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A Ertmer, V Huber, S Gilch, T Yoshimori, V Erfle, J Duyster, H-P Elsa¨sser and HM Scha¨tzl; Leukemia (2007) 21, 936–942. The tyrosine kinase inhibitor imatinib (Gleevec, Novartis Pharmaceuticals Corporation; Basel, Switzerland) is a powerful drug for treatment of chronic myelogenous leukemia (CML) and other malignancies. It selectively targets various tyrosine kinases, thereby leading to growth arrest of respective cancer cells. Given its wide application, it is of high importance to know all related underlying molecular mechanisms. We had previously found that imatinib increases the cellular clearance of intracellular protein aggregates by targeting the abl pathway and thereby up-regulating lysosomal activity. Here, we describe that imatinib dose dependently activates the cellular autophagy machinery in mammalian cells, independently of tissue type, species origin or immortalization status of cells. Autophagy is an archetypical cellular degradation mechanism implicated in many physiological and pathophysiological conditions. Our data link for the first time the process of autophagy with the mode of action of imatinib. Induction of autophagy might represent an additional mechanism of imatinib to induce growth arrest, promote apoptosis in cancer cells and eventually even promote tumor regression.

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Z. Davidovitch, E. Korostoff, M. D. Finkelson, R. W. Yost, P. C. Montgomery, S. Steigman and J. L. Shanfeld Departments of Orthodontics and Pedodontics, Restorative Dentistry and Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, U. S. A. Journal of Periodontal Research 15: 353-362, 1980. Electric currents have been shown to affect a variety of tissues. The objective of this investigation was to determine whether the application of minute electric currents, noninvasively, to cat gingival tissues would alter the immunohistochemical staining pattern of gingival cells for cyclic AMP and cyclic GMP, substances associated with cell stimulation. Three groups of 4 cats each were treated with an electric device delivering 15 ± 2 n amperes d. c. current to the gingiva near one maxillary canine far 1, 3 and 7 days, respectively. Horizontal sections of each maxilla were stained immunohistochemically for either cyclic AMP or cyclic GMP and intensely stained cells near the cathode and anode were counted. Near the cathode the number of gingival cells intensely stained for cyclic nucleotides was doubled by days 1 and 7 but not at day 3. Near the anode larger increases for both cyclic nucleotides were observed at all time periods. Changes were observed in the cellular staining patterns for cyclic AMP and cyclic GMP as a result of the electric stimulation suggesting activation of nuclear protein kinases. These results demonstrate that the stimulation of gingival cells by electric currents involves cyclic nucleotide fluctuations similar to those observed following the application of hormones and drugs.

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Gary N. Landis*, Diana Abdueva*, Dmitriy Skvortsov*, Junsheng Yang*, Beth E. Rabin*, James Carrick*, Simon Tavare´*†, and John Tower (2003) *Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-1340; and †Department of Oncology, Cambridge University, Cambridge, United Kingdom: Affymetrix GeneChips were used to measure RNA abundance for 13,500 Drosophila genes in young, old, and 100% oxygen stressed flies. Data were analyzed by using a recently developed background correction algorithm and a robust multichip modelbased statistical analysis that dramatically increased the ability to identify changes in gene expression. Aging and oxidative stress responses shared the up-regulation of purine biosynthesis, heat shock protein, antioxidant, and innate immune response genes. Results were confirmed by using Northerns and transgenic reporters. Immune response gene promoters linked to GFP allowed longitudinal assay of gene expression during aging in individual flies. Immune reporter expression in young flies was partially predictive of remaining life span, suggesting their potential as biomonitors of aging.

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Mae-Wan Ho (1996) Thus, the essence of the organic whole is that it is distributed throughout its constituent parts, with no centre of control, no governors, no hierarchical levels of line-managers or regulators processing information down the line of command. Instead, pervasive, moment to moment intercommunication throughout the system renders part and whole, local and global completely indistinguishable... One distinguishing feature of the living system is its exquisite sensitivity to weak signals. For example, the eye can detect single photons falling on the retina, and the presence of several molecules of pheromones in the air is sufficient to attract male insects to their mates. That exquisite sensitivity applies to all levels of `information processing' in the organism, and is the direct consequence of its energy self-sufficiency. No part of the system has to be pushed or pulled into action, nor be subjected to mechanical regulation and control. Instead, coordinated action of all the parts depends on rapid intercommunication throughout the system. The organism is a system of "excitable media" (see Goodwin, 1994, 1995), or excitable cells and tissues poised to respond specifically and disproportionately to weak signals because the large amount of energy stored can amplify weak signals into macroscopic actions. It is by virtue of its energy self-sufficiency, therefore, that an organism is a sentient being -- a system of sensitive parts all set to intercommunicate, to respond and to act appropriately as a whole to any contingency.

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Andreas Ladurner PhD (2008), University of Cambridge, UK. Chromatin packages our cellular DNA, protects it from damage and ensures access by the right machines, at the right time. The smallest unit of chromatin is the nucleosome, a tightly-knit and stable assembly of histones and DNA. Yet, chromatin is a dynamic and versatile (“plastic”) substrate. We now know that it regulates gene expression and the inheritance of our genome. Biochemical and proteomic approaches show that proteins rarely act in isolation. Rather, they often form larger molecular assemblies. Importantly, it is often only in the context of these larger protein complexes that many proteins reveal their specific activity. In an on-going, ambitious project with Damian Brunner in EMBL’s Cell Biology Unit and with Robin Allshire at the Wellcome Trust Centre for Cell Biology in Edinburgh (UK), we are seeking to identify novel protein complexes involved in heterochromatin formation and in centromere function in a model organism, the fission yeast S. pombe. We will report progress on this challenging project in future reports.

Johns Hopkins Medical Institutions (2008) Researchers from Johns Hopkins have discovered the presence of functional ion channels in human embryonic stem cells (ESCs). These ion channels act like electrical wires and permit ESCs, versatile cells that possess the unique ability to become all cell types of the body, to conduct and pass along electric currents. If researchers could selectively block some of these channels in implanted cells, derived from stem cells, they may be able to prevent potential tumor development. The paper appears Aug. 5 online in the journal Stem Cells. "A major concern for human ESC-based therapies is the potential for engineered grafts to go haywire after transplantation and form tumors, for instance, due to contamination by only a few undifferentiated human ESCs," says Ronald A. Li, Ph.D., an assistant professor of medicine at The Johns Hopkins University School of Medicine and senior author of the study. "Our discovery of functional ion channels, which are valves in a cell's outer membrane allowing the passage of charged atoms, the basis of electricity, provides an important link to the differentiation, or maturation, and cell proliferation, or growth of human ESCs." Because human ESCs can potentially provide an unlimited supply of even highly specialized cells, such as brain and heart cells, for transplantation and cell-based therapies, they may provide an ultimate solution to limited donor availability. In an earlier study, Li's lab genetically engineered heart cells derived from human ESCs, suggesting the possibility of transplanting unlimited supplies of healthy, specialized cells into damaged organs. "We do not want to be taking any chances of tumor formation. Based on our previous research, we therefore decided to explore the existence of ion channels in pluripotent, or versatile, human ESCs because electrical activity is known to regulate cell differentiation and proliferation," says Li. "To my knowledge, the electrical properties of human ESCs were never studied up to this point." In the current study, the researchers measured the electric currents of single human ESCs, discovered several channels that allow and control passage of potassium, and observed the electric current's effect on cell differentiation and proliferation. "In a number of different cell types, from cancer to T-lymphocytes, potassium channels are responsible for altering the membrane voltage of cells," says Li. "This in turn is required for the progression of certain cells into the next phase of a cell cycle." Li hopes the targeting of specific potassium channels will give scientists more understanding and control in engineering healthy cells for transplantation. "We found that blocking potassium channels in ESCs also slowed their growth," says Li. "Our findings may lead to genetic strategies that suppress undesirable cell division after transplantation, not only for ESCs and their derivatives, but perhaps for adult stem cells as well." Li adds that much more work is necessary to know for sure.

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IBM Blue Gene team: F. Allen, G. Almasi, W. Andreoni, D. Beece, B. J. Berne, A. Bright, J. Brunheroto, C. Cascaval, J. Castanos, P. Coteus, P. Crumley, A. Curioni, M. Denneau, W. Donath, M. Eleftheriou, B. Fitch, B. Fleischer, C. J. Georgiou, R. Germain, M. Giampapa, D. Gresh, M. Gupta, R.Haring, H. Ho, P. Hochschild, S. Hummel, T. Jonas, D. Lieber, G. Martyna, K.Maturu, J. Moreira, D. Newns, M. Newton, R. Philhower, T. Picunko, J. Pitera, M. Pitman, R. Rand, A. Royyuru, V. Salapura, A. Sanomiya, R. Shah, Y. Sham, S. Singh, M. Snir, F. Suits, R. Swetz, W. C. Swope, N. Vishnumurthy, T. J. C. Ward, H. Warren, R. Zhou. In December 1999, IBM announced the start of a five-year effort to build a massively parallel computer, to be applied to the study of biomolecular phenomena such as protein folding. The project has two main goals: to advance our understanding of the mechanisms behind protein folding via large-scale simulation, and to explore novel ideas in massively parallel machine architecture and software. This project should enable biomolecular simulations that are orders of magnitude larger than current technology permits. Major areas of investigation include: how to most effectively utilize this novel platform to meet our scientific goals, how to make such massively parallel machines more usable, and how to achieve performance targets, with reasonable cost, through novel machine architectures. This paper provides an overview of the Blue Gene project at IBM Research. It includes some of the plans that have been made, the intended goals, and the anticipated challenges regarding the scientific work, the software application, and the hardware design.

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Cell communication in Eukaryotes is very involved. Many sorts of cell junctions are used for various purposes. Communicating junctions allow things to move from one cell to another. They include: Synapses (allow chemical connection between nerve cells. Transduce electrical into chemical signals). Gap junctions, formed by connexin proteins, which allow electrical and some solute communication as well as anchoring cells together. Plasmodesmata (between SERs in plants). The distance involved in junctions can also be used to classify the types of communication possible. Autocrine (same cell). Synaptic (one cell immediately in contact). Tethered (one cell in immediate contact, but non-mobile ligand). Paracrine (nearby cell, community coherence, neuromodulation). Endocrine (hormonal, action-at-a-distance). Pheromonal (different organism). For cells to communicate, there must be a receptor and a ligand. Receptors in eukaryotes fall into several huge and diverse families. The immunoglobulin superfamily contains the immunoglobulins, T-cell receptors, many other immune-system receptors, and even some growth factors... The G-protein coupled (GPC) receptors are another ubiquitous group. A GPC receptor hat has bound its ligand activates a G-protein, which binds GTP. The alpha subunit of the G-protein dissociates from the beta-gamma subunit of the G-protein, and this activates a second messenger. This may be one of: Adenylate cyclase, making cAMP. cAMP binds PKA (protein kinase-A), whose activity regulates other proteins. Phospholipase-C (PLC). PLC yields diacylglycerol (DAG) and inositol triphosphate (IP3) from phophoinositol. IP3 releases calcium from the SER, which causes calmodulin to bind CAM-KII, a kinase. Calcium and DAG also activate protein kinase-C (PKC).

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Bok Y. Lee, MD, FACS, Alfred J. Koonin, M.B., Ch, B., Ph.D., FRCS, Keith Wendell, Ph.D., John Hillard, RN (2005) In conclusion, 25 chronic skin ulcers present for an average of 18.5 months and not responding to standard conservative treatment in a hospital setting were treated with the ultra-low current, ultra-low frequency device. 100% showed response to the treatment. 100% healed in a maximum time of 7 weeks. Average time of healing was 48 hours of treatment over 16 days. Surgical debridement was unnecessary as the necrotic tissue appeared to disappear spontaneously. The ages of the patients ranged between 20 and 85 years of age. Many studies have shown that the rate of wound healing of an individual is directly proportional to their age. From this study it can be seen that treating chronic skin ulcers with the ultra-low current device eliminates the age factor by equalizing the healing rate at all ages (fig.14). The only limiting factor in healing time with this method seems to be the duration of the lesion (fig.15). This study therefore suggests that treatment with the ultra-low current device eliminates the restrictions that aging brings to the healing process.

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X Weiss, (2008) Aging is not just the sum total of individually deteriorating cells. Aging is the dynamic process of increasing imbalances in the systemic organization of these cells. Anti-aging reflects a multilevel approach that simultaneously targets a number of biological network modules. Identifying these dynamically organized network modules will be very important in formulating a model of how and why the aging process takes place and whether or not we can reverse aging by reorganizing an aged network model. The old, the ill, and the injured all suffer from disarranged patterns of atoms, whether disarranged by aging and accumulated free radicals, invading viruses, or unfortunate accidents. Aged and young are the Gestalts on opposite poles composed of variations in the arrangement of their dynamically organized networks. Modern electronics and molecular biology research are combined to deduce the specifications for a technology that promotes Healthy Anti-aging. Resonating the firings, spatial organization and rhythms of electrically excitable cells leads to healing and rejuvenation in a completely safe, noninvasive method.