bluuebunny/crossref_metadata_2025 huggingface dataset:
European Manifesto on Basic Standards of Health Care For People with Intellectual Disabilities
Authors: Meijer M. M. , Carpenter S. , Scholte F. A.
Published: March 2004

Abstract An invitational conference organized by the Netherlands Society of Physicians for Persons with Intellectual Disabilities (NVAVG) and the European Association of Intellectual Disability Medicine (MAMH), in collaboration with the Erasmus Medical Center's Department of Specialist Training for Physicians for People with Intellectual Disabilities, had as its aim the development and issuance of an European manifesto on adequate health care for people with intellectual disabilities (ID). This paper provides an overview of the basis for the conference and the manifesto and lays out recommendations for the implementation of the manifesto's main points. The group's product, the European Manifesto on Basic Standards of Health Care for People with Intellectual Disabilities, summarizes the core elements of adequate health care for individuals with ID, and offers guidance on how Europe's nations may address deficiencies in health provision for people with ID. The manifesto's main points include a call for greater available and accessible health care, increasing the competencies in ID of health professionals, educators, and researchers, a greater reliance on a multidisciplinary approach to health care, more specialist services, and a proactive emphasis on personal health management.
Disease Epidemiology and Aging People with Intellectual Disabilities
Authors: Haveman Meindert J.
Published: March 2004

Abstract Various conceptional dimensions of aging are relevant for epidemiological research on health issues for individuals with intellectual disabilities (ID). In a review of the literature results of mortality and morbidity studies are documented and discussed regarding the actual health status of elderly adults with ID. Most of these studies are based on indirect assessments with several sources for detection bias. As a consequence, health problems are systematically undocumented and underreported for this target group and affect the effectiveness and adequacy of health service delivery. Direct assessment procedures and methods in epidemiological research are suggested as one means to improve research used to support health care planning. Such a methodological target can be combined with the more important goal on service level of finding and helping persons with unrecognized treatable conditions.
Genetically‐Linked Syndromes in Intellectual Disabilities
Authors: Henderson C. Michael
Published: March 2004

Abstract Comprehensive medical research is optimally based on a clear understanding of the pathogenesis of disease. It follows that a research agenda designed to promote healthy aging in persons with genetic syndromes linked to intellectual disabilities is best based upon a clear understanding of biological events that have occurred at early stages of development. The pathogenesis of such genetic syndromes encompasses a number of concepts including: (1) the locus and form of the genetic abnormality, (2) the mode of inheritance, and (3) the relationship between the genetic abnormality and the resulting phenotypic abnormalities. Recent research has increased our knowledge about such disorders; however, much remains to be learned. Genetic, clinical, and epidemiological perspectives on several genetic intellectual/developmental disability syndromes, including fragile X syndrome, myotonic dystrophy, Rett syndrome, mitochondrial genome disorders, Down syndrome, Smith–Lemli–Opitz syndrome, and phenylketonuria, are described to demonstrate directions for future research to promote longevity and healthy aging in people with these disorders.
The role of endothelial cell Ca2+ store release in the regulation of microvascular permeability in vivo
Authors: Glass C. A. , Bates D. O.
Published: March 2004

Microvascular permeability is regulated by changes in intracellular calcium concentration. The mechanism by which this increase in calcium determines permeability under normal conditions and during stimulation with agonists remains to be elucidated. In order to determine whether calcium release from intracellular stores could contribute towards the regulation of vascular permeability, hydraulic conductivity (Lp) was measured in frog mesenteric microvessels during stimulation of the endothelial cells of these vessels with agonists that release calcium from the intracellular stores. ATP (which acts through activation of inositol 1,4,5‐trisphosphate (IP3) receptors) increased Lp in the absence of calcium influx across the plasma membrane 2.3 ± 0.3 fold (mean ±s.e.m.., P < 0.01, n= 8), which was less than the increase in the presence of calcium influx (3.1 ± 1.1 fold). Caffeine (which acts through activation of ryanodine receptors) also increased Lp in the absence of calcium influx across the plasma membrane 3.8 ± 1.0 fold (P < 0.01, n= 9), but by at least as much as it does in the presence of calcium influx (2.8 ± 0.5 fold). It is surprising that there was a strong positive correlation between the size of the response during store release and the baseline permeability (r = 0.91 for ATP, r = 0.75 for caffeine). This suggests that the filling state of the stores may regulate the baseline permeability of the microvessels.
Nitric oxide and thyroid gland: modulation of cardiovascular function in autonomic‐blocked anaesthetized rats
Authors: Fellet Andrea Lorena , Arza Patricia , Arreche Noelia , Arranz Cristina , Balaszczuk Ana Mar'a
Published: March 2004

We have previously reported that acute administration of NG‐nitro‐l‐arginine methyl ester (l‐NAME) increases the mean arterial pressure (MAP) and heart rate (HR) in autonomic‐blocked (CAB) anaesthetized rats. In the present study we examined whether thyroid and adrenal glands are involved in these pressor and chronotropic responses. Sprague‐Dawley rats were studied after bilateral vagotomy and ganglionic blockade with hexamethonium (10 mg kg−1), and stabilization of MAP with infusion of phenylephrine (PE) (6 μg kg−1 min−1). The rats were divided into groups: L, CAB; PE, CAB + PE bolus (6 μg kg−1); L‐TX, thyroidectomy + CAB; L‐AX, adrenalectomy + CAB; TX, only thyroidectomy; C, CAB. L, L‐AX and L‐TX groups received a bolus of l‐NAME (7.5 mg kg−1). Triiodothyronine (T3), thyroxin (T4) and thyrotropin (TSH) levels were measured in L and L‐TX rats before and after l‐NAME administration. Reduced nicotamide adenine dinucleotide (NADPH) diaphorase activity was determined in heart and aorta of the TX group. The pressor response induced by l‐NAME was similar in all groups. l‐NAME‐induced‐tachycardia was associated with this rise in MAP. Adrenalectomy did not modify this chronotropic response, but it was attenuated by thyroidectomy. Thyroidectomy by itself decreased the circulating levels of T3 but it had no effect on the plasma levels of T4 and TSH. L and L‐TX groups showed similar levels of circulating T4 and TSH, meanwhile the plasma level of T3 decreased in the L group. Nitric oxide synthase (NOS) activity in atria as well as in aorta was greater in the TX group compared with C. When autonomic influences are removed, the thyroid gland modulates intrinsic heart rate via a mechanism that involves, at least in part, the nitric oxide pathway.
Elevated blood pressure in normotensive rats produced by ‘knockdown’ of the angiotensin type 2 receptor
Authors: Wang HongWei , Gallinat Stefan , Li Hong‐wei , Sumners Colin , Raizada Mohan K. , Katovich Michael J.
Published: March 2004

Most of our knowledge of the function of the angiotensin type 2 receptor (AT2R) has been obtained from transgenic mouse models. The aim of the present study was to investigate the role of the AT2R in normotensive Sprague–Dawley (SD) rats by using antisense gene transfer technology to ‘knockdown’ this specific receptor subtype. A retroviral vector containing full‐length AT2R antisense cDNA (AT2R‐AS) was constructed and the effectiveness of the transduction of AT2R‐AS was studied in vitro. In subsequent in vivo studies, 5‐day‐old normotensive SD rats received a single intracardiac bolus (25 μl) of AT2R‐AS viral particles. When animals reached adulthood, direct blood pressure (BP), and both pressor and dipsogenic responses to angiotensin II were investigated. Long‐lasting expression of the AT2R‐AS transcript and a reduction in mRNA and binding of the AT2R was observed in vitro. Expression of AT2R‐AS transcript was maintained for 90 days in heart, kidney, lung and brain, indicating a high degree of transgene transduction in vivo. As adults, systolic BP and the pressor responses to angiotensin were significantly elevated in AT2R‐AS‐treated rats. However, AT2R‐AS‐treated rats displayed significantly reduced dipsogenic responses to both angiotensin and water deprivation. Collectively, these data demonstrate that a single neonatal injection of the retroviral vector containing antisense to the AT2 receptors in rats results in similar cardiovascular and dipsogenic responses as reported in AT2R knockout mice. The actions of the AT2 receptors appear to be antagonistic to the cardiovascular actions of the AT1 receptors, whereas AT1 and AT2 receptors appear to act synergistically in the regulation of water intake.
Prenatal stress alters cardiovascular responses in adult rats
Authors: Igosheva N. , Klimova O. , Anishchenko T. , Glover V.
Published: March 2004

Environmental factors in early life are clearly established risk factors for cardiovascular disease in later life. Most studies have focused on nutritional programming and analysed basal cardiovascular parameters rather than responses. In the present study we have investigated whether prenatal stress has long‐term effects on cardiovascular responses in adult offspring. Female pregnant Sprague‐Dawley rats were subjected to stress three times daily from day 15 to day 21 of gestation. Litters from stressed and control females were cross‐fostered at birth to control for mothering effects. When the offspring were 6 months old, blood pressure was measured in the conscious rats through implanted catheters at rest, during restraint stress and during recovery. Basal haemodynamic parameters were similar in the different groups but the pattern of cardiovascular responses during stress and recovery differed markedly between prenatally stressed (PS) and control animals. PS rats had higher and longer‐lasting systolic arterial pressure elevations to restraint stress than control animals. They also showed elevated systolic and diastolic blood pressure values during the recovery phase. PS rats demonstrated a greater increase in blood pressure variability compared with control animals during exposure to restraint stress, and showed more prolonged heart rate responses to acute stress and delayed recovery than controls. There was no effect of prenatal stress on baroreflex regulation of heart rate. PS females showed a greater increase in systolic arterial pressure and blood pressure variability and delayed heart rate recovery following return to the home cage then did PS males. These findings demonstrate for the first time that prenatal stress can induce long‐term, sex‐related changes in the sensitivity of the cardiovascular system to subsequent stress.
‘Deaf, mute and whispering’ silent synapses: their role in synaptic plasticity
Authors: Voronin Leon L. , Cherubini Enrico
Published: March 2004

Mechanisms of long‐term potentiation (LTP) maintenance are discussed in the light of the phenomenon of silent synapses. Evidence that LTP is associated with the insertion of new AMPA receptors (AMPARs) in postsynaptically silent (deaf) synapses expressing only NMDA receptors (NMDARs) before LTP induction has led to the assumption that the debate on pre‐ versus postsynaptic locus of LTP expression has been resolved in favour of the latter. However, recent data indicate that these synapses are mainly presynaptically silent (mute or whispering), because the probability of glutamate release (Pr) or glutamate concentration in the cleft is too low to activate AMPARs. In this case LTP could be explained by an increase in Pr or enhanced glutamate concentration to activate low affinity AMPARs. Optical methods to probe calcium transients in dendritic spines have revealed an increase in Pr during LTP with concomitant postsynaptic modifications. A hypothesis is considered that accounts for the differences in both the initial failure rates between AMPAR‐ and NMDAR‐mediated responses, and the LTP‐associated decrease in failures of AMPAR‐mediated responses. According to this hypothesis, glutamate release is potentiated by the strong postsynaptic depolarization used to identify NMDAR‐mediated responses. We suggest that the expression of LTP may depend on coordinated pre‐ and postsynaptic modifications whose relative contributions vary according to the initial state of the synapse, the experimental protocol and time after induction.
Characterization of the Kv channels of mouse carotid body chemoreceptor cells and their role in oxygen sensing
Authors: Pérez‐García M. Teresa , Colinas Olaia , Miguel‐Velado Eduardo , Moreno‐Domínguez Alejandro , López‐López José Ramón
Published: March 2004

As there are wide interspecies variations in the molecular nature of the O2‐sensitive Kv channels in arterial chemoreceptors, we have characterized the expression of these channels and their hypoxic sensitivity in the mouse carotid body (CB). CB chemoreceptor cells were obtained from a transgenic mouse expressing green fluorescent protein (GFP) under the control of tyrosine hydroxylase (TH) promoter. Immunocytochemical identification of TH in CB cell cultures reveals a good match with GFP‐positive cells. Furthermore, these cells show an increase in [Ca2+]i in response to low PO2, demonstrating their ability to engender a physiological response. Whole‐cell experiments demonstrated slow‐inactivating K+ currents with activation threshold around −30 mV and a bi‐exponential kinetic of deactivation (τ of 6.24 ± 0.52 and 32.85 ± 4.14 ms). TEA sensitivity of the currents identified also two different components (IC50 of 17.8 ± 2.8 and 940.0 ± 14.7 μm). Current amplitude decreased reversibly in response to hypoxia, which selectively affected the fast deactivating component. Hypoxic inhibition was also abolished in the presence of low (10–50 μm) concentrations of TEA, suggesting that O2 interacts with the component of the current most sensitive to TEA. The kinetic and pharmacological profile of the currents suggested the presence of Kv2 and Kv3 channels as their molecular correlates, and we have identified several members of these two subfamilies by single‐cell PCR and immunocytochemistry. This report represents the first functional and molecular characterization of Kv channels in mouse CB chemoreceptor cells, and strongly suggests that O2‐sensitive Kv channels in this preparation belong to the Kv3 subfamily.
On STEP-NC and the Complexities of Product Data Integration
Authors: Hardwick Martin
Published: March 2004

For twenty years the manufacturing domain has been seeking to share product model data by defining an entity relationship model covering the life cycle of geometrically defined products. The data sharing is implemented by selecting subsets of these entities and relationships to define data exchange standards for CAD, CAE, CAM, CNC and PDM systems. The approach requires agreement on how data will be reused across the domains so an organization has been meeting to manage the required data definitions. Considerable success was achieved in 1995 when a standard was proposed and implemented by industry as a way to move 3D geometry between CAD systems. Now, a new protocol for exchanging manufacturing process information between CAM systems and CNC devices is being released. This protocol reuses much of the data defined for the other domains and will allow CNC manufacturing tools to process 3D data, but the complexity of the specification is causing controversy. In this paper we report on the new specification and analyze the advantages and disadvantages of its approach to defining CNC control programs.
Equivalence Classes for Shape Synthesis of Moving Mechanical Parts
Authors: Ilies¸ Horea T. , Shapiro Vadim
Published: March 2004

Moving parts in contact have been traditionally synthesized through specialized techniques that focus on completely specified nominal shapes. Given that the functionality does not completely constrain the geometry of any given part, the design process leads to arbitrarily specified portions of geometry, without providing support for systematic generation of alternative shapes satisfying identical or altered functionalities. Hence the design cycle of a product is forced to go into numerous and often redundant iterative stages that directly impact its effectiveness. We argue that the shape synthesis of mechanical parts is more efficient and less error prone if it is based on techniques that identify the functional surfaces of the part without imposing arbitrary restrictions on its geometry. We demonstrate that such techniques can be formally defined for parts moving in contact through equivalence classes of mechanical parts that satisfy a given functionality. We show here that by replacing the completely specified geometry of the traditional approaches with partial geometry and functional specification, we can formally define classes of mechanical parts that are equivalent, in the sense that all members of the class satisfy the same functional specifications. Moreover, these classes of functionally equivalent parts are computable, may be represented unambiguously by maximal elements in each class, and contain all other functional designs that perform the same function.
Investigation of Hand Motion Language in Shape Conceptualization
Authors: Horva´th Imre
Published: March 2004

This paper summarizes the results of an empirical study concerning the use of hand motions as one of the input mechanisms of a multi-modal interface of computer aided conceptual design systems for initial shape design of consumer durables. A hand motion language (HML) has been developed and used in designed experiments to describe simple, compound and hybrid shapes. The subjects were asked to reconstruct the presented shapes by sketching on paper. Comprehension of the hand motion language has been evaluated in terms of fidelity and efficiency. The results clearly indicate the potentials of a HML in shape conceptualization. In addition, the experiments revealed several new issues related to the application of the hand motion language in a multi-modal interface.
A New Approach to Structure Sharing
Authors: Chakrabarti Amaresh
Published: March 2004

Structure sharing means fulfilment of several functions or functional properties by the same physical structure, and is an important concept in product design. However, few guidelines and methods for supporting structure sharing, especially on computers, are currently available. The aim of this paper is to present a new, computational approach, for supporting structure sharing in design, that can automatically create, and offer designers for evaluation, a variety of alternative solution principles as well as their potential, minimal, qualitative embodiments that can fulfil a given intended sensor functionality. These potential alternatives are structure-shared where possible.
TORquing Toxins
Authors: Davenport R. John
Published: March 2004

SAN FRANCISCO, CALIFORNIA--
A protein that distorts body movements when it malfunctions protects nerves in its normal form, according to work presented here 14 December at the American Society for Cell Biology annual meeting. In high doses, the protein helps worm neurons resist oxidative damage, the study reveals. The results suggest a role for the molecule in protecting against Parkinson's disease.
Picky Eater
Authors: Davenport R. John
Published: March 2004

SAN FRANCISCO, CALIFORNIA--
In a restaurant or a cell, a voracious eater can still have refined tastes. A cellular hog is even more discriminating than previously thought, according to work presented here 14 December at the American Society for Cell Biology annual meeting. The protein-digesting organelle known as the lysosome prefers oxidized molecules, according to the study. Because this cellular component loses its appetite with age, the new study suggests one way that marred proteins accumulate over time.
Weak of Body, Weak of Mind?
Authors: Leslie Mitch
Published: March 2004

SCOTTSDALE, ARIZONA--
Falling testosterone concentrations turn older men's abs to flab and can reduce their sex life to memories. A new study reveals that the hormone's decline could prime men for one of aging's most dreaded scourges. The lower a man's concentration of blood testosterone, the more likely he is to develop Alzheimer's disease, according to research presented here on 12 December at the Phoenix Conference on Longevity Health Sciences. The results support preliminary studies suggesting that testosterone treatment eases the brain-destroying disease.
Tasting Longevity
Authors: Leslie Mitch
Published: March 2004

Unlike guys, nematodes gain from being insensitive: Mutations that deaden their senses also prolong their survival. New work identifies the neurons that underlie this life-extending effect, supporting the idea that worms alter their life span based on perceptions of their surroundings.
UnSIRtainty Principle
Authors: Davenport R. John
Published: March 2004

Stemming sugar intake sparks a yeast longevity protein, and two new studies offer differing views of the mechanism. The data clash on whether cutting calories reduces amounts of a particular enzyme blocker. Resolving this issue could help clarify how metabolic changes induced by this diet lengthen life in yeast--and whether related changes might do the same in mammals.
Sticking It to Tau
Authors: Leslie Mitch
Published: March 2004

Hanging out with the wrong crowd is bad for teenagers and for proteins. New research shows that consorting with a particular enzyme can convert the brain protein tau into a cell killer. The work bolsters the hypothesis that phosphate additions to tau underlie its lethal transformation.
To Age or Not to Age--What Is the Question?
Authors: Day Troy
Published: March 2004

Over the past 50 years, a generally accepted theory about the evolution of aging has been developed. One common conclusion that has been deduced from this theory is that aging is inevitable in organisms in which there is a difference between offspring and parents. A
recent paper
by Sozou and Seymour questions this prediction using a mathematical model, but it remains to be seen whether their new results stand up to more general analysis.
Can the Clock Be Turned Back on Ovarian Aging?
Authors: Hoyer Patricia B.
Published: March 2004

A basic tenet of reproductive biology is that female mammals are born with a set number of germ cells (oocytes). A new study by Johnson
et al.
challenges these beliefs by demonstrating that the postnatal mouse ovary contains actively dividing germ cells. These findings have implications for prolonging the reproductive life span of women.
Exploiting Proteomics in the Discovery of Drugs That Target Mitochondrial Oxidative Damage
Authors: Gibson Bradford W.
Published: March 2004

To understand how oxidative stress contributes to aging and age-related diseases and to better evaluate the therapeutic effect of antioxidant drugs, it would be highly desirable to have a comprehensive and detailed readout of the types of oxidative damage that occur to proteins at a global or proteome level. In this Perspective, I examine how proteomics, defined here as the science of examining all proteins in an organelle, cell, or tissue in the context of biological phenomena, can be used to provide molecular details of mitochondrial protein oxidative damage. Specifically, I discuss approaches that combine knowledge of the mitochondrial proteome with newer mass spectrometry-based techniques that are capable of identifying proteins and sites of oxidative modification in a high-throughput manner.
Androgens, ApoE, and Alzheimer's Disease
Authors: Raber Jacob
Published: March 2004

Increasing evidence indicates that there are reductions in estrogen and androgen levels in aged men and women. These hormonal reductions might be risk factors for cognitive impairments and the development of Alzheimer's disease (AD). Aged people show improved cognition after treatments with sex steroids. Therefore, ongoing clinical AD trials have been designed to evaluate the potential benefits of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E (apoE) plays an important role in the metabolism and redistribution of lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3, and apoE4, differ in their effects on AD risk and pathology. Here I review various mechanisms proposed to mediate the differential effects of apoE isoforms on brain function and highlight the potential contribution of detrimental isoform-dependent effects of apoE on androgen- and androgen receptor (AR)-mediated pathways. I also discuss potential interactions of androgens with other AD-related factors.
Skeleton Key
Authors: Davenport R. John
Published: March 2004

A protein that oxidizes fat molecules also whittles bones, according to new research. The work shows that rodents with alterations in this enzyme gain a stronger skeleton. The molecule might exert its power by persuading stem cells to become fat cells rather than bone cells.
β Amyloid's Accomplice?
Authors: Leslie Mitch
Published: March 2004

Alzheimer's disease (AD) decimates not only neurons, but also the white matter, the information-transmitting interior of the brain. A new study suggests that β amyloid, the protein that accumulates in the brains of AD patients, incites this devastation by recruiting another molecule that provokes cell suicide. The results could help researchers craft ways to spare the brain in AD patients, although some experts are skeptical of the finding.
Getting Connected
Authors: Leslie Mitch
Published: March 2004

After enough beers, even the shyest bar patrons will tell their life stories to complete strangers. Brain cells also need chemical help to make connections. A new study reveals that an unlikely protein prompts brain cells to sprout extensions, a key step in making memories. The work could help researchers understand how neurons network and why these branches shrivel in some diseases.
Dear Old Dad
Authors: Glaser Rivka L. , Jabs Ethylin Wang
Published: March 2004

The origin and frequency of spontaneous mutations that occur with age in humans have been a topic of intense discussion. The mechanisms by which spontaneous mutations arise depend on the parental germ line in which a mutation occurs. In general, paternal mutations are more likely than maternal mutations to be base substitutions. This is likely due to the larger number of germ cell divisions in spermatogenesis than in oogenesis. Maternal mutations are more often chromosomal abnormalities. Advanced parental age seems to influence some mutations, although it is not a factor in the creation of others. In this review, we focus on patterns of paternal bias and age dependence of mutations in different genetic disorders, and the various mechanisms by which these mutations arise. We also discuss recent data on age and the frequency of these mutations in the human male germ line and the impact of these data on this field of research.
When Spacing Out Brings Clarity
Authors: Tuma Rabiya S.
Published: March 2004

NEW YORK CITY
--Everyone has slow-witted moments: entering a room only to forget why, putting ice cream into the fridge, or blanking out on how to use the microwave. Some clinicians think that periodic mental lapses might help diagnose dementia with Lewy bodies (DLB), a scourge that kills brain cells (see
DLB Case Study
), although not all experts agree. Now, scientists have found that some cognitive blunders crop up more frequently in patients with DLB than in those with Alzheimer's disease (AD) or in healthy elderly individuals, according to work presented here on 15 January 2004 at an American Medical Association briefing for media.
Hampering a Heartbreaker
Authors: Leslie Mitch
Published: March 2004

A TV ad urges people who think they're having a heart attack to pop an aspirin before rushing to the emergency room. They might be even better off taking antibiotics, according to a new study. The work shows that an antibiotic stems a previously untreatable form of heart damage not by killing bugs but by suppressing cellular enzymes.
Placing Bets
Authors: Beckman Mary
Published: March 2004

The winner of this race won't be the first to finish but the last. The National Institute on Aging's Interventions Testing Program has chosen three compounds to test in mouse longevity studies. The program is sponsoring rigorous, simultaneous experiments in three labs to determine which drugs or lifestyle interventions are most likely to prolong human life (see "
Intervention Venture
").
Cell Death, Start to Finish
Authors: Davenport R. John
Published: March 2004

A panorama gives a wide view that a series of snapshots only suggests, and a new study provides such a perspective on how two signaling molecules kill neurons. The work brings into focus the roles of nitric oxide and zinc in strangling overexcited brain cells. It might help researchers in their efforts to prevent brain damage associated with several age-related conditions.
Overcoming Inertia
Authors: Davenport R. John
Published: March 2004

Taking off a car's parking brake won't necessarily start the vehicle rolling. Similarly, releasing a neuron's brake isn't enough to get it growing, a new study reveals. The results suggest that multiple signals must combine to maximize neuron growth after an injury.
Is Akt the Mastermind Behind Age-Related Heart Disease?
Authors: Kaminker Patrick
Published: March 2004

Over the past several years, the insulin/insulin-like growth factor (IGF) signaling pathway has become a central figure in the study of organismal aging. Mutations in components of this pathway have led to enhanced longevity in several organisms, but it is still not clear whether and how this pathway contributes to human aging and aging-related diseases. In a new study, Miyauchi and colleagues propose that Akt, a member of the phosphatidylinositol 3-kinase family and a downstream component of the insulin/IGF pathway, plays a central role in the life span of endothelial cells. These findings implicate the insulin/IGF pathway in the development and progression of cardiovascular disease.
Tying It Together
Authors: Chen Ingfei
Published: March 2004

Rudi Westendorp, a Dutch physician-scientist known for his love of bow ties, seeks elegant solutions in his work as a clinical epidemiologist, geriatrician, and gerontologist at Leiden University Medical Center in the Netherlands. After completing his residency training and earning a Ph.D., in 1993 he made a detour into clinical epidemiology, studying patient populations to identify underlying risk factors for disease. He now supervises the long-running Leiden 85-plus study, which tracks cognitive decline, heart disease, and other illnesses in very old people. To round out his knowledge, Westendorp spent 1998 studying the biology of aging at the University of Manchester, U.K. His quest to test the evolutionary theory of the tradeoff between fertility and longevity has led him into the genealogical archives of British aristocrats and, more recently, to Ghana.
All-or-None No More
Authors: Leslie Mitch
Published: March 2004

"Reduce, reuse, recycle" isn't just an environmental mantra. According to a new study, it's standard procedure for some brain cells, which utilize the tiny sacs that carry neurotransmitters more than once. The work challenges the standard view that the sacs release their contents in one burst, a finding that might someday help researchers develop better treatments for illnesses in which neurotransmitter supplies plunge, such as Parkinson's disease.
Copper Stopper
Authors: Davenport R. John
Published: March 2004

Copper in mitochondria tarnishes a fungus, according to new work. The study suggests that a dearth of the metal forces the organism to switch to a metabolic strategy that extends life. The results add to the evidence that fine-tuning metabolism can minimize cellular damage and delay death, although the organism sacrifices robust growth for that benefit.
Ultrahigh Strength and High Electrical Conductivity in Copper
Authors: Lu Lei , Shen Yongfeng , Chen Xianhua , Qian Lihua , Lu K.
Published: March 2004

Methods used to strengthen metals generally also cause a pronounced decrease in electrical conductivity, so that a tradeoff must be made between conductivity and mechanical strength. We synthesized pure copper samples with a high density of nanoscale growth twins. They showed a tensile strength about 10 times higher than that of conventional coarse-grained copper, while retaining an electrical conductivity comparable to that of pure copper. The ultrahigh strength originates from the effective blockage of dislocation motion by numerous coherent twin boundaries that possess an extremely low electrical resistivity, which is not the case for other types of grain boundaries.
Genetic Dissection of Complex Traits with Chromosome Substitution Strains of Mice
Authors: Singer Jonathan B. , Hill Annie E. , Burrage Lindsay C. , Olszens Keith R. , Song Junghan , Justice Monica , O'Brien William E. , Conti David V. , Witte John S. , Lander Eric S. , Nadeau Joseph H.
Published: March 2004

Chromosome substitution strains (CSSs) have been proposed as a simple and powerful way to identify quantitative trait loci (QTLs) affecting developmental, physiological, and behavioral processes. Here, we report the construction of a complete CSS panel for a vertebrate species. The CSS panel consists of 22 mouse strains, each of which carries a single chromosome substituted from a donor strain (A/J) onto a common host background (C57BL/6J). A survey of 53 traits revealed evidence for 150 QTLs affecting serum levels of sterols and amino acids, diet-induced obesity, and anxiety. These results demonstrate that CSSs greatly facilitate the detection and identification of genes that control the wide diversity of naturally occurring phenotypic variation in the A/J and C57BL/6J inbred strains.
Functional Conversion Between A-Type and Delayed Rectifier K
+
Channels by Membrane Lipids
Authors: Oliver Dominik , Lien Cheng-Chang , Soom Malle , Baukrowitz Thomas , Jonas Peter , Fakler Bernd
Published: March 2004

Voltage-gated potassium (Kv) channels control action potential repolarization, interspike membrane potential, and action potential frequency in excitable cells. It is thought that the combinatorial association between distinct α and β subunits determines whether Kv channels function as non-inactivating delayed rectifiers or as rapidly inactivating A-type channels. We show that membrane lipids can convert A-type channels into delayed rectifiers and vice versa. Phosphoinositides remove N-type inactivation from A-type channels by immobilizing the inactivation domains. Conversely, arachidonic acid and its amide anandamide endow delayed rectifiers with rapid voltage-dependent inactivation. The bidirectional control of Kv channel gating by lipids may provide a mechanism for the dynamic regulation of electrical signaling in the nervous system.
Focus Issue: A Dangerous Detour–Cell Signaling Pathways Involved in Cancer Progression
Authors: Adler Elizabeth M. , Gough Nancy R.
Published: March 2004

The intensive effort poured into cancer research over the last 30 years has led to a tremendous increase in our understanding of cancer biology and of the cellular processes whose dysregulation has been implicated in cancer pathogenesis and progression. In many cases, the road to cancer pathogenesis and progression represents a detour from the normal pathways involved in cell signaling. This Focus Issue of
Science
's STKE highlights cell signaling pathways implicated in various aspects of cancer progression.
Epithelial Barriers, Compartmentation, and Cancer
Authors: Mullin J. M.
Published: March 2004

Epithelial cells, and the tight junctions between them, form a polarized barrier between luminal and serosal fluid compartments and segregate luminal growth factors from their basal-lateral receptors. Breakdown of this barrier should allow access of growth factors in the luminal fluid to their receptors on the basal-lateral cell membranes, as recently demonstrated for heregulin and erbB receptors in airway epithelia. It should also allow luminal growth factors to access the stroma. This property may have adaptive value for epithelial tissues in general, as an elegant response to injury, but may also promote cancer formation in premalignant epithelial tissues in which the tight junctions have become chronically leaky to growth factors.
Nuclear Receptors: The Evolution of Diversity
Authors: Schwabe John W. R. , Teichmann Sarah A.
Published: March 2004

Nuclear receptors are an ancient family of transcription factors. Some receptors are regulated by small lipophilic ligands, whereas others are constitutive transcriptional activators or repressors. The evolution of this diversity is poorly understood, and it remains an open question as to whether or not the ancestral receptor was ligand-regulated. The recent cloning, from a snail, of an estrogen receptor that does not bind estrogen not only suggests that the steroid receptors are much more ancient than previous thought, but also points toward a mechanism through which nuclear receptors can lose the ability to be ligand regulated.
Heterotrimeric G Protein Cycle
Authors: Preininger Anita M. , Hamm Heidi E.
Published: March 2004

This teaching resource provides two types of insight into the heterotrimeric G protein cycle. The interactive animation shows the basic heterotrimeric G protein cycle and allows the user to then add three different regulators of the cycle, an RGS (regulator of G protein signaling) protein, a GDI (guanine nucleotide dissociation inhibitor) protein, or a guanine nucleotide exchange factor (GEF). G proteins are comprised of two subunits, α and an obligate dimer βγ. The structure movie shows an computer-generated interpretation of the conformational changes in the α subunit that are associated with GTP binding and hydrolysis. The basic G protein cycle consists of a G protein-coupled receptor (GPCR) activating the G protein by promoting the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP), which allows the α and βγ subunits to separate and activate downstream targets. The signal is terminated when the α subunit hydrolyzes GTP and the α and βγ subunits reassociate. The animation allows the user to choose to play the cycle with or without additional regulators and see the effect on the signaling duration. RGS stimulates the GTPase activity of the α subunit and terminates signaling faster. GDI prevents the dissociation of GDP from the α subunit and blocks reassociation of the βγ subunit, thus extending βγ signaling. GEF enhances the rate of GTP loading in the presence of an activated receptor thus accelerating the speed of the response.
Focus Issue: Computational Approaches in Signal Transduction
Authors: Ray L. Bryan , Adler Elizabeth M. , Gough Nancy R. , Chong Lisa D.
Published: March 2004

This STKE Focus Issue describes the STKE contribution to a coordinated effort by
Science
and
Science
's Online products to bring together a series of resources highlighting the importance and application of mathematics in biology. In addition to several articles on the topic, STKE will host a Forum that will allow users to discuss modeling and simulation environments available for analysis of cellular signaling processes with the authors of the articles.
Computational Alanine Scanning of Protein-Protein Interfaces
Authors: Kortemme Tanja , Kim David E. , Baker David
Published: March 2004

Protein-protein interactions are key components of all signal transduction processes, so methods to alter these interactions promise to become important tools in dissecting function of connectivities in these networks. We have developed a fast computational approach for the prediction of energetically important amino acid residues in protein-protein interfaces (available at
http://robetta.bakerlab.org/alaninescan
), which we, following Peter Kollman, have termed "computational alanine scanning." The input consists of a three-dimensional structure of a protein-protein complex; output is a list of "hot spots," or amino acid side chains that are predicted to significantly destabilize the interface when mutated to alanine, analogous to the results of experimental alanine-scanning mutagenesis. 79% of hot spots and 68% of neutral residues were correctly predicted in a test of 233 mutations in 19 protein-protein complexes. A single interface can be analyzed in minutes. The computational methodology has been validated by the successful design of protein interfaces with new specificity and activity, and has yielded new insights into the mechanisms of receptor specificity and promiscuity in biological systems.
Developing Complex Signaling Models Using GENESIS/Kinetikit
Authors: Vayttaden Sharat Jacob , Bhalla Upinder Singh
Published: March 2004

The development of biologically realistic models of signaling pathways is a demanding process, involving computational challenges as well as those arising from the complexity of detailed pathway models. We have developed the General Neural Simulation System (GENESIS) and Kinetikit (GENESIS/Kinetikit), a graphical simulation environment for modeling biochemical signaling pathways using deterministic and stochastic methods. A library of models of several common signaling pathways complements the software. This combination of numerical computation engines, graphical modeling tools, and library of models is designed to build on the cumulative development of models and techniques from many sources. The complete simulation environment and demonstration models are available from (
http://stke.sciencemag.org/cgi/content/full/sigtrans;2004/219/pl4/DC1
; also at
http://www.ncbs.res.in/~bhalla/kkit/download.html
). The associated library of signaling pathways is based on published experimental and simulation studies and is curated to ensure that the simulation outcomes match published results. Models in the library are maintained in a database (
http://doqcs.ncbs.res.in
). Individual pathway models can be combined to build complex signaling network simulations. The overall goal of this process is to attain sufficient biological realism in models to directly compare their outcomes with experiments and to improve our understanding of complex signaling.
TARGETing "When" and "Where"
Authors: Wang Yalin , Zhong Yi
Published: March 2004

In
Drosophila
, the cyclic adenosine monophosphate (cAMP) pathway has been shown to be crucial for learning and memory, but whether this represents a developmental or a specific effect has not been resolved. Research with a new targeting system that allows both spatial and temporal control of gene expression shows that expression of
rutabaga
-encoded adenylyl cyclase, a component of the cAMP signaling pathway, in the mushroom bodies of adult flies is necessary and sufficient to rescue the learning defect of
rutabaga
mutant. This demonstrates an acute role for Rutabaga in learning and memory.
Spatiotemporal Gene Expression Targeting with the TARGET and Gene-Switch Systems in
Drosophila
Authors: McGuire Sean E. , Mao Zhengmei , Davis Ronald L.
Published: March 2004

Targeted gene expression has become a standard technique for the study of biological questions in
Drosophila
. Until recently, transgene expression could be targeted in the dimension of either time or space, but not both. Several new systems have recently been developed to direct transgene expression simultaneously in both time and space. We describe here two such systems that we developed in our laboratory. The first system provides a general method for temporal and regional gene expression targeting (TARGET) with the conventional GAL4-upstream activator sequence (UAS) system and a temperature-sensitive GAL80 molecule, which represses GAL4 transcriptional activity at permissive temperatures. The second system, termed Gene-Switch, is based on a GAL4-progesterone receptor chimera that is hormone-inducible. We have used both systems for simultaneous spatial and temporal rescue of memory dysfunction in the
rutabaga
(
rut
) memory mutant of
Drosophila
. In this protocol, we provide guidelines for the use of these two novel systems, which should have general utility in studying
Drosophila
biology and in using the fly as a model for human disease.
Singlet Oxygen Signaling: From Intimate to Global
Authors: Kochevar Irene E.
Published: March 2004

Reactive oxidizing species (ROS), such as hydrogen peroxide, nitric oxide, superoxide anion, and singlet oxygen, can damage cells as well as initiate responses such as new gene expression. The cell response evoked is strongly dependent on several factors. The subcellular location for formation of an ROS may be especially important for a highly reactive ROS, because it diffuses only a very short distance before reacting with a cellular molecule. How does a short-lived, locally acting ROS trigger responses at distant subcellular sites? This issue is discussed in light of a study of gene expression initiated by singlet oxygen, a ROS that exists for less than 100 ns in cells. Singlet oxygen is generated after a photosensitizer absorbs light energy and transfers the energy to molecular oxygen. To assess the role of singlet oxygen in light-induced gene expression in
Arabidopsis
, a mutant was used that accumulates the photosensitizer protochlorphyllide in chloroplasts. Three mechanisms are discussed that may connect the site of singlet oxygen formation to the signal transduction components: (i) direct oxidation of a signaling component by singlet oxygen, (ii) formation of oxidation products near the sites of singlet oxygen formation that diffuse to and react with signaling components, and (iii) alteration of the redox balance of the cell to a more oxidized state such that a greater proportion of a signaling pathway component is oxidized.
Sensing Cellular Stress: Another New Function for the Nucleolus?
Authors: Olson Mark O. J.
Published: March 2004

Recent research suggests that the nucleolus communicates with the p53 regulatory system and acts as a stress sensor. Cellular stress causes nucleolar disruption, triggering the release of regulatory factors to the nucleoplasm. These factors, especially ARF (alternative reading frame), inhibit the degradation of p53, thereby facilitating its intracellular accumulation.
Highly Purified Vitamin B2 Presents a Promising Therapeutic Strategy for Sepsis and Septic Shock
Authors: Toyosawa Toshio , Suzuki Mamoru , Kodama Kohtarou , Araki Seiichi
Published: March 2004

Highly purified vitamin B2 (riboflavin 5′-sodium phosphate; purity > 97%) treatment by intravenous infusion at doses above those used clinically to treat vitamin B2 deficiency showed therapeutic effects in mice not only in cases of endotoxin- and exotoxin-induced shock but also in cases of gram-negative and gram-positive bacterial infection even after the toxemia had already begun.