidity and firms’ value. The findings of the empirical analysis confirm the existence of a direct causal relationship between stock liquidity and firm value, stemming from an improved operating performance.

The terminal step of ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of DNA ligases in all mammals. DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of DNA Ligase I, a therapeutic strategy to impede proliferation of cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesised putative DNA Ligase I inhibitors. Based on various biochemical and biophysical screening approaches, we identify two prospective DNA Ligase I inhibitors, SCR17 and SCR21. Both the inhibitors blocked ligation of nicks on DNA in a concentration-dependent manner, when catalysed by cell-free extracts or purified Ligase I. Docking studies in conjunction with biolayer interferometry and gel shift assays revealed that both SCR17 and SCR21 can bind to Ligase I, particularly to the DNA Binding Domain of Ligase I with KD values in nanomolar range. The inhibitors did not show significant affinity towards DNA Ligase III and DNA Ligase IV. Further, addition of Ligase I could restore the joining, when the inhibitors were treated with testicular cell-free extracts. Ex vivo studies using multiple assays showed that even though cell death was limited in the presence of inhibitors in cancer cells, their proliferation was compromised. Hence, we identify two promising DNA Ligase I inhibitors, which can be used in biochemical and cellular assays, and could be further modified and optimised to target cancer cells. © 2016 Wiley Periodicals, Inc.

Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and eukaryotes encode one or more DNA ligases. DNA ligases are indispensable in various DNA repair and replication processes and a deficiency or an inhibition of their activity can lead to accumulation of DNA damage and strand breaks. DNA damage, specially strand breaks at unsustainable levels can lead to replication block and/or cell death. DNA ligases as potential anticancer targets have been realized only recently. There is enough rationale to suggest that ligases have a tremendous potential for novel therapeutics including anticancer and antibacterial therapy, specially when the world is facing acute problems of drug resistance and chemotherapy failure, with an immediate need for new therapeutic targets. Here, we review the current state of the art in the development of human ligase inhibitors, their structures, molecular mechanisms, physiological effects, and their potential in future cancer therapy. Citing examples, we focus on strategies for improving the activity and specificity of existing and novel inhibitors by using structure-based rational approaches. In the end, we describe potential new sites on the ligase I protein that can be targeted for the development of novel inhibitors. This is the first comprehensive review to compile all known human ligase inhibitors and to provide a rationale for the further development of ligase inhibitors for cancer therapy.

Software organizations are increasingly combining agile methodologies and distributed software development (DSD) for efficiently and effectively built software products. There are numerous...

Myelomatous pleural effusion is a very rare presentation of multiple myeloma. A 65-year-old male patient presented to us with complaints of dyspnea and left-sided chest pain. His contrast enhanced computed tomography of the thorax showed left-sided pleural effusion with multiple pleural nodules. His pleural fluid cytology shows malignant plasma cells with eccentric nuclei and cart wheel chromatin and a few cells showing binucleation and multinucleation suggestive of plasma cell myeloma. His pleural fluid and serum electrophoresis showed a distinct band in the gamma globulin region (M-spike). On immunofixation of pleural fluid and serum, immunoglobulin G lambda light chain band was detected. Bone marrow aspiration showed sheets of malignant plasma cells with large and binucleated cells suggestive of multiple myeloma. The patient was diagnosed with multiple myeloma presenting as myelomatous pleural effusion. Intercostal tube drainage and then pleurodesis with talc was performed.