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| April 30,2004 | Chromatin remodeling by RNA polymerases | ||||||||
| Chromatin packages DNA tightly into the eukaryotic nucleus and maintains its proper functioning. Recent studies suggest the existence of two distinct mechanisms of progression of RNA polymerases through chromatin. The first is characteristic of eukaryotic RNA polymerase III, bacteriophage RNA polymerases, and probably ATP-dependent chromatin remodeling complexes. In this mechanism, nucleosomes are translocated without release of the octamer into solution. By contrast, transcription by RNA polymerase II (Pol II) involves displacement of one H2A-H2B dimer. | |||||||||
| April 29,2004 | A resource for large-scale RNA-interference-based screens in mammals | ||||||||
| Gene silencing by RNA interference (RNAi) in mammalian cells using small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) has become a valuable genetic tool1-10. Here, we report the construction and application of a shRNA expression library targeting 9,610 human and 5,563 mouse genes. This library is presently composed of about 28,000 sequence-verified shRNA expression cassettes contained within multi-functional vectors, which permit shRNA cassettes to be packaged in retroviruses, tracked in mixed cell populations by means of DNA 'bar codes', and shuttled to customized vectors by bacterial mating. In order to validate the library, we used a genetic screen designed to report defects in human proteasome function. | |||||||||
| April 28,2004 | Update in Hospital Medicine | ||||||||
| The articles chosen for this update cover topics important for general internists with active inpatient practices. These original research papers published in 2002 gave new insights into common inpatient diagnoses and frequent challenges for inpatient physicians. The articles were identified through MEDLINE searches and review journals, such as ACP Journal Club and Journal Watch. Local and national experts were polled to help prioritize the list and highlight the work with the highest perceived impact. These papers question several conventional practices in inpatient medicine or point the direction into which the field may be heading. | |||||||||
| April 27,2004 | Emerging infectious diseases | ||||||||
| Human population growth, technological advances, and changing social behaviors lead to the selection of new microbial pathogens. Antimicrobial drugs, vaccines, diagnostics, and treatments for emerging infectious diseases must be developed. The selective forces that drive the emergence of new infectious diseases, and the implications for our survival, are just beginning to be understood. | |||||||||
| April 26,2004 | Hypertrophic Obstructive Cardiomyopathy | ||||||||
| A 28-year-old man presents with a two-year history of increasing dyspnea on strenuous exertion and is found to have hypertrophic cardiomyopathy, with a septal thickness of 23 mm and a left ventricular outflow gradient of 80 mm Hg. There is no family history of hypertrophic cardiomyopathy or sudden death. Forty-eight-hour Holter monitoring shows infrequent premature ventricular contractions. How should this patient be treated? | |||||||||
| April 25,2004 | Mitochondrial pharmaceutics | ||||||||
| Since the end of the 1980s, key discoveries have been made which have significantly revived the scientific interest in a cell organelle, which has been studied continuously and with steady success for the last 100 years. It has become increasingly evident that mitochondrial dysfunction contributes to a variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Moreover, since the middle of the ‘1990s, mitochondria, the ‘power house’ of the cell, have also become accepted as the cell’s ‘arsenals’ reflecting their increasingly acknowledged key role during apoptosis. | |||||||||
| April 24,2004 | TUMOUR-SUPPRESSOR FUNCTION IN THE NERVOUS SYSTEM | ||||||||
| Tumour suppressors prevent cancer by regulating processes such as cell proliferation and survival. However, their functions are diverse, and are often related to the cell type and tissue context. Mutations of tumour-suppressor genes result in unique outcomes in the nervous system that contrast with their roles in other organs. This is closely related to the cell types in which mutations occur and the developmental stage of the tissues that are affected. How can studying the tissue-specific functions of tumour suppressors in the nervous system help us to understand signalling pathways that are relevant to cancer and what are the therapeutic implications of this? | |||||||||
| April 23,2004 | Multiple sclerosis | ||||||||
| Multiple sclerosis is a complex genetic disease associated with inflammation in the CNS white matter thought to be mediated by autoreactive T cells. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. This review discusses new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understanding of and therapies for this disease. | |||||||||
| April 22,2004 | Plasticity of Adult Stem Cells | ||||||||
| Recent years have seen much excitement over the possibility that adult mammalian stem cells may be capable of differentiating across tissue lineage boundaries, and as such may represent novel, accessible, and very versatile effectors of therapeutic tissue regeneration. Yet studies proposing such "plasticity"of adult somatic stem cells remain controversial, and in general, existing evidence suggests that in vivo such unexpected transformations are exceedingly rare and in some cases can be accounted for by equally unex- pected alternative explanations. | |||||||||
| April 21,2004 | DIAGNOSTICS FOR THE DEVELOPING WORLD | ||||||||
| Although ‘diseases of affluence’, such as diabetes and cardiovascular disease, are increasing in developing countries, infectious diseases still impose the greatest health burden. Annually, just under 1 million people die from malaria, 4.3 million from acute respiratory infections, 2.9 million from enteric infections and 5 million from AIDS and tuberculosis. Other sexually transmitted infections and tropical parasitic infections are responsible for hundreds of thousands of deaths and an enormous burden of morbidity. More than 95% of these deaths occur in developing countries. | |||||||||
| April 20,2004 | THE COMPLEX INTERPLAY AMONG FACTORS THAT INFLUENCE ALLELIC ASSOCIATION | ||||||||
| Small effect sizes, common-disease/common-variant versus rare variant influences, biased single nucleotide polymorphism ascertainment and low linkage disequilibrium have recently been discussed as impediments to association studies. Such a focus on the individual factors that highlight their maximum potential effect (whether positive or deleterious) is often optimistic as, in practice, they do not operate in isolation. Instead, they work jointly to generate the disease gene architecture and to determine the ability of a study to discover it. | |||||||||
| April 19,2004 | Review of aldosterone- and angiotensin II-induced target organ damage and prevention | ||||||||
| Aldosterone is well recognized as a cause of sodium reabsorption, water retention, and potassium and magnesium loss; however, it also produces a variety of other actions that lead to progressive target organ damage in the heart, vasculature, and kidneys. Aldosterone interacts with mineralocorticoid receptors to promote endothelial dysfunction, facilitate thrombosis, reduce vascular compliance, impair baroreceptor function, and cause myocardial and vascular fibrosis. Although angiotensin II has been considered the major mediator of cardiovascular damage, increasing evidence suggests that aldosterone may mediate and exacerbate the damaging effects of angiotensin II. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers reduce plasma aldosterone levels initially, aldosterone rebound, or ‘escape’ may occur during long-term therapy. | |||||||||
| April 18,2004 | DYNAMICS OF CANCER PROGRESSION | ||||||||
| Evolutionary concepts such as mutation and selection can be best described when formulated as mathematical equations. Cancer arises as a consequence of somatic evolution. Therefore, a mathematical approach can be used to understand the process of cancer initiation and progression. But what are the fundamental principles that govern the dynamics of activating oncogenes and inactivating tumour-suppressor genes in populations of reproducing cells? Also, how does a quantitative theory of somatic mutation and selection help us to evaluate the role of genetic instability? | |||||||||
| April 17,2004 | Update in Infectious Diseases | ||||||||
| This year's Update in Infectious Diseases focuses on the severe acute respiratory syndrome (SARS), hepatitis B, respiratory viruses, antibiotic resistance, and vaccination. The past year held both alarming findings about emerging infectious diseases and drug-resistant bacteria as well as exciting findings about new vaccines and more effective therapy for infectious diseases. | |||||||||
| April 16,2004 | Transcriptional control of B cell development and function | ||||||||
| The generation, development, maturation and selection of mammalian B lymphocytes is a complex process that is initiated in the embryo and proceeds throughout life to provide the organism an essential part of the immune system it requires to cope with pathogens. Transcriptional regulation of this highly complex series of events is a major control mechanism, although control is also exerted on all other layers, including splicing, translation and protein stability. This review summarizes our current understanding of transcriptional control of the well-studied murine B cell development, which bears strong similarity to its human counterpart. Animal and cell models with loss of function (gene ‘‘knock outs’’) or gain of function (often transgenes) have significantly contributed to our knowledge about the role of specific transcription factors during B lymphopoiesis. | |||||||||
| April 15,2004 | Type 1 diabetes: recent developments | ||||||||
| Type 1 diabetes is one of the most common chronic childhood illnesses, affecting 18 to 20 per 100 000 children a year in the United Kingdom.1 The American Diabetes Association committee recommends the term type 1A diabetes for immune mediated diabetes with its destruction of the islet β cells of the pancreas.2 Nonimmune mediated diabetes with severe insulin deficiency is termed type 1B. In this review, we will use the term type 1 diabetes to refer to immune mediated type 1A diabetes.At present, the development of type 1 diabetes is a life sentence to a difficult therapeutic regimen that is only partially effective in preventing acute and chronic complications. We will concentrate here on recent advances in our understanding of the epidemiology, pathogenesis, prediction, and prevention of type 1 diabetes and new treatments for the disease. | |||||||||
| April 14,2004 | Cardiac physiology at the cellular level | ||||||||
| HL-1 cells are currently the only cardiomyocyte cell line available that continuously divides and spontaneously contracts while maintaining a differentiated cardiac phenotype. Extensive characterization using microscopic, genetic, immunohistochemical, electrophysiological, and pharmacological techniques has demonstrated how similar HL-1 cells are to primary cardiomyocytes. In the few years that HL-1 cells have been available, they have been used in a variety of model systems designed to answer important questions regarding cardiac biology at the cellular and molecular levels. Whereas HL-1 cells have been used to study normal cardiomyocyte function with regard to signaling, electrical, metabolic, and transcriptional regulation, they have also been used to address pathological conditions such as hypoxia, hyperglycemia-hyperinsulinemia, apoptosis, and ischemia-reperfusion. | |||||||||
| April 13,2004 | Cytokine function of heat shock proteins | ||||||||
| Extensive work in the last 10 years has suggested that heat shock proteins (HSPs) may be potent activators of the innate immune system. It has been reported that Hsp60, Hsp70, Hsp90, and gp96 are capable of inducing the production of proinflammatory cytokines by the monocyte-macrophage system and the activation and maturation of dendritic cells (antigen-presenting cells) in a manner similar to the effects of lipopolysaccharide (LPS) and bacterial lipoprotein, e.g., via CD14/ Toll-like receptor2 (TLR2) and CD14/TLR4 receptor complex-mediated signal transduction pathways. However, recent evidence suggests that the reported cytokine effects of HSPs may be due to the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) as being responsible for the reported HSP cytokine effects include failure to use highly purified, low-LPS preparations of HSPs; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS. | |||||||||
| April 12,2004 | The translationally controlled tumour protein (TCTP) | ||||||||
| The translationally controlled tumour protein (TCTP) is a highly conserved protein that is widely expressed in all eukaryotic organisms. Based on its sequence, TCTP was listed as a separate protein family in protein databases but the recent elucidation of the solution structure of the fission yeast orthologue places it close to a family of small chaperone proteins. The molecular functions determined so far, Ca2+- and microtubule-binding, have been mapped to an α-helical region of the molecule. TCTP expression is highly regulated both at the transcriptional and translational level and by a wide range of extracellular signals. TCTPhas been implicated in important cellular processes, such as cell growth, cell cycle progression, malignant transformation and in the protection of cells against various stress conditions and apoptosis. In addition, an extracellular, cytokine-like function has been established for TCTP, and the protein has been implicated in various medically relevant processes. | |||||||||
| April 11,2004 | Evaluation of health information systems—problems and challenges | ||||||||
| Information technology (IT) is emerging in health care. A rigorous evaluation of this technology is recommended and of high importance for decision makers and users. However, many authors report problems during the evaluation of information technology in health care. In this paper, we discuss some of these problems, and propose possible solutions for these problems. Methods: Based on own experience and backed up by a literature review, some important problems during IT evaluation in health care together with their reasons, consequences and possible solutions are presented and structured. Results and conclusions: We de.ne three main problem areas-the complexity of the evaluation object, the complexity of an evaluation project, and the motivation for evaluation. Many evaluation problems can be subsumed under those three problem areas. | |||||||||
| April 10,2004 | On the rotational operators in protein structure simulations | ||||||||
| The reduction of the computational complexity of the algorithms dealing with protein structure analysis and conformation predictions is of prime importance. One common element in most of these algorithms is the process of transforming geometrical information between dihedral angles and Cartesian coordinates of the atoms in the protein using rotational operators. In the literature, the operators used in protein structures are rotation matrices, quaternions in vector and matrix forms and the Rodrigues-Gibbs formula. In the protein structure-related literature, the most widely promoted rotational operator is the quaternions operator. In this work, we studied the computational effciency of the mathematical operations of the above rotational operators applied to protein structures. A similar study applied to protein structures has not been reported previously. | |||||||||
| April 9,2004 | THE MANY IMPORTANT FACETS OF T-CELL REPERTOIRE DIVERSITY | ||||||||
| In the thymus, a diverse and polymorphic T-cell repertoire is generated by random recombination of discrete T-cell receptor (TCR)-αβ gene segments. This repertoire is then shaped by intrathymic selection events to generate a peripheral T-cell pool of self-MHC restricted, non-autoaggressive T cells. It has long been postulated that some optimal level of TCR diversity allows efficient protection against pathogens. This article focuses on several recent advances that address the required diversity for the generation of an optimal immune response. | |||||||||
| April 8,2004 | PROGRESS IN ANTISENSE TECHNOLOGY | ||||||||
| Antisense technology exploits oligonucleotide analogs to bind to target RNAs viaWatson-Crick hybridization. Once bound, the antisense agent either disables or induces the degradation of the target RNA. Antisense agents can also alter splicing. During the past decade, much has been learned about the basic mechanisms of antisense, the medicinal chemistry, and the pharmacologic, pharmacokinetic, and toxicologic properties of antisense molecules. Antisense technology has proven valuable in gene functionalization and target validation. With one drug marketed, Vitravene?, and approximately 20 antisense drugs in clinical development, it appears that antisense drugs may prove important in the treatment of a wide range of diseases. | |||||||||
| April 7,2004 | 2-Hydroxyoleic Acid | ||||||||
| Recent studies have shown that diets rich in monounsaturated fatty acids (MUFAs) from olive oil, a natural source of oleic acid, have beneficial effects on blood pressure (BP) in hypertensive patients. With this in mind, we investigated whether a synthetic derivative of the MUFA oleic acid, 2-hydroxyoleic acid (2-OHOA), was capable of regulating the BP of Sprague-Dawley rats. Intraperitoneal and oral administration of 2-OHOA to rats induced significant and sustained decreases in BP in a time-dependent manner. Without affecting heart rate, treatments for 7 days provoked reductions in systolic BP of 20 to 26 mm Hg. At the molecular level, the density of Gαs, but not Gαi2 or Gαo, increased in membranes from the hearts and rtas of 2-OHOA–treated rats, whereas in heart membranes, the density of Gαq/11 and protein kinase Cα proteins was also augmented. | |||||||||
| April 6,2004 | Role of Platelets in the Development of Atherosclerosis | ||||||||
| Platelets are blood cell fragments that originate from the cytoplasm of megakaryocytes in the bone marrow and circulate in blood to play a major role in the hemostatic process and in thrombus formation after an endothelial injury. Recent studies have provided insight into platelet functions in inflammation and atherosclerosis. A range of molecules, present on the platelet surface and/or stored in platelet granules, contributes to the cross-talk of platelets with other inflammatory cells during the vascular inflammation involved in the development and progression of atherosclerosis. This review discusses the nature of these molecules and the mechanisms involved in the participation of platelets in atherosclerosis, with emphasis on P-selectin, platelet¨Cmonocyte interactions, chemokines, and inflammatory cytokines. | |||||||||
| April 5,2004 | Laboratory animals:The Renaissance rat | ||||||||
| Thanks to the availability of its genome sequence, and the promise of new genetically engineered strains, the rat is restoring its reputation as researchers’ favourite lab animal. Alison Abbott hails a remarkable rodent.Rats tend to provoke strong reactions.
Many people, repulsed by the rodents’
tendency to feast on refuse and to
spread disease, hate them. But physiologists,
pharmacologists, toxicologists and pathologists
are among the rat’s biggest fans. For
them, the rat is the most important experimental
animal — and one for which they
can’t hide their affection.
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| April 4,2004 | MEMBRANE TRAFFICKING OF G PROTEIN–COUPLED RECEPTORS | ||||||||
| G protein-coupled receptors (GPCRs) modulate diverse physiological and behavioral signaling pathways by virtue of changes in receptor activation and inactivation states. Functional changes in receptor properties include dynamic interactions with regulatory molecules and trafficking to various cellular compartments at various stages of the life cycle of a GPCR. This review focuses on trafficking of GPCRs to the cell surface, stabilization there, and agonist-regulated turnover. GPCR interactions with a variety of newly revealed partners also are reviewed with the intention of provoking further analysis of the relevance of these interactions in GPCR trafficking, signaling, or both. The disease consequences of mislocalization of GPCRs also are described. | |||||||||
| April 3,2004 | Principles of Tumor Suppression | ||||||||
| Molecular genetic studies of familial cancer syndromes identified and defined the recessive nature of tumor suppressor genes and resolved the paradox of why tumors arising in such families exhibited an autosomally dominant pattern of inheritance. Subsequent characterization of tumor suppressor proteins revealed their widespread involvement in sporadic cancers and pinpointed key mechanisms that protect animals against tumor development. We now recognize that tumor suppressor genes regulate diverse cel- lular activities, including cell cycle checkpoint responses, detection and repair of DNA damage, protein ubiquitination and degradation, mitogenic signaling, cell specification, differentiation and migration, and tumor angiogenesis. Their study has become a centerpiece of contemporary cancer research. | |||||||||
| April 2,2004 | Cancer Statistics, 2004 | ||||||||
| Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival rates based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and mortality rates are age standardized to the 2000 US standard million population. A total of 1,368,030 new cancer cases and 563,700 deaths are expected in the United States in 2004. Incidence rates stabilized among men from 1995 through 2000 but continued to increase among females by 0.4% per year from 1987 through 2000. Mortality rates have decreased by 1.5% per year since 1992 among men, but have stabilized from 1998 through 2000 among women. | |||||||||
| April 1,2004 | ENZYME-MEDIATED DNA LOOPING | ||||||||
| Most reactions on DNA are carried out by multimeric protein complexes that interact with two or more sites in the DNA and thus loop out the DNA between the sites. The enzymes that catalyze these reactions usually have no activity until they interact with both sites. This review examines the mechanisms for the assembly of protein complexes spanning two DNA sites and the resultant triggering of enzyme activity. There are two main routes for bringing together distant DNA sites in an enzyme complex: either the proteins bind concurrently to both sites and capture the intervening DNA in a loop, or they translocate the DNA between one site and another into an expanding loop, by an energy-dependent translocation mechanism. Both capture and translocation mechanisms are discussed here, with reference to the various types of restriction endonuclease that interact with two recognition sites before cleaving DNA. |
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