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PubMed2006

Tumor suppressive maspin and epithelial homeostasis.

Maspin is a 42-kDa novel serine protease inhibitor (serpin) with multifaceted tumor suppressive activities. To date, the consensus that maspin expression predicts a better prognosis still largely holds for breast, prostate, colon, and oral squamous cancers. Interestingly, however, more detailed analyses revealed a biphasic expression pattern of maspin in early steps of tumorigenicity and re-expression of maspin in dormant cancer metastatic revertants. These data suggest a sensitivity of maspin expression to changes of epithelial microenvironments, and a role of maspin in epithelial homeostasis. Experimental evidence consistently showed that maspin suppresses tumor growth, invasion and metastasis, induces tumor redifferentiation, and enhances tumor cell sensitivity to apoptosis. Maspin protein isolated from biological sources is a monomer, which is present as a secreted, a cytoplasmic, a nuclear, as well as a cell surface-associated protein. Nuclear maspin is associated with better prognoses of cancer. It is further noted that extracellular maspin is sufficient to block tumor induced extracellular matrix degradation, tumor cell motility and invasion, whereas intracellular maspin is responsible for the increased cellular sensitivity to apoptosis. Despite these exciting developments, the mechanistic studies of maspin have proven challenging primarily due to the lack of a prototype molecular model. Although the maspin sequence has overall homologies with other members in the serpin superfamily, it does not behave like a typical serpin, that is, non-inhibitory toward active serine proteases in solution. This novel feature is in line with the X-ray crystallographic evidence. Several recent studies dedicated to finding the maspin partners support a paradigm shift. The current review is intended to summarize these recent findings and discuss a new perspective of maspin in epithelial homeostasis.

Animals↗

PubMed2005

Framework-based design of a new all-purpose molecular simulation application: the Adun simulator.

Here we present Adun, a new molecular simulator that represents a paradigm shift in the way scientific programs are developed. The traditional algorithm centric methods of scientific programming can lead to major maintainability and productivity problems when developing large complex programs. These problems have long been recognized by computer scientists; however, the ideas and techniques developed to deal with them have not achieved widespread adoption in the scientific community. Adun is the result of the application of these ideas, including pervasive polymorphism, evolutionary frameworks, and refactoring, to the molecular simulation domain. The simulator itself is underpinned by the Adun Framework, which separates the structure of the program from any underlying algorithms, thus giving a completely reusable design. The aims are twofold. The first is to provide a platform for rapid development and implementation of different simulation types and algorithms. The second is to decrease the learning barrier for new developers by providing a rigorous and well-defined structure. We present some examples on the use of Adun by performing simple free-energy simulations for the adiabatic charging of a single ion, using both free-energy perturbation and the Bennett's method. We also illustrate the power of the design by detailing the ease with which ASEP/MD, an elaborated mean field QM/MM method originally written in FORTRAN 90, was implemented into Adun.

Algorithms↗

PubMed1995

Gap junctions in the vertebrate retina.

The vertebrate retina is a highly laminated assemblage of specialized neuronal types, many of which are coupled by gap junctions. With one interesting exception, gap junctions are not directly responsible for the 'vertical' transmission of visual information from photoreceptors through bipolar and ganglion cells to the brain. Instead, they mediate 'lateral' connections, coupling neurons of a single type or subtype into an extended, regular array or mosaic in the plane of the retina. Such mosaics have been studied by several microscopic techniques, but new evidence for their coupled nature has recently been obtained by intracellular injection of biotinylated tracers, which can pass through gap junctional assemblies that do not pass Lucifer Yellow. This evidence adds momentum to an existing paradigm shift towards a population-based view of the retina, which can now be envisaged both as an array of semi-autonomous vertical processing modules, each extending right through the retina, and as a multi-layered stack of interacting planar mosaics, bearing some resemblance to a set of interleaved neural networks. Junctional conductance across mosaics of horizontal cells is known to be controlled dynamically with a circadian rhythm, and other dynamically-regulated conductance changes are also likely to make important contributions to signal processing. The retina is an excellent system in which to study such changes because many aspects of its structure and function are already well understood. In this review, we summarize the microscopic appearance, coupling properties and functions of gap junctions for each cell type of the neural retina, the regulatory properties that could be provided by selective expression of different connexin proteins, and the evidence for gap junctional coupling in retina development.

Animals↗

PubMed2005

DSM-III and the revolution in the classification of mental illness.

A revolution occurred within the psychiatric profession in the early 1980s that rapidly transformed the theory and practice of mental health in the United States. In a very short period of time, mental illnesses were transformed from broad, etiologically defined entities that were continuous with normality to symptom-based, categorical diseases. The third edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-III) was responsible for this change. The paradigm shift in mental health diagnosis in the DSM-III was neither a product of growing scientific knowledge nor of increasing medicalization. Instead, its symptom-based diagnoses reflect a growing standardization of psychiatric diagnoses. This standardization was the product of many factors, including: (1) professional politics within the mental health community, (2) increased government involvement in mental health research and policymaking, (3) mounting pressure on psychiatrists from health insurers to demonstrate the effectiveness of their practices, and (4) the necessity of pharmaceutical companies to market their products to treat specific diseases. This article endeavors to explain the origins of DSM-III, the political struggles that generated it, and its long-term consequences for clinical diagnosis and treatment of mental disorders in the United States.

Diagnostic and Statistical Manual of Mental Disord↗

PubMed2001

Incidence and effects of Ha-ras codon 12 G-->A transition mutations in preneoplastic lesions induced by N-nitrosomethylbenzylamine in the rat esophagus.

N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis is an important model for squamous cell carcinoma of the human esophagus. In this model, previous studies have shown that the GGA-->GAA Ha-ras codon 12 mutation is present in the majority of papillomas. No other Ha-ras mutation has been identified. Studies using other models of chemical carcinogenesis suggest that Ha-ras activation has a critical role during tumor initiation. We have used laser-capture microdissection and polymerase chain reaction-restriction fragment length polymorphism analysis to study the role of codon 12 Ha-ras mutation at various stages of tumor development in the rat esophagus. Our results indicate that Ha-ras mutation was present infrequently (4.3%) in premalignant lesions. The incidence of Ha-ras mutation was high in papillomas (57.1%), however, and 50% of papillomas expressed mutant Ha-ras RNA message. Additionally, there was a linear trend correlating increased incidence of Ha-ras mutation with later papilloma stage. These data suggest the role of ras activation later in neoplastic development. To evaluate the potential mechanism of action by which Ha-ras contributes to promotion and progression in this model, we compared mRNA expression of cyclin D1 and p27 in Ha-ras mutant and Ha-ras normal papillomas. We found no differences in mRNA expression of either cyclin D1 or p27 between these two papilloma populations. Our data suggest an important paradigm shift for the role of ras mutations in this model of chemical carcinogenesis, indicating a functional role of Ha-ras activation in promotion/progression and not in the initiation phase of NMBA-induced papillomagenesis.

Animals↗

PubMed2006

Cyclooxygenase-2 as a signaling molecule in radiation-induced bystander effect.

Radiation-induced bystander effect represents a paradigm shift in our understanding of the radiobiological effects of ionizing radiation in that extranuclear and extracellular effects may also contribute to the final biological consequences of exposure to low doses of radiation. Evidence suggests that targeted cytoplasmic irradiation results in mutation in the nucleus of the "hit" cells and that cells, which are not directly hit by an alpha particle, whether nuclear or cytoplasm, but are in the vicinity of one that does get hit, contribute to the genotoxic response of the cell population. Although radiation-induced bystander effects have been well documented in a variety of biological systems, the mechanism is not known. Using the Columbia University charged particle beam in conjunction with a novel strip dish design, we showed recently that the cyclooxygenase-2 (COX-2) signaling cascade plays an essential role in the bystander process. Treatment of bystander cells with NS-398, which suppresses COX-2 activity, significantly reduced the bystander effect as well as the induction of the mitogen-activated protein kinase (MAPK) pathways. These results provided the first evidence that the COX-2-related pathway, which is essential in mediating cellular inflammatory responses, is the critical signaling link for the bystander phenomenon. A better understanding of the cellular and molecular mechanisms of the bystander phenomenon together with evidence of their occurrence in vivo will allow us to formulate a more accurate model in assessing the health effects of low doses of ionizing radiation.

Animals↗

PubMed2001

Sustainable wastewater management for small communities in the Middle East and North Africa.

Accelerated expansion of wastewater services to small communities in the Middle East and North Africa (MENA) is essential in order to address serious concerns over water scarcity and pollution in addition to meeting the demand for convenience and protecting public health. Centralized and conventional wastewater systems are currently the preferred choice of planners and decision-makers in MENA. Water and funding are not available to provide these centralized conventional services to small communities. This paper presents an integrated approach to sustainable wastewater management for small communities in MENA under the severe water resources crisis. The approach calls for a paradigm shift from centralized conventional wastewater systems to decentralized wastewater systems. Management of wastewater in MENA should start at home. Wastewater generation should be reduced through a combination of domestic water conservation measures. On-site systems must be improved and monitored to control pollution and to recover water for non-potable water uses. Should the circumstances not allow the use of on-site systems, wastewater should be transported and managed through a community system applying the principles of decentralized wastewater management and using the settled sewers for wastewater transportation where appropriate. This approach will facilitate the accelerated and sustainable extension of environmentally responsible wastewater services to MENA's small communities. It offers great potential for cost reduction, accommodates the necessary domestic water conservation efforts, reduces freshwater inputs in wastewater transportation thus eliminating unnecessary demand on freshwater, reduces associated environmental risks and increases wastewater reuse opportunities.

Africa, Northern↗

PubMed2001

Fractal methods to analyze ion channel kinetics.

We describe the traditional nonfractal and the new fractal methods used to analyze the currents through ion channels in the cell membrane. We discuss the hidden assumptions used in these methods and how those assumptions lead to different interpretations of the same experimental data. The nonfractal methods assumed that channel proteins have a small number of discrete states separated by fixed energy barriers. The goal was to determine the parameters of the kinetic diagram, which are the number of states, the pathways between them, and the kinetic rate constants of those pathways. The discovery that these data have fractal characteristics suggested that fractal approaches might provide more appropriate tools to analyze and interpret these data. The fractal methods determine the characteristics of the data over a broad range of time scales and how those characteristics depend on the time scale at which they are measured. This is done by using a multiscale method to accurately determine the probability density function over many time scales and by determining how the effective kinetic rate constant, the probability of switching states, depends on the effective time scale at which it is measured. These fractal methods have led to new information about the physical properties of channel proteins in terms of the number of conformational substates, the distribution of energy barriers between those states, and how those energy barriers change with time. The new methods developed from the fractal paradigm shifted the analysis of channel data from determining the parameters of a kinetic diagram to determining the physical properties of channel proteins in terms of the distribution of energy barriers and/or their time dependence.

Animals↗

PubMed1999

Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations.

The failure to find an increased frequency of ATM mutations in large cancer cohorts, especially breast cancer, is contrary to what was anticipated based on the increased cancer susceptibility of obligate ATM heterozygotes from families with ataxia-telangiectasia (A-T). We hypothesize that this paradox might be resolved if two types of ATM heterozygotes exist and the phenotypes differ, i.e., those with truncating types of mutations (ATM(trunc)), that make no protein, and those with missense types of mutations (ATM(mis)), that make reduced amounts of defective protein. The phenotype of ATM(trunc/trunc) mutations is the A-T syndrome; the phenotype of ATM(mis/mis) mutations, judging from the few homozygous patients that have been documented, appears to include some neurological features and cancer susceptibility but not the A-T syndrome. Evidence is reviewed which suggests that ATM(mis/wt) mutations are technically more difficult to detect than ATM(trunc/wt) mutations. Despite this, most large cancer cohort studies have identified mainly missense mutations and few truncating mutations. This model would require a paradigm shift for cancer risk analyses, to recognize the existence of different allele frequencies for the two types of A-T heterozygotes.

Ataxia Telangiectasia↗

PubMed2005

Treatment of adolescent alcohol-related problems. A translational perspective.

In the present chapter we have sought to articulate a translational perspective linking development during adolescence to alcohol treatment and its evaluation. Clearly adolescents with alcohol use disorders cannot be treated as younger versions of adults. The unique demands of their developmental stage permeate all aspects of their behavior, including alcohol use and abuse. Multi-dimensional developmental models help inform the design, implementation, and evaluation of alcohol and drug treatment programs. While an understanding of individual risk factors is informative, only through models integrating multiple risk pathways embedded in the context of adolescent development can we hope to build more efficacious and effective systems of intervention for youth with AUDs. Effective treatment of adolescent AUDs not only urges translation of the developmental perspective into pre-existing treatment approaches but argues for a paradigm shift towards alternative intervention designs and evaluation procedures and foci.

Adaptation, Psychological↗

PubMed2006

Antiviral applications of RNAi.

RNA interference is a natural mechanism by which small interfering (si)RNA operates to specifically and potently down-regulate the expression of a target gene. This down-regulation has been thought to predominantly function at the level of the messenger (m)RNA, post-transcriptional gene silencing (PTGS). Recently, the discovery that siRNAs can function to suppress a gene's expression at the level of transcription, i.e., transcriptional gene silencing (TGS), has created a major paradigm shift in mammalian RNAi. These recent findings significantly broaden the role RNA, specifically siRNAs and potentially microRNAs, plays in the regulation of gene expression as well as the breadth of potential siRNA target sites. Indeed, the specificity and simplicity of design makes the use of siRNAs to target and suppress virtually any gene or gene promoter of interest a realized technology. Furthermore, since siRNAs are a small nucleic acid reagent, they are unlikely to elicit an immune response, making them a theoretically good future therapeutic. This review will focus on the development, delivery, and potential therapeutic use of antiviral siRNAs in treating viral infections as well as emerging viral threats.

Animals↗

PubMed2004

Inhibition of angiogenesis as a therapeutic strategy against brain tumors.

Multidisciplinary treatment strategies for patients with malignant brain tumors have resulted in only small gains in terms of prognosis in spite of the use of aggressive therapy. There is a growing realization that a paradigm shift is needed in the conceptual approaches to glioma therapy. Such approaches will rely on identification and modification of key cellular targets that define the biological behavior of these tumors. Among the targets for such treatment approaches, tumor angiogenesis has captured the attention of not only the medical field but also of the lay public because of its conceptual departure from traditional methods of cancer therapy. Angiogenesis and vascular proliferation are particularly important in the growth and progression of malignant gliomas and are used as indicators of the degree of malignancy. Recent studies have helped us gain a better understanding of the molecular mediators of this process. It is now evident that after the initial formation of malignancy the continued growth of a glioma is critically dependent on its angiogenic potential. Hence, several approaches to control angiogenesis are being developed and tested. Preliminary results from clinical studies have shown that angiogenesis inhibition is a valid approach as a therapeutic strategy against gliomas but it is also becoming evident that inhibition of individual modulators of this process may not yield the expected impact on prognosis. To fully realize the potential of antiangiogenic therapy, a deeper understanding of the interplay between the tumor vasculature and its environment is needed. Angiogenesis inhibitors have made the transition from preclinical studies to the clinical arena; it remains for ongoing human trials of such agents to fully explore the feasibility and efficacy of these agents in order to exploit the potential of this approach.

Angiogenesis Inhibitors↗

PubMed2007

Integrating profiling data: using linear correlation to reveal coregulation of transcript and metabolites.

Recent advances in the medical and biological sciences have been characterized by a major paradigm shift from reductionism to integrated and holistic systems approaches. Such approaches are characterized at the experimental level by the multiparallel analysis of a multitude of parameters of a given biological system at a range of different molecular levels, following the systematic perturbation of the system in question. Although a multitude of studies have been carried out to assess the transcript, protein, and metabolite complements of cells under various conditions, to date, few have been attempted that encompass the profiling of more than one of these entities. In this chapter, we describe combined analysis of data obtained from transcript and metabolic profiling, and detail advantages of using both approaches in parallel.

Gas Chromatography-Mass Spectrometry↗

PubMed1994

Spirit possession in South Asia, dissociation or hysteria? Part 1: Theoretical background.

Psychoanalytic theory appears flawed in its notions of universal oedipal conflict and repression, and unsuitable for the study of pathological spirit possession in South Asia. The biological theory of contemporary psychiatry is no more effective in this analysis because mental illnesses are constituted within culture-bound categories of experience. Dissociation theory offers a better theoretical tool for this type of research. A summary of the history of paradigm shifts in psychiatric theory relevant to spirit possession is presented.

Anthropology, Cultural↗

PubMed1994

Effects of accumbens DALA microinjections on brain stimulation reward and behavioral activation in intact and 6-OHDA treated rats.

The effects of bilateral nucleus accumbens microinjections of d-ala-met-enkephalinamide (DALA) were assessed in behavioral activation and lateral hypothalamic self-stimulation (LHSS) rate-frequency curve-shift paradigms in normal and accumbens 6-OHDA (4.0 micrograms) treated rats. Microinjections of DALA (2.5 micrograms/microliters) in the behavioral activation paradigm had little effect on normal activity; however, DALA administered to 6-OHDA treated rats produced a significant overall increase in locomotion. The 6-OHDA DALA-induced locomotion effect peaked at 2 weeks after 6-OHDA treatment and then returned to baseline levels by week 5 post-treatment. Using LHSS, DALA tested over a range of doses (2.5, 5, 10, 20 micrograms/microliters) displayed a weak biphasic reward effect only at the highest dose, which was characterized by an initial suppression followed by an elevation. DALA significantly depressed initial operant motor/performance in LHSS in a dose dependent fashion. Microinjections of the normally ineffective low dose of DALA (2.5 micrograms/microliters) following accumbens 6-OHDA treatment produced a significant LHSS reward decrease 2 weeks post-treatment, while LHSS motor/performance was relatively unaffected. Results are discussed in terms of opiate-dopamine and limbic-motor interactions.

Animals↗

PubMed1995

Medical applications of virtual reality.

Medical applications for virtual reality (VR) are just beginning to emerge. These include VR surgical simulators, telepresence surgery, complex medical database visualization, and rehabilitation. These applications are mediated through the computer interface and as such are the embodiment of VR as an integral part of the paradigm shift in the field of medicine. The Green Telepresence Surgery System consists of two components, the surgical workstation and remote worksite. At the remote site there is a 3-D camera system and responsive manipulators with sensory input. At the workstation there is a 3-D monitor and dexterous handles with force feedback. The VR surgical simulator is a stylized recreation of the human abdomen with several essential organs. Using a helmet mounted display and DataGlove, a person can learn anatomy from a new perspective by 'flying' inside and around the organs, or can practice surgical procedures with a scalpel and clamps. Database visualization creates 3-D images of complex medical data for new perspectives in analysis. Rehabilitation medicine permits impaired individuals to explore worlds not otherwise available to them, allows accurate assessment and therapy for their disabilities, and helps architects understand their critical needs in public or personal space. And to support these advanced technologies, the operating room and hospital of the future will be first designed and tested in virtual reality, bringing together the full power of the digital physician.

Computer Graphics↗

PubMed1994

New and borrowed strategies for mental health systems in the decade of the 1990s.

Use of the paradigm shifts advocated by futurists and the supporters of total quality management can facilitate access to new options for mental health systems. New views and innovative systems, however, become difficult to maintain in the context of increasingly rapid and unexpected change occurring in the environment. One strategy that can be employed is the use of leverage, a term usually associated with finance or politics.

Community Mental Health Services↗

PubMedDate not supplied

Roots of the Pavlovian Society's missions of the past and present: the Pavlov dimension.

This paper offers an interpretation of the relation between Pavlov's life and work and the missions of the Pavlovian Society, both past ("observation and observation") and present ("interdisciplinary research on the integrated organism"). I begin with an account of Pavlov's life and his influence on contemporary thought. I then indicate the relation of some of Pavlov's attitudes (e.g., his motto, his epistemological stance) to the Society's past mission. In the concluding and most controversial section, I argue for six guiding principles derived from Pavlov, to be applied to the Society's mission. These are: (a) a confident methodological behaviorism; (b) a significant role assigned to both physiological and psychological factors in the prediction and control of the integrated organism; (c) approximately equal taxonomic precision of physiological and psychological explanatory concepts; (d) distrust of teleological explanatory concepts; (e) rejection of psychology's instrumentalist "cognitive paradigm shift"; and (f) rejection of the representational theory of knowledge.

Animals↗