| September 27,2002 |
The International Burden of Cardiovascular Disease: Responding to the Emerging Global Epidemic |
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World Heart Day is September 29, 2002. This occasion provides an opportunity to recognize our successes in science and clinical care, to survey the present and future
challenges at home and abroad, and to seek opportunities for international partnerships in addressing the burgeoning global epidemic of cardiovascular disease. |
| September 26,2002 |
Applications of antisense and siRNAs during preclinical drug development |
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Antisense and siRNA technologies offer exceptional speed and specificity to address this need. In particular, antisense and siRNAs are beginning to be used in combination with
expression profiling to evaluate drug specificity and mechanism-of-action,
aiding in the identification of better candidates earlier in the drug development process. |
| September 25,2002 |
Epithelial barrier function:assembly and structural features of the cornified cell envelope |
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Terminally differentiating stratified squamous epithelial cells assemble a specialized protective barrier structure on their periphery termed the cornified cell envelope (CE).Here we describe our current understanding of CE structure, a possible mechanism of its assembly, and various disorders that cause a defective barrier. |
| September 24,2002 |
Physiological regulation of the human genome through physical activity |
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We contend that the current scientific evidence supports the notion that disruptions in cellular
homeostasis are diminished in magnitude in physically active individuals compared with sedentary individuals due to the natural selection of gene expression that supports the physically active lifestyle displayed by our ancestors. We speculate that genes evolved with the expectation of requiring a certain threshold of physical activity for normal physiologic gene expression, and thus habitual exercise in sedentary cultures restores perturbed homeostatic mechanisms towards the
normal physiological range of the Palaeolithic Homo sapiens. |
| September 23,2002 |
A family of calcium-permeable channels in the kidney:distinct roles in renal calcium handling |
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The underlying transepithelial calcium transport mechanisms play crucial roles in calcium homeostasis. In this review, we present new developments in the area of calcium transport at the apical membrane, the first step in transepithelial calcium transport. |
| September 22,2002 |
A database of protein expression in lung cancer |
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We have developed a comprehensive approach to identifying molecular changes in
lung cancer that includes both genomic and proteomic analyses. The related effort
has produced a large amount of data pertaining to gene expression at the RNA and
protein levels. As a result, we have constructed a database that contains protein
expression data on lung cancer as well as other relevant data including DNA microarray derived data. |
| September 21,2002 |
Molecular Modeling in Cysteine Protease Inhibitor Design |
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The application of various molecular modeling techniques has been recently reported in the design of
several new cysteine protease inhibitors. Computational techniques have been used to understand and predict enzyme-inhibitor interactions and also to study enzyme mechanism and inhibitor reactivity. This review focuses on examples that use structure-based design or reflect cysteine proteases as a target class. |
| September 20,2002 |
The Protein Import Motor of Mitochondria |
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Proteins that are destined for the matrix of mitochondria are transported into this organelle by
two translocases: the TOM complex, which transports proteins across the outer mitochondrial
membrane; and the TIM23 complex, which gets them through the inner mitochondrial
membrane. Two models have been proposed to explain how this protein-import machinery
works — a targeted Brownian ratchet, in which random motion is translated into vectorial
motion, or a ‘power stroke’, which is exerted by a component of the import machinery.
Here, we review the data for and against each model. |
| September 19,2002 |
The post-genomic era of interactive proteomics:Facts and perspectives |
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In this
review, we discuss methods that have been recently developed in order to characterize protein interactions and their functional relevance on a large scale. We then focus onthose methodologies that are suitable for the identification and characterization of protein-protein interactions. |
| September 18,2002 |
The Renin-Angiotensin System and Vascular Disease in Diabetes |
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Angiotensin II, the effector molecule of the renin-angiotensin system, has profound
effects on endothelial and smooth muscle cells. These effects are not only hemodynamic
in nature, but also comprise inflammation, thrombosis, and cell proliferation through
stimulation of production of cytokines and growth factors. In diabetes mellitus these effects
seem amplified with adverse consequences like atherosclerosis and occlusive microangiopathy. |
| September 17,2002 |
A Review of Locus-Specific Mutation Databases |
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Mutation databases of human genes are assuming an increasing importance in all areas of health care. In
addition, more and more experts in the mutations and diseases of particular genes are curating published and
unpublished mutations in locus-specific databases (LSDB). These databases contain such extensive information
that they have become known as knowledge bases. |
| September 16,2002 |
ANTIBODIES, VIRUSES AND VACCINES
|
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Neutralizing antibodies
are crucial for vaccine-mediated protection against viral diseases.
They probably act, in most cases, by blunting the infection,
which is then resolved by cellular immunity. The protective
effects of neutralizing antibodies can be achieved not only
by neutralization of free virus particles, but also by several
activities directed against infected cells. In certain instances,
non-neutralizing antibodies contribute to protection. Several
viruses, such as HIV, have evolved mechanisms to evade neutralizing-antibody
responses, and these viruses present special challenges for
vaccine design that are now being tackled. |
| September 15,2002 |
A Personal History of The Mouse Genome |
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I have the privilege of being able to look back on mouse genetics over a very long
time and hence to have seen it develop from a very early stage. I obtained my Ph.D.
in 1950 when very little was known about the mouse genome, and now 50 years
later the prospect of the complete sequence of the mouse genome is imminent. This
chapter provides some of my personal reminiscences of different stages along the
way. It does not attempt to be a complete history, and I apologize to all those whose
important contributions I have omitted or understressed. |
| September 14,2002 |
Seven-Transmembrane Receptors |
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Seven-transmembrane
receptors, which constitute the largest, most ubiquitous and
most versatile family of membrane receptors, are also the most
common target of therapeutic drugs. Recent findings indicate
that the classical models of G-protein coupling and activation
of second-messenger-generating enzymes do not fully explain
their remarkably diverse biological actions. |
| September 13,2002 |
Information Concept
in Biology |
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Some say that molecular
biology has linked biology with physics and chemistry through
elucidation of mechanisms in phenomena of life at the molecular
level. Other people consider that novel concept ‘information’
introduced by molecular biology clarified the distinction between
the biological and the physical sciences and made their discontinuous
relationship more apparent (Watanabe, 1980). As this controversy
concerns the basis of Bioinformatics, it cannot be avoided.
I express my personal opinion in the following. |
| September 12,2002 |
The many faces of p75NTR |
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The neurotrophins utilize
a complex receptor system consisting of Trk receptor tyrosine
kinases and the structurally unrelated tumor necrosis factor
receptor family member, p75(NTR), to confer diverse and sometimes
opposing biological actions. The recent identification of selective
ligands for p75(NTR), novel isoforms of this receptor, as well
as new signaling partners, suggest that the numerous biological
actions of the neurotrophins via p75(NTR) may reflect selectivity
of ligand-receptor interactions and intracellular adaptor protein
recruitment. |
| September 11,2002 |
Selective translation
of mRNAs at synapses |
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Synaptic efficacy, a
phenomenon that may underlie long-term memory storage, is controlled
in part by the regulated translation of mRNAs stored in dendrites.
The molecular basis by which specific mRNAs are selected for
translation is beginning to emerge and appears to involve at
least one mechanism that helps program early metazoan development.
Because different neural transmitters elicit different synaptic
responses that rely on local protein synthesis, a number of
sequence-specific mRNA translational regulatory mechanisms are
likely to function in neurons. Such mechanisms may be inferred
from those operating in early development and in cognitive disease. |
| September 10,2002 |
Receptor trafficking
and the plasticity of excitatory synapses |
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Newly discovered features
of the trafficking of AMPA receptors to and from the postsynaptic
membrane of excitatory synapses are now bringing the mechanisms
of synaptic plasticity into focus. Recent advances, including
the existence of slots, anchors, transport factors and pathways
for activity-dependent control, have elucidated the role of
the individual AMPA receptor subunits and their binding partners.
The latest views describe how subunit type dictates the assembly
of heteromeric receptors, and how these heteromers interact
with the receptor trafficking machinery and synaptic anchorage
factors. Moreover, phosphorylation may play an important role
in receptor transport and synaptic turnover. |
| September 9,2002 |
Regulation of Endothelial
Cell Survival and Apoptosis During Angiogenesis |
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The process of angiogenesis
plays an important role in many physiological and pathological
conditions. Inhibition of endothelial cell (EC) apoptosis providing
EC survival is thought to be an essential mechanism during angiogenesis.
Many of the angiogenic growth factors inhibit EC apoptosis.
In addition, the adhesion of ECs to the extracellular matrix
or intercellular adhesion promotes EC survival. In contrast,
increasing evidence suggests that the induction of EC apoptosis
may counteract angiogenesis. In this review, we focus on the
regulation of EC survival and apoptosis during angiogenesis
and especially on the effects and intracellular signaling promoted
by angiogenic growth factors, endogenous angiogenic inhibitors
(such as angiostatin, endostatin, and thrombospondin-1), and
the adhesion to the extracellular matrix. Furthermore, we discuss
the effects of cross talk between adhesion molecules and growth
factors. Understanding the molecular mechanisms involved in
the regulation of EC survival and apoptosis may provide new
targets for the development of new therapies to enhance angiogenesis
in the case of tissue-ischemia (eg, the neovascularization of
myocardium) or to inhibit angiogenesis in the case of neovascularization-dependent
disease (eg, tumor, diabetic retinopathy). |
| September 8,2002 |
Axon guidance: receptor
complexes and signaling mechanisms |
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The generation of a
functional neuronal network requires that axons navigate precisely
to their appropriate targets. Molecules that specify guidance
decisions have been identified, and the signaling events that
occur downstream of guidance receptors are beginning to be understood.
New research shows that guidance receptor signaling can be hierarchical
-- one receptor silencing the other -- thereby allowing navigating
growth cones to interpret opposing guidance cues. Among the
known intracellular signaling molecules shared by all guidance
receptor families, Rho GTPases appear to be primary regulators
of actin dynamics and growth cone guidance. Novel effector molecules
complete the picture and suggest additional signaling mechanisms. |
| September 7,2002 |
Genotype to phenotype:
associations, errors and complexity |
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There is a lot of ground
between genotype and phenotype, but most of it was touched
on at some point during this conference. The unusually wide
range of topics provided everyone with at least some new and
challenging material. Early sessions presented a potpourri of
disease phenotypes and underlying disease mechanisms. Other
sessions addressed a variety of developments in methodology,
technology and information resources. |
| September 6,2002 |
Management of dyslipidemia |
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The 2 principal approaches
to management of dyslipidemias are lifestyle intervention and
lipid-modifying drug therapy. Recent revisions to the American
Heart Association's dietary guidelines for reducing cardiovascular
disease emphasize an overall healthy eating pattern and maintenance
of appropriate body weight, together with achieving a desirable
blood pressure and a desirable lipoprotein profile. New National
Cholesterol Education Program treatment guidelines include a
scoring system for calculating coronary heart disease (CHD)
risk that is adapted from the Framingham Heart Study, as well
as a category of CHD risk equivalents (e.g., diabetes) that
will encourage more aggressive therapeutic intervention for
individuals at high short-term risk for CHD, even in the absence
of clinically evident coronary disease. Classes of lipid-modifying
drugs include bile acid sequestrants (resins), fibrates, and
statins, with each class exerting different effects on the lipid
profile. Nicotinic acid (niacin) is also an approved lipid-modifying
agent. The armamentarium for treating lipid disorders and atherosclerosis
now includes statins that can decrease low-density lipoprotein
(LDL) cholesterol levels by up to 55%, as well as a resin with
improved tolerability. In patients with high levels of LDL cholesterol
and triglycerides, together with low concentrations of high-density
lipoprotein cholesterol, combination therapy may be effective.
Moreover, researchers are currently investigating the development
of drugs directed at molecular targets, including cholesterol
esterification and accumulation in macrophage foam cells (e.g.,
inhibiting acyl-coenzyme A : cholesterol acyltransferase), degradation
of atherosclerotic plaque (e.g., decreasing the expression of
matrix metalloproteinases), and reverse cholesterol transport
(e.g., stimulating ATP-binding cassette transporter A1). |
| September 5,2002 |
Who Is at Risk for
Atherosclerotic Disease? Lessons from Intravascular Ultrasound |
| |
The hypothesis that
arterial wall remodeling permits accumulation of a large atherosclerotic
burden before there is any detectable narrowing of the vessel
lumen has received support from necropsy and intravascular ultrasound
(IVUS) studies. In a series of transplant donors assessed by
IVUS, coronary atheromas were found in 17% of those younger
than 20 years, 37% of those aged 20 to 29 years, and 60% of
those aged 30 to 39 years, whereas angiography results were
negative in 97% of this population. Necropsy data indicate a
similar age-related prevalence and suggest that atherosclerosis
risk factors are operative from a very early age. The IVUS findings
show that disease is characteristically diffuse and involves
the entire arterial tree, with progression including formation
of multiple, potentially rupture-prone plaques that are not
associated with vessel stenosis. These findings indicate the
need for aggressive and early systemic intervention that targets
modifiable risk factors to reduce coronary artery disease morbidity
and mortality in the general population. |
| September 4,2002 |
Association analysis
of candidate genes for neuropsychiatric disease: the perpetual
campaign |
| |
Association studies
have been proposed to identify the genetic determinants of complex
neuropsychiatric traits. Although such studies of candidate
genes offer great potential to identify genetic variants that
contribute to the expression of psychiatric disease, no consistent
associations have been identified. Studies to date have focused
on candidate genes that are selected for analysis on the basis
of incomplete information about gene function in the brain,
therefore the majority of genes expressed in the brain have
been ignored. Additionally, most genetic determinants of psychiatric
disease will probably be of modest effect and therefore require
association studies of large samples. As genomic technologies
advance, massive genotyping of large samples should allow identification
of alleles that contribute to psychopathology. |
| September 3,2002 |
Model choice in gene
mapping: what and why |
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The choice of an appropriate
genetic model describing the genetic architecture underlying
a character of interest is an inherent part of the gene mapping
studies of human and other living organisms. The genetic model
specifies the statistical parameters for the number of genes,
their positions, and the types and magnitudes of their contributions
to the phenotype. There are many considerations involved in
model formulation (choice) ranging from the assumptions concerning
the data, the role of environment, and the number of oligogenes
(or quantitative trait loci) influencing the trait behavior.
There are several model selection procedures and criteria under
specific sampling designs in the genetic literature. These approaches
often have their origin in computer science or in general statistical
theory. Our aim here is to give an overview of the most popular
statistical criteria and to present principles behind them.
Bayesian model averaging is suggested as a robust alternative
for such methods. |
| September 2,2002 |
DNA
repair/pro-apoptotic dual-role proteins in five major DNA repair
pathways: fail-safe protection against carcinogenesis |
| |
Two systems are essential
in humans for genome integrity, DNA repair and apoptosis. Cells
that are defective in DNA repair tend to accumulate excess DNA
damage. Cells defective in apoptosis tend to survive with excess
DNA damage and thus allow DNA replication past DNA damages,
causing mutations leading to carcinogenesis. It has recently
become apparent that key proteins which contribute to cellular
survival by acting in DNA repair become executioners in the
face of excess DNA damage.Five major DNA repair pathways are
homologous recombinational repair (HRR), non-homologous end
joining (NHEJ), nucleotide excision repair (NER), base excision
repair (BER) and mismatch repair (MMR). In each of these DNA
repair pathways, key proteins occur with dual functions in DNA
damage sensing/repair and apoptosis. Proteins with these dual
roles occur in: (1) HRR (BRCA1, ATM, ATR, WRN, BLM, Tip60 and
p53); (2) NHEJ (the catalytic subunit of DNA-PK); (3) NER (XPB,
XPD, p53 and p33(ING1b)); (4) BER (Ref-1/Ape, poly(ADP-ribose)
polymerase-1 (PARP-1) and p53); (5) MMR (MSH2, MSH6, MLH1 and
PMS2). For a number of these dual-role proteins, germ line mutations
causing them to be defective also predispose individuals to
cancer. Such proteins include BRCA1, ATM, WRN, BLM, p53, XPB,
XPD, MSH2, MSH6, MLH1 and PMS2. |
| September 1,2002 |
Disassembly
of Transcriptional Regulatory Complexes by Molecular Chaperones |
| |
Many biological processes
are initiated by cooperative assembly of large multicomponent
complexes; however, mechanisms for modulating or terminating
the actions of these complexes are not well understood. For
example, hormone-bound intracellular receptors (IRs) nucleate
formation of transcriptional regulatory complexes whose actions
cease promptly upon hormone withdrawal. Here, we show that the
p23 molecular chaperone localizes in vivo to genomic response
elements in a hormone-dependent manner, disrupting receptor-mediated
transcriptional activation in vivo and in vitro; Hsp90 weakly
displayed similar activities. Indeed, p23 and Hsp90 also disrupted
the activities of some non-IR-containing transcriptional regulatory
complexes. We suggest that molecular chaperones promote disassembly
of transcriptional regulatory complexes, thus enabling regulatory
machineries to detect and respond to signaling changes. |
