A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components

Background: Ultraviolet radiations (UV) serve as an environmental stress for human skin, and result in melanogenesis, with the pigment melanin having protective effects against UV induced damage. This involves a dynamic and complex regulation of various biological processes that results in the expression of melanin in the outer most layers of the epidermis, where it can exert its protective effect. A comprehensive understanding of the underlying cross talk among different signalling molecules and cell types is only possible through a systems perspective. Increasing incidences of both melanoma and non-melanoma skin cancers necessitate the need to better comprehend UV mediated effects on skin pigmentation at a systems level, so as to ultimately evolve knowledge-based strategies for efficient protection and prevention of skin diseases. Methods: A network model for UV-mediated skin pigmentation in the epidermis was constructed and subjected to shortest path analysis. Virtual knock-outs were carried out to identify essential signalling components. Results: We describe a network model for UV-mediated skin pigmentation in the epidermis. The model consists of 265 components (nodes) and 429 directed interactions among them, capturing the manner in which one component influences the other and channels information. Through shortest path analysis, we identify novel signalling pathways relevant to pigmentation. Virtual knock-outs or perturbations of specific nodes in the network have led to the identification of alternate modes of signalling as well as enabled determining essential nodes in the process. Conclusions: The model presented provides a comprehensive picture of UV mediated signalling manifesting in human skin pigmentation. A systems perspective helps provide a holistic purview of interconnections and complexity in the processes leading to pigmentation. The model described here is extensive yet amenable to expansion as new data is gathered. Through this study, we provide a list of important proteins essential for pigmentation which can be further explored to better understand normal pigmentation as well as its pathologies including vitiligo and melanoma, and enable therapeutic intervention

The IntAct molecular interaction database in 2012

IntAct is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. Two levels of curation are now available within the database, with both IMEx-level annotation and less detailed MIMIx-compatible entries currently supported. As from September 2011, IntAct contains approximately 275 000 curated binary interaction evidences from over 5000 publications. The IntAct website has been improved to enhance the search process and in particular the graphical display of the results. New data download formats are also available, which will facilitate the inclusion of IntAct's data in the Semantic Web. IntAct is an active contributor to the IMEx consortium (http://www.imexconsortium.org). IntAct source code and data are freely available at http://www.ebi.ac.uk/intac

Cloning and Expression of an Acyl-CoA Dehydrogenase from Mycobacterium tuberculosis

A gene fromMycobacterium tuberculosiscoding for acyl-CoA dehydrogenase was cloned, overexpressed and characterized on the basis of enzyme activity with various chain length substrates. The results show that the protein is a medium chain acyl-CoA dehydrogenase (MCADH). The mycobacterium protein expressed appears to be unique, since by comparison, the active site glutamic acid of the protein does not lie in the same position as other well characterized MCADH, but in a position present in long chain and isovaleryl acyl-CoA dehydrogenases (LCADH and IVDH)

Cloning and expression of an Acyl-CoA dehydrogenase from Mycobacterium tuberculosis

A gene hom Mycobacterium tuberculosis coding for acyl-CoA dehydrogenase was cloned, overexpressed and characterized on the basis of enzyme activity with various chain length substrates, The results show that the protein is a medium chain acyl-CoA dehydrogenase (MCADH). The mycobacterium protein expressed appears to be unique, since by comparison, the active site glutamic acid of the protein does not lie in the same position as other well characterized MCADH, but in a position present in long chain and isovaleryl acyl-CoA dehydrogenases (LCADH and IVDH). (C) 1998 Academic Press

Pseudoathetosis in a patient with leprosy

A 35-year-old man with borderline tuberculoid leprosy developed Type I lepra reaction 12 days after anti-leprosy treatment. There was acute worsening of neuropathic symptoms and skin lesions. He developed severe sensory ataxia and pseudoathetosis resulting in marked disability. His symptoms significantly improved on corticosteroid therapy

Cytochrome P-450 in drug-resistant Mycobacterium tuberculosis

Methods for the isolation and spectrophotometric determination of cytochrome P-450 in mycobacteria were standardized. Cytochrome P-450 levels were estimated in Mycobacterium tuberculosis organisms sensitive to both isoniazid and rifampicin and resistant to any of the two drugs. Cytochrome P- 450 was isolated and its presence was shown in M. smegmatis, M. fortuitum, M. chelonae and M. tuberculosis H(37)Rv. The cytochrome P-450 content was significantly elevated in M. tuberculosis, resistant to both isoniazid and rifampicin when compared with the corresponding sensitive strains. It therefore appears that cytochrome P-450 might play a role in causing drug resistance in tuberculosis