Cellular copper distribution: a mechanistic systems biology approach

Copper is an essential but potentially harmful trace element required in many enzymatic processes involving redox chemistry. Cellular copper homeostasis in mammals is predominantly maintained by regulating copper transport through the copper import CTR proteins and the copper exporters ATP7A and ATP7B. Once copper is imported into the cell, several pathways involving a number of copper proteins are responsible for trafficking it specifically where it is required for cellular life, thus avoiding the release of harmful free copper ions. In this study we review recent progress made in understanding the molecular mechanisms of copper transport in cells by analyzing structural features of copper proteins, their mode of interaction, and their thermodynamic and kinetic parameters, thus contributing to systems biology of copper within the cell.     

Periostin in the pathogenesis of skin diseases

Skin is an organ that is susceptible to damage by external injury, chronic inflammation, and autoimmunity. Tissue damage causes alterations in both the configuration and type of cells in lesional skin. This phenomenon, called tissue remodeling, is a universal biological response elicited by programmed cell death, inflammation, immune disorders, and tumorigenic, tumor proliferative, and cytoreductive activity. In this process, changes in the components of the extracellular matrix are required to provide an environment that facilitates tissue remodeling. Among these extracellular matrix components, periostin, a glycoprotein that is predominantly secreted from dermal fibroblasts, has attracted attention. Periostin localizes in the papillary dermis of normal skin, and is aberrantly expressed in the dermis of lesional skin in atopic dermatitis, scar, systemic/limited scleroderma, melanoma, cutaneous T cell lymphoma, and skin damage caused by allergic/autoimmune responses. Periostin induces processes that result in the development of dermal fibrosis, and activate or protract the immune response. The aim of this review was to summarize recent knowledge of the role of periostin in the pathogenesis of dermatoses, and to explore whether periostin is a potential therapeutic target for skin diseases.     

mTOR signaling in neural stem cells: from basic biology to disease

The mammalian target of rapamycin (mTOR) pathway is a central controller of growth and homeostasis, and, as such, is implicated in disease states where growth is deregulated, namely cancer, metabolic diseases, and hamartoma syndromes like tuberous sclerosis complex (TSC). Accordingly, mTOR is also a pivotal regulator of the homeostasis of several distinct stem cell pools in which it finely tunes the balance between stem cell self-renewal and differentiation. mTOR hyperactivation in neural stem cells (NSCs) has been etiologically linked to the development of TSC-associated neurological lesions, such as brain hamartomas and benign tumors. Animal models generated by deletion of mTOR upstream regulators in different types of NSCs reproduce faithfully some of the TSC neurological alterations. Thus, mTOR dysregulation in NSCs seems to be responsible for the derangement of their homeostasis, thus leading to TSC development. Here we review recent advances in the molecular dissection of the mTOR cascade, its involvement in the maintenance of stem cell compartments, and in particular the implications of mTOR hyperactivation in NSCs in vivo and in vitro.     

Eosinophils in the pathogenesis of allergic airways disease

Eosinophils are traditionally thought to form part of the innate immune response against parasitic helminths acting through the release of cytotoxic granule proteins. However, they are also a central feature in asthma. From their development in the bone marrow to their recruitment to the lung via chemokines and cytokines, they form an important component of the inflammatory milieu observed in the asthmatic lung following allergen challenge. A wealth of studies has been performed in both patients with asthma and in mouse models of allergic pulmonary inflammation to delineate the role of eosinophils in the allergic response. Although the long-standing association between eosinophils and the induction of airway hyper-responsiveness remains controversial, recent studies have shown that eosinophils may also promote airway remodelling. In addition, emerging evidence suggests that the eosinophil may also serve to modulate the immune response. Here we review the highly co-ordinated nature of eosinophil development and trafficking and the evolution of the eosinophil as a multi-factoral leukocyte with diverse functions in asthma. Received 6 December 2006; received after revision 11 January 2007; accepted 15 February 2007     

In vitro culture of chick down feather bulbi: a tool to obtain proliferating and differentiating keratinocytes in an organotypic structure

Chick down feather bulbi can be cultured in different culture systems. Morphological analysis and 3H-thymidine incorporation measurements prove that the majority of cells are viable epithelial cells.     

Lymphocyte-fibroblast interaction in the pathogenesis of inflammatory gingival disease

Zusammenfassung Eine morphometrische Analyse menschlicher, entzündeter Gingiva ergab im Vergleich zu normalem Bindegewebe 70% weniger Kollagenfasern, dreifach vergrösserte und pathologisch veränderte Fibroblasten und eine kleine Population charakteristischer Immunoblasten mit einer Zellansammlung, die zu 76% aus Zellen der Lymphozytenserie bestand. Die Grösse der Fibroblasten war positiv mit der steigenden Zahl der Lymphozyten korreliert. Diese Befunde weisen auf eine Immunreaktion mit zytotoxischen Auswirkungen auf Fibroblasten des gingivalen Bindegewebes hin.     

Language understanding is grounded in experiential simulations: a response to Weiskopf

Several disciplines within the cognitive sciences have advanced the idea that people comprehend the actions of others, including the linguistic meanings they communicate, through embodied simulations where they imaginatively recreate the actions they observe or hear about. This claim has important consequences for theories of mind and meaning, such as that people’s use and interpretation of language emerges as a kind of bodily activity that is an essential part of ordinary cognition. Daniel Weiskopf presents several arguments against the idea that experiential simulations play a major role in immediate language use and meaning. We offer several rebuttals to Weiskopf, in which we critique his interpretation of simulation theory, present additional psycholinguistic evidence supportive of the simulation perspective, and suggest that a more traditional theory of linguistic meaning and processing has little psychological and empirical validity.     

From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance

The ATP binding cassette (ABC) superfamily of membrane transporters is one of the largest protein classes known, and counts numerous proteins involved in the trafficking of biological molecules across cell membranes. The first known human ABC transporter was P-glycoprotein (P-gp), which confers multidrug resistance (MDR) to anticancer drugs. In recent years, we have obtained an increased understanding of the mechanism of action of P-gp as its ATPase activity, substrate specificity and pharmacokinetic interactions have been investigated. This review focuses on the functional characterization of P-gp, as well as other ABC transporters involved in MDR: the family of multidrug-resistance-associated proteins (MRP1-7), and the recently discovered ABC half-transporter MXR (also known as BCRP, ABCP and ABCG2). We describe recent progress in the analysis of protein structure-function relationships, and consider the conceptual problem of defining and identifying substrates and inhibitors of MDR. An in-depth discussion follows of how coupling of nucleotide hydrolysis to substrate transport takes place, and we propose a scheme for the mechanism of P-gp function. Finally, the clinical correlations, both for reversal of MDR in cancer and for drug delivery, are discussed.     

On the role of non-specific factors in the pathogenesis of infectious disease

Zusammenfassung Es wird einleitend darauf hingewiesen, dass mehr und mehr die Bedeutung von unspezifischen Faktoren für die Resistenz gegen Infektionen erkannt wird. Solche Faktoren können wohl auch in der Pathogenese von Infektionskrankheiten eine Rolle spielen, so zum Beispiel eine erhöhte Sensibilität gegen Endotoxin, die während den verschiedensten experimentellen Infektionen in Tieren nachgewiesen werden kann. An Hand von Experimenten an Mäusen wird dargestellt, in welchem Ausmass eine vorausgehende Impfung mit BCG den Ablauf einer nachfolgenden Infektion mitSalmonella typhimurium in verschiedenster Weise beeinflussen kann. Dies hängt weitgehend davon ab, ob grosse oder kleine Dosen zur Infektion verwendet werden.     

Robertsonian fusion leading to the formation of stable dicentric chromosome in an ascites cell line of the mouse

Summary The dicentric nature of a marker metacentric chromosome originated by robertsonian fusion has been established in the ascites cells of mouse sarcoma 180. C-banding analysis has revealed that the metacentric is actually a dicentric with 2 closely situated C-positive heterochromatic zones. The nature of the centromeres and the NF value of the cell indicate that this meta-dicentric marker has orginated by breakage and fusion within each of the short arms of 2 acrocentric chromosomes.Acknowledgment. Grateful acknowledgment is made to Dr N. Chatterji, former Director, CNCRC, Calcutta, for supplying the cell-line to the first author. Sincere thanks are due to Prof. Sujit K. Dasgupta, Head, Dept. of Zoology, H. M. Govt. College and to Dr A. K. Roy of the same department for encouragement.     

Catalysis in abiotic structured media: an approach to selective synthesis of biopolymers

Micro- and nanoenvironments formed by amphiphile self-assembled structures, water-ice lattices and minerals have well-defined, repeating, chemical and physical properties that can be used for selective synthesis of biopolymers, such as RNAs and proteins. The advances made in the development of polymerization supported by these micro- and nanosystems are reviewed here. In particular, it is shown that these systems promote non-enzymatic biopolymerization, yielding long polymers whose sequence composition is determined by the interactions between monomers and the supporting environment. When used to compartmentalize enzymatic biopolymerization, micro- and nanostructures allow the implementation of molecular selection and evolution schemes, which are difficult in homogeneous medium, yielding very active molecules. Thus, micro- and nanoenvironment approaches to the synthesis and selection of biopolymers could be developed into a new biotechnological tool for the production of biopolymers with novel functions.Received 3 August 2004; received after revision 6 October 2004; accepted 21 October 2004     

Towards an understanding of the role of glutamate in neurodegenerative disorders: energy metabolism and neuropathology

It is thought that impairment, of energy metabolism that results in deterioration of membrane function, leading to loss of the Mg²⁺ block on NMDA receptors, and allowing persistent activation of these receptors by glutamate, might be a cause of neuronal death in neurodegenerative disorders. Studies in rodents using mitochondrial respiratory chain toxins, such as aminooxyacetic acid, 1-methyl-4-phenylpyridinium, malonic acid and 3-nitropropionic acid, suggest that such processes may indeed be involved in neurotoxicity. Striatal and nigral degeneration induced by mitochondrial toxins in rodents resembles the neuropathology seen in humans suffering from Huntington's or Parkinson's disease, and can be prevented either by decortication or by NMDA receptor antagonists. Such experimental observations suggest that glutamate may be involved in neuronal death leading to neurodegenerative disorders in humans. If so, glutamate antagonists may offer a therapeutic approach for retarding the progression of these disabling disorders.     

A leading indicator approach to predicting short‐term shifts in demand for business travel by air to and from the UK

This paper uses the probit model to examine whether leading indicator information could be used for the purpose of predicting short‐term shifts in demand for business travel by air to and from the UK. Leading indicators considered include measures of business expectations, availability of funds for corporate travel and some well‐known macroeconomic indicators. The model performance is evaluated on in‐ and out‐of‐sample basis, as well as against a linear leading indicator model, which is used to mimic the current forecasting practice in the air transport industry. The estimated probit model is shown to provide timely predictions of the early 1980s and 1990s industry recessions and is shown to be more accurate than the benchmark linear model. Copyright © 2005 John Wiley & Sons, Ltd.     

In vitro culture of chick down feather bulbi: A tool to obtain proliferating and differentiating keratinocytes in an organotypic structure

Summary Chick down feather bulbi can be cultured in different culture systems. Morphological analysis and³H-thymidine incorporation measurements prove that the majority of cells are viable epithelial cells.     

Aristotle and Galen on sex difference and reproduction: a new approach to an ancient rivalry

[I]n contrast to Aristotle's male oriented explanation of procreation the Galenic was 'feminist' inasmuch as both sexes were presented as contributing equally in conception and accordingly both had to experience pleasure... Anatomically, the two sexes were presented in Galenic accounts as complementary, the difference being that the man's genitalia were on the outside and the woman's on the inside. The clitoris was likened to the penis and the ovaries considered 'testicles' or 'stones' that produced seed. The male seed was, it is true, depicted by Galenists as superior in having 'spiritual' qualities lacking in the female, but Galen's reproductive schema was far more egalitarian than Aristotle's. (McLaren, 1985, p. 327)