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July June May April Jan 2001

August 31,2002 The Structure of Haplotype Blocks in the Human Genome
  Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.
August 30,2002 Identification of Signal Peptide Peptidase, a Presenilin-Type Aspartic Protease
  Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. In humans, SPP activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein. We have identified human SPP as a polytopic membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. SPP and potential eukaryotic homologs may represent another family of aspartic proteases that promote intramembrane proteolysis to release biologically important peptides.
August 29,2002 Cardiovascular properties of the kallikrein-kinin system
  All the components of the kallikrein-kinin system are located in the vascular smooth muscle as well as in the heart. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischaemia, myocardial infarction and left ventricular hypertrophy, have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental in the induction of cardiovascular-related diseases. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.
August 28,2002 On the TRAIL to apoptosis
  Apoptosis in mammalian cells can be initiated through two major interrelated pathways, one involving engagement of the TNF family of death receptors, the other involving the release of cytochrome c from mitochondria. Unlike other members of the TNF ligand family, TNF-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cell lines, but not in normal cells, suggesting that TRAIL could potentially represent a powerful cancer therapeutic. Recent experiments have revealed that one of the key regulators of TRAIL expression in lymphocytes is the NF-B transcription factors. Several TRAIL receptors have been identified: two of these receptors TRAIL-R1/DR4 and TRAIL-R2/DR5 contain cytoplasmic death domains and signal apoptosis, while two other decoy receptors, TRAIL-R3/DcR1 and TRAIL-R4/DcR2 lack a functional death domain and do not mediate apoptosis. Many cancer cell lines preferentially express TRAIL-R1 and TRAIL-R2, suggesting differential regulation of the death and decoy receptors. Further knowledge of the regulation and physiological role of TRAIL and TRAIL receptors may aid in the rational design of regimens that utilize the TRAIL signaling pathway to eliminate tumor cells.
August 27,2002 Stem cells on the way to restorative medicine
 

Stem cells are defined by their nique properties of self-renewal and multilineage differentiation. Several decades ago, cells with such developmental plasticity have been identified in the embryo and in the bone marrow of the adult; in other organs, such cells could not be demonstrated. Here, recent findings are briefly summarized indicating that the elementary stem cell capabilities are retained by a limited number of cells present in many organs of the adult. Other data suggest that, on response to another microenvironment, ‘rgan-specific’ stem cells are able to acquire differrent fates. If onfirmed these findings will have considerable impact on the future of clinical stem cell therapy.

August 26,2002 The family of IL-10-related cytokines and their receptors: related, but to what extent?
  Five novel cytokines (IL-19, IL-20, IL-22 (IL-TIF), IL-24 (human MDA-7, mouse FISP, rat C49A/Mob-5), and IL-26 (AK155)) demonstrating limited primary sequence identity and probable structural homology to IL-10 have been identified. These cellular cytokines, as well as several cytokines encoded in viral genomes (viral cytokines), form a family of IL-10-related cytokines or the IL-10 family. These cytokines share not only homology but also receptor subunits and perhaps activities. Receptors for these cytokines belong to the class II cytokine receptor family. The receptors are IL-10R2 (CRF2-4), IL-22R1 (CRF2-9), IL-22BP (CRF2-10), IL-20R1 (CRF2-8) and IL-20R2 (CRF2-11). Biological activities of these cytokines, receptor utilization and signaling, as well as expression atterns for cytokines and their receptors are summarized. Although data indicate that these cytokines are involved in regulation of inflammatory and immune responses, their major functions remain to be discovered.
August 25,2002 Recent advances in recombinant adeno-associated virus vector production
  Adeno-associated virus (AAV) is a replication-defective parvovirus that is being developed as a vector for human gene transfer. Recombinant AAV (rAAV) vectors are being proposed as a gene transfer vehicle for an array of human diseases.
August 24,2002 The T cell as a bridge between innate and adaptive immune systems
  Ischemic acute renal failure, a major cause of native kidney and allograft dysfunction, is mediated in part by inflammatory components nonspecific resistance to pathogens, whereas adaptive im- of the innate immune system. Recent data from experimental models in kidney as well as liver, intestine, brain and heart implicate T cells as important mediators of ischemia reperfusion injury.
August 23,2002 New directions in vaccine research
  There are at least three reasons to renew our efforts to develop new and better vaccines. First, with the notable exception of smallpox, the organisms that cause most of these diseases continue to circulate in the population worldwide. Second, in addition to these persisting scourges, new diseases continue to emerge. Perhaps the most frightening example is AIDS, with its devastating effect on millions of people throughout the world. Third, as both scientists and the public have recently come to appreciate, the use of infectious agents as bioterrorist or biowarfare weapons represents a potent threat to individuals and society.
August 22,2002

Molecules in focus: Calpain

The calcium-dependent thiol proteases, calpains, are widely expressed with ubiquitous and tissue specific isoforms. Calpains have been implicated in basic cellular processes including cell proliferation, apoptosis and differentiation. The focus of the current review is to summarize recent findings implicating calpains in cytoskeletal rearrangements and cell migration.

August 21,2002

Extraction of knowledge on protein-protein interaction by association rule discovery

Protein-protein interactions are systematically examined suing the yeast 2-hybrid method.Consequently, a lot of interaction data are currently being accumulated. Nevertheless,general infromation or knowledge on interactions is poorly extracted from these data.Thus we have been trying to extract the knowledge from the data using data mining.

August 20,2002

Liver Transplantation:Making the Best out of What We Have

One of the major challenges facing the liver transplant community is the shortage of donor organs. Possible approaches to overcoming this problem include changes in legislation, setting up of organizational structures, more effective use of marginal donor livers, splitting livers, and the development of living related transplants.

August 19,2002

Calcium signaling: A tale for all seasons

The rapid advancement of the Ca2+ field has now swollen the literature to a size where it would be impossible to cover all of it in a few pages. This contribution will focus only on the most significant recent advances. The choice will be unavoidably arbitrary, but it should give readers the feeling for the most exciting developments in the area.

August 18,2002

Current and future relevance of guidelines

There is a widely held belief that guidelines improve the quality of care for patients. However, there is also potential for harm, as any attempt to standardise care ignores the heterogeneity of patients and the complexity of medical decisions.

August 17,2002

Gene transfer into eukaryotic cells using activated polyamidoamine dendrimers

Activated polyamidoamine PAMAM -dendrimers provide a new technology for gene transfer that offers significant advantages over classical methods. Reagents based on this technology provide high gene transfer efficiencies, minimal cytotoxicity, and can be used with a broad range of cell types.

August 16,2002

Sudden Death Predictors

Pharmaceutical strategies to prevent sudden cardiac death have been largely ineffective, and because device therapy is designed to rescue patients once an event has already occurred, primary SCD prevention has become one of today’s most critical public health challenges.

August 15,2002

Molecules in focus: Urocortin

Urocortin (Ucn) is a 40 amino acid peptide which is closely related to corticotrophin-releasing factor (CRF). It is expressed in specific regions of the brain but is also detectable in other organs notably the heart. It has potent effects on the neural and cardiovascular system.

August 14,2002

RTS1 — an eukaryotic terminator of replication

Recently, a site-specific terminator of replication named RTS1 was shown to play an important role in mating-type switching in Schizosaccharomyces pombe.This is the first replication terminator shown to play a role in cellular differentiation.

August 13,2002

Global high-throughput screens for cellular function

We present here a survey of these technologies and their applications. We discuss their promise and limitations in addressing the vast number of candidate molecules of disease relevance that are emerging from genomics and proteomics.

August 12,2002

Education and training in internal medicine in Europe

The author try to develop a point of view for the European internist, a blueprint of internal medicine founded on the philosophy of internal medicine, the present legislation, the practice of internal medicine in Europe, and on images of Europe.

August 11,2002

Acute heart failure: a novel approach to its pathogenesis and treatment

Acute heart failure (HF) is one of the most common syndromes in emergency medicine, however, its exact pathogenesis has remained largely unknown. Based on clinical and hemodynamic data we have sub-divided acute HF into four syndromes: cardiogenic shock, pulmonary edema, hypertensive crisis and exacerbated HF.

August 10,2002

Modulation of the Ras/Raf/MEK/ERK pathway by Ca2+, and Calmodulin

We present our results from combining the predictions of an ensemble of neural networks for the diagnosis of hepatobiliary disorders.We discuss how the overall predictive accuracy can be improved by introducing bias during the training of the level one networks.

August 9,2002

Modulation of the Ras/Raf/MEK/ERK pathway by Ca2+, and Calmodulin

We review here evidence showing that calcium (Ca2+ ) and calmodulin (CaM) are able to regulate the Ras/Raf/MEK/ERK pathway. CaM-binding proteins (CaMBPs) as Ras-GRF and CaMdependent protein kinase IV (CaMKIV) positively modulate ERK1/2 activation induced by either NGF or membrane depolarisation in neurones.

August 8,2002

The thyroid axis just got more complicated

Now, a new pituitary hormone, termed hyrostimulin, may change our established view of the thyroid axis.Nakabayashi et al. in this issue of the JCI (2) describe a novel heterodimeric glycoprotein hormone containing two unique subunits.

August 7,2002

Src in cancer: deregulation and consequences for cell behaviour

Evidence now exists to suggest that Src may also influence the life or death decisions that cells make during many biological processes. Thus, Src modulation in cancer cells can alter cell responses that are often perturbed in cancer.Consequently, there is optimism that drugs which inhibit Src’s kinase activity, or the activity of its downstream effectors, might have profound effects on cancer cell behaviour and be useful therapeutic agents.

August 6,2002

Fatty acid metabolism in cardiac failure

In this review, we will focus on the molecular and biochemical players as well as the events that occur in both the genetic abnormalities in fatty acid metabolism that lead to cardiomyopathy and cardiac failure, as well as in cardiac hypertrophy and apoptosis.

August 5,2002

The genetics of the E2F family of transcription factors: shared functions and unique roles

This review will focus on biological functions of E2F elucidated via genetic studies that are expanding our understanding of how E2F family members are integrated into pathways controlling proliferation, apoptosis, development and tumorigenesis.

August 4,2002

Recent advances in cancer research: mouse models of tumorigenesis

In this review, we discuss mouse tumor models that have contributed substantially to the identification and characterization of novel tumor pathways. In particular, we focus on transgenic and knockout mouse models that closely mimic human cancer and thus can be used as model systems for cancer research.

August 3,2002

Hsp90 as a capacitor of phenotypic variation

Heat-shock protein 90 (Hsp90) chaperones the maturation of many regulatory proteins and buffers genetic variation in morphogenetic pathways.Manipulating Hsp90’s buffering capacity offers a tool for harnessing cryptic genetic variation and for elucidating the interplay between genotypes, environments and stochastic events in the determination of phenotype.

August 2,2002

PI 3-Kinases and PTEN: How Opposites Chemoattract

Phosphatidylinositol lipids, such as PI(4,5)P2 and PI(3,4,5)P3, are key mediators in diverse intracellular signaling pathways. Two recent reports examine how the metabolism of these lipids by phosphatidylinositol 3-kinases and the PTEN 3-phosphoinositide phosphatase may coordinate G protein coupled signaling pathways during eukaryotic chemotaxis.

August 1,2002

AP-1 as a regulator of cell life and death

The transcription factor AP-1 (activator protein-1) is involved in cellular proliferation, transformation and death.Using mice and cells lacking AP-1 components, the target-genes and molecular mechanisms mediating these processes were recently identified.