bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary Study of Oscillatory Radial Flow between Disks and Its Acoustic Field
Authors: Chanaud R. C.
Published: September 2005

The radial flow between coaxial parallel disks (one of which is rigid and contains the source; the other of which is free) has been observed to be self-oscillatory. A preliminary study of the motion indicates that a nonlinear feedback loop exists between the fluid and the free disk. The fundamental frequency was always higher than the calculated free-free natural frequencies of the disk, and suggested the importance of fluid compressibility. Excitation was found to occur only when there was a shock wave between the disks. Instability associated with the shock position is proposed as the self-excitation mechanism. The acoustic field is described and is composed of both dipole and monopole components.
New High-Power Underwater Sound Source for the Low-Audio Range
Authors: Donovan J. E. , Kieser R. J.
Published: September 2005

A new moving-coil underwater sound transducer can be used singly or in pairs to generate greater underwater sound-pressure levels in the frequency range from 20 to approximately 100 Hz than are possible with any other wide-band transducer. The mean transmitting current response of the single transducer in the frequency range 20 to 10 000 Hz is approximately 50 dB re 1 μbar/A at 1 m. When driven by about 2000 electrical watts, the transducer will generate approximately 8 acoustic watts at 80 Hz. It will accommodate more than 3000 electrical watts, being displacement limited. It is designed for use at depths to 90 ft; with additional pressure compensation, the depth can be increased. It is planned to use this transducer in arrays for even higher acoustic outputs.
Determination of the Large-Amplitude Properties of Magnetostrictive Materials
Authors: Whymark R. R.
Published: September 2005

An experimental perturbation technique is described for determining, at large amplitudes, the complex transformation ratio of magnetostrictive materials. A ferrite magnetostrictive is coupled to a ceramic transducer that is linearly excited in variable phase so as either to increase, or reduce the displacement of the ferrite. The magnitude of the magnetostrictive transformation ratio is proportional to the change in the displacement produced by the ceramic drive. The phase angle of the transformation ratio is determined from the phase of this drive. Absolute, rather than relative measurement of the transformation ratio is obtained at moderate strains (<10−4) for which the magnetic permeability is assumed to be constant. Back driving allows the fields of the clamped and the free specimen to be determined at constant permeability from which the vector strain field, and hence the complex transformation ratio, is calculated. The variation of the transformation ratio is determined for Ni-Co ferrite at induction peaks to 400 lines/cm2 and strains of 2×10−4. High-power impedance circles and resonance curves are evaluated in terms of the measured transformation characteristics. [Supported by Office of Naval Research.]
Vibration Isolation of Pressure Transducers for Determination of Acoustic Environment
Authors: Paranjape S. V. , Simon E.
Published: September 2005

Measurement of pressure fluctuations due to acoustic environment is important in the investigation of turbulent flow phenomena associated with several classes of aerospace problems. These measurements, utilizing piezoelectric transducers, are accompanied by noise from vibrations of the structure on which the transducers are mounted. Two schemes for the vibration isolation of the transducers are experimentally investigated. These are: individual isolation of transducers, and isolation of an insert on which the transducers are mounted. Experiments were conducted in a 14 in.×14-in. supersonic wind tunnel at a nominal Much number of 1.96 and stagnation pressures of 30 and 45 psia. Comparison of the spectra of the pressure fluctuations measured by transducers mounted on a flat wall of the tunnel shows that structural noise above 3 kc/sec may be eliminated by any one of the two schemes, and that below 3 kc/sec may be eliminated by any one of the two schemes, and that below 3 kc/sec the structural noise is considerably reduced by these isolation techniques. In order to attain further insight into the manner in which a pressure transducer is affected by structural vibrations, coherence functions have been calculated for structural noise and observed pressure fluctuations.
Accuracy of Electrostatic Actuators in Microphone Calibrations
Authors: Rasmussen Gunnar
Published: September 2005

Absolute calibration of microphones in a free field at high frequency is a tedious and time-consuming job. If a high degree of accuracy is required, it is also difficult and expensive to establish. The electrostatic actuator method of calibration offers advantages, which will be discussed along with some of the problems involved.
Will We Find Biomarkers of Aging?
Authors: Davenport R. John
Published: September 2005

Because aging takes a lifetime to study, answers about it can be slow in coming. Scientists have to wait for an organism to die to gain insight into its demise. Moreover, that requirement renders the study of aging in humans--and tests of interventions that might retard it--nearly impossible. However, physiological or molecular measures besides life span that would provide a more practical indicator of aging might exist. Can we find such biomarkers?
How Can We Use Moderate Stresses to Fortify Humans and Slow Aging?
Authors: Leslie Mitch
Published: September 2005

Toss out the Prozac. Shelve that DVD of relaxation techniques. Give the yoga mat to the dog. The secret to a long, healthy life lies not in cultivating inner peace but in embracing stress. That's the lesson some researchers draw from more than a century of work on the counterintuitive phenomenon called hormesis, in which moderate doses of radiation, noxious compounds, and other hazards prove beneficial rather than harmful. Hormesis intrigues gerontologists because lab organisms often survive longer after exposure to stress, and researchers are eager to learn whether they can harness this response to strengthen our bodies as we age. But before patients start lining up for a salubrious blast of radiation or an invigorating injection of poison, scientists need to address a slew of issues, from what stresses are most effective to how to make treatments palatable to a discomfort-averse population. Most important, researchers need to tackle the biggest question of all: Will hormesis work in humans?
How Can We Craft a Better Theory to Explain the Evolution of Aging?
Authors: Leslie Mitch
Published: September 2005

The leading evolutionary explanation for senescence has hit middle age. Born in the late 1940s, the theory matured in the 1960s and flourished in the following decades, as researchers amassed evidence supporting its predictions. But like many of its contemporaries, the theory now needs to have a little work done. Evolution experts don't envision a makeover, merely a few nips and tucks to explain some vexing results from field studies and mathematical models.
Engine Trouble
Authors: Leslie Mitch
Published: September 2005

Like big-city garbage trucks, molecular transporters in cells have to keep moving or trash piles up, according to a new study. The work shows that faulty haulers stall the removal of contorted proteins like those that accumulate in brain illnesses such as Parkinson's disease and Alzheimer's disease. The results support the idea that spurring cells to tidy up might stave off brain deterioration.
Falling Apart
Authors: Davenport R. John
Published: September 2005

In a premature aging disease, deteriorating DNA takes the body down with it, according to new work. Damaged DNA plagues mice with a molecular change linked to Hutchinson-Gilford progeria syndrome, the findings reveal. The work illuminates a potential cause of the disease.
Metabolomics: Opening Another Window into Aging
Authors: Kristal Bruce S. , Shurubor Yevgeniya I.
Published: September 2005

Metabolomics is based on the simultaneous analysis of multiple low-molecular-weight metabolites from a given sample. As such, metabolomics seeks the most up-to-date information about the state of interaction between an organism and its environment. The ability to use metabolomics approaches for classification and mechanistic studies may influence and augment our ability to study and address the aging process scientifically and clinically.
Reactive Oxygen Species and Aging: Evolving Questions
Authors: Dugan Laura L. , Quick Kevin L.
Published: September 2005

Over the past 50 years, reactive oxygen species (ROS) have been investigated as putative mediators of the process of aging. As specific genes and pathways that are involved with ROS homeostasis have been linked to aging in lower organisms, such as
Caenorhabditis elegans
and
Drosophila
, the questions of how ROS regulate aging in higher organisms, and whether they do so to the same extent as in lower organisms, have emerged.
Odd SOD
Authors: Leslie Mitch
Published: September 2005

A squirming 5-year-old is annoying, but proteins that can't settle down might be lethal, according to new work. The study suggests that unstable versions of an oxidation-battling enzyme spark the fatal nerve disorder amyotrophic lateral sclerosis. The work supports preliminary studies that used molecular guardians to keep the protein in line.
Hair Trigger
Authors: Davenport R. John
Published: September 2005

Like fertilizer on a sparse lawn, a chemical enticement encourages the skin to fill in hair-growing structures, new results reveal. The finding clarifies which cells produce new follicles and might point toward improved ways of encouraging hair growth in balding oldsters.
T-CIA: Investigating T Cells in Aging
Authors: Koch Sven , Kempf Juergen , Pawelec Graham
Published: September 2005

Over the past few decades it has become clear that the immune system and especially T cells are instrumental in achieving a long and healthy life. The European Union (EU) previously supported several pan-European research projects coordinated from Tuebingen, Germany, aimed at providing a better understanding of immunosenescence. For 3 years, until the end of 2005, the EU is supporting a project called T cells in aging (T-CIA). The aim of T-CIA is to spy out and combine current efforts in immunology, molecular biology, and gerontology for a better understanding of why the elderly often have dysregulated immune responses and are more susceptible to infections and cancer.
Pathological Partnership
Authors: Leslie Mitch
Published: September 2005

The protein huntingtin leads a molecular conspiracy that destroys brain cells and kills patients with Huntington's disease, and now researchers have captured one of its minions. The new study identifies the cancer-fighting protein p53 as one of huntingtin's gang, a discovery that might help researchers devise treatments for the incurable disease.
Not Like the Other
Authors: Davenport R. John
Published: September 2005

Hang around with identical twins long enough, and you'll spot nuances that distinguish them. The same holds true for their DNA, according to a new study. Researchers have found that as identical twins age, the patterns of chemical changes to their chromosomes grow increasingly dissimilar. The findings might explain why one twin doesn't always get the same diseases as her sibling.
Bombshell
Authors: Leslie Mitch
Published: September 2005

Like vain Hollywood stars, our cells have kept their true ages secret. But a new technique similar to the method for dating Egyptian mummies can determine cells' birth dates. Researchers have now used the technique to demonstrate that certain brain cells don't replenish themselves.
Allelic Variation and Human Longevity
Authors: Nebel Almut , Schreiber Stefan
Published: September 2005

Human longevity is a complex phenotype with a strong genetic contribution. The search for allelic variation that impacts on longevity often involves population-based association studies of long-lived individuals (centenarians and nonagenarians) and younger controls. A major methodological problem with this approach is that the cases and controls in these experiments are often born several generations apart. The inherent absence of "age matching" can lead to serious misinterpretations. For example, allele frequency differences between long-lived individuals and younger controls may not reflect an effect on longevity but rather a change in population structure over time or different gene-environment interactions across generations.
Fat-Free Longevity
Authors: Davenport R. John
Published: September 2005

Living long and slimming down figure prominently on many people's wish lists, and new results bolster hope for achieving both. Worms without a particular gene retain fat and cheat death, but different molecular pathways control the two outcomes. The study helps flesh out connections between fat and longevity.
How Long Do I Have, Doc?
Authors: Leslie Mitch
Published: September 2005

Star Trek
fans know that the unnamed crewman will usually die before the episode's first commercial. In real life, however, even doctors can't make such accurate predictions about a person's remaining time. But researchers might achieve the feat for nematodes, according to a new study suggesting that a worm's output of a stress-fighting protein forecasts its life span. The work might eventually allow scientists to devise tests to estimate human longevity.
Not a Chip off the Old Block
Authors: Leslie Mitch
Published: September 2005

Like a headstrong teen who refuses to enter the family accounting business and joins a rock band instead, the mammalian protein SIRT1 breaks with its relatives, according to a new study. SIRT1's kin in yeast promotes cell division, but the protein prods mouse cells to abandon reproduction. The work reveals SIRT1's previously unknown role in handling long-lasting stress.
Detour to Death
Authors: Davenport R. John
Published: September 2005

Construction signs steer traffic around trouble, but new work reveals a diversion that routes cells into danger. A protein named p66
Shc
funnels electrons down an unusual path and uses them to make cell-killing compounds instead of energy. The results might help researchers understand why mice without the protein survive unusually well.
From Bedside to Bench: Research Agenda for Frailty
Authors: Fried Linda P. , Hadley Evan C. , Walston Jeremy D. , Newman Anne B. , Guralnik Jack M. , Studenski Stephanie , Harris Tamara B. , Ershler William B. , Ferrucci Luigi
Published: September 2005

The American Geriatrics Society sponsored a working conference in January 2004, funded by the National Institute on Aging, to establish the state of the art in frailty research and to set a research agenda for the future. The invited participants included senior basic biologists, epidemiologists, geneticists, and clinical investigators who study aging-related issues. This article summarizes the central theoretical observations on frailty and research needs and opportunities presented and discussed at this conference, and lays out an agenda for future research on frailty.
Partly Cloudy
Authors: Davenport R. John
Published: September 2005

A gene version that can lead to foggy thinking might also precipitate blurry vision, new results suggest. The gene variant, connected to Alzheimer's disease in humans, destroys the retinas of mice over time. The findings conflict with data from humans hinting that the gene protects eyes.
Up to Speed
Authors: Leslie Mitch
Published: September 2005

Mice are already jittery, so giving them amphetamines might seem superfluous. But a new study suggests that Ecstasy--one type of amphetamine--can restore movement in mice suffering symptoms similar to those of Parkinson's disease. The work hints that the brain carries back-up circuits for controlling movement and might help scientists develop new drugs to combat the incurable disease.
Hairy Breakup
Authors: Beckman Mary
Published: September 2005

When actors Ronald Reagan and Jane Wyman split up, she remained a film performer whereas he moved on to politics. Likewise, a protein set free from its partner proves to have an unexpected talent--and this one has stem-cell biologists seeing stars. The protein component of telomerase, famous for maintaining chromosome ends, also stimulates stem cells in hair follicles, new research reveals. The results add to the growing body of evidence that telomerase performs multiple tasks.
Making Young Tumors Old: A New Weapon Against Cancer?
Authors: Sage Julien
Published: September 2005

As the population of industrial nations ages, the incidence of cancer and cancer mortality is increasing. Intuitively, older organisms may be less able to cope with accumulated damage and thus be more prone to develop cancer. However, so far, the links between aging and cancer have been only partially explored. Strikingly, four recent studies now indicate that premature senescence accompanied by cell cycle arrest occurs in tumors initiated by an oncogenic mutation. Thus, senescence may act as a key tumor suppressor mechanism in young tumors in vivo.
Brain Tumor-Associated Dementia
Authors: Noble James McC. , Canoll Peter , Honig Lawrence S.
Published: September 2005

In this case study, we describe a patient with a dementia due to a brain tumor. This unusual cause of dementia illustrates the importance of a thorough evaluation of anyone who experiences relatively sudden changes in cognitive functions. The disorder had features common to other dementias but also had some unusual attributes that made a diagnosis of neurodegenerative disease less likely. Common features included intellectual decline involving difficulties in word-finding, the occurrence of paraphasia, poor concentration, disorientation in familiar environments, problems performing routine complex tasks, and elements of social withdrawal. Unlike more common degenerative dementias, however, there was no marked memory involvement. In addition, the onset of illness was rapid and associated with headaches, incontinence, and some gait and motor dysfunction.
Tuning Up the Pancreas
Authors: Leslie Mitch
Published: September 2005

Even the most adept mechanic can't make a Ford Focus run like a Porsche. But genetic tinkering can transform base-model mouse pancreas cells into high-performance insulin producers, according to new research. Cranking up a protein that promotes longevity in yeast and worms helps mice control their blood sugar, suggesting a new target for drugs to prevent and treat diabetes.
Another Knock Against Cholesterol
Authors: Leslie Mitch
Published: September 2005

In a cruel double whammy, many patients suffering from Alzheimer's disease (AD) also have atherosclerosis. New work might clarify the connection between the two illnesses. The study reveals that copper and the AD protein β amyloid gang up on cholesterol and spawn brain-injuring compounds. Drugs that separate β amyloid from its metallic accomplice might help forestall neural damage, the results suggest.
Numb Together
Authors: Davenport R. John
Published: September 2005

Like bullies who move into peaceful neighborhoods and cause trouble, bone marrow cells fuse with and short-circuit neurons in diabetic rodents, new work reveals. The findings uncover a new trigger for diabetes-related nerve damage and suggest that diverting the errant bone marrow cells might alleviate the complication.
Get Out of the Way
Authors: Davenport R. John
Published: September 2005

When a crew builds a house, plumbing installation speeds up if the carpenters get out of the way. Similarly, a bone-manufacturing protein works better in animals that lack another bone molecule, new work reveals. The findings might help researchers fine-tune therapy for osteoporosis patients.
No Parkin Zone
Authors: Leslie Mitch
Published: September 2005

Like a kid who misbehaves while her mother naps, a protein might run amok when cellular supervision wanes, triggering Parkinson's disease (PD). According to new work, quantities of the protein soar when another molecule that normally keeps it in check falters. The study suggests a new way to stanch the loss of brain cells in PD.
Metals on the Brain
Authors: Treiber Carina
Published: September 2005

Current research suggests that imbalances in metal-ion homeostasis play a critical role in neurodegenerative disorders, such as Alzheimer's disease and transmissible spongiform encephalopathy, and in cancer. It is thus important to elucidate the mechanisms by which homeostasis is maintained and how metals function in cellular processes, including cell signaling, neurotransmission, and protein transport and storage. This summary of a meeting recently held in Barcelona, Spain, highlights some of the latest findings on intra- and extracellular zinc signaling, the consequences of zinc imbalances on cells and on the brain, the mechanisms of metal-ion influx and efflux, how metal ions are sequestered by metallothioneins, and the development of candidate drugs to treat brain injury due to metal-ion imbalances.
Bridging Dimensions: Demultiplexing Ultrahigh-Density Nanowire Circuits
Authors: Beckman Robert , Johnston-Halperin Ezekiel , Luo Yi , Green Jonathan E. , Heath James R.
Published: September 2005

A demultiplexer is an electronic circuit designed to separate two or more combined signals. We report on a demultiplexer architecture for bridging from the submicrometer dimensions of lithographic patterning to the nanometer-scale dimensions that can be achieved through nanofabrication methods for the selective addressing of ultrahigh-density nanowire circuits. Order log
2
(
N
) large wires are required to address
N
nanowires, and the demultiplexer architecture is tolerant of low-precision manufacturing. This concept is experimentally demonstrated on submicrometer wires and on an array of 150 silicon nanowires patterned at nanowire widths of 13 nanometers and a pitch of 34 nanometers.
Bats Are Natural Reservoirs of SARS-Like Coronaviruses
Authors: Li Wendong , Shi Zhengli , Yu Meng , Ren Wuze , Smith Craig , Epstein Jonathan H. , Wang Hanzhong , Crameri Gary , Hu Zhihong , Zhang Huajun , Zhang Jianhong , McEachern Jennifer , Field Hume , Daszak Peter , Eaton Bryan T. , Zhang Shuyi , Wang Lin-Fa
Published: September 2005

Severe acute respiratory syndrome (SARS) emerged in 2002 to 2003 in southern China. The origin of its etiological agent, the SARS coronavirus (SARS-CoV), remains elusive. Here we report that species of bats are a natural host of coronaviruses closely related to those responsible for the SARS outbreak. These viruses, termed SARS-like coronaviruses (SL-CoVs), display greater genetic variation than SARS-CoV isolated from humans or from civets. The human and civet isolates of SARS-CoV nestle phylogenetically within the spectrum of SL-CoVs, indicating that the virus responsible for the SARS outbreak was a member of this coronavirus group.
Wrestling with SUMO in a New Arena
Authors: Wilson Van G. , Rosas-Acosta Germán
Published: September 2005

Sumoylation is a widespread posttranslational modification thought to affect primarily nuclear proteins, especially transcription factors for which sumoylation usually results in repression of their transactivational function. Recent proteomics studies have greatly expanded the cadre of known SUMO substrates, and an increasing number of cytoplasmic proteins have been identified as SUMO targets. However, very few of these cytosolic proteins have been evaluated for the functional consequences of sumoylation. Rajan
et al
. now demonstrate that the activity of an integral cytoplasmic membrane channel-forming protein, K2P1, is completely abrogated by sumoylation at a single lysine residue on the cytoplasmic tail. This is the first report of a plasma membrane protein as a SUMO substrate and explains the long-standing inability to demonstrate functionality of K2P1. Apparently, K2P1 is stoichiometrically sumoylated under most cellular conditions, so it is constitutively inactive until desumoylated. These observations raise several intriguing questions, including: How and where does K2P1 become sumoylated? Why, unlike most known substrates, is K2P1 so efficiently sumoylated? and, What are the signals and SUMO proteases that trigger K2P1 desumoylation? But most importantly, the report by Rajan
et al
. expands the functional roles attributed to sumoylation into the new arena of membrane protein functional regulation and suggests that similar mechanisms may regulate the function of other pore proteins.
Quantum Dot-Based Cell Motility Assay
Authors: Gu Weiwei , Pellegrino Teresa , Parak Wolfgang J. , Boudreau Rosanne , Le Gros Mark A. , Gerion Daniele , Alivisatos A. Paul , Larabell Carolyn A.
Published: September 2005

Because of their favorable physical and photochemical properties, colloidal CdSe/ZnS-semiconductor nanocrystals (commonly known as quantum dots) have enormous potential for use in biological imaging. In this report, we present an assay that uses quantum dots as markers to quantify cell motility. Cells that are seeded onto a homogeneous layer of quantum dots engulf and absorb the nanocrystals and, as a consequence, leave behind a fluorescence-free trail. By subsequently determining the ratio of cell area to fluorescence-free track area, we show that it is possible to differentiate between invasive and noninvasive cancer cells. Because this assay uses simple fluorescence detection, requires no significant data processing, and can be used in live-cell studies, it has the potential to be a powerful new tool for discriminating between invasive and noninvasive cancer cell lines or for studying cell signaling events involved in migration.
Sensory Systems: Taste Perception
Authors: Margolskee Robert F.
Published: September 2005

This Teaching Resource provides lecture notes and slides for a class covering the human taste system and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of five distinct qualities of taste and then proceeds to describe receptors and signaling mechanisms.
c-Src: Bridging the Gap Between Phosphorylation- and Acidification-Induced Gap Junction Channel Closure
Authors: Lau Alan F.
Published: September 2005

Gap junctions are a unique type of intercellular junction that mediate the direct exchange of small molecules between neighboring cells and play critical roles in the normal function of numerous organs. Mutations in the connexin proteins that make up gap junctions have been implicated in numerous human skin and neurosensory disorders. The ability of gap junctions to transmit molecules between cells is regulated by intracellular pH, the phosphorylation state of connexin, and the interaction of connexin with other cellular proteins. This Perspective focuses on the novel and complex events initiated by intracellular acidification resulting from tissue ischemia or hypoxia that lead to the interruption of intercellular communication between astrocytes. These events include alterations in connexin43 (Cx43) phosphorylation, disruption of β-actin binding to Cx43, and the induced interaction of Cx43 with the c-Src tyrosine kinase, extracellular signal-regulated kinase 1 and 2, and mitogen-activated protein kinase phosphatase 1.
That Which Does Not Kill You Makes You Stronger: A Molecular Mechanism for Preconditioning
Authors: McDunn Jonathan E. , Cobb J. Perren
Published: September 2005

Preconditioning by sublethal stress can protect a cell from subsequent injury and apoptosis through a mechanism that has been unclear. Many such stresses stimulate the formation of stress granules: transient cytoplasmic foci that contain heat shock protein as well as translationally stalled mRNA and various mRNA-binding proteins. Recent research suggests that sequestration in stress granules of TRAF2, an adaptor protein that is required for tumor necrosis factor receptor 1 signaling, may underlie preconditioning by sublethal stresses.
Natural Killer Cell Receptor Signaling Pathway
Authors: Vély Frédéric , Vivier Eric
Published: September 2005

NK (natural killer) cells are lymphocytes of the innate immune system that are involved in early defense mechanisms against foreign cells as well as autologous cells that are undergoing various forms of stress, such as microbial infection (viral, bacterial, or parasitic), tumor transformation, or nonmalignant activation. NK cell activation is controlled by a dynamic balance between complementary and antagonist pathways that are initiated when they bind a cell targeted for destruction. The Natural Killer Cell Signaling Pathway illustrates the signals produced by the activating cell surface receptors that initiate PTK (protein tyrosine kinase)-dependent pathways through their noncovalent association with transmembrane signaling adaptors that harbor ITAMs (immunoreceptor tyrosine-based activation motifs). This Connections Map also describes the mechanism by which these positive pathways are antagonized by intracytoplasmic PTPs (protein tyrosine phosphatases) that are activated upon engagement of cell surface receptors with intracytoplasmic ITIMs (immunoreceptor tyrosine-based inhibition motifs). The tyrosine phosphorylation status of several signaling components that are substrates for both PTKs and PTPs is thus key to the propagation of the NK cell effector pathways. Additional cell surface receptors that are not directly coupled to ITAMs also participate in NK cell activation, such as NKG2D (which is noncovalently associated with the DAP10 transmembrane signaling adaptor), adhesion molecules, and cytokine receptors. Understanding the integration of these signals into the "canonical" PTK-PTP equilibrium represents the future challenge for the elucidation of NK cell effector signaling pathways.
Natural Killer Cell Receptor Signaling Pathway in Mammals
Authors: Vély Frédéric , Vivier Eric
Published: September 2005

NK (natural killer) cells are large granular lymphocytes of the innate immune system. They are widespread throughout the body, being present in both lymphoid organs and nonlymphoid peripheral tissues. NK cells are involved in direct innate immune reactions against viruses, bacteria, parasites, and other triggers of pathology, such as malignant transformation, all of which cause stress in affected cells. Importantly, NK cells also link the innate and adaptive immune responses, contributing to the initiation of adaptive immune responses. NK cell responses are mediated through two major effector functions, the direct cytolysis of target cells and the production of cytokines and chemokines. We focus here on how recognition events are integrated to trigger distinct and graded effector functions.
β-Catenin, Cancer, and G Proteins: Not Just for Frizzleds Anymore
Authors: Malbon Craig C.
Published: September 2005

The lipid metabolite lysophosphatidic acid (LPA) mediates an impressive set of responses that includes morphogenesis, cell proliferation, cell survival, cell adhesion, and cell migration. LPA exerts its downstream signaling by binding to the LPA
1
, LPA
2
, and LPA
3
(formerly Edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors. LPA actions of therapeutic interest include effects on wound healing, atherogenesis, thrombogenesis, and, of course, cancer. LPA has been implicated in the progression of human breast, ovarian, prostate, head and neck, and colon malignancies. In view of these earlier observations, a recent report that LPA stimulates the proliferation of colon cancer–derived cell lines was greeted with great anticipation for its possible contribution to the unraveling of details of cancer signaling downstream of LPA. LPA was shown to stimulate nuclear accumulation of β-catenin in a manner that depended on activation of Gα
q
by LPA
2,3
, activation of phospholipase Cβ, activation of a conventional protein kinase C, and phosphorylation and inhibition of glycogen synthase kinase 3-β. The phosphorylation of β-catenin by this kinase marks the protein for intracellular degradation; LPA suppresses this degradation and stimulates β-catenin accumulation. β-catenin is a pivotal molecule in the control of cell cycle progression and gene expression, activating both processes in combination with lymphoid-enhancing factor/T cell–factor–sensitive transcription and inhibiting both processes in combination with FOXO transcription factors. The ability of LPA to increase the cytoplasmic and nuclear accumulation of β-catenin provides a new dimension of knowledge linking lipid mediators to the dysregulation of β-catenin signaling in cancer.
Interleukin-13 (IL-13) Pathway
Authors: Kelly-Welch Ann , Hanson Erica M. , Keegan Achsah D.
Published: September 2005

Interleukin-13 (IL-13), like IL-4, is a cytokine produced by T
H
2 type helper T cells in response to signaling through the T cell antigen receptor and by mast cells and basophils upon cross-linkage of the high-affinity receptor for immunoglobulin E (IgE). It is also produced by activated eosinophils. IL-13 induces many of the same responses as IL-4 and shares a receptor subunit with IL-4. IL-13 has been implicated in airway hypersensitivity and mucus hypersecretion, inflammatory bowel disease, and parasitic nematode expulsion.
Interleukin-4 (IL-4) Pathway
Authors: Kelly-Welch Ann , Hanson Erica M. , Keegan Achsah D.
Published: September 2005

Interleukin-4 (IL-4) is a cytokine produced by T
H
2 type helper T cells and by mast cells, basophils, and eosinophils. This cytokine can elicit many responses, some of which are associated with allergy and asthma. Studies with long-term cell lines and primary cells have revealed differences in the signaling between these two experimental systems. Understanding these differences is important because therapeutic strategies targeting IL-4 and its signaling pathways are currently being tested to treat allergy and asthma.
Adult Bone Marrow Stem/Progenitor Cells (MSCs) Are Preconditioned by Microenvironmental "Niches" in Culture: A Two-Stage Hypothesis for Regulation of MSC Fate
Authors: Gregory Carl A. , Ylostalo Joni , Prockop Darwin J.
Published: September 2005

Mesenchymal stem cells (MSCs) are clonal, plastic adherent cells from bone marrow that can differentiate into various tissue lineages, including osteoblasts, adipocytes, chondrocytes, myoblasts, hepatocytes, and possibly even neural cells. Because MSCs are multipotent and their numbers are easily expanded in culture, there has been much interest in their clinical potential for tissue repair and gene therapy. Consequently, numerous studies have been carried out demonstrating the migration and multiorgan engraftment potential of MSCs in animal models and in human clinical trials. Understanding the mechanisms behind MSC cell fate determination is not easy, because the molecular processes that drive engraftment and differentiation are complex. Even in an in vitro system, the molecular cues necessary to induce differentiation are not easily identified or reproduced. In this Perspective, we emphasize the importance of microenvironmental factors in culture and suggest that MSC differentiation in vitro is regulated by a two-stage mechanism involving preconditioning by factors in the culture microenvironment followed by response to soluble differentiating factors.
Focus Issue: Drug Discovery
Authors: Gough Nancy R.
Published: September 2005

This week’s issues of
Science
and
Science’
s
STKE
focus on issues related to the development of therapeutics, including new methods for identifying drug targets and the goal of personalized medicine based on an individual's genetics. STKE specifically looks at the roles the RNAi can play in the drug target identification process, how understanding the genetics behind disease can lead to new options for therapeutic intervention, and how analysis of the signaling network may provide insight for personalized medicine.
How Will RNAi Facilitate Drug Development?
Authors: Bartz Steven , Jackson Aimee L.
Published: September 2005

Development of effective drugs for treatment of human disease relies on identification of therapeutic molecular targets. The identification of targets to treat human disease has previously relied on genetic screens in model organisms, and less robust or lower throughput approaches in mammalian systems. RNA interference (RNAi) makes possible, for the first time, the use of large-scale functional genomics approaches for target identification in human cells. This remarkable breakthrough has the potential to influence every facet of the drug discovery process, and is poised to revolutionize drug development. Reports of RNAi screens for the identification of novel genes implicated in apoptosis, cell division, and drug resistance support the enormous promise of this technology. Here, we discuss the potential impact of RNAi screens on target identification and validation and consider issues that warrant caution when interpreting RNAi screening results.
Embracing Complexity, Inching Closer to Reality
Authors: Schadt Eric E. , Sachs Alan , Friend Stephen
Published: September 2005

Drugs designed against targets in presumably simple linear signaling pathways found to be associated with disease are often less effective than predicted. One reason for this is the overly simplistic view of the molecular mechanisms underlying common human diseases. This viewpoint is a consequence of biological reductionism, brought about by the need to form a basic understanding of the fundamental attributes of biological systems and by limitations in the set of tools available for analysis of biological systems. However, complex biological systems are best modeled as highly modular, fluid systems exhibiting a plasticity that allows them to adapt to a vast array of conditions. Historically, this viewpoint has long represented the ideal, but the tools needed to examine and describe this complexity were often lacking. Here we argue that the tools of biological science now allow for a more network-oriented view of biological systems and for explaining the underlying causes of disease, as well as the best ways to target disease. Ultimately, this will help to ensure that the right drug is administered to the right patient at the right time. Focusing on well-studied signaling pathways, refining the definition of disease, and identifying disease subtypes, we demonstrate a more holistic approach to elucidating common human diseases, with the potential to revolutionize treatment of these diseases.
14-3-3 Proteins: A Number of Functions for a Numbered Protein
Authors: Bridges Dave , Moorhead Greg B. G.
Published: September 2005

Many signal transduction events are orchestrated by specific interactions of proteins mediated through discrete phosphopeptide-binding motifs. Although several phosphospecific-binding domains are now known, 14-3-3s were the first proteins recognized to specifically bind a discrete phosphoserine or phosphothreonine motif. The 14-3-3 proteins are a family of ubiquitously expressed, exclusively eukaryotic proteins with an astonishingly large number of binding partners. Consequently, 14-3-3s modulate an enormous and diverse group of cellular processes. The effects of 14-3-3 proteins on their targets can be broadly defined using three categories: (i) conformational change; (ii) physical occlusion of sequence-specific or structural protein features; and (iii) scaffolding. This review will describe the current state of knowledge on 14-3-3 proteins, highlighting several important advances, and will attempt to provide a framework by which 14-3-3 functions can be understood.
Slowing Down the Ras Lane: miRNAs as Tumor Suppressors?
Authors: Morris John P. , McManus Michael T.
Published: September 2005

MicroRNAs (miRNAs) are small noncoding transcripts that regulate gene expression by promoting the degradation of transcribed messages or by inhibiting translation. Although bioinformatic approaches suggest that miRNAs may regulate the expression of a large fraction of the genome, the determination of miRNA gene targets and biological functions has been comparatively limited. Emerging studies suggest that many miRNAs may participate in human disease, including oncogenesis; but for the most part, the observations have been correlative. A recent study by Johnson and colleagues indicates that the
let-7
miRNA negatively regulates the oncogenic family of Ras guanosine triphosphatases in both
Caenorhabditis elegans
and human tumor cell lines, suggesting that
let-7
may act as a tumor suppressor. This work raises several important questions: Can other miRNAs act as tumor suppressors or oncogenes? Is miRNA deregulation a critical aspect of tumor development and maintenance? A number of recent studies have begun to address some of these functional questions, providing the field with a greater understanding of the role of miRNAs in cancer.
Regulation of Ion Channels by G Proteins
Authors: Diversé-Pierluissi María
Published: September 2005

This Teaching Resource provides lecture notes and slides for a class covering regulation of ion channels by G proteins and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with an overview of calcium channels and then proceeds to describe the interaction of signaling molecules with calcium channels.
Robust Enrichment of Phosphorylated Species in Complex Mixtures by Sequential Protein and Peptide Metal-Affinity Chromatography and Analysis by Tandem Mass Spectrometry
Authors: Collins Mark O. , Yu Lu , Husi Holger , Blackstock Walter P. , Choudhary Jyoti S. , Grant Seth G. N.
Published: September 2005

Reversible protein phosphorylation mediated by kinases, phosphatases, and regulatory molecules is an essential mechanism of signal transduction in living cells. Although phosphorylation is the most intensively studied of the several hundred known posttranslational modifications on proteins, until recently the rate of identification of phosphorylation sites has remained low. The use of tandem mass spectrometry has greatly accelerated the identification of phosphorylation sites, although progress was limited by difficulties in phosphoresidue enrichment techniques. We have improved upon existing immobilized metal-affinity chromatography (IMAC) techniques for capturing phosphopeptides, to selectively purify phosphoproteins from complex mixtures. Combinations of phosphoprotein and phosphopeptide enrichment were more effective than current single phosphopeptide purification approaches. We have also implemented iterative mass spectrometry-based scanning techniques to improve detection of phosphorylated peptides in these enriched samples. Here, we provide detailed instructions for implementing and validating these methods together with analysis by tandem mass spectrometry for the study of phosphorylation at the mammalian synapse. This strategy should be widely applicable to the characterization of protein phosphorylation in diverse tissues, organelles, and in cell culture.
An Interactive Course in Nuclear Receptor Signaling: Concepts and Models
Authors: McKenna Neil J. , O'Malley Bert W.
Published: September 2005

This interactive online course sketches some of the landmark studies and discoveries in the field of nuclear receptors since the field's inception. Although the course is primarily focused at advanced life sciences students and scientists from other disciplines wishing to become acquainted with the field, it is likely to also be a useful resource for anyone associated with the discipline of nuclear receptor signaling. This animated course was created by members of the Nuclear Receptor Signaling Atlas (NURSA;
www.nursa.org
), which is an NIH-funded research consortium formed with the aim of providing a repository of nuclear receptor-related data for use of the scientific community.
Mesodermal Differentiation: Signal Integration During Development
Authors: Weinstein Daniel C.
Published: September 2005

This Teaching Resource provides a summary and slides derived from a lecture on the signaling cascades that mediate early embryogenesis and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture focuses on the mechanisms underlying germ layer formation, patterning, and suppression in the vertebrate embryo, with particular emphasis on the regulation of mesodermal development in the model organism
Xenopus laevis
.
Focus Issue: RNA, A Multifunctional Molecule
Authors: Gough Nancy R. , Adler Elizabeth M.
Published: September 2005

This week’s issues of
Science, Science’
s STKE, and SAGE KE (
www.sciencemag.org/sciext/rna/
) focus on the increasing complexity that RNA brings to cellular biology. STKE resources include Reviews, Perspectives, and Teaching Resources. STKE specifically looks at the roles for small RNAs in regulation of gene expression and how mRNAs can be selectively activated from cytoplasmic macromolecular structures, RNA granules, to contribute to such processes as synaptic plasticity.
MicroRNA-Dependent Trans-Acting siRNA Production
Authors: Vaucheret Hervé
Published: September 2005

Less than a year has elapsed between the discovery of trans-acting small interfering RNAs (tasiRNAs) in plants and the elucidation of the major steps of the corresponding pathway. During tasiRNA biogenesis, polyadenylated RNAs transcribed from non–protein-coding
TAS
genes are cleaved by a microRNA (miRNA)–programmed RNA-induced silencing complex. In contrast to classical miRNA targets, RDR6 and SGS3 convert one of the
TAS
RNA cleavage products into double-stranded RNA, which is subsequently processed, in a phase determined by the initial miRNA cleavage site, by DICER-LIKE 4 to generate a 21-nucleotide tasiRNA population. tasiRNAs guide endogenous mRNA cleavage through the action of AGO1 or, perhaps in some cases, AGO7. Some of the tasiRNA targets probably regulate the juvenile-to-adult phase transition, but the roles of other tasiRNA targets remain to be determined.
Can You Hear Me Now? Regulating Transcriptional Activators by Phosphorylation
Authors: Gardner Kevin H. , Montminy Marc
Published: September 2005

Extracellular signals often modulate the expression of specific genetic programs by triggering the phosphorylation of relevant transcription factors (TFs). Phosphorylation in turn regulates such TFs by altering their cellular localization, DNA binding affinity, or transcriptional activity. Structural approaches have revealed how phosphorylation turns some TFs on or off; but less is known about how phosphorylation regulates other transcription factors in a graded manner that depends on signal intensity. A recent paper by Graves and colleagues reveals how a group of phosphorylation sites in Ets-1 regulates its DNA binding activity. Their studies provide new insight into the importance of multisite phosphorylation for the graded regulation of transcription and highlight the involvement of allosteric mechanisms in this process.
Learning the Chemical Language of Cell-Surface Interactions
Authors: Groves Jay T.
Published: September 2005

Harvesting, training, and domesticating living organisms to apply their intrinsic capabilities to desired applications is one of the most fundamental of human accomplishments. Extending this concept to the cellular level requires precise control of the chemical interface between live cells and synthetic materials. One great challenge is to progress from empirically surveying cellular behaviors to the predictive design of synthetic substrates that communicate specific signals to cells. This requires a detailed understanding of cell signaling mechanisms as well as the ability to synthesize hybrid materials that incorporate biological molecules in precisely defined ways. A number of promising advances in the development of synthetic interfaces with cells suggest that the move to predictive design is under way.