| 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. |