bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional role of TRPC proteins in native systems: implications from knockout and knock‐down studies
Authors: Freichel Marc , Vennekens Rudi , Olausson Jenny , Stolz Susanne , Philipp Stephan E. , Weißgerber Petra , Flockerzi Veit
Published: June 2005

Available data on transient receptor potential channel (TRPC) protein functions indicate that these proteins represent essential constituents of agonist‐activated and phospholipase C‐dependent cation entry pathways in primary cells which contribute to the elevation of cytosolic Ca2+. In addition, a striking number of biological functions have already been assigned to the various TRPC proteins, including mechanosensing activity (TRPC1), chemotropic axon guidance (TRPC1 and TRPC3), pheromone sensing and the regulation of sexual and social behaviour (TRPC2), endothelial‐dependent regulation of vascular tone, endothelial permeability and neurotransmitter release (TRPC4), axonal growth (TRPC5), modulation of smooth muscle tone in blood vessels and lung and regulation of podocyte structure and function in the kidney (TRPC6). The lack of compounds which specifically block or activate TRPC proteins impairs the analysis of TRPC function in primary cells. We therefore concentrate in this contribution on (i) studies of TRPC‐deficient mouse lines, (ii) data obtained by gene‐silencing approaches using antisense oligonucleotides or RNA interference, (iii) expression experiments employing dominant negative TRPC constructs, and (iv) recent data correlating mutations of TRPC genes associated with human disease.
Hormone Give-and-Take
Authors: Leslie Mitch
Published: June 2005

Short stature didn't improve Napoleon's personality, but being small can add months to a rodent's life. Contradicting conventional wisdom about the cause of this extended longevity, a new study suggests that paring growth-spurring hormones doesn't prolong life. The results reinforce the view that the molecules exert different effects on health at different ages.
Feeling Spunky With JNK
Authors: Davenport R. John
Published: June 2005

Only a masochist would choose a life of stress and starvation, yet organisms can last unusually long if they exploit molecular pathways that respond to these pressures. Now, scientists reveal how one molecule connects two such pathways and lengthens the lives of worms and flies. The protein is linked to diabetes in mammals, suggesting that what benefits invertebrates might not be good for humans. Researchers need to probe deeper to understand how it shapes mammalian longevity, experts say.
Mopping Up Nuclear Waste
Authors: Leslie Mitch
Published: June 2005

A cell relies on molecular janitors to clear away trashed proteins, but researchers didn't know whether these cleanup crews tidied the nucleus. However, a new study identifies a housekeeping molecule that works in that structure, dispatching damaged proteins to the cell's refuse incinerator. The molecule may play a role in illnesses that involve protein buildup in the nucleus, such as Parkinson's disease.
Dementia of the Alzheimer's Type and Accelerated Aging in Down Syndrome
Authors: Devenny D. A. , Wegiel J. , Schupf N. , Jenkins E. , Zigman W. , Krinsky-McHale S. J. , Silverman W. P.
Published: June 2005

This case study, of a woman with Down syndrome and dementia of the Alzheimer's type (DAT), follows the course of her decline over an 11-year period until death at age 57. Detailed neuropathological findings are also presented. This case illustrates features of premature aging that are typically associated with Down syndrome, and the progressive changes in memory and cognition that are usually associated with DAT. Although the subject's cardiovascular condition and thyroid disorder were treated, they may have contributed to the decline of her memory. This case shows the difficulty in diagnosing dementia in an individual with mental retardation who suffered comorbid episodes of depression and psychosis.
Power Cut
Authors: Leslie Mitch
Published: June 2005

Like California air conditioners in the summer of 2000, an elderly person's muscles run low on power. The brownouts stem not from the shenanigans of unscrupulous energy brokers but from faltering mitochondria, a new study shows. The work suggests that DNA damage in the cellular power plants unleashes changes that sabotage energy production.
Giant Steps
Authors: Davenport R. John
Published: June 2005

It's a stretch to connect muscle fibers and genes, a new study suggests. Working muscles activate genes when they elongate a giant protein within their cells, the work reveals. Faults in the system underlie a rare muscle disease, but glitches might also contribute to weakness in the elderly.
Inflaming Chronic Pain
Authors: Leslie Mitch
Published: June 2005

Certain molecules help immune cells recognize bacteria and viruses. But prodding one of these so-called receptors might help trigger a form of pain, neuropathy, that even powerful drugs can't quell, according to new research. The work shows that obliterating a Toll-like receptor in a type of immune cell that lurks in the nervous system alleviates the rodent version of this condition. The results might help researchers illuminate the pathway that torments many patients and tease out immune cells' role in pain.
Time and Aging--Mechanisms and Meanings
Authors: Wollscheid-Lengeling Evi
Published: June 2005

A recent European Molecular Biology Laboratory Conference on Science and Society entitled "Time & Aging--Mechanisms & Meanings" fascinated scientists from different research areas as well as nonscientists. Topics discussed included not only the biological aging process but also the psychological effects of aging and social influences that affect this process.
Harden My Heart
Authors: Davenport R. John
Published: June 2005

It's a cruel irony of old age: Calcium leaks from bones, weakening them, yet accrues in blood vessels, hampering circulation. Researchers have now pinpointed a control circuit that prompts blood vessels to lay down calcium. Understanding the pathway could help researchers devise ways to dissolve the mineral buildup and maintain healthy blood flow.
Sins of Synuclein
Authors: Leslie Mitch
Published: June 2005

As any makeover expert will attest, the wrong accessories can spoil even the most stylish outfit. But when a brain protein implicated in Parkinson's disease (PD) dons an extra chemical group, the result is worse than a fashion faux pas. The protein becomes poisonous, according to new research. The work also stokes a controversy in the PD field by suggesting that the protein knots that infest brain cells of patients are helpful--not harmful, as many scientists argue.
Defining the Diet
Authors: Davenport R. John
Published: June 2005

Mice that consume less methionine but otherwise eat a full diet live unusually long, according to a new study. The modified meal induces many of the same physiological changes as does a reduced-calorie diet, an intervention that extends life span in many species. Elucidating the mechanisms behind both gastronomic regimes should reveal the simplest dietary changes that bestow the greatest benefit.
Shields Down
Authors: Leslie Mitch
Published: June 2005

β amyloid, the brain-clogging protein in Alzheimer's disease, recruits other molecules to do its dirty work. It kills cells by enlisting certain proteins to sabotage oxidant defenses, a new study reveals. The work suggests that drugs that break the chain between β amyloid and its henchmen might save neurons.
Optimistic for Longevity
Authors: Davenport R. John
Published: June 2005

Turn that frown upside-down, and you might live longer. Happier people have smaller quantities of two compounds connected with heart disease, diabetes, and other illnesses, new work reveals. The results mesh with the notion that folks with sunny dispositions enjoy better health than do those with a dark outlook and suggest a biological mechanism for that protection.
The Art and Science of Anti-Aging Therapies
Authors: Trojanowski John Q. , Jedrziewski M. Kathryn , Johnson Brad , Whitaker Linton A.
Published: June 2005

A meeting entitled "The Art and Science of Anti-Aging Therapies: Convergence of Theory and Practice" took place on 18 and 19 March 2005 at the University of Pennsylvania School of Medicine. The symposium was held for health care professionals, researchers, and consumers to provide them with information about current trends in anti-aging therapies. The program, which combined medical, surgical, and nonpharmacological approaches to healthy successful aging, gave attendees the opportunity to make sense of the issues at hand and to sort out safe treatments from perilous quick fixes.
Good as New
Authors: Leslie Mitch
Published: June 2005

Weary office workers who long for a "regenerating vacation" envision a spa weekend, not a summary beheading. But that rough treatment works wonders for flatworms, spurring each fragment to grow into a new animal. For the first time, researchers have analyzed large numbers of flatworm genes to pinpoint ones that confer this ability. The work could provide hints about how our tissues manage renovations.
Carnosine: A Versatile Antioxidant and Antiglycating Agent
Authors: Reddy V. Prakash , Garrett Matthew R. , Perry George , Smith Mark A.
Published: June 2005

Carnosine (β-alanyl-L-histidine) has recently attracted much attention as a naturally occurring antioxidant and transition-metal ion sequestering agent. It has also been shown to act as an anti-glycating agent, inhibiting the formation of advanced glycation end products (AGEs). Through its distinctive combination of antioxidant and antiglycating properties, carnosine is able to attenuate cellular oxidative stress and can inhibit the intracellular formation of reactive oxygen species and reactive nitrogen species. By controlling oxidative stress, suppressing glycation, and chelating metal ions, carnosine is able to reduce harmful sequelae such as DNA damage. AGEs are known contributors to the pathology of Alzheimer's disease, and carnosine therefore merits serious attention as a possible therapeutic agent.
Death in the Dirt
Authors: Leslie Mitch
Published: June 2005

Lab life is sweet for the average nematode, but it's particularly congenial for some mutant worms. Luxuriating on a comfy bed of agar and feasting on bacteria, the creatures can survive more than twice as long as nonmutants. But new work suggests that the altered worms falter in the wild. Mutants that live unusually long in the lab die abruptly when raised in soil. The findings add to the evidence that organisms can't get extra time for free.
Heart, Heal Thyself
Authors: Leslie Mitch
Published: June 2005

Much as children eventually lose interest in their
Star Wars
action figures, heart cells are supposed to grow out of the ability to divide. But a new study shows that with the right chemical coaxing, adult heart cells from rodents can duplicate, at least in the lab dish. If the results hold true for humans, such youthful cells might eventually allow patients to refurbish cardiac tissue sapped by heart disease.
Keep Time, Stay Healthy
Authors: Block Gene
Published: June 2005

Recent studies reveal that sleep loss in humans leads to metabolic disorders. A new study reports the development of metabolic syndrome in mice with altered circadian timing brought about by a mutation in a gene that functions in the biological clock. An intriguing and unanswered question is the relation between a healthy biological clock and normal appetite and weight regulation.
Spring Forward
Authors: Davenport R. John
Published: June 2005

Girls who are born as the days warm confront hot flashes sooner, according to new work. Women with March birthdays experience menopause nearly a year and a half earlier than those born in October. The findings add to the idea that the fetal environment can alter health in later life, although researchers aren't sure what triggers the difference in menopause timing.
MiMage: A Pan-European Project on the Role of Mitochondria in Aging
Authors: Scheckhuber C. , Osiewacz H. D.
Published: June 2005

The new European research project MiMage, supported by the European Community's Sixth Framework for Research and Technological Development, focuses on elucidating the role of mitochondria in conserved mechanisms of aging. Expertise in different research areas, including biochemistry, cell biology, genetics, molecular biology, and physiology, is provided by twelve research teams from seven European countries, together with one associated team from Canada and the United States. This report provides an introduction to the participating laboratories and the topics that will be addressed within the project, together with a concise report on the first symposium on the role of mitochondria in aging.
Hush, Little Gene
Authors: Leslie Mitch
Published: June 2005

As new mothers quickly learn, quieting a howling infant is easier if you've got support. To quiet genes, the protein Sir2p makes its own helper, new research on yeast reveals. The molecular assistant coaxes proteins to gather into a gene-blocking formation. The work raises the possibility that the same mechanism operates in mammals.
The Skeleton Goes to Pot
Authors: Davenport R. John
Published: June 2005

In the kids' cartoon, slacker Shaggy and his canine sidekick Scooby Doo snarfed Scooby Snacks that, according to urban lore, contained a magic ingredient: marijuana. Maybe that's why Shaggy had bad posture. New results reveal that activating a marijuana receptor spurs bone loss, and obstructing it reinforces bone, at least in mice. If the findings hold up in people, receptor-blocking drugs--already in trials to battle obesity--might combat osteoporosis.
Nitric Oxide and Oxidative Stress in Cardiovascular Aging
Authors: Raju Shubha V. Y. , Barouch Lili A. , Hare Joshua M.
Published: June 2005

The long-standing free radical theory of aging, which attributes cellular pathology to the relentless accumulation of reactive oxygen species (ROS), remains attractive but controversial. Emerging insights into the molecular interactions between ROS and reactive nitrogen species (RNS) such as nitric oxide suggest that, in biological systems, one effect of increased ROS is the disruption of protein S-nitrosylation, a ubiquitous posttranslational modification system. In this way, ROS may not only damage cells but also disrupt widespread signaling pathways. Here, we discuss this phenomenon in the context of the cardiovascular system and propose that ideas regarding oxidative stress and aging need to be reevaluated to take account of the balance between oxidative and nitrosative stress.
Ties That Bind the Brain
Authors: Davenport R. John
Published: June 2005

To expose mob scams and shady corporations, investigators must make connections between key wrongdoers. Now, researchers have linked two perpetrators that contribute to Parkinson's disease (PD). A defect in an antioxidant system that doesn't by itself cause trouble for flies exacerbates neuron loss in insects with a PD-associated mutation. The findings suggest that PD arises when antioxidants can't counteract mounting protein damage.
New Trick for an Old Enzyme
Authors: Leslie Mitch
Published: June 2005

Telomerase doesn't just work for tips. The enzyme rebuilds telomeres, the protective caps on chromosomes, but new work suggests it also helps cells repair damaged DNA elsewhere. The results might help doctors tailor treatments to kill cancer cells.
Misdirection on the Road to Shangri-La
Authors: Olshansky S. Jay , Carnes Bruce A. , Hershow Ronald , Passaro Doug , Layden Jennifer , Brody Jacob , Hayflick Leonard , Butler Robert N. , Allison David B. , Ludwig David S.
Published: June 2005

Will life expectancy in the United States rise or fall in this century? The implications of either scenario are far reaching. We contend that the rise of childhood obesity in the United States in the past three decades has been so dramatic that it will soon lead to higher than expected death rates at middle ages and a possible decline in life expectancy by midcentury. The most detrimental health and longevity effects will not be seen for decades--a phenomenon that cannot be detected by current methods used to forecast life expectancy or estimate the number of deaths currently attributable to obesity. This scenario contrasts sharply with the views of mathematical demographers who generate forecasts by relying on the assumption that the U.S. pattern of longevity will follow that of other longer lived nations and on the extrapolation of historical trends in life expectancy into the future.
Brain Drain
Authors: Leslie Mitch
Published: June 2005

Having cancer is devastating enough, but fresh research identifies a new detriment from the disease. Cancer survivors can suffer long-term mental decline, the study found. The work is the first to suggest that cancer or its treatment can trigger cognitive deficits that last many years.
Cleaning House
Authors: Davenport R. John
Published: June 2005

When clearing out the attic, a sentimentalist won't toss out that ruffled powder-blue tuxedo without a little prodding. Similarly, a protein-folding molecule coaxes cells to trash a useless protein, new work shows. The study reveals fresh details about how cells junk proteins and might lead to new treatments for diseases that result when molecules become misshapen.
Mars and Venus
Authors: Davenport R. John
Published: June 2005

Much of current medical practice uses research on men to guide treatment for women. But many illnesses don't hit both sexes equally hard. For example, at any particular age, the incidence of heart disease for men exceeds that for women. Moreover, heart attack symptoms aren't the same for both sexes. Researchers are uncovering unique aspects of women's physiology that might underlie their particular disease profiles and potentially lead to sex-tailored therapies.
The Longevity Gender Gap: Are Telomeres the Explanation?
Authors: Aviv Abraham , Shay Jerry , Christensen Karre , Wright Woodring
Published: June 2005

In this Perspective, we focus on the greater longevity of women as compared with men. We propose that, like aging itself, the longevity gender gap is exceedingly complex and argue that it may arise from sex-related hormonal differences and from somatic cell selection that favors cells more resistant to the ravages of time. We discuss the interplay of these factors with telomere biology and oxidative stress and suggest that an explanation for the longevity gender gap may arise from a better understanding of the differences in telomere dynamics between men and women.
Why Females Live Longer Than Males: Control of Longevity by Sex Hormones
Authors: Viña Jose , Borrás Consuelo , Gambini Juan , Sastre Juan , Pallardó Federico V.
Published: June 2005

Females live longer than males in many species, including humans. We have traced a possible explanation for this phenomenon to the beneficial action of estrogens, which bind to estrogen receptors and increase the expression of longevity-associated genes, including those encoding the antioxidant enzymes superoxide dismutase and glutathione peroxidase. As a result, mitochondria from females produce fewer reactive oxygen species than those from males. Administering estrogens has serious drawbacks, however--they are feminizing (and thus cannot be administered to males) and may increase the incidence of serious diseases such as uterine cancer in postmenopausal women. Phytoestrogens, which are present in soy or wine, may have some of the favorable effects of estrogens without their undesirable effects. Study of gender differences in longevity may help us to understand the basic processes of aging and to devise practical strategies to increase the longevity of both females and males.
Before Their Time
Authors: Davenport R. John
Published: June 2005

Like young wines, immature eggs, known as oocytes, must chill out for years. Now, research reveals that a molecule that helps unveil oocytes at the right moment also staves off age-related infertility. Understanding the mechanisms involved could reveal ways to maintain women's childbearing capacities later in life.
Premature Emission
Authors: Leslie Mitch
Published: June 2005

An actor who misses his cue can spoil a scene. Timing is equally important to keep metabolism running smoothly, according to a new study. The work suggests that a premature jump in the hormone leptin soon after birth boosts susceptibility to obesity later in life. The results might help explain why babies whose mothers are undernourished often grow into hefty adults.
Sticking It to Parkinson's Disease
Authors: Leslie Mitch
Published: June 2005

Vaccines have subdued once-dreaded killers such as polio and smallpox, and new research suggests they might help battle Parkinson's disease as well. Mice receiving shots containing a protein that accumulates in Parkinson's disease suffered less brain deterioration, suggesting a possible new means for fighting the incurable neurodegenerative illness.
Releasing the Pressure
Authors: Davenport R. John
Published: June 2005

Diabetes patients want to get a tighter grip on their metabolism without holding onto excess water, and new work might lead the way. Mice with a particular genetic alteration don't suffer from fluid accumulation, a dangerous side effect triggered by some antidiabetes drugs. The findings might help researchers fine-tune therapies.
Endothelial Progenitor Cell Therapy for Atherosclerosis: The Philosopher's Stone for an Aging Population?
Authors: Kravchenko Julia , Goldschmidt-Clermont Pascal J. , Powell Tiffany , Stallard Eric , Akushevich Igor , Cuffe Michael S. , Manton Kenneth G.
Published: June 2005

Much of the increased risk for atherosclerosis progression with age may be a result of age-related declines in the capacity of precursor cells to repair damage in the arterial endothelium. To estimate the impact of progenitor cell therapy for atherosclerosis on cardiovascular disease (CVD) mortality, life expectancy, and survival, as compared with the lifetime control of conventional risk factors, we modeled the health effects of bone marrow-derived endothelial progenitor cell therapy using data from the 1950 to 1996 follow-up of the Framingham Heart Study. To model cardiovascular disease mortality, we assumed that progenitor cell therapy was applied at age 30, with the effect assumed to be a 10-year delay in atherosclerosis progression. Age projections were constructed analytically using the stochastic process model for risk factor dynamics and mortality and microsimulation techniques. We considered three types of interventions: (i) keeping risk factors within selected limits to model current clinical recommendations; (ii) an age shift of 10 years to model the effects of progenitor cell therapy; and (iii) elimination of a competing risk (such as cancer). Our study suggests that progenitor cell therapy might increase life expectancy in the population as much as the complete elimination of cancer (in females, an additional 3.67 versus 3.37 years; in males, an additional 5.94 versus 2.86 years, respectively).
Antagonistic Control of Disease Resistance Protein Stability in the Plant Immune System
Authors: Holt Ben F. , Belkhadir Youssef , Dangl Jeffery L.
Published: June 2005

Pathogen recognition by the plant immune system is governed by structurally related, polymorphic products of disease resistance (
R
) genes. RAR1 and/or SGT1b mediate the function of many R proteins. RAR1 controls preactivation R protein accumulation by an unknown mechanism. We demonstrate that
Arabidopsis
SGT1b has two distinct, genetically separable functions in the plant immune system: SGT1b antagonizes RAR1 to negatively regulate R protein accumulation before infection, and SGT1b has a RAR1-independent function that regulates programmed cell death during infection. The balanced activities of RAR1 and SGT1, in concert with cytosolic HSP90, modulate preactivation R protein accumulation and signaling competence.
Ice Sheet and Solid Earth Influences on Far-Field Sea-Level Histories
Authors: Bassett Sophie E. , Milne Glenn A. , Mitrovica Jerry X. , Clark Peter U.
Published: June 2005

Previous predictions of sea-level change subsequent to the last glacial maximum show significant, systematic discrepancies between observations at Tahiti, Huon Peninsula, and Sunda Shelf during Lateglacial time (∼14,000 to 9000 calibrated years before the present). We demonstrate that a model of glacial isostatic adjustment characterized by both a high-viscosity lower mantle (4 × 10
22
Pa s) and a large contribution from the Antarctic ice sheet to meltwater pulse IA (∼15-meters eustatic equivalent) resolves these discrepancies. This result supports arguments that an early and rapid Antarctic deglaciation contributed to a sequence of climatic events that ended the most recent glacial period of the current ice age.
Permanent El Niño-Like Conditions During the Pliocene Warm Period
Authors: Wara Michael W. , Ravelo Ana Christina , Delaney Margaret L.
Published: June 2005

During the warm early Pliocene (∼4.5 to 3.0 million years ago), the most recent interval with a climate warmer than today, the eastern Pacific thermocline was deep and the average west-to-east sea surface temperature difference across the equatorial Pacific was only 1.5 ± 0.9°C, much like it is during a modern El Niño event. Thus, the modern strong sea surface temperature gradient across the equatorial Pacific is not a stable and permanent feature. Sustained El Niño-like conditions, including relatively weak zonal atmospheric (Walker) circulation, could be a consequence of, and play an important role in determining, global warmth.
Cytokinin Oxidase Regulates Rice Grain Production
Authors: Ashikari Motoyuki , Sakakibara Hitoshi , Lin Shaoyang , Yamamoto Toshio , Takashi Tomonori , Nishimura Asuka , Angeles Enrique R. , Qian Qian , Kitano Hidemi , Matsuoka Makoto
Published: June 2005

Most agriculturally important traits are regulated by genes known as quantitative trait loci (QTLs) derived from natural allelic variations. We here show that a QTL that increases grain productivity in rice,
Gn1a
, is a gene for cytokinin oxidase/dehydrogenase (OsCKX2), an enzyme that degrades the phytohormone cytokinin. Reduced expression of
OsCKX2
causes cytokinin accumulation in inflorescence meristems and increases the number of reproductive organs, resulting in enhanced grain yield. QTL pyramiding to combine loci for grain number and plant height in the same genetic background generated lines exhibiting both beneficial traits. These results provide a strategy for tailormade crop improvement.
Food Fight: The NPY-Serotonin Link Between Aggression and Feeding Behavior
Authors: Emeson Ronald B. , Morabito Michael V.
Published: June 2005

Aggressive behavior in mammals is linked to feeding. Interactions between neuropeptide tyrosine (NPY) and serotonergic neurons provide this link. Studies of aggressive behavior in mice in which the Y1subtype of NPY receptor was knocked out further define the synaptic circuits responsible for the interrelation of these instinctive behaviors.
Orchestration of Aberrant Epithelial Signaling by
Helicobacter pylori
CagA
Authors: Peek Richard M.
Published: June 2005

Persistent colonization by
Helicobacter pylori
is the strongest risk factor for distal gastric adenocarcinoma, and
H. pylori
strains that harbor the
cag
pathogenicity island further augment cancer risk. The
H. pylori
cag
island encodes a secretion system, and the product of the terminal gene in the island (CagA) is translocated into host epithelial cells after bacterial attachment, where it undergoes tyrosine phosphorylation by Src kinases and binds the eukaryotic phosphatase SHP-2. Higashi
et al
. now demonstrate that CagA-dependent SHP-2 activation leads to sustained activation of ERK (extracellular signal-regulated kinase), culminating in morphological changes that mimic unrestrained stimulation by growth factors. These data implicate the
cag
island as a key mediator of pathogenic epithelial responses that may heighten the risk for gastric cancer.
Central and Peripheral Signaling Mechanisms Involved in Endocannabinoid Regulation of Feeding: A Perspective on the Munchies
Authors: Sharkey Keith A. , Pittman Quentin J.
Published: June 2005

The endocannabinoid system is a critical regulator of energy homeostasis and food intake. Through cannabinoid (CB)
1
receptors in the brain and periphery, endocannabinoids exert powerful effects on the systems of the body that coordinate the balance between food intake, metabolism, and energy expenditure. These integrative systems control food intake both by modulating the inputs to various brain areas that monitor energy balance and by increasing the hedonic or reward value of the food consumed. Cannabinoids also alter metabolism, acting through both centrally located CB
1
receptors that drive neuronal pathways controlling metabolism and peripheral CB
1
receptors located in tissues throughout the body.
Meeting Report: The Future and Limits of Systems BiologyReport of the meeting "International Conference on Systems Biology," Heidelberg, Germany, 9 to 13 October 2004.
Authors: Werner Eric
Published: June 2005

Systems biology has enjoyed explosive growth in both the number of people participating in this area of research and the number of publications on the topic. And yet, the paradigms that underlie the field have not seen a similar expansiveness. Instead, most of these paradigms have been carried over from other fields like engineering, physics, and mathematics. As a result, a small set of concepts dominate the field. The traditional biologist is seen by many as outmoded and tolerated only as a source of data. In this view, the biologist’s ideas may even be considered conceptually and theoretically irrelevant. In this Perspective, we take a critical look at some of the paradigms of systems biology and question whether the biologist’s ideas, methods, and theories have really become outmoded. We see the future of systems biology as a tight coupling of in vivo and in vitro methods for bioengineering with in silico multicellular modeling and simulation.
G Protein–Coupled Receptors
Authors: Sealfon Stuart C.
Published: June 2005

This Teaching Resource provides lecture notes and slides for a class covering G protein–coupled receptors (GPCRs) and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of the major classes of GPCRs and then proceeds to describe the mechanisms of receptor diversity, ligand interaction, desensitization, coupling, and mutations associated with human diseases.
Ligand-Gated Ion Channels
Authors: Blitzer Robert D.
Published: June 2005

This Teaching Resource provides a summary and slides derived from a lecture covering ligand-gated ion channels (LGICs), and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture focuses on two families of LGICs: the Cys-loop receptors and the ionotropic glutamate receptors. For Cys-loop receptors, much of the material is based on studies of the nicotinic acetylcholine receptor, including overall receptor topology, the basis for ionic selectivity, the identity of the gate, and the coupling of agonist binding to the opening of the gate. In the glutamate receptors, the conserved topology, and the differential kinetics and ion selectivities, among the AMPA-type and NMDA-type glutamate receptors are covered. The unique voltage-dependence of NMDA-type receptors is addressed, with special reference to the role of these receptors in synaptic plasticity.
Bayesian Network Analysis of Signaling Networks: A Primer
Authors: Pe'er Dana
Published: June 2005

High-throughput proteomic data can be used to reveal the connectivity of signaling networks and the influences between signaling molecules. We present a primer on the use of Bayesian networks for this task. Bayesian networks have been successfully used to derive causal influences among biological signaling molecules (for example, in the analysis of intracellular multicolor flow cytometry). We discuss ways to automatically derive a Bayesian network model from proteomic data and to interpret the resulting model.
Inducible Covalent Posttranslational Modification of Histone H3
Authors: Bode Ann M. , Dong Zigang
Published: June 2005

The physiological state of a eukaryotic cell is determined by endogenous and exogenous signals, and often the endpoint of the pathways that transmit these signals is DNA. DNA is organized into chromatin, a nucleoprotein complex, which not only facilitates the packaging of DNA within the nucleus but also serves as an important factor in the regulation of gene function. The nucleosome is the basic unit of chromatin and generally consists of approximately two turns of DNA wrapped around an octamer of core histone proteins. Each histone also contains an accessible N-terminal tail that extends outside the chromatin complex and is subject to posttranslational modifications that are crucial in the regulation of gene expression. Two distinct categories of histone posttranslational modification have been observed: (i) inducible or stimulation-dependent and (ii) mitosis-dependent. Stimulation by mitogens or stress leads to rapid transient posttranslational modifications of histones, in particular histone H3, which are mechanistically and temporarily distinct from modifications associated with mitosis. This Review focuses mainly on the inducible phosphorylation of histone H3 brought about by different stimuli, such as epidermal growth factor, 12-O-tetradecanoylphorbol-13-acetate, arsenite, or ultraviolet radiation. We examine the most recent, and at times controversial, research data concerning the identity of the histone H3 kinases responsible for this phosphorylation. In addition, the interdependence of phosphorylation and acetylation will be discussed in light of data showing patterns of inducible modification at specific genes.
Ubiquitin Chains in the Ladder of MAPK Signaling
Authors: Laine Aaron , Ronai Ze′ev
Published: June 2005

With a better understanding of the cellular stress response, it has become evident that catalytic modules consisting of kinases that mediate the activation of downstream effector components are subject to multiple layers of regulation. Such regulatory mechanisms are not limited to those involving scaffold proteins or protein phosphatases, and they appear to include a growing number of modifications by ubiquitin and ubiquitin-like proteins. The role of ubiquitin in the regulation of mitogen-activated protein kinase (MAPK) emerges as a paradigm for understanding the role of ubiquitination in regulating other signal transduction pathways. Ubiquitination influences signal diversification and limits the duration of the signal through its role in the assembly of protein kinase complexes, subcellular localization, and the actual degradation of the kinase or its substrate. This review summarizes our current understanding of the roles of ubiquitin in regulating MAPK signaling.
G Protein Effectors
Authors: Diverse-Pierluissi Maria
Published: June 2005

This Teaching Resource provides lecture notes and slides for a class covering two aspects of G protein–mediated signaling and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of the regulation of receptor-G protein coupling and then proceeds to describe the specificity of the response achieved through regulation of specific isoforms of effectors.
Membrane Resealing: Synaptotagmin VII Keeps Running the Show
Authors: Andrews Norma W.
Published: June 2005

Ca
2+
influx, an immediate consequence of plasma membrane disruption, triggers a resealing mechanism involving exocytosis. Although this has been known for about a decade, a better understanding of the organelles involved and of the molecular machinery controlling membrane repair has been slower to emerge. Recent studies have changed this picture, by identifying lysosomes as exocytotic vesicles involved in membrane resealing and the Ca
2+
-binding protein synaptotagmin VII as a regulator of this process. New evidence reinforces the role of the C
2
A and C
2
B domains of synaptotagmin VII in plasma membrane repair, highlighting the importance of this molecule as a powerful tool for future studies.
Sensing Your Surroundings: How Transcription-Regulatory Networks of the Cell Discern Environmental Signals
Authors: Balázsi Gábor , Oltvai Zoltán N.
Published: June 2005

Accumulating evidence indicates that cells differentially regulate parts of their biochemical networks in various environmental conditions. Two recent studies, focused on the yeast transcription-regulatory network, have identified the characteristics and some of the regulatory logic that defines such conditional regulation on a system level. But what is the underlying basis of such environment-dependent dynamic network utilization? We propose that with simultaneous changes in many environmental variables, cells detect and process the incoming pieces of information individually with the use of receptors and sensor transcription factors specialized to a given type of signal. In turn, transcriptional subnetworks affected by the activity of these proteins reassemble the processed signals deeper inside the network, ultimately resulting in the development of an integrated cellular response.
TRP Channels
Authors: Rohacs Tibor
Published: June 2005

This Teaching Resource provides lecture notes and slides for a class covering TRP channels and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with an overview of calcium signaling and then proceeds to describe the function, regulation, and activation of different TRP channel families.
Drosophila Wnt/Fz Pathways
Authors: DasGupta Ramanuj , Boutros Michael , Perrimon Norbert
Published: June 2005

Wnts [also known as Wingless (Wg)] are a family of conserved signaling molecules involved in a plethora of fundamental developmental and cell biological processes, such as cell proliferation, differentiation, and cell polarity. Dysregulation of the pathway can be detrimental, because several components are tumorigenic when mutated and are associated with hepatic, colorectal, breast, and skin cancers. First identified in the fruit fly
Drosophila melanogaster
as a gene family responsible for patterning the embryonic epidermis, the
Wnt
gene family, including
Wg
, encode secreted glycoproteins that activate receptor-mediated signaling pathways leading to numerous transcriptional and cellular responses. The main function of the canonical Wg pathway is to stabilize the cytoplasmic pool of a key mediator, beta-catenin [β-catenin, known as Armadillo (Arm) in fruit flies], which is otherwise degraded by the proteasome pathway. Initially identified as a key player in stabilizing cell-cell adherens junctions, Arm is now known to also act as a transcription factor by forming a complex with the lymphoid enhancer factor (LEF)/T cell-specific transcription factor (TCF) family of high mobility group (HMG)-box transcription factors. Upon Wnt/Wg stimulation, stabilized Arm translocates to the nucleus, where, together with LEF/TCF transcription factors, it activates downstream target genes that regulate numerous cell biological processes.
Text Mining for Metabolic Pathways, Signaling Cascades, and Protein Networks
Authors: Hoffmann Robert , Krallinger Martin , Andres Eduardo , Tamames Javier , Blaschke Christian , Valencia Alfonso
Published: June 2005

The complexity of the information stored in databases and publications on metabolic and signaling pathways, the high throughput of experimental data, and the growing number of publications make it imperative to provide systems to help the researcher navigate through these interrelated information resources. Text-mining methods have started to play a key role in the creation and maintenance of links between the information stored in biological databases and its original sources in the literature. These links will be extremely useful for database updating and curation, especially if a number of technical problems can be solved satisfactorily, including the identification of protein and gene names (entities in general) and the characterization of their types of interactions. The first generation of openly accessible text-mining systems, such as iHOP (Information Hyperlinked over Proteins), provides additional functions to facilitate the reconstruction of protein interaction networks, combine database and text information, and support the scientist in the formulation of novel hypotheses. The next challenge is the generation of comprehensive information regarding the general function of signaling pathways and protein interaction networks.
A Life Science Semantic Web: Are We There Yet?
Authors: Neumann Eric
Published: June 2005

More than ever, life science researchers depend on information from multiple sources. The Semantic Web offers a powerful new strategy for consolidating both text and structured data into a comprehensive collections and views. In addition, these aggregates are readable by both humans and machines and could be the basis of information management and knowledge exchange.
A Rationally Designed Small Molecule That Inhibits the HIF-1α–ARNT Heterodimer from Binding to DNA in Vivo
Authors: Vinson Charles
Published: June 2005

Modern drug development is focused on two steps: the identification of new molecular targets and the development of drugs that affect these targets. A molecular target can be an enzymatic activity or a macromolecular interface that is important in a disease pathway. Current drugs on the market are biased toward targeting cell surface receptors and intracellular enzymatic activities. However, macromolecular interfaces can also serve as potential molecular targets. A recent paper from Kaelin and Dervan's groups examined an underused molecular target—transcription factor DNA binding. To specifically disrupt transcriptional activation, they used a rationally designed small molecule that binds specifically in the minor groove of a DNA sequence that in vivo is bound by a bHLH heterodimer transcription factor.
Regulating Inducible Transcription Through Controlled Localization
Authors: Ziegler Elizabeth C. , Ghosh Sankar
Published: June 2005

Many signaling pathways regulate the activity of effector transcription factors by controlling their subcellular localization. Until recently, the cytoplasmic retention of inactive transcription factors was mainly attributed to binding partners that mask the nuclear localization signals (NLSs) of target proteins. Inactive transcription factors were thought to be exclusively cytoplasmic until their activation, after which the NLSs were unmasked to allow nuclear translocation. There is now a growing body of evidence, however, that challenges this simple model. This Review discusses recent reports that suggest that inducible transcription factors can constantly shuttle between the cytoplasm and the nucleus, and that their apparent cytoplasmic retention can be achieved by binding partners that mask the NLSs, tether the transcription factor to cytoplasmic structures, or mark the transcription factor for proteasomal degradation. We also discuss the possibility that this more complex model of cytoplasmic retention might be applicable to a broader range of transcription factors and their associated signaling pathways.
Class 3 Semaphorin Signaling: The End of a Dogma
Authors: Potiron Vincent , Roche Joëlle
Published: June 2005

Semaphorins—a family of secreted, membrane-bound, and transmembrane proteins—play an important role in the development of various organs, as well as in axonal pathfinding, angiogenesis, tumorigenesis, and the immunological response. Neuropilins 1 and 2 (NRP1 and 2) are receptors for the class 3 secreted semaphorins (SEMA3s) but not for the other classes of semaphorins. NRPs are also coreceptors for vascular endothelial growth factor 165 (VEGF
165
), suggesting that SEMA3s could inhibit the VEGF
165
-VEGF receptor (VEGFR) pathway during angiogenesis. Until recently, it was believed that binding of SEMA3s to neuropilins was necessary to initiate signaling from plexins, the active players in semaphorin signal transduction. However, Gu and colleagues have recently described an exception: Their research suggests that SEMA3E signal transduction may be neuropilin independent. This Perspective focuses on this recent finding in the context of semaphorin signaling outside the nervous system.
One Neuron–Multiple Receptors: Increased Complexity in Olfactory Coding?
Authors: Spehr Marc , Leinders-Zufall Trese
Published: June 2005

Olfaction—the sense of smell—is responsible for detecting molecules of immense structural variety. Precise recognition of such diverse stimuli requires a massive receptor repertoire. This functional challenge has been met by simultaneous expression of a multitude of odor-detecting receptors that all belong to the superfamily of heterotrimeric GTP-binding protein (G protein)–coupled receptors. Studies conducted over the past decade have led to the assumption that an individual olfactory sensory neuron expresses only a single odorant receptor, consequently giving rise to the "one receptor–one neuron" hypothesis. This idea is attractive because of its simplicity and has served as the basis for models of olfactory coding. However, recent reports regarding
Drosophila
have found exceptions to the rule that could have important implications for the logic of olfactory coding.
Proteases and Signaling
Authors: Wilk Sherwin
Published: June 2005

This Teaching Resource provides lecture notes and slides for a class covering proteases and signaling and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of protease-activated receptors and the ubiquitin-proteasome system and then proceeds to describe some of the ways that proteolysis can function in signal transduction.
Apoptosis
Authors: Wilk Sherwin
Published: June 2005

This Teaching Resource provides lecture notes and slides for a class covering apoptosis and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture contains a discussion of the apoptosis genes in
Caenorhabditis elegans
, the properties of the caspases, the major components of the extrinsic apoptotic signal transduction pathway, and the major components of the intrinsic (mitochondrial) apoptotic pathway.
The Many Faces of SAM
Authors: Qiao Feng , Bowie James U.
Published: June 2005

Protein-protein interactions are essential for the assembly, regulation, and localization of functional protein complexes in the cell. SAM domains are among the most abundant protein-protein interaction motifs in organisms from yeast to humans. Although SAM domains adopt similar folds, they are remarkably versatile in their binding properties. Some identical SAM domains can interact with each other to form homodimers or polymers. In other cases, SAM domains can bind to other related SAM domains, to non–SAM domain–containing proteins, and even to RNA. Such versatility earns them functional roles in myriad biological processes, from signal transduction to transcriptional and translational regulation. In this review, we describe the structural basis of SAM domain interactions and highlight their roles in the scaffolding of protein complexes in normal and pathological processes.
Nuclear Receptors
Authors: Taneja Reshma
Published: June 2005

This Teaching Resource provides lecture notes and slides for a class covering nuclear receptors and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of the structure of nuclear hormone receptors and then proceeds to describe mechanisms of transcriptional regulation, modulation of nuclear receptor activity by phosphorylation, and the role of nuclear receptors in cancer.