bluuebunny/crossref_metadata_2025 huggingface dataset:
Beamformer performance with acoustic vector sensors in air
Authors: Lockwood Michael E. , Jones Douglas L.
Published: January 2006

For some time, compact acoustic vector sensors (AVSs) capable of sensing particle velocity in three orthogonal directions have been used in underwater acoustic sensing applications. Potential advantages of using AVSs in air include substantial noise reduction with a very small aperture and few channels. For this study, a four-microphone array approximating a small (1cm3) AVS in air was constructed using three gradient microphones and one omnidirectional microphone. This study evaluates the signal extraction performance of one nonadaptive and four adaptive beamforming algorithms. Test signals, consisting of two to five speech sources, were processed with each algorithm, and the signal extraction performance was quantified by calculating the signal-to-noise ratio (SNR) of the output. For a three-microphone array, robust and nonrobust versions of a frequency-domain minimum-variance (FMV) distortionless-response beamformer produced SNR improvements of 11to14dB, and a generalized sidelobe canceller (GSC) produced improvements of 5.5to8.5dB. In comparison, a two-microphone omnidirectional array with a spacing of 15cm yielded slightly lower SNR improvements for similar multi-interferer speech signals.
A study of the influence of mounting conditions on the measured sound absorption in laboratory tests of suspended ceilings
Authors: de Godoy Marcelo , Barry Peter J. , Bistafa Sylvio R.
Published: January 2006

This letter presents the results of an investigation into the influence of mounting conditions on the measured sound absorption coefficients of a suspended ceiling specimen. A series of measurements and analyses were carried out using a fixed standard sample, varying independently different mounting parameters and introducing controlled leaks. A correction of room volume in the calculation of the sound absorption coefficients was also examined. The tests were carried out in accordance with the ISO 354:2003 standard (International Organisation for Standardisation, Geneva, 2003), using the type E mounting. The test specimen consisted of fiberglass wool panels covered with a plastic film. Some of the experiments resulted in no statistically significant alteration. This included, unexpectedly, the sealing requirements of E type mountings.
Differentiation of speech and nonspeech processing within primary auditory cortex
Authors: Whalen D. H. , Benson Randall R. , Richardson Matthew , Swainson Brook , Clark Vincent P. , Lai Song , Mencl W. Einar , Fulbright Robert K. , Constable R. Todd , Liberman Alvin M.
Published: January 2006

Primary auditory cortex (PAC), located in Heschl’s gyrus (HG), is the earliest cortical level at which sounds are processed. Standard theories of speech perception assume that signal components are given a representation in PAC which are then matched to speech templates in auditory association cortex. An alternative holds that speech activates a specialized system in cortex that does not use the primitives of PAC. Functional magnetic resonance imaging revealed different brain activation patterns in listening to speech and nonspeech sounds across different levels of complexity. Sensitivity to speech was observed in association cortex, as expected. Further, activation in HG increased with increasing levels of complexity with added fundamentals for both nonspeech and speech stimuli, but only for nonspeech when separate sources (release bursts∕fricative noises or their nonspeech analogs) were added. These results are consistent with the existence of a specialized speech system which bypasses more typical processes at the earliest cortical level.
Auditory-nerve first-spike latency and auditory absolute threshold: A computer model
Authors: Meddis Ray
Published: January 2006

A computer model of the auditory periphery was used to address the question of what constitutes the physiological substrate of absolute auditory threshold. The model was first evaluated to show that it is consistent with experimental findings that auditory-nerve fiber spikes can be predicted to occur when the running integral of stimulus pressure reaches some critical value [P. Heil and H. Neubauer, J. Neurosci. 15, 7404–7415 (2001)]. It was then modified to examine two ways in which the accumulation and clearance of receptor presynaptic calcium might explain this effect. Both methods gave results that matched the animal data. It was also shown how the rate of clearance of presynaptic calcium could be used to explain the origin of differences between low and high spontaneous-rate fiber types. When spiking activity is aggregated across a number of similar high spontaneous-rate fibers and used as the input to a model of a cochlear nucleus coincidence neuron, its response can be used to judge whether or not a stimulus is present. A simulated psychophysical experiment then demonstrated that this simple decision procedure can reproduce measurements of absolute auditory threshold for tones in quiet where the threshold is a joint function of both time and level.
Ternary and quadriphase sequence diffusers
Authors: Cox Trevor J. , Angus James A. S. , D'Antonio Peter
Published: January 2006

A room acoustic diffuser breaks up reflected wavefronts, and this can be achieved by presenting a spatially varying surface impedance. In hybrid surfaces, varying impedance is achieved by patches of absorption and reflection, giving reflection coefficients nominally of 0 and 1. These surfaces are hybrids, absorbing some of the incident sound while diffusing any reflected energy. A problem with planar hybrid surfaces is that specular energy is only removed by absorption. By exploiting interference, by reflecting waves out-of-phase with the specular energy, it is possible to diminish the specular energy further. This can be achieved by using a diffuser based on a ternary sequence that nominally has reflection coefficients of 0, −1, and +1. Ternary sequences are therefore a way of forming hybrid absorber-diffusers that achieve better scattering performance without additional absorption. This paper discusses methods for making ternary sequence diffusers, including giving sequence generation methods. It presents prediction results based on Fourier and boundary element method models to examine the performance. While ternary diffusers have better performance than unipolar binary diffusers at most frequencies, there are frequencies at which the performances are the same. This can be overcome by forming diffusers from four-level, quadriphase sequences.
Two Ways About It
Authors: Davenport R. John
Published: December 2005

The fast lane or the slow lane will eventually get you to the same place. Similarly, neurons can die quickly or slowly after a stroke, and new work reveals two different proteins that control which route a cell takes. The study clarifies the mechanisms that obliterate neurons and suggests a new target for drug designers.
Plumbing Problem
Authors: Leslie Mitch
Published: December 2005

For some patients, obesity could be a matter of bad drainage, a new study suggests. The work shows that mice with defective lymphatic systems amass fat. The results suggest a possible explanation for some cases of human obesity.
Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases
Authors: Lashuel Hilal A.
Published: December 2005

Protein aggregation--and, more specifically, amyloid fibril formation--has been implicated as a primary cause of neurodegeneration in Alzheimer's disease, Parkinson's disease, and related disorders, but the mechanism by which this process triggers neuronal death is unknown. Mounting evidence from in vitro studies, cell culture, and animal models of these diseases supports the hypothesis that a structural intermediate on the pathway to fibril formation, rather than amyloid fibrils themselves, may be the pathogenic species. Characterization of these intermediates in solution or upon interactions with membranes indicate that these intermediates form pores and suggests that neurons could be killed by unregulated membrane permeabilization caused by such "amyloid pores."
Appetite Suppressant
Authors: Leslie Mitch
Published: December 2005

The protein Bcl-2 performs cellular interventions, preventing hard-pressed cells from killing themselves. New research shows that this molecular rescuer also stops cells from gobbling their own contents. The work clarifies how hungry cells control recycling of their raw materials.
Battle of the Sexes
Authors: Davenport R. John
Published: December 2005

A henpecked husband might gripe that his wife's nagging is taking years off his life. But in bean weevils at least, one sex can stretch rather than shorten the other's life span, according to new work. In the beetles, selecting males to delay breeding extends the longevity of females with whom they mate. The study provides new insight into the evolutionary forces that alter aging rates.
From Bedside to Bench: Research in Comorbidity and Aging
Authors: Wieland G. Darryl
Published: December 2005

As their patients age, clinicians are increasingly confronted with diseases, impairments, or conditions that complicate the diagnosis and treatment of index diseases and with the management challenge of the overall burden of morbidity in their patients. Nevertheless, there has been little applicable conceptual work and empirical research on the nature, impact, and management of comorbid and multiple morbid conditions. Advancing research in this area has been the goal of a recent National Institute on Aging Task Force on Comorbidity Research Issues, as well as a working conference of the American Geriatrics Society. Both efforts highlighted current knowledge and thinking about comorbidity in the context of caring for an aging population, in preparation for research ultimately leading to better understanding of comorbidity and improvement in clinical practice. This Perspective provides a brief overview of these developments.
Turning Back the Clock
Authors: Davenport R. John
Published: December 2005

It could be a fountain of youth--for the already young. A spate of papers published over the last several months reveals that a type of tumor-shrinking drug also corrects flaws in cells of children with progeria, a disease that resembles accelerated aging. However, further tests on animals are necessary before researchers can embark on clinical trials.
Cut the Fat
Authors: Leslie Mitch
Published: December 2005

Fat not only spoils our figures and jams our arteries, but it can also stick to and mar DNA. A new study reports that bacteria tackle this problem by deploying an enzyme that snips off the fatty bits. The work hints that similar enzymes help fend off cancer by tidying our DNA.
Revising the Standard Wisdom of
C. elegans
Natural History: Ecology of Longevity
Authors: Caswell-Chen E. P. , Chen J. , Lewis E. E. , Douhan G. W. , Nadler S. A. , Carey J. R.
Published: December 2005

Here, we consider that most of the research concerning
Caenorhabditis elegans
has been laboratory focused and that only limited research has directly considered the worm's biology relative to its natural history in the wild. We describe that, although the worm has traditionally been considered a soil nematode, we could not find it in soil but frequently recovered it from snails. Finally, we discuss how a better understanding of the natural history of
C. elegans
may enhance its usefulness as a model organism for studying aging and other phenomena.
Fatal Hunger
Authors: Leslie Mitch
Published: December 2005

The ovaries are cradles of life, but they are also chambers of death. Droves of egg cells commit suicide there during a woman's life. The cells might off themselves because they run out of food, according to a new study. The work could inspire new treatments for age-related infertility.
C. elegans
Gives the Dirt on Aging
Authors: Hertweck Maren
Published: December 2005

The worm
Caenorhabditis elegans
has become a popular model organism for the study of mechanisms involved in aging. The
C. elegans
life span is controlled by several pathways that have been extensively characterized at the molecular level. These include pathways that regulate metabolism and development (namely, the insulin/IGF-1 pathway), nutrition, mitochondrial activity, and reproduction. Presentations at a recent
C. elegans
conference add to the growing body of knowledge about the genetic networks that control the complex process of aging and suggest new avenues for further investigations.
Caught With Their Proboscises in the Sugar Water
Authors: Leslie Mitch
Published: December 2005

Like people who sneak downstairs at midnight for a slice of cake, calorie-restricted flies cheat on their diets. The hungry bugs lap up more food than scientists thought, according to a new study. The authors argue that researchers need to take a closer look at the animals' dining habits.
Trapped Inside
Authors: Leslie Mitch
Published: December 2005

It's a familiar-sounding scenario: Pumps that are the last defense against a rising tide falter, leading to a toxic buildup. It happened in New Orleans, compounding the damage from Hurricane Katrina, and it might also occur in Alzheimer's disease (AD). A new study suggests that disabling a protein that shuttles molecules out of the brain promotes the accumulation of noxious AD-associated plaques. Drugs that accelerate pumping might protect against the illness, the results suggest.
Neurochemical Insights
Authors: Treiber Carina
Published: December 2005

The 20th biennial meeting of the International Society for Neurochemistry was recently held in Innsbruck, Austria. This meeting gave an overview of the latest findings in the field of molecular mechanisms and diagnosis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion disease. There was a focus on the molecular pathogenesis of protein misfolding in these disorders as well as on the association between oxidative metabolism and neurological diseases. RNA interference, metal chelators, and the use of metallopeptidases were discussed as possible therapeutic strategies.
Drug Bust
Authors: Leslie Mitch
Published: December 2005

The nightly news might not show handcuffed doctors marching off to jail any time soon. But the widespread use of growth hormone to fight aging breaks the law, warns a group of researchers--plus it relies on shaky science.
Developing a Research Agenda in Biogerontology: Basic Mechanisms
Authors: Warner Huber R.
Published: December 2005

The National Institute on Aging (NIA) began operation in 1975, splitting off from the National Institute of Child Health and Human Development. The first 10 years of NIA's existence were characterized by funding descriptive and discovery research, as the field by then had not come of age. With the isolation of long-lived animal mutants and the application of the tools of molecular biology (including whole-genome sequencing) and transgenic technology to biogerontology research, the situation has changed dramatically since then, and aging-related research has become increasingly mechanistic and respectable. This transition has been aided by research initiatives implemented by NIA staff, and the goal of this article is to describe how NIA develops such research initiatives using research progress made in biogerontology over the past 20 years as the basis for the discussion.
Keeping Priorities: The Role of Working Memory and Selective Attention in Cognitive Aging
Authors: de Fockert Jan W.
Published: December 2005

Cognitive aging is associated with impairments to working memory and top-down control in selective attention, two components of cognitive control associated with the frontal lobes. Recent findings indicate that working memory and selective attention may be interdependent, making a better understanding of their involvement in cognitive aging particularly challenging. A paper in a recent issue of
Nature Neuroscience
has provided evidence that a reduction in the ability to keep a clear distinction between information to be stored in working memory and information that should be ignored and subsequently suppressed is associated with poor working memory performance. These results are in line with previous evidence for a specific age-related impairment in the ability to separate irrelevant from relevant information and may be able to explain a range of age-related cognitive changes.
Shortchanged by Sir2
Authors: Leslie Mitch
Published: December 2005

Sir2 giveth and Sir2 taketh away. The yeast protein and its relatives in other organisms stretch longevity, previous studies have found. But new work suggests that, under harsh conditions, Sir2 impedes yeast survival.
Mitochondrial Dynamics in Cell Life and Death
Authors: Scheckhuber Christian
Published: December 2005

Mitochondria are dynamic organelles that are able to change their morphology during cellular development and to meet the energetic needs of the cell, for example. During the past several years, knowledge about the molecular machinery involved in the control of mitochondrial shape has improved considerably. In August 2005, leading researchers in the field of mitochondrial dynamics met at the Venetian Institute of Molecular Medicine in Padova, Italy, to discuss novel and intriguing findings presented at the first workshop on "Mitochondrial Dynamics in Cell Life and Death." Some of the findings related to apoptosis and aging are described in this Perspective.
Down With p53!
Authors: Leslie Mitch
Published: December 2005

Tampering with a cancer-preventing protein sounds like a prescription for early death. But fruit flies last longer if researchers cut the protein's activity in the bugs' neurons, according to new research. The findings suggest that hampering a protein called p53 in particular tissues might slow aging.
T Cell Immunity and Aging
Authors: Koch Sven Dominik , Kempf Juergen , Pawelec Graham
Published: December 2005

The effect of age on the immune system is generally detrimental and results in "immunosenescence," a poorly-defined state inadequately reflected in clinical data and for which few reliable "biomarkers of aging" are available. The multinational consortium "T-Cell Immunity in Ageing," T-CIA, was set up to examine these issues specifically as applied to T lymphocytes. This Perspective discusses some of the outcomes of a recent conference that considered progress toward resolving these questions in humans.
Living Longer and Paying the Price?
Authors: Trojanowski John Q. , Jedrziewski M. Kathryn , Asch David A.
Published: December 2005

Over the past century, there have been tremendous increases in longevity in the United States and most other developed countries. If these trends continue, the costs of paying for public programs like Social Security, Medicare, and Medicaid will escalate at a startling rate with the aging of the "baby boomer" generation. A meeting titled "Living Longer and Paying the Price?" was organized to consider whether current trends in longevity will continue at the current pace, accelerate, or decelerate as a result of public health problems such as obesity and infectious diseases. Further, speakers presented their views on covering the costs of public and private programs for future generations of older adults.
Harnessing Hormonal Signaling for Cardioprotection
Authors: Ballard Victoria L. , Edelberg Jay M.
Published: December 2005

Cardiovascular disease is the leading cause of death in women in the Western world and is predominant among the elderly. A large body of evidence suggests that hormonal signaling plays a critical role in the regulation of cardioprotective mechanisms, as premenopausal women are at significantly lower risk of heart disease compared with men, but the risk greatly increases with the onset of menopause. This association indicates that estrogen may protect the heart from cardiovascular disease. Whereas a number of analyses of the effects of hormone replacement therapy (HRT) on postmenopausal women supported the idea that estrogen is a cardioprotective factor, the findings of the more recent Women's Health Initiative (WHI) study suggested that HRT may actually increase the risk of cardiovascular events. These conflicting reports have left both patients and clinicians reluctant to continue using current HRT regimes. The WHI findings do not, however, negate the epidemiological link between menopause and increased cardiovascular risk. Hence, the identification of the specific actions of estrogen that promote cardioprotective pathways without enhancing deleterious vascular mechanisms may provide novel estrogen-based alternatives to current HRT strategies. In this Review, we outline the known actions of estrogen on the cardiovascular system, focusing on cardioprotective mechanisms that may be targeted for the development of new therapeutic approaches.
Response to Comment on "A Hydrogen-Rich Early Earth Atmosphere"
Authors: Tian Feng , Toon Owen B. , Pavlov Alexander A.
Published: January 2006

Catling speculates that the exobase of early Earth was hot and that the ancient nonthermal escape rate was more than 1000 times the present rate. However, low oxygen and high carbon dioxide on early Earth yields a cold exobase, and nonthermal escape rates are limited and cannot balance the volcanic outgassing of hydrogen.
Steps to the Light Fantastic
Authors: Webb Colin
Published: January 2006

Beam
. The Race to Make the Laser.
By Jeff Hecht
. Oxford University Press, New York, 2005. 284 pp. $29.95, £18.50. ISBN 0-19-514210-1.

Building on recent memoirs and his own extensive research, the author provides a balanced account of the race to develop the laser and assesses the conflicting claims surrounding the invention.
Seven-Transmembrane Receptor Signaling Through β-Arrestin
Authors: Shenoy Sudha K. , Lefkowitz Robert J.
Published: December 2005

Cell surface receptors are important communicators of external stimuli to the cell interior where they lead to initiation of various signaling pathways and cellular responses. The largest receptor family is the seven-transmembrane receptor (7TMR) family, with approximately 1000 coding genes in the human genome. When 7TMRs are stimulated with agonists, they activate heterotrimeric guanine nucleotide-binding proteins (G proteins), leading to the production of signaling second messengers, such as adenosine 3′,5′-monophosphate, inositol phosphates, and others. Activated receptors are rapidly phosphorylated on serine and threonine residues by specialized enzymes called G protein–coupled receptor kinases. Phosphorylated receptors bind the multifunctional adaptor proteins β-arrestin1 and β-arrestin2 with high affinity. β-arrestin binding blocks further G protein coupling, leading to "desensitization" of G protein–dependent signaling pathways. For several years, this was considered the sole function of β-arrestins. However, novel functions of β-arrestins have been discovered. β-arrestins are now designated as important adaptors that link receptors to the clathrin-dependent pathway of internalization. β-arrestins bind and direct the activity of several nonreceptor tyrosine kinases in response to 7TMR stimulation. β-arrestins also bind and scaffold members of such signaling cascades as the mitogen-activated protein kinases (MAPKs). β-arrestins are crucial components in 7TMR signaling leading to cellular responses that include cell survival and chemotaxis. β-arrestins act as endocytic adaptors and signal mediators not only for the 7TMRs, but also for several receptor tyrosine kinases.
Evaluation of Selective Prostaglandin E2(PGE2) Receptor Agonists as Therapeutic Agents for the Treatment of Asthma
Authors: Chung K. F.
Published: December 2005

Prostaglandin E2(PGE2) released in asthmatic airways has bronchodilator properties and inhibits allergen-induced bronchoconstriction and release of inflammatory mediators. Although considered as a potential treatment for asthma, PGE2also has some proinflammatory properties. PGE2acts through four different receptor subtypes (EP1, EP2, EP3, and EP4) that may explain some of PGE2’s diverse effects. In a mouse model of allergic inflammation in which the four receptors were individually deleted, only EP3−/−mice showed an enhancement of inflammation, whereas an EP3 agonist was inhibitory, with PGE2being inactive. Thus, EP3 agonists may lead to a new approach for the treatment of asthma. However, other PGE2receptor subtypes may also have beneficial effects, and a greater understanding of the signaling pathways of these receptor subtypes will help to clarify the role of these receptors in asthma.
Shaky Ground for Lysosome-Dependent Membrane Repair
Authors: Steinhardt Richard A.
Published: December 2005

Richard Steinhardt comments on the Perspective by Andrews entitled
"Membrane Resealing: Synaptotagmin VII Keeps Running the Show."
Response to "Shaky Ground for Lysosome-Dependent Membrane Repair"
Authors: Andrews Norma W.
Published: December 2005

Norma Andrews responds to a letter by Richard Steinhardt about views presented in her STKE Perspective entitled "Membrane Resealing: Synaptotagmin VII Keeps Running the Show."
Intracellular Glucocorticoid Signaling: A Formerly Simple System Turns Stochastic
Authors: Chrousos George P. , Kino Tomoshige
Published: December 2005

Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. The major roles of these steroids in physiology are amply matched by their remarkable contributions to pathology. Glucocorticoids influence about 20% of the expressed human genome, and their effects spare almost no organs or tissues. For many years we thought that the numerous actions of glucocorticoids were mediated by a single receptor molecule: the classic glucocorticoid receptor (GR) isoform α, a complex, multifunctional domain protein, operating as a ligand-dependent transcription factor. The GR gene, however, encodes two 3′ splicing variants, GRα and GRβ, from alternative use of two distinct terminal exons (9α and 9β), and each variant mRNA is translated from at least eight initiation sites into multiple GRα and possibly GRβ isoforms, amounting to a minimum of 16 GR monomers and 256 different homo- or heterodimers. The translational GRα isoforms may be produced variably in target tissues, have varying intrinsic transcriptional activities, and influence different complements of glucocorticoid-responsive genes. It is likely that expression and functional differences might also be present between the putative GRβ translational isoforms. The presence of multiple GR monomers and dimers in different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic.
SLIM Trims STATs: Ubiquitin E3 Ligases Provide Insights for Specificity in the Regulation of Cytokine Signaling
Authors: Ungureanu Daniela , Silvennoinen Olli
Published: December 2005

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has evolved to serve highly specialized functions in the regulation of hematopoiesis, cell metabolism, and immune responses. The duration, strength, and specificity of cytokine signaling are controlled by several mechanisms, including the ubiquitin-proteasome pathway, which modulates the turnover of cytokine receptors and activated JAKs. The specificity of the ubiquitin pathway is achieved through various E3 ligase complexes that recognize and interact with distinct target proteins, often in a phosphorylation-dependent manner. Intriguing new information about the ubiquitin pathway came with the identification of an E3 ubiquitin ligase, SLIM, that specifically interacts with activated STAT1 and STAT4 and induces their ubiquitination and degradation. These findings, together with the evidence from paramyxoviruses about the role of ubiquitination as a highly specific STAT inhibition mechanism, highlight the role of E3 ubiquitin ligases as specificity determinants in the regulation of STAT activation, and open the field for investigation of additional E3s that target other STAT proteins.
Cell Signaling: From Beginning to End
Authors: Gough Nancy R. , Adler Elizabeth M. , Ray L. Bryan
Published: December 2005

The Connections Maps database and the graphical Web interface at
Science's
STKE for accessing the data represent an emerging Web-based tool through which researchers in cell signaling can share their knowledge with the scientific community. This tool provides a mechanism by which researchers, students, and clinicians can transform information about interactions between biomolecules into knowledge about a cellular process. In 2005, new Pathways were added to the Connections Maps database and several of the existing Pathways were updated.
Integration of Oxygen Signaling at the Consensus HRE
Authors: Wenger Roland H. , Stiehl Daniel P. , Camenisch Gieri
Published: December 2005

The hypoxia-inducible factor 1 (HIF-1) was initially identified as a transcription factor that regulated erythropoietin gene expression in response to a decrease in oxygen availability in kidney tissue. Subsequently, a family of oxygen-dependent protein hydroxylases was found to regulate the abundance and activity of three oxygen-sensitive HIFα subunits, which, as part of the HIF heterodimer, regulated the transcription of at least 70 different effector genes. In addition to responding to a decrease in tissue oxygenation, HIF is proactively induced, even under normoxic conditions, in response to stimuli that lead to cell growth, ultimately leading to higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli–activated signaling pathways that influence the abundance and activity of HIFs include pathways in which kinases are activated and pathways in which reactive oxygen species are liberated. These pathways signal to the HIF protein hydroxylases, as well as to HIF itself, by means of covalent or redox modifications and protein-protein interactions. The final point of integration of all of these pathways is the hypoxia-response element (HRE) of effector genes. Here, we provide comprehensive compilations of the known growth stimuli that promote increases in HIF abundance, of protein-protein interactions involving HIF, and of the known HIF effector genes. The consensus HRE derived from a comparison of the HREs of these HIF effectors will be useful for identification of novel HIF target genes, design of oxygen-regulated gene therapy, and prediction of effects of future drugs targeting the HIF system.
Electrifying Phosphatases
Authors: Horn Richard
Published: December 2005

Ci-VSP, a recently described protein with sequence similarity to both the voltage-sensing domain of a voltage-gated potassium channel and the phosphatase PTEN, functions as a transmembrane phosphoinositide phosphatase that is regulated by changes in voltage across the plasma membrane. Ci-VSP dephosphorylated phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P
3
] in vitro, exhibited capacitative currents that resembled ion channel gating currents, and, when coexpressed with potassium channels that are regulated by PtdIns(4,5)P
2
, conferred sensitivity of potassium current amplitude to prolonged changes in membrane potential. How the voltage-sensing (VS) domain of Ci-VSP communicates with the phosphatase domain, and how the VS domain moves its charges across the membrane electric field in the absence of a transmembrane pore domain, remain to be determined.
G Protein Signaling in the Regulation of
Arabidopsis
Seed Germination
Authors: Assmann Sarah M.
Published: December 2005

Seed germination and early seedling growth are regulated by an intricate network of hormonal signaling pathways. The plant hormones gibberellic acid (GA) and brassinosteroids (BRs) are important positive regulators of these processes, whereas the hormone abscisic acid (ABA) is a potent negative regulator. In
Arabidopsis
, analysis of mutant plants has implicated heterotrimeric guanine nucleotide-binding protein (G protein) components in regulation of seed germination by all three of these hormones.
Focus Issue: Memories of Signals Past—Plastic Changes in Nervous System Function
Authors: Adler Elizabeth M. , Gough Nancy R.
Published: December 2005

Plasticity encompasses the ability of the nervous system to adapt to injury and the ability of the developing and mature brain to change in response to experience. This week's Special Issue of
Science
focuses on systems-level approaches to understanding cortical plasticity, especially during development. The accompanying Focus Issue of
Science's STKE
features articles and resources that address issues related to the molecular changes that underlie synaptic plasticity in response to physiological or pathological stimuli.
Endocannabinoid Identification in the Brain: Studies of Breakdown Lead to Breakthrough, and There May Be NO Hope
Authors: Alger Bradley E.
Published: December 2005

Endocannabinoids are a class of fatty acid derivatives defined by their ability to interact with the specific cannabinoid receptors that were originally identified as the targets of Δ
9
-tetrahydocannabinol (Δ
9
-THC), the psychoactive component of cannabis. Endocannabinoids have been implicated in a growing number of important physiological and behavioral events. A full understanding of the functions of endocannabinoids will involve knowing which ones are active, and how they are produced, during any given physical event. However, studying these small lipids in the brain presents many technical challenges. New selective pharmacological tools promise to be very useful in unraveling the complexities of endocannabinoid signaling, but parallel developments from the investigation of the cellular neurophysiology of the endocannabinoid systems highlight the difficulties remaining.
Hijacking the ERK Signaling Pathway:
Mycobacterium leprae
Shuns MEK to Drive the Proliferation of Infected Schwann cells
Authors: Noon Luke A. , Lloyd Alison C.
Published: December 2005

Schwann cells are the target of
Mycobacterium leprae
, the pathogen responsible for leprosy. Once inside the cell,
M. leprae
activates the host’s proliferative machinery, thereby increasing the number of cells susceptible to infection. This astonishing manipulation of the mammalian cell cycle is the subject of recent work by Tapinos and Rambukkana, who show that
M. leprae
drives proliferation through a novel route to extracellular signal–regulated kinase (ERK). In this Perspective, we discuss this important piece of work and highlight the noncanonical pathway used by
M. leprae
to induce proliferation.
The "Ups and Downs" of Signaling Cascades in Addiction
Authors: Ron Dorit , Jurd Rachel
Published: December 2005

Drug addiction is a chronic disease characterized by compulsive drug use despite the severe negative consequences associated with it. Repeated exposure to drugs of abuse results in molecular adaptations in neuronal signaling pathways, which eventually manifest in the complex behavioral alterations that characterize addiction. These include tolerance, sensitization, dependence, drug craving, and relapse. In this Review, we focus on recent studies highlighting signaling cascades initiated by cocaine, as a representative of a drug of abuse with a defined site of action, and alcohol, as a drug with an undefined primary site of action. Specifically, we describe recent studies that emphasize the role of protein-protein interactions, phosphorylation, and compartmentalization in the molecular mechanisms that result in the cellular and behavioral adaptations that underlie addiction. Signaling cascades that contribute to addiction, as well as those that protect or delay the development of addiction, are presented.
Long-Term Potentiation: Mechanisms of Induction and Maintenance
Authors: Blitzer Robert D.
Published: December 2005

Synapses in general exhibit various forms of plasticity; that is, the efficiency of transmission across the synapse can be potentiated or depressed in response to a prior history of stimulation. The persistence of the change in efficiency can be relatively brief, exemplified by post-tetanic potentiation (PTP), which decays within a few seconds. At the other extreme, very stable forms of plasticity, long-term potentiation (LTP) and long-term depression (LTD), can be established at many synapses in the brain. LTP is often proposed as a candidate for the cellular basis of memory, but direct evidence for this hypothesis is lacking. That said, a large body of research has provided correlative evidence for LTP as a process that underlies memory formation. This lecture, which is a part of the course "Cell Signaling Systems: A Course for Graduate Students," describes LTP from a cell biological perspective. Topics include the signaling network responsible for LTP induction, evidence for upregulated postsynaptic mechanisms in LTP, and the role of gene expression regulation, at the transcriptional and translational levels, in the maintenance of LTP.
G Protein Signaling in the Regulation of Rice Seed Germination
Authors: Assmann Sarah M.
Published: December 2005

Seed germination and early seedling growth are regulated by an intricate network of hormonal signaling pathways. The plant hormones gibberellic acid (GA) and abscisic acid (ABA) are particularly important positive and negative regulators of these processes, respectively. In the cereal rice, mutant analysis has implicated heterotrimeric guanine nucleotide–binding protein (G protein) signaling in GA-stimulated expression of several genes, including expression of the gene encoding the hydrolytic enzyme α-amylase, which breaks down carbohydrate reserves and thus mobilizes nutrients that nourish the young seedling.
G Protein Regulation of Disease Resistance During Infection of Rice with Rice Blast Fungus
Authors: Assmann Sarah M.
Published: December 2005

When the effects of specific pathogen-produced elicitor compounds on plant cells are recognized by specific plant resistance (R) gene products, a local defense response called the hypersensitive response is triggered. Production of reactive oxygen species (ROS) and induction of defense genes are components of this response. In rice cultivars harboring null mutations in the G protein α subunit, RGA1, ROS production and defense gene induction by the rice blast fungus
Magnaporthe grisea
and its sphingolipid elicitors are reduced or delayed. These results implicate heterotrimeric guanine nucleotide–binding proteins (G proteins) as important players in plant pathogen response.
Angiotensin II–Stimulated Signaling Through G Proteins and β-Arrestin
Authors: Shenoy Sudha K. , Lefkowitz Robert J.
Published: December 2005

β-Arrestin, originally identified as a protein that inhibits heterotrimeric guanine nucleotide–binding protein (G protein) coupling to cognate seven-transmembrane receptors [(7TMRs), also known as G protein–coupled receptors (GPCRs)], is currently being appreciated as a positive signaling mediator for various cell surface receptors. Activation of mitogen-activated protein kinases (MAPKs), especially extracellular signal regulated kinases 1 and 2 (ERK1/2), is a hallmark of intracellular signaling resulting from stimulation of various growth factor receptors, as well as 7TMRs. The resulting ERK activity can occur through multiple parallel or converging mechanisms. Using human embryonic kidney 293 (HEK-293) cells as a model system and utilizing RNA interference technology, two distinct pathways of angiotensin II-mediated ERK activation have been uncovered: (i) a G protein–dependent pathway that produces a transient activation of nuclear ERK and (ii) a β-arrestin–dependent pathway that leads to sustained activation of ERK that is localized to the cytosol and endosomes. The spatial and temporal segregation of ERK activated by G protein and β-arrestin pathways suggests that the physiological consequences may be different, and thus ligands that selectively stimulate or inhibit one of these pathways may be therapeutically valuable.
The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code"
Authors: Love Dona C. , Hanover John A.
Published: December 2005

A dynamic cycle of addition and removal of O-linked
N
-acetylglucosamine (O-GlcNAc) at serine and threonine residues is emerging as a key regulator of nuclear and cytoplasmic protein activity. Like phosphorylation, protein O-GlcNAcylation dramatically alters the posttranslational fate and function of target proteins. Indeed, O-GlcNAcylation may compete with phosphorylation for certain Ser/Thr target sites. Like kinases and phosphatases, the enzymes of O-GlcNAc metabolism are highly compartmentalized and regulated. Yet, O-GlcNAc addition is subject to an additional and unique level of metabolic control. O-GlcNAc transfer is the terminal step in a "hexosamine signaling pathway" (HSP). In the HSP, levels of uridine 5′-diphosphate (UDP)-GlcNAc respond to nutrient excess to activate O-GlcNAcylation. Removal of O-GlcNAc may also be under similar metabolic regulation. Differentially targeted isoforms of the enzymes of O-GlcNAc metabolism allow the participation of O-GlcNAc in diverse intracellular functions. O-GlcNAc addition and removal are key to histone remodeling, transcription, proliferation, apoptosis, and proteasomal degradation. This nutrient-responsive signaling pathway also modulates important cellular pathways, including the insulin signaling cascade in animals and the gibberellin signaling pathway in plants. Alterations in O-GlcNAc metabolism are associated with various human diseases including diabetes mellitus and neurodegeneration. This review will focus on current approaches to deciphering the "O-GlcNAc code" in order to elucidate how O-GlcNAc participates in its diverse functions. This ongoing effort requires analysis of the enzymes of O-GlcNAc metabolism, their many targets, and how the O-GlcNAc modification may be regulated.
Focus Issue: Signaling Across Membranes
Authors: Gough Nancy R.
Published: December 2005

This week’s issues of
Science
and
Science’
s STKE focus on movement of molecules and information across cellular membranes.
Science
highlights the mechanisms by which proteins, ions, and DNA cross the membranes of eukaryotic and prokaryotic cells. STKE addresses how information is transmitted across cell membranes to allow cells to communicate with each other and to respond to signals in their environments.
Novel Compartment Implicated in Calcium Signaling—Is It an "Induced Coupling Domain"?
Authors: Hisatsune Chihiro , Mikoshiba Katsuhiko
Published: December 2005

The endoplasmic reticulum (ER) is not simply a uniform continuous organelle, but is spatially and functionally heterogeneous with nonuniform distribution of endoplasmic Ca
2+
-handling proteins, such as Ca
2+
-binding proteins, Ca
2+
pumps, and Ca
2+
-release channels. Such nonuniform distribution of Ca
2+
-handling proteins is thought to create a spatially divided calcium store and to contribute to the generation of complex intracellular Ca
2+
dynamics. In addition to the particular distribution of these Ca
2+
-handling proteins within ER, extracellular stimuli may also stimulate the formation of dynamic new ER compartments containing Ca
2+
-handling proteins. These compartments containing Ca
2+
-handling proteins have potential roles in Ca
2+
signaling; specifically, they may function as "induced coupling domains" between the ER and plasma membrane, thereby allowing Ca
2+
entry into the ER.
Transduction Peptides Within Naturally Occurring Proteins
Authors: Joliot Alain
Published: December 2005

First identified as peptides derived from the human immunodeficiency virus (HIV) transcriptional regulator Tat and the
Drosophila
transcription factor Antennapedia, transduction (or cell-penetrating) peptide sequences enable soluble proteins to cross biological membranes and interact with cytosolic and nuclear targets. Proteins containing such sequences have been found to function as transcription factors, to inhibit apoptosis, to play roles in axon guidance, or to transport viral mRNA between cells. The recent demonstration that dynorphins are able to act as transduction peptides suggests that these neuropeptides may have roles independent of opiate receptor activation.
Long-Distance Calls Between Cells Connected by Tunneling Nanotubules
Authors: Önfelt Björn , Purbhoo Marco A. , Nedvetzki Shlomo , Sowinski Stefanie , Davis Daniel M.
Published: December 2005

Long membrane tethers between cells, known as membrane nantotubes or tunneling nanotubules, create supracellular structures that allow multiple cell bodies to act in a synchronized manner. Calcium fluxes, vesicles, and cell-surface components can all traffic between cells connected by nanotubes. Thus, complex and specific messages can be transmitted between multiple cells, and the strength of signal will suffer relatively little with the distance traveled, as compared to the use of soluble factors to transmit messages. Connecting multiple antigen-presenting cells, for example, can help amplify and coordinate immune responses that are distal to an antigenic site. Conversely, because the ability of a pathogen to spread between cells is a key determinant of its capacity to multiply, pathogens may exploit nanotubes for their own transmission.
Regulation of Complexes by Cytoskeletal Elements: Integrins Serve as Force Transducers Linking Mechanical Stimuli and Biochemical Signals
Authors: Felsenfeld Dan P.
Published: December 2005

This Teaching Resource provides a summary and slides derived from a lecture on the integrin family members and the downstream signaling pathways they activate; it is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture focuses on the capacity of integrins to serve as mechanotransducers, with particular emphasis on signaling mechanisms downstream of integrins.
Imaging Signal Transduction in Living Cells with Fluorescent Proteins
Authors: Philips Mark R.
Published: December 2005

Until recently, studies in this field of signal transduction have involved the "what" and "when" of signaling. Who talks to whom and for how long? With the advent of genetically encoded fluorescent proteins, it has become possible to monitor signaling events in living cells in real time. This has added the dimension of "where" to the study of cellular signaling. This lecture, which is a part of "Cell Signaling Systems: A Course for Graduate Students," provides a survey of how green fluorescent protein (GFP)-tagged probes for signaling events have been used to elucidate new pathways, to describe the kinetics of signaling events at the single-cell level, and to reveal upon which subcellular compartments these events take place. Some of the findings confirm previous ones using biochemical techniques, and others have been surprising. Examples include those utilizing protein localization, relocalization, fluorescence recovery after photobleaching (FRAP), and fluorescence resonance energy transfer (FRET). The design of FRET probes is described. The detection of small guanosine triphosphatase (GTPase) signaling in living cells is used as an example to explore the creative and diverse ways investigators have developed to look at this system.
Regulation of Voltage-Gated Ca
2+
Channels by Calmodulin
Authors: Halling D. Brent , Aracena-Parks Paula , Hamilton Susan L.
Published: December 2005

Calmodulin, a highly versatile and ubiquitously expressed Ca
2+
sensor, regulates the function of many enzymes and ion channels. Both Ca
2+
-dependent inactivation and Ca
2+
-dependent facilitation of the voltage-gated Ca
2+
channels Cav1.2 and Cav2.1 are regulated through an interaction with Ca
2+
-bound calmodulin. This review addresses the functional regulation of Cav1.2 and Cav2.1 by calmodulin and discusses how Ca
2+
binding to a single calmodulin molecule can regulate opposing functions of the voltage-gated Ca
2+
channels.