Epigenetics in human disease and prospects for epigenetic therapy

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of 'epigenetic therapies'--several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.     

Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer

CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.     

Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

The large conductance calcium-sensitive potassium (BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the alpha subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca(2+) sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.     

Studies on benzene mutagenesis. I. The micronucleus test

Summary The mutagenic action of benzene was studied by means of the micronucleus test performed on mice. A linear dose effect relationship was found for the percentage of micronucleated erythrocytes, against the benzene-dose logarithms. A significant dose effect correlation was found either after the standard 30-h experiments or after a prolonged 54-h one. A higher effect was found in the prolonged experiments, suggesting the induction of a delay in the cell cycle by benzene.     

CCD摄象器件的技术特点

介绍了彩色电视摄象机用ＣＣＤ图象传感器的技术特点，讨论了新型ＣＣＤ图象传感器的特性以及ＨＤＴＶ摄象机用ＣＣＤ图象传感器的情况。     

Autophagy fights disease through cellular self-digestion

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.     

Identification of cells initiating human melanomas

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.     

Effective global conservation strategies

Using data on the global distribution of mammal, bird and amphibian species, Grenyer et al. conclude that planning based on individual taxa does not provide efficient solutions for the conservation of other taxa. They also report that the performance of existing global conservation strategies-endemic bird areas, biodiversity hotspots and global 200 ecoregions-in representing those taxa is often no better (and in some cases worse) than random. I argue here that the methodology used by Grenyer et al. was not appropriate for purported globally comprehensive analyses. Focusing on analyses of rare species as an example, I demonstrate how the data actually reveal substantial cross-taxon surrogacy and good performance of existing global conservation strategies.     

Revisiting the similar process to engineer the contemporary systems

This paper addresses the present-day context of Systems Engineering, revisiting and setting up an updated framework for the SIMILAR process in order to use it to engineer the contemporary systems. The contemporary world is crowded of large interdisciplinary complex systems made of other systems, personnel, hardware, software, information, processes, and facilities. An integrated holistic approach is crucial to develop these systems and take proper account of their multifaceted nature and numerous interrelationships. As the system’s complexity and extent grow, the number of parties involved (stakeholders and shareholders) usually also raises, bringing to the interaction a considerable amount of points of view, skills, responsibilities, and interests. The Systems Engineering approach aims to tackle the complex and interdisciplinary whole of those socio-technical systems, providing the means to enable their successful realization. Its exploitation in our modern world is assuming an increasing relevance noticeable by emergent standards, academic papers, international conferences, and post-graduate programmes in the field. This work aims to provide “the picture” of modern Systems Engineering, and to update the context of the SIMILAR process model in order to use this renewed framework to engineer the challenging contemporary systems. The emerging trends in the field are also pointed-out with particular reference to the Model-Based Systems Engineering approach.     

Aquaglyceroporins: implications in adipose biology and obesity

Aquaporins (AQPs) are membrane water/glycerol channels that are involved in many physiological processes. Their primary function is to facilitate the bidirectional transfer of water and small solutes across biological membranes in response to osmotic gradients. Aquaglyceroporins, a subset of the AQP family, are the only mammalian proteins with the ability to permeate glycerol. For a long time, AQP7 has been the only aquaglyceroporin associated with the adipose tissue, which is the major source of circulating glycerol in response to the energy demand. AQP7 dysregulation was positively correlated with obesity onset and adipocyte glycerol permeation through AQP7 was appointed as a novel regulator of adipocyte metabolism and whole-body fat mass. Recently, AQP3, AQP9, AQP10 and AQP11 were additionally identified in human adipocytes and proposed as additional glycerol pathways in these cells. This review contextualizes the importance of aquaglyceroporins in adipose tissue biology and highlights aquaglyceroporins’ unique structural features which are relevant for the design of effective therapeutic compounds. We also refer to the latest advances in the identification and characterization of novel aquaporin isoforms in adipose tissue. Finally, considerations on the actual progress of aquaporin research and its implications on obesity therapy are suggested.