Going beyond the limits: effect of clock disruption on human health

Abstract

Synchronisation of organisms’ physiology and behaviour with the external environment is necessary for survival and reproductive fitness. This is critical for human health also. In the past, humans were exposed to predictable natural day and night cycles that allowed the internal clock to synchronise the daily rhythms in physiology and behaviour with the external environment. However, the industrial revolution has made us a 24*7 society and forced the extension of day into night via adoption of artificial light in our lives. This has altered the perception of day and night and made it difficult for the biological processes to synchronise. Such weak synchronisation can be seen in different physiological and behavioural functions that are under circadian control, such as sleep–wake behaviour, melatonin and cortisol rhythms, core body temperature cycle, etc. This also influences the regulatory mechanism at cell and gene levels. Circadian disruption has resulted in increasing incidences of certain cancers, metabolic dysfunction and mood disorders. Several evidence suggest that exposure to aberrant light alters the brain functions that regulate emotion and mood. The present discussion focuses on understanding the effect of circadian disruption on human health, and its various aspects.     

Melioration in Anti-staphylococcal Activity of Conventional Antibiotic(s) by Organic Acids Present in the Cell Free Supernatant of <Emphasis Type="Italic">Lactobacillus paraplantarum</Emphasis>

In view of emerging drug resistance in pathogens, there is a need to explore alternative strategies to combat infections. Use of probiotics is one such option. In this regard, efficacy of Lactobacillus plantarum has been reported against Staphylococcus aureus. Here, we propose that cell free supernatant (CFS) of Lactobacillus paraplantarum when used in combination with conventional antibiotics viz. ampicillin and oxacillin [to which the methicillin resistant Staphylococcus aureus (MRSA) strains were originally resistant] reduce the minimum inhibitory concentrations of these antibiotics, rendering the combination either synergistic or additive against the tested MRSA strain. The anti-staphylococcal activity was observed to be due to organic acids (acetic acid and lactic acid as confirmed by HPLC analysis) present in the CFS, as neutralization of the CFS with an alkali, sodium hydroxide (NaOH), caused the complete abrogation of its activity. The role of H₂O₂ and bacteriocin present in the CFS was also ruled out. The findings of this study suggest that cell free supernatant and ampicillin/oxacillin combination(s) might help in rejuvenating the use of conventional anti-staphylococcal antibiotics for the treatment of multi-drug resistant strains.     

Estimation of Mineral and Trace Element Profile in Bubaline Milk Affected with Subclinical Mastitis

The milk samples from buffaloes of Murrah breed at mid lactation stage, reared at an organised dairy farm, were screened for subclinical mastitis based on bacteriological examination and somatic cell count following International Dairy Federation criteria. Milk samples from subclinical mastitis infected and healthy buffaloes were analysed to evaluate physicochemical alterations in terms of protein, fat, pH, electrical conductivity, chloride, minerals (sodium, potassium and calcium) and trace elements (iron, zinc, copper and selenium). In the present study, protein, fat, zinc, iron, calcium and selenium content was significantly lower (P < 0.001), while pH and electrical conductivity were significantly higher in mastitic milk as compared to normal milk. Concentration of electrolytes mainly sodium and chloride significantly increased with higher somatic cell count in mastitic milk and to maintain osmolality; potassium levels decreased proportionately. Correlation matrix revealed significantly positive interdependences of somatic cell count with pH, electrical conductivity, sodium and chloride. However, protein, fat, calcium and potassium were correlated negatively with elevated somatic cell count in mastitic milk. It is concluded that udder infections resulting in elevated somatic cells may alter the mineral and trace element profile of milk, and magnitude of changes may have diagnostic and prognostic value.     

Towards defining the nuclear proteome

Background

The nucleus is a complex cellular organelle and accurately defining its protein content is essential before any systematic characterization can be considered.

Results

We report direct evidence for 2,568 mammalian proteins within the nuclear proteome: the nuclear subcellular localization of 1,529 proteins based on a high-throughput subcellular localization protocol of full-length proteins and an additional 1,039 proteins for which clear experimental evidence is documented in published literature. This is direct evidence that the nuclear proteome consists of at least 14% of the entire proteome. This dataset was used to evaluate computational approaches designed to identify additional nuclear proteins.

Conclusion

This represents direct experimental evidence that the nuclear proteome consists of at least 14% of the entire proteome. This high-quality nuclear proteome dataset was used to evaluate computational approaches designed to identify additional nuclear proteins. Based on this analysis, researchers can determine the stringency and types of lines of evidence they consider to infer the size and complement of the nuclear proteome.     

Role of cervical dendritic cell subsets,co-stimulatory molecules,cytokine secretion profile and beta-estradiol in development of sequalae to Chlamydia trachomatis infection

Background  

Chlamydia trachomatis infection of the female genital tract can lead to serious sequelae resulting in fertility related disorders. Little is known about the mechanism leading to Chlamydia induced pathology and factors responsible for it. As only some of the women develops reproductive disorders while majority of the women clears infection without any severe sequalae, mucosal immune response in women with or without fertility disorders was studied to identify factors which may lead to final clinical outcome of chlamydial infection.     

1-Toluene-sulfonyl-3-[(3'-hydroxy-5'-substituted)-gamma-butyrolactone]-indoles: synthesis, COX-2 inhibition and anti-cancer activities

Indoles carrying a cyclic ester (gamma-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin).     

RetroPred: A tool for prediction, classification and extraction of non-LTR retrotransposons (LINEs & SINEs) from the genome by integrating PALS, PILER, MEME and ANN

The problem of predicting non-long terminal repeats (LTR) like long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs) from the DNA sequence is still an open problem in bioinformatics. To elevate the quality of annotations of LINES and SINEs an automated tool "RetroPred" was developed. The pipeline allowed rapid and thorough annotation of non-LTR retrotransposons. The non-LTR retrotransposable elements were initially predicted by Pairwise Aligner for Long Sequences (PALS) and Parsimonious Inference of a Library of Elementary Repeats (PILER). Predicted non-LTR elements were automatically classified into LINEs and SINEs using ANN based on the position specific probability matrix (PSPM) generated by Multiple EM for Motif Elicitation (MEME). The ANN model revealed a superior model (accuracy = 78.79 +/- 6.86 %, Q(pred) = 74.734 +/- 17.08 %, sensitivity = 84.48 +/- 6.73 %, specificity = 77.13 +/- 13.39 %) using four-fold cross validation. As proof of principle, we have thoroughly annotated the location of LINEs and SINEs in rice and Arabidopsis genome using the tool and is proved to be very useful with good accuracy. Our tool is accessible at http://www.juit.ac.in/RepeatPred/home.html.     

Role of cyclooxygenase-2 functional gene polymorphisms in Helicobacter pylori induced gastritis and gastric atrophy

In India, the role of host genetic factors is poorly studied for Helicobacter pylori associated diseases. Therefore, we evaluated the association of functionally relevant COX-2 gene polymorphisms (-765 G>C and +8473 T>C) in gastritis and precancerous lesions susceptibility. After upper GI endoscopy, 130 rapid urease test positive patients with non-ulcer dyspepsia, also showed positivity for H. pylori using modified Geimsa staining and anti-CagA IgG serology were included. All patients and 260 asymptomatic controls were genotyped for COX-2 variations using PCR-RFLP. COX-2 -765 (GC+CC) genotypes, -765 C allele, +8473 CC genotype, +8473 (TC+CC) genotypes, +8473 C allele, and variant haplotypes imparted high risk for gastritis (P = 0.036, OR = 1.82; P = 0.007, 1.92; P = 0.025, OR = 2.13; P = 0.017, OR = 1.80; P = 0.017, OR = 1.45; P = 0.010, OR = 2.40; P = 0.023, OR = 1.50 and P = 0.012, OR = 2.20 folds, respectively). In contrast, COX-2 -765 C allele carriers had low risk for lymphocyte (P = 0.020, OR = 0.35), plasma cell infiltrations (P = 0.016, OR = 0.33), and gastric atrophy (GA) development (P = 0.019, OR = 0.35). In conclusion, COX-2 variant allele/genotype/haplotype carriers may be at high risk for gastritis. However, COX-2 -765 C allele carriers may be at low risk for GA development.     

Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression

Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth. The existence of a BM reservoir of EPCs, and the selective involvement of EPCs in neovascularization, have attracted considerable interest because these cells represent novel target for therapeutic intervention. In addition, EPCs are also being used as pharmacodynamic surrogate markers for monitoring cancer progression, as well as for optimizing efficacy of anti-angiogenic therapies in the clinic. This review will focus primarily on recent advances and emerging concepts in the field of EPC biology and discuss ongoing debates involving the role of EPCs in tumor neovascularization. For detailed information on the in vitro characterization of EPCs contribution to non-tumor pathologies, the reader is directed towards several excellent reviews and publications [F. Bertolini, Y. Shaked, P. Mancuso and R.S. Kerbel, Nat. Rev., Cancer 6 (2006) 835–845. [1]] [J.M. Hill, T. Finkel and A.A. Quyyumi, Vox Sang. 87 Suppl 2 (2004) 31–37. [2]] [A.Y. Khakoo and T. Finkel, Annu. Rev. Med. 56 (2005) 79–101. [3]] [H.G. Kopp, C.A. Ramos and S. Rafii, Curr. Opin. Hematol. 13 (2006) 175–181. [4]; K.K. Hirschi, D.A. Ingram and M.C. Yoder, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1584–1595. [5]; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87–102. [6]] and reviews by Bertolini, Voest and Yoder in this issue.