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This work describes the synthesis, spectroscopy, time-dependent density-functional theory (TDDFT) studies and electrocatalytic activity towards the CO2 reduction of 4′-substituted terpyridine ligand-coordinated Re(i) complexes.

Human DNA ligase (hLigI) plays an important role in the process of DNA replication and repair, making it an important target for cancer. In our tireless efforts for finding selective inhibitors against hLigI, this article reports the design, synthesis and biological activity of a series of 71 curcumin-monocarbonyl-dithiocarbamate hybrid molecules. Many of the synthetic compounds tested in this study show a significant inhibitory effect on the human DNA ligase 1 (hLig1) activity (> 90% inhibition) and demonstrated significant anti-proliferative activity against colon cancer cells (DLD-1) in a concentration dependent manner. In addition, at a concentration of 10 µM, certain compounds showed selective activity towards DLD-1 cells as compared to the normal HEK-293 cells. Overall, our studies demonstrate that two compounds in this series (27 and 49) have significantly better DNA ligase 1 inhibition and anti-proliferative activities than the previously reported monocarbonyl-curcumin hybrid (compound 23*). This study brings us closer towards our quest to explore the molecular space for novel hLig1 inhibitors and to find inhibitors that will be suitable for clinical trials in cancer patients.

The present paper develops a two-sector, specific factor general equilibrium framework for analyzing endogenous skill formation in a dynamic set-up and examining the consequence of a public subsidy policy on education on the skilled-unskilled wage inequality in a small open economy. It shows that given the technologies of production the policy produces a favorable impact on the wage inequality only in one of the two periods while producing an adverse consequence in the other. If the wage income inequality improves (deteriorates) in period 1 it worsens (ameliorates) in period 2 under the same sufficient conditions. The results are found to be more or less valid even in the presence of unemployment of unskilled labour. Finally, some composite policy recommendations have been suggested so that the relative wages always move in favor of the poorer section of the working population.

After the works of Lahiri and Banerjee [6] on the idea of relative order (p, q) of entire functions, we introduce in this paper hyper relative order (p, q) of entire functions where p, q are positive integers with p>q and prove sum theorem, product theorem and theorem on derivative.

The value of the herbal medicine market size was USD 71.19 billion globally in 2016 and is expected to grow even more in the near future. The main obstacle to the growth of herbal medicine is its quality control. The scientific validation by standardization, evaluation of purity, and demonstration of its efficacy in animal models and in humans will increase the trust of users and increase its acceptability. There are various guidelines available for standardization of herbal medicines. Globally each country has its own rules and regulations. In the USA, guidelines for botanical drugs have been revised in 2016. The phytopharma guidelines also came in existence in India in 2015. The scientific validation of herbal drugs requires information regarding pharmacognostic description like taxonomic classification and quality specifications in which heavy metals, ash, and impurity data are important. The herbal medicines which are already used in human do not require any animal studies but if there are any changes in method of extraction and formulation then animal safety data is essential. The toxicity studies in two species are minimally required. The clinical trials are necessary to demonstrate its efficacy for newer drugs. The phase I clinical studies are conducted to assess the maximum tolerated dose of medicine and its safety. The proof of concept and confirmatory clinical trials should be conducted as randomized placebo control trials and as per good clinical practice norms. The regulatory requirements of herbal drugs for clinical trials and marketing permission may be abbreviated, modified or relaxed based on adequate evidence from market or research published in peer-reviewed journals. The current book chapter will discuss the requirements of herbal drugs and practical issue in scientific validation of herbal medicines.

Cathepsin S (CatS) is one of the cysteinyl cathepsins widely studied for its clinical significance and found to be a promising therapeutic target for several diseases; to name a few is arthritis, allergic inflammation, cancer, diabetes, obesity, and cystic fibrosis. Elevated CatS level is a contributing factor for related disorders, and therefore among different strategies to regulate the activity of CatS, one is to design a quality inhibitor. Earlier, we have demonstrated a highly selective CatS inhibitor, RO5444101 interacts primarily with the S2 pocket of the protein which is structurally unique in contrast to other variants of cathepsin. However, the molecular properties of RO5444101 can question its efficacy at the clinical level. In the present study, we have implemented a series of molecular modeling methods to screen the Maybridge library considering the pharmacophoric features of RO5444101 and other relevant inhibitors of CatS. Based on the priority list, eight hits were subjected to biological evaluation. Subsequently, KM07987 was found to be most potent, with the IC50 of

Terrorism and anti-national activities reduce the capital stock of a country, increase levels of uncertainty, and promote counterterrorism expenditures by drawing resources from productive sectors. This chapter analyzes the issue of anti-national activities using a static general equilibrium framework. Anti-nationals appropriate or destroy a part of the existing capital stock. Governments hold preventive or regulatory sectors that monitor and provide security service to reduce such socially deviant activities and, thereby, to prevent misutilization of capital. Incorporating these issues, a general equilibrium model has been developed to examine the impact of a government’s stringent regulatory policies and the expansion of a country’s capital base on the volume of the anti-national sector and its consequent impact on national income as well. The study finds that, contrary to common wisdom, stringent governmental regulatory policies expand the prevalence of anti-national activities and may produce negative impact on national income. Accumulation of capital stock, however, is found to produce a positive impact on the volume of the anti-national sector and national income. Hence, the solution to this problem does not lie in stricter governmental regulation but rather in a conducive environment for capital accumulation. Such a scenario needs to be created.

Fungal infections are one of the most common infections in humans and other animals. Fungal diseases are more common in tropical and subtropical countries. Worldwide more than a billion people suffer from fungal infections annually. Fungal pathogens (yeasts and molds) are diverse in their pathogenesis and they can cause mild infections to life-threatening fungal diseases. For the treatment of fungal infections, only a few classes of antifungal drugs are available because there are many similarities between fungal and human cells. Treatment of fungal infections is becoming more challenging because of the emergence of resistance to currently available drugs. Azole drug is the most common class of antifungal drug which is widely used for the treatment of superficial to systemic infections but unfortunately, many fungal pathogens (e.g., Candida, Aspergillus, Histoplasma, and Paracoccidioides etc.) have developed resistance. Most of the azole resistant fungi also develop resistance against the echinocandin class of drugs. The most common drug-resistance mechanisms include hyphal switching, alteration of drug targets, increased drug efflux by transporter proteins (ABC transporters or Facilitated diffusion superfamily transporter), and permeability barriers associated with biofilms. Thus, this area is in need of some outstanding work to control drug resistant fungal infections. Recently some new therapeutic approaches such as new formulations for antifungal agents, nanoparticle based drugs and immunotherapy (such as vaccines) are under trial to prevent and treat fungal diseases and inducing the production of host antimicrobial molecules. In this book chapter, we describe common fungal diseases, fungal pathogens, disease-causing factors, drug resistant fungal pathogens, mechanisms involved in the emergence of drug resistance, epidemiology of fungal diseases, advanced diagnostic techniques, current and future treatment plans and discuss new approaches for the management of fungal diseases.

A pharmacophore model was generated and validated by using known human DNA ligase inhibitors for the identification of a novel series of monocarbonyl curcumin–thiourea/thiazole hybrids as human DNA ligase I (hLigI) inhibitors. These compounds (14–49) were synthesized and their antiligase and cytotoxic activities were evaluated in vitro. Several compounds from this series have shown significant inhibition of purified hLigI activity and exhibited a low micro molar range of cytotoxic activity against one or more cancer cell lines, with IC50 values ranging from 1.3–48.8 μM. Among these, compound 23 showed antiligase activity at an IC50 value 24.9 ± 1.8 μM, and selective cytotoxicity against DLD1 cancer cell line (IC50 value 8.7 ± 1.9 μM) compared to the reference curcumin (IC50 values were 51.9 ± 8.7 μM and 33.2 ± 1.8 μM for antiligase and cytotoxic activities against DLD1 cell line, respectively), and docking studies showed considerable interactions of compound 23 with hLigI. This new class of potent hLigI inhibitors will serve as a potential lead for further optimization and drug development.

A series of new dihydropyrimidinone–semicarbazone hybrids were successfully synthesised by integrating regioselective multicomponent reaction with the pharmacophore hybridization approach. All the synthesised compounds were evaluated for their hLig1 inhibition potency and most of them were found to be good to moderately active. Out of the tested derivatives, compound 6f showed selective anti-proliferative activity against HepG2 cells in a dose-dependent manner with an IC50 value of 10.07 ± 1.2. It also reduced cell survival at ≤20 μM concentration. Further, analysis of treated HepG2 cell lysates by western blot assay showed increased γ-H2AX levels and upregulation of p53, leading to apoptosis. In silico docking results explain the binding modes of compound 6f to the DNA-binding domain of hLig1 enzyme thereby preventing its nick sealing activity. In addition, the favourable pharmacokinetic properties suggest that this new class of hLig1 inhibitors could be promising leads for further drug development.

The processes of DNA replication and repair are accomplished by the concerted action of several proteins. Among them human DNA ligases play an important role during the last step of almost all DNA replication and repair processes, where they seal the nicks between DNA strands. In humans, three kinds of DNA ligases (human DNA ligase I, III, IV) are found. DNA ligase I (hLigI) is involved in both DNA replication as well as in DNA repair pathways and is reported to be over-expressed in rapidly dividing cells, including cancer cells. For this reason, in this study we have targeted hLigI for studying its response as a novel anticancer target. We have screened for ligase I inhibitors from our in-house small molecule library by a previously validated pharmacophore based virtual screening method and found a novel hLigI inhibitor. This compound (S-097/98) demonstrated antiproliferative activities specifically in DLD-1 (colon), MDA-MB-231 (triple negative breast) and HepG2 (liver) cancer cell lines at low micromolar concentrations of 6–7 μM. Mechanistic studies show that the compound can directly interacts with the hLigI protein and inhibits ligation of both the purified protein in vitro, as well as in cell lysate of DLD-1 cells treated with the inhibitor. The compound also arrests cell cycle progression at the G2/M phase and increases the nuclear size of DLD-1 cancer cells, thereby demonstrating its antiproliferative activity. Finally, the compound promotes cellular apoptosis in DLD-1 cells.

Lysosome has been long understood as a vital digestive organelle. Increasing reports indicate that the lysosome also plays a crucial role in the pathogenesis of a variety of neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Abnormal protein degradation and deposition stimulated by lysosomal dysfunction may cause age-related neurodegeneration. Enormous efforts have been devoted to the development of effective therapeutics against Alzheimer's disease, the most debilitating neurodegenerative disease. Endopeptidase activity of the Cathepsin-B is associated with the pathological processes. Work presented here focuses on identification of new inhibitors against Cathepsin-B protein using diverse computational approaches together. The inhibitors identified were further tested for in-vitro activity using enzyme based assay method. The identified inhibitors provided interesting understanding on how the water thermodynamic properties along with hydrophobic, steric, electronic, and structural requirements contribute to cathepsin-B inhibitory activity. These water thermodynamic studies, may further be used in computer aided drug discovery pipeline to design and predict more potent derivatives of various scaffolds as cathepsin-B inhibitors.

There has been an increasing prevalence of dermatophytosis among the females in India, over the last 5-6 years. Similarly an increase in the occurrence of vulvovaginal infections has also been observed. The recommendations from existing guidelines do not focus on these infections in females and provide optimal outcomes in real world setting. Hence, the aim of the present consensus was to formulate recommendations based on current clinical experience to address these infections. A multispecialty panel of 12 members consisting of 7 gynecologists and 5 dermatologists participated in the pursuit of obtaining consensus by modified Delphi process. All the panelists formulated questionnaire after critical review of literature. Four rounds of questionnaires containing a total of 63 questions were floated through Google docs survey and responses were marked by all the panelists. Agreement for a given question/statement as ≥75% was set to achieve consensus. Out of the 63 questions/statements, consensus was obtained on diagnosis and treatment of dermatophytosis and VVI in non-pregnant and pregnant females, in 61 statements. The panel also formulated treatment algorithm for dermatophytosis and VVI. The present consensus will provide a guidance to the clinicians in India regarding management of dermatophytosis and VVI in pregnant and non-pregnant females in the current scenario of therapeutic challenges in both the infections.

S012-1332 is the first DNA ligase I inhibitor that demonstrated in vivo anti-breast cancer activity. The present study aimed to assess the in vivo pharmacokinetics of S012-1332 in rats and interpret them with in vitro findings. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S012-1332. Following oral administration, the absolute bioavailability was 7.04%. The absorption was prolonged which can be explained by low solubility in simulated gastric fluid and several folds higher solubility in simulated intestinal fluid. The effective permeability across the intestinal membrane in in situ single pass perfusion study for S012-1332 was 5.58 ± 1.83 * 10−5 cm/sec compared to 5.99 ± 0.65 * 10−5 cm/sec for carbamazepine, with no significant difference, indicating S012-1332 has high permeability. It was rapidly partitioning into plasma in blood, where it was stable. Plasma protein binding was moderate which may have attributed to the rapid distribution out of the vascular compartment. The pharmacokinetics of S012-1332 was characterized by extensive clearance as seen with rat liver and intestinal microsomes. In vitro results elucidate the in vivo pharmacokinetic data. These findings provide crucial information for further development of S012-1332 as anti-breast cancer agent.

A series of cationic lipo-benzamide compounds with varying lengths of hydrocarbon chains (C2M–C18M) were evaluated for anti-Candida activity. Four compounds harbouring 8–11 hydrocarbon chains demonstrated concentration-dependent inhibition of fungal cell growth with Minimum Inhibitory Concentration (MIC) of ≤6.2 µg ml−1. The most active compound (C9M) inhibited growth of both Candida albicans and non-albicans strains and is equally active against pairs of azole sensitive and resistant clinical isolates of C. albicans. Compound C9M also inhibited different stages of Candida biofilms. Scanning Electron Microscopy (SEM) of Candida cells after C9M treatment was also done and no significant cell lysis was observed. Hemolysis assay was performed and only 2.5% haemolysis was observed at MIC concentration.

Probiotics are live microorganisms like bacteria and yeast that are consumed along with food for various health benefits. These microorganisms play a very important role not only in intestinal microbial balance but also in maintaining health protection of the host organism against harmful microbiota. Probiotic term means “for life.” The sale of these products has increased worldwide, and sale figures are estimated to cross $45B by the year 2018 due to its wide range of health profits. Humans have used probiotics for decades and centuries involuntarily. Food additives like fermented milk and yogurt have been a major part in regular meals and diet in several parts of the world. Nowadays, probiotics are the most important prescription by gastrointestinal physicians’ because of its potential role in curing certain diseases for which treatment options are limited. The use of probiotics that were initially restricted for antibiotic-associated diarrhea now extends as powerful anti-allergic and anti-inflammatory factors. Lactobacillus and Bifidobacterium are the most important probiotic groups; however, the probiotic potential of Pediococcus, Lactococcus, Bacillus, and yeast is also well known. Probiotics are not only used as food to enhance health but also to cure specific gastrointestinal conditions such as irritable bowel syndrome, inflammatory bowel disease (IBD), and infectious diarrhea (caused by viruses, bacteria, or parasites). They also play an important role in improving skin conditions like eczema. Urinary and vaginal health, allergy prevention, colds, and oral health can be treated with probiotics. This chapter throws light on different probiotics, their health benefits, and regulatory or safety issues linked with their usage.

The present article illustrates the serendipitous discovery of a cationic-lipid-based human DNA ligase (hLig) I inhibitor and the development of siRNA delivering, a hLigI-targeted cationic-lipid-based nonviral vector. We have tested a small in-house library of structurally similar cationic lipo-anisamides for antiligase activity, and amongst tested, N-dodecyl-N-(2-(4-methoxybenzamido)ethyl)-N-methyldodecan-1-ammonium iodide (C12M) selectively and efficiently inhibited the enzyme activity of hLigI, compared to other human ligases (hLigIIIβ and hLigIV/XRCC4) and bacterial T4 DNA ligase. Furthermore, upon hydration with equimolar cholesterol, C12M produced antiligase cationic liposomes, which transfected survivin siRNA and showed significant inhibition of tumor growth.

The histone acetyl transferase (HAT) are involved in acetylation of histones that lead to transcription activation in numerous gene regulatory mechanisms. There are very few GCN5 HAT inhibitors reported despite of their role in cancer progression. In this study, we have utilized in-silico virtual screening approaches based on various machine learning algorithm to identify potent inhibitors of GCN5 HAT from commercially available Maybridge library. We have generated predictive chemoinformatics models based on k-Nearest neighbour, naive Bayesian, Random Forest and Support Vector Machine. Based on statistical parameters, the RF and SVM models have shown comparative performance. Therefore, we performed the virtual screening with these two models and the consensus hits were selected for further evaluation using molecular docking into the active site of GCN-5 HAT. Finally, a set of 10 molecules were selected and subjected to biological evaluation. Subsequently, inhibition of acetylation shown by three out of the ten molecules in the in-vitro experiments validated their utility as potential HAT inhibitors. Furthermore, the selected hits have also shown weak cell growth decrease in MCF-7 cancer cell lines, which suggests that after subsequent structural optimization the identified molecules may further be explored for the development of anti-cancer agents.

Purpose. Candida species have become resistant to commonly used anti-fungal drugs like fluconazole and echinocandins. In our screen, a series of quaternary ammonium compounds (QACs) emerged as an alternative treatment choice for drug-resistant Candida infections. Methodology. Medium alkyl chain cationic lipo-oxazoles comprising six to thirteen twin carbon chains and a quaternary ammonium unit were synthesized and evaluated for their in vitro anti-Candida and biofilm inhibition activity. SEM was performed to visualize membrane distortion. Results/Key findings. Heptyl and octyl chain analogues (5c, 6b and 6c) showed promising anti-fungal activity. Compound 5c was active against both fluconazole-sensitive and resistant clinical isolates of Candida albicans as well as non-albicans Candida strains. 5c also inhibited the adhesion of C. albicans cells to a polystyrene surface and restricted biofilm formation. SEM further confirmed Candida cell membrane distortion by 5c. Conclusion. A novel class of QACs, called cationic lipo-oxazoles, was tested and found to exhibit anti-fungal activity against planktonic cells as well as biofilms of Candida.

Human Flap endonuclease1 (FEN1) is an enzyme that is indispensable for DNA replication and repair processes and inhibition of its Flap cleavage activity results in increased cellular sensitivity to DNA damaging agents (cisplatin, temozolomide, MMS, etc.), with the potential to improve cancer prognosis. Reports of the high expression levels of FEN1 in several cancer cells support the idea that FEN1 inhibitors may target cancer cells with minimum side effects to normal cells. In this study, we used large publicly available, high-throughput screening data of small molecule compounds targeted against FEN1. Two machine learning algorithms, Support Vector Machine (SVM) and Random Forest (RF), were utilized to generate four classification models from huge PubChem bioassay data containing probable FEN1 inhibitors and non-inhibitors. We also investigated the influence of randomly selected Zinc-database compounds as negative data on the outcome of classification modelling. The results show that the SVM model with inactive compounds was superior to RF with Matthews's correlation coefficient (MCC) of 0.67 for the test set. A Maybridge database containing approximately 53 000 compounds was screened and top ranking 5 compounds were selected for enzyme and cell-based in vitro screening. The compound JFD00950 was identified as a novel FEN1 inhibitor with in vitro inhibition of flap cleavage activity as well as cytotoxic activity against a colon cancer cell line, DLD-1.

DNA replication and repair are complex processes accomplished by the concerted action of a network of enzymes and proteins. DNA ligases play a crucial role in these processes by catalyzing the nick joining between DNA strands. As compared to normal cells, elevated levels of human DNA ligase I (hLigI) is reported in some cancers. We studied the inhibition of hLigI mediated DNA nick sealing activity followed by the antiproliferative activity of novel indole-chalcone based benzopyran compounds on cancer cells. One molecule called compound 27 showed a notable preference for inhibition of hLigI as compared to other ligases and showed enhanced cytotoxicity against colon cancer (DLD-1) cells as compared to normal cells. Mechanistic studies showed that compound 27 directly interacts with hLigI in a competitive manner and did not interact with the DNA substrate during ligation. This novel and potent hLigI inhibitor showed significant inhibition of both monolayer culture as well as 3D culture of DLD-1 cells that mimic solid tumor. It also affected the migration of DLD-1 cells indicating the potential anti-metastatic activity. This novel hLigI inhibitor could therefore serve as a promising lead for anticancer drug development.

The bioassay guided fractionation of methanolic extract of Murraya koenigii (L.) Spreng. leaves resulted in the isolation of seven pyranocarbazoles. These were evaluated against four bacterial strains and ten Candida sp. including two matched pair of fluconazole sensitive/resistant clinical isolates. Out of seven, three i.e. Koenine (mk279), Koenigine (mk309) and Mahanine (mk347) exhibited significant antibacterial activity MIC90 3.12–12.5 μg/mL against bacterial strains Streptococcus aureus and Klebsiella pneumonia compared with standard drug Kanamycin MIC90 12.5 μg/mL. However, only mk309 was found active against variety of Candida species MIC90 12.5–100 μg/mL. It was observed that hydroxylation at C-6 and C-7 positions in the studied pyranocarbazoles activate the bioactivity. Simultaneously, decrease in Log P value compares with −H and −O−CH3 substituted derivatives. The study is focused on selective antifungal and antibacterial activity of pyranocarbazoles on bacterial strains S. aureus, K. pneumonia and variety of Candida species with structure activity relationship observations.

A series of multifunctional directed 3-arylcoumarin-tetracyclic tacrine derivatives was designed and synthesized for the treatment of Parkinson's disease (PD). A number of derivatives (18, 19, 20, 21, and 24) demonstrated significant reduction of aggregation of "human" alpha-synuclein (α-synuclein) protein, expressing on transgenic Caenorhabditis elegans (C. elegans) model NL5901. Moreover, compounds 16, 18, and 24 also exhibited good antioxidant properties and significantly increased the dopamine (DA) content in N2 and NL5901 strains of C. elegans. Interestingly, the protective efficacy of these hybrids seems to be mediated via activation of longevity promoting transcription factor DAF-16. In addition, molecular modeling studies have evidenced the exquisite interaction of most active compounds 18 and 24 with α-synuclein protein. Taken together, the data indicate that the derivatives may be useful leads against aging and age associated PD.

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.

The present study involved the assessment of potential generation of acid drainage from a coal mining area in India. Laboratory-based static and kinetic tests on overburden samples were conducted. Results of the static tests using acid base accounting indicate that all samples may be acid generators, and their generation capacity varied between likely, possible and low. To verify the acid generation potentiality of those samples showing a high acid drainage production in the static test, the kinetic test, using humidity cell, was conducted for a period of 15 weeks. The samples were leached with simulated rain water to mimic the chemical weathering under controlled laboratory conditions and imitate actual mine site leaching. Data obtained from chemical analysis of collected leachate were used to estimate production and reaction rates of acid generation and neutralizing capacity. Based on the kinetic test, it can be concluded that presently the neutralizing capacity of the samples is better than the oxidation capacity (acid generation). But due to the high weathering rate of carbonates, as reflected by the simulated leaching test, the neutralizing materials (carbonates) will eventually be exhausted earlier (since they showed dissolution rate) than the acid generation species (sulfates). Thus, acid drainage production is predicted from that point of time, when the neutralizing capacity has been exhausted for these mine

Background: Previous studies have provided evidence about chronic night noise exposure and sleep disturbance, which is indicator of more serious health conditions. Such studies have never been reported for the Indian population. This study aimed to further explore the association between nocturnal transportation noise exposure and self-reported sleep disturbances in an adult Indian population. Methods: The cross-sectional study used results from a pilot study, from a large scale social survey in the urban municipality of Asansol, an industrial city, situated in western India. The survey included responses from 221 adults (19–59 year old) residing within 100 meters buffer of the major and arterial roadways, with criteria of minimum 10 years stay in the study area. Association of self-reported sleep disturbance was studied by multiple logistic regression analysis with adjusting for age, gender and period of residence. Results: Sleep disturbance was more marked at levels of 61–65 dB(A) night noise exposure, OR (95% CI) 2.36 (1.13–4.94. For a 5dB(A) increase in night noise exposure, the OR (95% CI) was 1.30 (1.04–1.64). For every 10 years addition to age of the respondents, odds of sleep disturbance was estimated to increase by 1.17 over non-exposure individuals. Women reported higher sleep disturbance, OR (95% CI) 1.23 (0.65–1.92) in comparison to men A period of residence of 10 years in study area showed an OR (95% CI) of 1.33 (0.86–2.06) for sleep disturbance among exposed respondents. Further it was estimated with 95% confidence that the attributable fraction for sleep disturbance among those noise exposed within the population was 16% to 80%. Conclusions: The study results support an association between higher nocturnal road traffic noise and self-reported sleep disturbance in comparison to areas with quieter nights. Further sleep disturbance among women was significantly associated with higher night noise exposure.

Existing cancer therapies are often associated with drug resistance and toxicity, which results in poor prognosis and recurrence of cancer. This necessitates the identification and development of novel therapeutics against existing as well as novel cellular targets. In this study, a novel class of Benzocoumarin-Stilbene hybrid molecules were synthesized and evaluated for their antiproliferative activity against various cancer cell lines followed by in vivo antitumor activity in a mouse model of cancer. The most promising molecule among the series, i.e. compound (E)-4-(3,5-dimethoxystyryl)-2H-benzo[h]chromen-2-one (19) showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. The mechanistic studies of compound 19 by various biochemical, cell biology and biophysical approaches suggest that the compound binds to and inhibits the human DNA ligase I enzyme activity that might be the cause for significant reduction in tumor growth and may constitute a promising next-generation therapy against breast cancers.

DNA replication is a complex phenomenon that requires the concerted action of several enzymes, together with their protein and non-protein cofactors. In the nucleus, the two DNA strands are duplicated by two completely independent methods due to their anti-parallel orientation and the restrictive nature of DNA polymerases that allow DNA synthesis in the 5'-3' direction only. In this review, we focus on the proteins that are involved in the more complex and discontinuous process of lagging strand DNA synthesis by the formation of small DNA fragments called Okazaki fragments which are later sealed to form a continuous strand of DNA. We try and connect all the protein-protein interactions important for lagging strand synthesis in the S-phase of the cell cycle, describe the dynamics of these interactions and go on to discuss the post-translational modifications that affect them. We also look at how mutations in any of the players of the lagging strand synthesis can cause genomic instability leading to cancer and discuss if any of the players may be targeted for cancer therapy.

Background and Aims: A febrile response is a common phenomenon in the ICU (Intensive Care Unit), often with complex and unknown origins. Fever is only one component of a febrile response and may or may not be an indication of severe infection. Subjects and Methods: A febrile response caused by severe infection/s is often accompanied by neutropenia where the absolute neutrophil count goes below 500/mm3, or is predicted to go below 500/mm3 over the next 48 hours. Febrile neutropenia is generally an indication for an infection requiring the commencing of empirical antibiotics after taking appropriate cultures. However, severe infections may also occur in the absence of fever or neutropenia. Conclusion: In cases of new fever, or fever of unknown origin, it is highly recommended that the latest IDSA (Infectious Disease Society of America) or SCCM (Society of Critical Care Medicine) guidelines be followed. Some recently launched antimicrobials not yet covered by the IDSA are discussed and maybe useful for treatment of drug resistant cases. It may also be useful to remember that fever is more often a friend than a foe.

The repair of reactive oxygen species-induced base lesions and single strand breaks (SSBs) in the nuclear genome via the base excision (BER) and SSB repair (SSBR) pathways, respectively, is well characterize, and important for maintaining genomic integrity. However, the role of mitochondrial (mt) BER and SSBR proteins in mt genome maintenance is not completely clear. Here we show the presence of the oxidized base-specific DNA glycosylase Nei-like 2 (NEIL2) and the DNA end-processing enzyme polynucleotide kinase 3′-phosphatase (PNKP) in purified human mitochondrial extracts (MEs). Confocal microscopy revealed co-localization of PNKP and NEIL2 with the mitochondrion-specific protein cytochrome c oxidase subunit 2 (MT-CO2). Further, chromatin immunoprecipitation analysis showed association of NEIL2 and PNKP with the mitochondrial genes MT-CO2 and MT-CO3 (cytochrome c oxidase subunit 3); importantly, both enzymes also associated with the mitochondrion-specific DNA polymerase γ. In cell association of NEIL2 and PNKP with polymerase γ was further confirmed by proximity ligation assays. PNKP-depleted ME showed a significant decrease in both BER and SSBR activities, and PNKP was found to be the major 3′-phosphatase in human ME. Furthermore, individual depletion of NEIL2 and PNKP in human HEK293 cells caused increased levels of oxidized bases and SSBs in the mt genome, respectively. Taken together, these studies demonstrate the critical role of NEIL2 and PNKP in maintenance of the mammalian mitochondrial genome.

Preferential repair of bulky DNA adducts from the transcribed genes via nucleotide excision repair is well characterized in mammalian cells. However, definitive evidence is lacking for similar repair of oxidized bases, the major endogenous DNA lesions. Here we show that the oxidized base-specific human DNA glycosylase NEIL2 associates with RNA polymerase II and the transcriptional regulator heterogeneous nuclear ribonucleoprotein-U (hnRNP-U), both in vitro and in cells. NEIL2 immunocomplexes from cell extracts preferentially repaired the mutagenic cytosine oxidation product 5-hydroxyuracil in the transcribed strand. In a reconstituted system, we also observed NEIL2-initiated transcription-dependent base excision repair of 5-hydroxyuracil in the transcribed strand, with hnRNP-U playing a critical role. Chromatin immunoprecipitation/reimmunoprecipitation studies showed association of NEIL2, RNA polymerase II, and hnRNP-U on transcribed but not on transcriptionally silent genes. Furthermore, NEIL2-depleted cells accumulated more DNA damage in active than in silent genes. These results strongly support the preferential role of NEIL2 in repairing oxidized bases in the transcribed genes of mammalian cells.