bluuebunny/crossref_metadata_2025 huggingface dataset:
No Association of C677T Methylenetetrahydrofolate Reductase and an Endothelial Nitric Oxide Synthase Polymorphism with Recurrent Pregnancy Loss
Authors: Makino Aiko , Nakanishi Tamao , Sugiura‐Ogasawara Mayumi , Ozaki Yasuhiko , Suzumori Nobuhiro , Suzumori Kaoru
Published: June 2004

Problem:  It is controversial whether polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and the endothelial nitric oxide synthase (eNOS) are associated with recurrent pregnancy loss.

Method of study:  We studied the frequency of the C677T polymorphism of MTHFR and a eNOS gene polymorphism, as well as the plasma levels of homocysteine and NO, in 85 cases with a history of two or more unexplained embryonal losses, 40 patients suffering fetal loss and 76 controls.

Results:  The frequency of the MTHFR gene T allele, which has been reported to be associated with miscarriages, in patients suffering fetal loss was rather significantly lower than in controls whereas there was no difference in the frequency of the eNOS gene A allele. There were no differences in the plasma homocysteine levels among the three groups. However, the NO concentrations in the embryonal loss and fetal loss groups were significantly higher than that in controls.

Conclusion:  We conclude that the NO concentration but not the polymorphism of MTHFR and eNOS gene and hyperhomocysteinemia are associated with recurrent pregnancy loss in Japanese.
Expression of Toll‐like Receptors in Human Endometrial Epithelial Cells and Cell Lines
Authors: Young Steven L. , Lyddon Terri D. , Jorgenson Rebecca L. , Misfeldt Michael L.
Published: June 2004

Problem:  Are toll‐like receptors (TLRs) expressed by human endometrium and endometrial cell lines?

Methods of study:  Expression of each TLR mRNA species was determined by reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis of proliferative‐phase human endometrium, separated endometrial epithelial cells, and the Ishikawa and RL95‐2 endometrial epithelial cell lines. U‐937 and SKW 6.4 cell lines were used as positive controls. Functional relevance of PCR findings was tested by enzyme‐linked immunsorbent assay (ELISA)analysis of IL‐8 production after stimulating cell lines with ligands for TLR2‐5.

Results:  TLR1‐6 and 9 mRNA species were detected in both whole endometrium and separated endometrial epithelial cells. Ishikawa cells expressed TLR2 and TLR5, while RL95‐2 cells expressed TLR3, 5, and 9. Response of RL95‐2, Ishikawa, and U‐937 cells to TLR2‐5 ligands was consistent with RT‐PCR findings except response to flagellin by Ishikawa cells.

Conclusion:  These studies provide the first evidence of TLR expression in the endometrium of any species and suggest the usefulness of endometrial cell lines to study TLR function.
Lectin Receptors for Endometrial H‐type 1 Antigen on Goat Conceptuses
Authors: Woldesenbet S. , Garcia R. , Igbo N. , Leake J. , Lewis S. K. , Newton G. R.
Published: June 2004

Problem:  The goal of this study was to determine if caprine conceptuses express lectin‐like receptors for endometrial H‐type 1 (HT1) antigen.

Method of study:  Conceptus tissues were collected during the apposition, adhesion and attachment phases of placentation and evaluated using immunofluorescence microscopy.

Results:  Conceptus staining for the trisaccharide lacto‐N‐fucopentaose‐1 was strong and uniform during apposition of fetal and maternal tissues but changed by day 25 of pregnancy when large aggregates of intense staining were observed. Monoclonal antibodies to galectin‐3 did not stain conceptus tissue during the apposition phase but intense punctate staining was observed after day 25. Strong uniform staining for Lewis Y antigen was detected only on day 17 of pregnancy.

Conclusion:  Conceptus tissue expresses potential receptors for endometrial HT1 antigen. Carbohydrate–lectin interactions may facilitate attachment of the apical surfaces of uterine epithelial cells and trophectoderm during the early stages of placentation.
Granulocyte Colony‐stimulating Factor Suppresses Autologous Tumor Killing Activity of the Peripheral Blood Lymphocytes in the Patients with Ovarian Carcinoma
Authors: Ohta Yoshiaki , Hayakawa Satoshi , Karasaki‐Suzuki Miki , Sugita Kenji , Komine Shihoko , Chishima Fumihisa , Hatta Yoshihiro , Horie Takashi , Seo Naohiro , Sheikh Aleemuzzaman , Nemoto Norimichi , Yamamoto Tatsuo
Published: June 2004

Problem:  Granulocyte colony‐stimulating factor (G‐CSF) is often administered to patients with chemotherapy‐induced leukocytopenia. However, adequate attention has not been paid to its effects on cancer immunology. Reported by us and others, G‐CSF often induces immunosuppression and down‐regulation of response T helper (Th)2 directed immune reaction both in vivo and in vitro. In this study, we analyzed the effects of G‐CSF on interferon (IFN)‐γ production and autologous tumor killing (ATK) activities of peripheral blood mononuclear cells (PBMCs).

Methods of study:  In order to evaluate the cytokine‐induced activation of peripheral T and natural killer (NK) cells, we analyzed IFN‐γ production by interleukin (IL)‐2‐ and IL‐12‐stimulated PBMCs, using the ELISPOT assay. Specific killing of autologous tumor cells was evaluated by lactate dehydrogenase (LDH) release assay.

Results:  The PBMC collected from both cancer‐bearing patients and healthy subjects showed IL‐2‐ and/or IL‐12‐induced IFN‐γ production. The frequency of IFN‐γ producing cells was significantly higher in the normal subjects compared with the patients with advanced ovarian carcinoma. The ATK activity was also enhanced in IL‐2‐ and/or IL‐12‐stimulated PBMCs of patients with ovarian carcinoma. G‐CSF almost completely abolished IFN‐γ production and ATK activity of PBMC stimulated with IL‐2 and/or IL‐12.

Conclusions:  The G‐CSF appears to be a suppressor of antitumor immunity. Routine administration of G‐CSF to cancer patients may not be recommended, except for febrile neutropenia.
Cytogenetic Abnormalities in Products of Conception: A Relationship Revisited
Authors: Yusuf Rushdia Z. , Naeem Rizwan
Published: June 2004

Objectives:  Cytogenetic evaluation of product of conception (POC) is essential to determine the cause of pregnancy loss and aid the prenatal diagnosis of subsequent pregnancies. The purpose of this study is twofold. (1) To profile cytogenetic abnormalities, their relationship with maternal and gestational age and analyze sex ratios in our case series of 2052 consecutive samples of POC referred to the Baystate Medical Center, Laboratory Genetics between January 1992 and January 1999. (2) To present a comprehensive review of such data published in the last 15 years, in order to study temporal differences in the above parameters and make this information readily available for cytogeneticists and genetic counselors.

Materials and methods:  Data was entered and analyzed in Epi Info version 6.0 using the Z‐test, chi‐square test of significance and linear correlation coefficient.

Results and conclusions:  The profile of cytogenetic abnormalities detected in POC has not changes significantly over time. The mean maternal age in our study (overall and for trisomies) was higher than that reported previously, which is consistent with the noted trend of increasing age at pregnancy in recent years. Our study provides evidence that abnormal karyotypes are aborted earlier and that tetraploidies have the least survival amongst all abnormalities. The higher mean gestational age for trisomic abortions in our study, as compared with previously reported figures, can be attributed to the increasing practice of active maternal screening with subsequent therapeutic abortions. Analysis of sex ratios may reaffirm a female specific developmental disadvantage in early stages of pregnancy.
More Without TOR
Authors: Beckman Mary
Published: June 2004

Scarfing pizzas wouldn't shorten a person's life if the body didn't notice the extra intake. Similarly, flies can eat rich food and not die early if a nutrient-sensing gadget is turned down, according to a new study. Quelling a protein that detects an abundance of food delays fly death, the work shows. The result suggests a potential mechanistic connection between decreased insulin-like signaling and calorie restriction, two manipulations that increase life span.
Composed by Leptin
Authors: Beckman Mary
Published: June 2004

Like many bands remembered for one popular song, leptin has been thought of as a one-hit wonder for suppressing appetite in adults. Now, research shows that the hormone plays another tune: It orchestrates the routing of key circuits in developing mouse brains that it uses to suppress appetite later in life. The results reveal how appetite-regulating brain regions develop and might explain why low-birth-weight babies often grow up to be obese.
Hidden Talents
Authors: Leslie Mitch
Published: June 2004

To stem the damage from Alzheimer's disease, researchers hope to slice the supply of β amyloid, a protein that fouls the brains of AD patients. But new work suggests that eliminating two proteins that help make β amyloid undermines long-term memory and incites brain deterioration. The finding raises questions about the safety of anti-AD drugs that curtail the production of β amyloid.
Puzzling Out the Pieces
Authors: Landhuis Esther
Published: June 2004

Solving a particular jigsaw puzzle from a mound of pieces poses a challenge, especially when the pieces are from multiple puzzles. Scientists face a similar hurdle when fitting together the mechanisms of two well-studied life-extending methods, given the huge number of molecules in an organism. Using gene-chip technology, they have now pulled out some probable key components. The work supports the notion that two life-extension pathways harness some of the same molecules, and it also focuses researchers on specific genes that participate in these pathways.
Fork in the Road
Authors: Davenport R. John
Published: June 2004

A protein signal takes an unexpected detour to influence worm life span, new work reveals. The study uncovers a crucial protein that separates an insulin-like pathway's effects on longevity and hibernation.
Lightheaded
Authors: Leslie Mitch
Published: June 2004

That slice of chocolate cake is going straight to the hips, many a dieter frets after a splurge. Whether that's true depends in part on the fat our calorie counter already packs, according to new work. The study shows that a hormone released by fat tissue heads for the brain and helps tweak energy balance and body mass. Understanding how the hormone throws its weight around might help researchers develop therapies to keep our waistlines in check.
A New Way to Lose Your Nerve
Authors: Basbaum Allan I.
Published: June 2004

Perpiheral nerve damage results in loss of sensation in the affected region of the body. Oaklander and Brown now report that, in the rat, transection of a peripheral nerve in only one side of the body also results in profound loss of the innervation of the same region on the opposite side of the body. Peripheral nerve damage may also produce persistent (neuropathic) pain conditions that are presumed to arise from maladaptive reorganization of the central nervous system. Thus, the possibility that comparable bilateral changes occur in patients and that such changes contribute to neuropathic pain conditions must be considered.
Physiological Complexity, Aging, and the Path to Frailty
Authors: Lipsitz Lewis A.
Published: June 2004

Healthy physiological processes require the complex interaction of multiple control systems operating over multiple time scales. The output of these processes (for example, heart rate, blood pressure, hormonal rhythms, or postural sway) demonstrates complex variability that can be quantified using the concept of fractals, derived from the field of nonlinear dynamics. Complex physiological dynamics enable an organism to rapidly respond to the internal and external perturbations of everyday life. Aging and disease are associated with a loss of complexity in the dynamics of many physiological systems. This loss of complexity may reduce the ability to adapt to stress and lead to the syndrome of frailty.
Bad to the Bone
Authors: Leslie Mitch
Published: June 2004

A turncoat lurks in the elderly skeleton. New research shows that proteins that build bone during youth promote its destruction later in life by prodding bone-dissolving cells into action. The results could lead to treatments to strengthen aging bone and fight diseases such as osteoporosis.
Slacking Off
Authors: Landhuis Esther
Published: June 2004

Like students whose motivation level wanes as summer nears, a molecular crew that mends fractured DNA gets lazy toward the end of an animal's life, according to new work. The findings spotlight a pathway whose breakdown could explain how elderly genomes become riddled with errors, which boosts cancer risk.
If Telomeres Thrive, You Will Survive
Authors: Leslie Mitch
Published: June 2004

Much as cutting the biblical muscleman Samson's hair sapped his strength, trimming telomeres weakens a cell's power to survive. A new study of nematodes backs the idea that extending chromosome tips prolongs an animal's life span. The findings add a new twist by suggesting that lengthy telomeres stretch life not by affecting cell duplication, but by solidifying defenses against stress.
Come One, Come All
Authors: Lee Siu Sylvia
Published: June 2004

Aging is a complex process that involves the gradual functional decline of many different tissues and cells. Gene expression microarray analysis provides a comprehensive view of the gene expression signature associated with age and is particularly valuable for understanding the molecular mechanisms that contribute to the aging process. However, because of the stochastic nature of the aging process, animals of the same chronological age often manifest great physiological differences. Therefore, profiling the gene expression pattern of a large population of aging animals risks either exaggerating or masking the changes in gene expression that correspond to physiological aging. In a recent paper, Golden and Melov surveyed the gene expression profiles of individual aging
Caenorhabditis elegans
, hoping to circumvent the problem of variability among worms of the same chronological age. This initial analysis of age-dependent gene expression in individual aging worms is an important step toward deciphering the molecular basis of physiological aging.
Calorie Restriction Un-SIR-tainty
Authors: Davenport R. John
Published: June 2004

HERSONISSOS, CRETE, GREECE
--Like connections between characters in a Greek tragedy, the relation between calorie restriction (CR) and a longevity gene might not be what it has seemed. New work presented here 1 May at the 2nd International Conference on Functional Genomics of Ageing suggests that curbing food intake doesn't require the
SIR2
gene to extend yeast longevity. The result challenges the prevailing model for how CR works, although some researchers don't rule out a contribution from
SIR2
.
Slipshod Survival
Authors: Beckman Mary
Published: June 2004

Sloppiness has unexpected virtues. Mice with slovenly metabolism live longer than their neat-freak cousins, new research shows. The finding supports the idea that reactive oxygen species, troublemaking molecules that attack cells, shorten life span.
Learning Is in the Blood
Authors: Leslie Mitch
Published: June 2004

A well-tuned immune system not only rebuffs noxious invaders but keeps the brain sharp, a new study suggests. The work shows that hobbling the immune system in mice impairs learning and memory. The results raise the possibility that enhancing immunity might bolster brain acuity in illnesses such as Alzheimer's disease and stave off the mental declines of aging.
The Ageless Question--What Accounts for Age-Related Cognitive Decline?
Authors: Nagahara Alan , Tuszynski Mark H.
Published: June 2004

Recent studies have provided partial insight into mechanisms underlying age-related declines in brain function. However, precisely where in the brain these changes occur is not entirely clear. A new report suggests that the hippocampal dentate gyrus may be the earliest locus of age-related memory decline.
A Life of Fusion
Authors: Chen Ingfei
Published: June 2004

Gerontologist Olivia Pereira-Smith was born and educated in Bombay, India, but in the early 1970s, prospects for a science career in that country seemed dim for lack of resources. So she immigrated to the United States for master's degree studies at the University of California, Berkeley, training that led her into the field of cellular aging. After earning a Ph.D., she conducted experiments that helped elucidate the genetics of cell immortality. Today she is following the same scientific trail at the University of Texas Health Science Center, San Antonio, where she collaborates closely with her husband and research partner, James Smith.
GEHA--The Pan-European "Genetics of Healthy Aging" Project
Authors: Nebel Almut , Schreiber Stefan
Published: June 2004

The pan-European "Genetics of Healthy Aging" (GEHA) consortium is undertaking a large study of long-lived individuals, which officially began on 22 May 2004. The consortium aims to identify genes that promote longevity and good health during the process of aging. The project will involve scientists working in multiple disciplines and using a variety of techniques.
Breaking in a New Function for Casein Kinase 2
Authors: Morales Julio C. , Carpenter Phillip B.
Published: June 2004

DNA damage response mechanisms help ensure the fidelity of chromosomal transmission, and the failure of such mechanisms might lead to premature aging and cancer. A new report has established that casein kinase 2 (CK2), a protein that functions in diverse cellular processes, controls the activity of the DNA repair protein XRCC1. These results indicate that CK2 is a key participant in the cellular response to DNA damage.
Counterattack
Authors: Landhuis Esther
Published: June 2004

Like a cutthroat politician, a potential longevity protein acts by derailing another molecule with opposing aims. According to new work, SIRT1 seems to spur fat breakdown in food-deprived animals by thwarting the actions of PPARγ, a protein that activates fat-storage genes. Fat loss prolongs life in mice, so the findings suggest a possible molecular pathway that links diet to mammalian longevity.
Inside Insulin Signaling, Communication Is Key to Long Life
Authors: Antebi Adam
Published: June 2004

In a recent
Nature
paper (
1
), Tatar and colleagues show that inhibition of insulin/insulin-like growth factor (IGF) signaling specifically in the adipose tissue of
Drosophila melanogaster
retards organismal aging, increases resistance to oxidative stress, augments lipid deposition, and restricts insulin signaling in peripheral tissues by a cell-non-autonomous mechanism. Consistent with recent work in the worm, these results suggest that insulin/IGF signaling itself may mediate communication among various tissues to influence organismal longevity.
On Trial
Authors: Davenport R. John
Published: June 2004

As researchers uncover basic mechanisms that underlie aging, they hope that lessons learned from mice, worms, flies, and other lab denizens will apply to people. Making that leap requires a new set of scientific approaches, from observational studies to the most rigorous of tests, the double-blind, randomized, placebo-controlled clinical trial. Navigating this unique scientific terrain presents new obstacles for basic-science researchers but can provide the ultimate payoff.
Obesity Over the Life Course
Authors: Mizuno Tooru , Shu I-Wei , Makimura Hideo , Mobbs Charles
Published: June 2004

Obesity in middle-aged humans is a risk factor for many age-related diseases and decreases life expectancy by about 7 years, which is roughly comparable to the combined effect of all cardiovascular disease and cancer on life span. The prevalence of obesity increases up until late middle age and decreases thereafter. Mechanisms that lead to increased obesity with age are not yet well understood, but current evidence implicates impairments in hypothalamic function, especially impairments in the ability of hypothalamic pro-opiomelanocortin neurons to sense nutritional signals. The rapid increase in the prevalence of obesity at all ages in the past decade suggests that, in the next two or three decades, diseases associated with obesity, especially diabetes, will begin to rise rapidly. Indeed, these trends suggest that for the first time in modern history, the life expectancy of people in developed societies will begin to decrease, unless the rapid increase in the prevalence of obesity can be reversed.
Low-Cal Connections
Authors: Beckman Mary
Published: June 2004

Less food can mean more protein--a specific protein, that is. The life-prolonging regime of calorie restriction (CR) boosts quantities of SIRT1, a potential mammalian longevity molecule, new research shows. The protein protects cells by blocking stress-induced suicide, suggesting that CR lengthens animals' lives at least in part by preserving irreplaceable cells. The results hint that several seemingly disparate life-extending methods overlap.
Stem Cell Savior
Authors: Leslie Mitch
Published: June 2004

Stem cells are like the first players picked in the NBA draft--everyone expects wonders from them. A new study reveals a compound that might help stem cells live up to their promise in treating Parkinson's disease (PD). By reducing damage inflicted by a traditional PD treatment, the drug might allow patients to benefit from the standard therapy and stem cells.
S.W.A.T.--SOD Weapons and Tactics
Authors: Sampayo James N. , Lithgow Gordon J.
Published: June 2004

The accumulation of damage caused by reactive oxygen species (ROS) is held to be one of the underlying causes of age-related decline and has been shown to be involved in a number of pathological states. Inherent defense mechanisms have evolved to limit this damage by reducing the levels of ROS, which are produced mainly by the mitochondria in aerobic organisms. One such defense is superoxide dismutase 1 (SOD1). It is well established that oxidative stress results in increased transcription and translation of the
SOD1
gene, but it is now known that an additional level of posttranslational control exists. A recent paper describes the presence of an inactive pool of SOD1 whose activation is wholly reliant on the presence of superoxide or oxygen and a specific copper-containing chaperone. This mechanism highlights the importance of rapid responses in the fight against oxidative stress.
Deficit in Attachment Behavior in Mice Lacking the µ-Opioid Receptor Gene
Authors: Moles Anna , Kieffer Brigitte L. , D'Amato Francesca R.
Published: June 2004

Endogenous opioid binding to μ receptors is hypothesized to mediate natural rewards and has been proposed to be the basis of infant attachment behavior. Here, we report that μ-opioid receptor knockout mouse pups emit fewer ultrasonic vocalizations when removed from their mothers but not when exposed to cold or male mice odors. Moreover these knockout pups do not show a preference toward their mothers' cues and do not show ultrasonic calls potentiation after brief maternal exposure. Results from this study may indicate a molecular mechanism for diseases characterized by deficits in attachment behavior, such as autism or reactive attachment disorder.
Regulation of Dendritic Protein Synthesis by Miniature Synaptic Events
Authors: Sutton Michael A. , Wall Nicholas R. , Aakalu Girish N. , Schuman Erin M.
Published: June 2004

We examined dendritic protein synthesis after a prolonged blockade of action potentials alone and after a blockade of both action potentials and miniature excitatory synaptic events (minis). Relative to controls, dendrites exposed to a prolonged blockade of action potentials showed diminished protein synthesis. Dendrites in which both action potentials and minis were blocked showed enhanced protein synthesis, suggesting that minis inhibit dendritic translation. When minis were acutely blocked or stimulated, an immediate increase or decrease, respectively, in dendritic translation was observed. Taken together, these results reveal a role for miniature synaptic events in the acute regulation of dendritic protein synthesis in neurons.
Antarctic Timing of Surface Water Changes off Chile and Patagonian Ice Sheet Response
Authors: Lamy Frank , Kaiser Jérôme , Ninnemann Ulysses , Hebbeln Dierk , Arz Helge W. , Stoner Joseph
Published: June 2004

Marine sediments from the Chilean continental margin are used to infer millennial-scale changes in southeast Pacific surface ocean water properties and Patagonian ice sheet extent since the last glacial period. Our data show a clear “Antarctic” timing of sea surface temperature changes, which appear systematically linked to meridional displacements in sea ice, westerly winds, and the circumpolar current system. Proxy data for ice sheet changes show a similar pattern as oceanographic variations offshore, but reveal a variable glacier-response time of up to ∼1000 years, which may explain some of the current discrepancies among terrestrial records in southern South America.
The Natural Forces of Metaphor
Authors: Cokinos Christopher
Published: June 2004

Conserving Words
How American Nature Writers Shaped the Environmental Movement. by Daniel J. Philippon. University of Georgia Press, Athens, 2004. 391 pp. $39.95. ISBN 0-8203-2576-7.

Philippon explores the influence of five writers whose work helped shape important conservation organizations: Teddy Roosevelt (Boone & Crockett Club), Mabel Osgood Wright (National Audubon Society), John Muir (Sierra Club), Aldo Leopold (Wilderness Society), and Ed Abbey (Earth First!).
Life's Daily Beat
Authors: Gwinner Eberhard
Published: June 2004

Rhythms of Life
The Biological Clocks that Control the Daily Lives of Every Living Thing. by Russell G. Foster and Leon Kreitzman. Profile, London, 2004. 288 pp. £20. ISBN 1-86197-235-0. Forthcoming from Yale University Press. ISBN 0-300-10574-6.

Writing for a broad, popular audience, the authors explore circadian rhythms and their influences on our lives and health.
Dynamics of Slow-Moving Landslides from Permanent Scatterer Analysis
Authors: Hilley George E. , Bürgmann Roland , Ferretti Alessandro , Novali Fabrizio , Rocca Fabio
Published: June 2004

High-resolution interferometric synthetic aperture radar (InSAR) permanent scatterer data allow us to resolve the rates and variations in the rates of slow-moving landslides. Satellite-to-ground distances (range changes) on landslides increase at rates of 5 to 7 millimeters per year, indicating average downslope sliding velocities from 27 to 38 millimeters per year. Time-series analysis shows that displacement occurs mainly during the high-precipitation season; during the 1997–1998 El Niño event, rates of range change increased to as much as 11 millimeters per year. The observed nonlinear relationship of creep and precipitation rates suggests that increased pore fluid pressures within the shallow subsurface may initiate and accelerate these features. Changes in the slope of a hill resulting from increases in the pore pressure and lithostatic stress gradients may then lead to landslides.
RNAi-Independent Heterochromatin Nucleation by the Stress-Activated ATF/CREB Family Proteins
Authors: Jia Songtao , Noma Ken-ichi , Grewal Shiv I. S.
Published: June 2004

At the silent mating-type interval of fission yeast, the RNA interference (RNAi) machinery cooperates with
cenH
, a DNA element homologous to centromeric repeats, to initiate heterochromatin formation. However, in RNAi mutants, heterochromatin assembly can still occur at low efficiency. Here, we report that Atf1 and Pcr1, two ATF/CREB family proteins, act in a parallel mechanism to the RNAi pathway for heterochromatin nucleation. Deletion of
atf1
or
pcr1
alone has little effect on silencing at the mating-type region, but when combined with RNAi mutants, double mutants fail to nucleate heterochromatin assembly. Moreover, deletion of
atf1
or
pcr1
in combination with
cenH
deletion causes loss of silencing and heterochromatin formation. Furthermore, Atf1 and Pcr1 bind to the mating-type region and target histone H3 lysine-9 methylation and the Swi6 protein essential for heterochromatin assembly. These analyses link ATF/CREB family proteins, involved in cellular response to environmental stresses, to nucleation of constitutive heterochromatin.
Neuronal Oscillations in Cortical Networks
Authors: Buzsáki György , Draguhn Andreas
Published: June 2004

Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain's design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.
A Code in the Nose
Authors: Firestein Stuart
Published: June 2004

The mammalian nose is arguably the best chemical detector on the planet, capable of detecting and discriminating among many thousands of compounds. This ability is mediated at the earliest steps by a large family of G protein (heterotrimeric guanine nucleotide-binding protein)–coupled receptors (GPCRs). The capacity to detect and discriminate odors depends on a combinatorial code, in which any given receptor recognizes many odors and any given odor compound might serve as a ligand at multiple receptors. Recent research adds a layer of complexity to the interpretation of this olfactory code, suggesting that the overall effect of a mixture of odorants is not simply equal to the sum of its parts. Rather, individual odorants can act as antagonists at the level of individual GPCRs, thereby suppressing some of the signaling pathways activated by structurally related compounds. Thus, the odor code not only is a function of the pattern of activated receptors, but also may be further sharpened by the action of antagonism. It seems that odor coding is now a division of pharmacology.
Allosteric Modulation of Ion Channels: The Case of Maxi-K
Authors: Rothberg Brad S.
Published: June 2004

Maxi-K channel gating is modulated by both membrane voltage and cytoplasmic Ca
2+
. Recent work has led to a quantitative understanding of this dual regulatory mechanism, derived from classical allosteric principles, in terms of the energetic coupling among membrane voltage, Ca
2+
binding, and opening of the channel’s gate. Our new understanding of the gating pathway can be applied to the interpretation of mutagenesis experiments and may serve as an example in the analysis of other dually regulated signaling molecules.
Promotion and Attenuation of FGF Signaling Through the Ras-MAPK Pathway
Authors: Tsang Michael , Dawid Igor B.
Published: June 2004

The fibroblast growth factors (FGFs) represent a large family of ligands that activate signal transduction pathways leading to diverse biological responses, including many involved in various processes during development. Here, we discuss the discovery of a subset of conserved FGF target genes that encode feedback regulators of FGF signaling itself. Members of the Sprouty, Sef, and mitogen-activated protein kinase phosphatase families are negative modulators of FGF signaling, whereas positive factors that promote FGF signaling include the ETS transcription factors ERM and PEA3 and the transmembrane protein XFLRT3. These molecules affect the FGF signaling cascade at different levels to regulate the final output of the pathway. This multilayered regulation suggests that precise adjustment of FGF signaling is critical in development.
Glioblastomas on the Move
Authors: Merlo Adrian , Bettler Bernhard
Published: June 2004

The mechanism by which the tumor suppressor
PTEN
slows tumor cell migration is not well characterized. A recent study by Raftopoulou
et al
. shows that a lack of PTEN protein phosphatase activity accelerates the migration of glioblastoma cells. The protein phosphatase activity of PTEN is directly or indirectly responsible for dephosphorylating a PTEN residue, threonine-383, which is necessary for slowing cell migration. These findings have implications for the design of new therapies against glioblastomas and other highly invasive cancers.
Discrete Intracellular Signaling Domains of Soluble Adenylyl Cyclase: Camps of cAMP?
Authors: Bundey Richard A. , Insel Paul A.
Published: June 2004

Soluble adenylyl cyclase can function in the nucleus, defining a nuclear microdomain of adenosine 3′,5′-monophosphate (cAMP) signaling. Bundey and Insel discuss the evidence for discrete signaling microdomains of cAMP, including the nucleus and caveolae, and conclude that such microdomains may be defined by the localized, subcellular expression of adenylyl cyclase isoforms.
Hysteresis vs. Graded Responses: The Connections Make All the Difference
Authors: Ninfa Alexander J. , Mayo Avraham E.
Published: June 2004

Biological regulatory systems have the potential to provide graded responses to stimuli or may demonstrate switch-like properties. Our understanding of the system design principles controlling these responses is still at a rudimentary stage, and here we consider several recent experimental and theoretical studies that focus on these system design principles. Overt positive feedback loops, or double-negative feedback loops, can produce bistable or multistable systems under the appropriate conditions and can produce graded responses under other conditions. Several design features favor bistability in negatively controlled genetic systems, including a high kinetic order for repression and a large difference in the rates of gene expression in the "on" and "off" states. In positive feedback, a high kinetic order for the activation of gene expression favors bistability. Multistability can result from the combined effects of positive and negative regulators, or from the combined effects of regulators that each demonstrate bistability. Finally, bistability can result in enzymatic systems in which multiple reversible covalent modifications occur, even when no overt feedback loops are present.
Focus Issue: Tuning in to the Ion Channel
Authors: Adler Elizabeth M.
Published: June 2004

In this second Focus Issue in an ongoing series of articles on the regulation and function of ion channels,
Science
's STKE presents four articles that highlight various aspects of ion channel function. A Review by Faundez and Hartzell concerns the functions of intracellular chloride channels in endosomes and related organelles, concluding with an intriguing scenario whereby chloride channels in the membranes of synaptic vesicles could help determine their neurotransmitter content. A Perspective by DeCoursey on the functions of ion channels in phagocytes critically evaluates the possible contributions of proton channels and large-conductance calcium- and voltage-activated potassium channels to phagosomal destruction of microbes. Trauner and Kramer discuss various examples of metabolic regulation of potassium channels, speculating that other classes of potassium channels may be similarly subject to regulation by various small metabolites. Wolf discusses recent research implicating the TRPM7 "chanzyme" in magnesium homeostasis, research that has turned our previous concepts of the regulation of magneisum homeostasis upside down.
Metabolic Modulation of Potassium Channels
Authors: Trauner Dirk , Kramer Richard H.
Published: June 2004

Recent investigations have shown that a range of small molecules that reflect the metabolic state of a cell regulate the activity of potassium channels. For instance, hydrogen peroxide has been shown to activate adenosine 5′-triphosphate–sensitive potassium channels (K
ATP
channels), whereas heme closes certain calcium-activated potassium channels. Although the exact function of the β subunit associated with voltage-gated potassium channels is still unclear, its crystal structure suggests that membrane excitability is directly coupled to metabolism.
TRPM7: Channeling the Future of Cellular Magnesium Homeostasis?
Authors: Wolf Federica I.
Published: June 2004

A recent paper by Schmitz and colleagues provides persuasive evidence that the ion channel transient receptor potential melastatin 7 (TRPM7) may be the long-sought regulator of magnesium (Mg) homeostasis in mammalian cells. This finding is not unexpected, because TRPM channels contain a kinase domain that allows them to participate in signal transduction pathways and regulatory networks. However, these studies introduce an exciting new twist into our understanding of Mg homeostasis; TRPM7 facilitates Mg entry into the cell, whereas other putative Mg transporters apparently operate in the opposite direction. By combining electrophysiological, biochemical, and genetic approaches, Schmitz and colleagues characterized most of the key features that demonstrate a well-defined and biologically plausible regulator of Mg homeostasis. TRPM7 genetics are well in hand, its regulation by intracellular free Mg
2+
unravels the mechanisms of regulatory feedback loops, and its kinase domain modulates its sensitivity to free Mg
2+
. These findings are discussed in light of the indirect and descriptive information we had about Mg regulation before this rigorous characterization of TRPM7 brought it to the center of the Mg stage. Although the molecular events downstream of TRPM7 phosphorylation and dephosphorylation await in-depth elucidation, these results open up exciting perspectives in Mg research and may provide a much-needed tool with which to reexamine the role of Mg in cell proliferation and other important pathophysiologic events. Likewise, these findings will offer guidelines for research on disease states that are characterized by Mg imbalance.
Chloride Concentration and pH Along the Endosomal Pathway
Authors: Faundez Victor , Hartzell H. Criss , Adler Elizabeth M.
Published: June 2004

This animation depicts three membrane trafficking routes in a mammalian neurosecretory cell, highlighting the changing Cl
–
concentrations and pH values of the various endosomal subcompartments. The focus is on the endocytotic pathway and the different paths taken by clathrin-coated vesicles: the pathway for receptor recycling to the plasma membrane, the lysosomal pathway, or the pathway for synaptic vesicle recycling (in neurons). Each compartment shown has a distinctive pH and [Cl
–
], with values for pH indicated in blue and values for Cl
–
indicated in orange. This animation will be useful for teaching cell biology and highlighting both the dynamic nature of vesicular traffic and the changes in ionic balance associated with different cellular compartments.
Spatial and Temporal Dynamics of Signaling Components Involved in the Control of Chemotaxis in
Dictyostelium discoideum
Authors: Kimmel Alan R. , Parent Carole A. , Gough Nancy R.
Published: June 2004

This animation shows the redistribution of several proteins during the chemotactic response of the single-celled organism
Dictyostelium discoideum
to the chemoattractant cAMP. Much like neutrophils, this organism is able to sense and move toward very shallow gradients of chemoattractant. Mutant strains carrying mutations in genes encoding various signaling components are available and, thus,
D. discoideum
serves as a model organism for the study of the cellular mechanisms that control chemotaxis and amplification of a signaling gradient across a single cell. The animation would be useful in depicting the dynamic nature of signal transduction, the ability of cells to polarize to allow for directional movement, and the spatial and temporal changes in the activity of specific proteins that accompany chemotactic responses.
From Cell Death to Neuronal Regeneration, Effects of the p75 Neurotrophin Receptor Depend on Interactions with Partner Subunits
Authors: Bandtlow Christine , Dechant Georg
Published: June 2004

In the adult mammalian central nervous system (CNS), growth of neuronal fibers is actively inhibited by myelin. The proteins myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgP), and Nogo-66 have been identified as inhibitory components present in CNS myelin. All three proteins exert their inhibitory activity by binding to a neuronal receptor complex containing the Nogo-66 receptor (NgR) and the neurotrophin (NT) receptor p75
NTR
. In their recent publication, Mi
et al
. identify the novel protein Lingo-1 as an interactor of p75
NTR
and NgR. The Lingo-1-NgR-p75
NTR
complex is shown to confer the inhibitory effects on nerve cell regeneration of Nogo-66, OMgP, and MAG by activating the small guanosine triphosphatase (GTPase) RhoA. Together with the recent finding that p75
NTR
interacts with the transmembrane protein sortilin to form a different receptor complex with cell death-promoting activity, the results of Mi
et al
. indicate that p75
NTR
exerts its diverse cellular functions by associating with function-specific co-receptors.
Symptom expression in conifers infected with Armillaria ostoyae and Heterobasidion annosum
Authors: Omdal Daniel W , Shaw, III Charles G , Jacobi William R
Published: June 2004

Crown symptoms and other aboveground variables were examined on 36 Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco.) (40209 years old), 46 white fir (Abies concolor (Gord. & Glend.) Lindl.) (36165 years old), and 97 ponderosa pine (Pinus ponderosa Dougl. ex Laws.) (64220 years old) trees in northern New Mexico and southern Colorado. Root systems of all trees were excavated to determine extent of root disease. Symptoms observed on infected trees, including reductions in height growth, changes in foliage characteristics, and crown dieback, worsened as the number of infected roots increased. Trees with aboveground symptoms had a significantly higher (p < 0.05) number of infected lateral roots than trees without symptoms. In mixed conifer stands on the Archuleta Mesa, Colo., four qualitative crown symptoms were used to accurately detect Armillaria ostoyae (Romagn.) Herink and (or) Heterobasidion annosum (Fr.) Bref. infection of Douglas-fir (21/22, or 95%) and white fir (19/28, or 68%). Similarly, 61% (48/79) of the A. ostoyae infected ponderosa pine trees on the Jemez site, N.M., were detected using the qualitative Thomson vigor rating system. Discriminate analysis, using more thorough variables and analysis, resulted in correct infection classifications of 82%, 85%, and 78% for Douglas-fir, white fir, and ponderosa pine, respectively, suggesting that aboveground variables are reasonable indicators of root disease.
Assessment of interspecific competition using relative height and distance indices in an age sequence of seral interior cedarhemlock forests in British Columbia
Authors: Simard Suzanne W , Sachs Donald L
Published: June 2004

Treatments that reduce neighbour density are widely applied in the belief they will improve conifer growth in mixed forests. However, our understanding of stand composition and age effects on competition is poor. We used neighbourhood analysis for 748 target conifer trees to examine interspecific competition within 11-, 25-, and 50-year-old mixed, even-aged stands of paper birch (Betula papyrifera Marsh.), Douglas-fir (Pseudotsuga menziesii var. glauca (Beissn.) Franco), western redcedar (Thuja plicata Donn ex D. Don), and western larch (Larix occidentalis Nutt.) in southern interior British Columbia. Critical neighbourhood height and distance were identified where competition accounted for the greatest variation in target conifer diameter. Competition processes were emperically examined using relative height indices. We found that critical neighbourhood distance increased with stand age and was greater for larch than for cedar. Critical neighbourhood height was higher for cedar than for Douglas-fir or larch in the 11-year-old stands but lower in the older stands. The most important competitors in the 11-year-old stands were tall neighbours, whereas those in the older stands were short neighbours. We found asymmetrical relationships between target conifers and neighbours for all species and age-classes, indicating a resource preemption mode of competition. To be useful in developing prescriptions for competition management in mixed species stands, competition indices should consider neighbour identity and critical height for each target species. Assessment radius must also be sufficiently large to adequately characterize competition.
Comparing site productivity of mature fire-origin and post-harvest juvenile lodgepole pine stands in Alberta
Authors: Huang Shongming , Monserud Robert A , Braun Thomas , Lougheed Hugh , Bakowsky Olenka
Published: June 2004

Twenty-two paired-plot sample locations were revisited to re-examine the site indices of mature fire-origin and adjacent post-harvest juvenile lodgepole pine (Pinus contorta var. latifolia Engelm.) stands occurring on the same physiographic sites. The post-harvest juvenile stands followed harvesting and drag scarification, whereas the mature fire-origin stands received no stand treatment. Results showed that the site index of post-harvest juvenile stands was 27% to 35% higher than that of the mature fire-origin stands. Calculation of the rate of change in site index indicated that the site index estimates of post-harvest stands were stable after 5 years breast height age was reached. This suggests that the increase in site index in post-harvest stands is not a short-term artifact, but a sustained gain that will be maintained over time. Simulations of post-harvest yield based on the Alberta growth and yield projection system (GYPSY) for lodgepole pine suggested that the increase in post-harvest site index will likely result in substantial gains in the mean annual increment and total yield of post-harvest lodgepole pine stands in the study area. The results of this study indicate that post-harvest lodgepole pine stands are growing significantly faster than their fire-origin counterparts on equivalent sites.
Understorey plant communities in boreal cutblocks with different sizes and numbers of residual tree patches
Authors: Bradbury Steve
Published: June 2004

The influence of residual tree patch size after harvest on understorey plant communities was investigated in aspen and pine  black spruce forests in boreal Alberta, Canada. Three different patch size treatments were created in both study areas; patches amounted to 3% residual merchantable timber in each cutblock. In the aspen study area, species richness was higher in cutover matrix than in preharvest forests and large residual patches. Species richness was larger in small residual patches and the cutovers than in the preharvest forests. In contrast, in pine  black spruce stands, species richness did not differ between the preharvest forests, the large and small residual patches, and the cutover matrix; however, lower richness was observed in medium-sized residual patches than in the cutover matrix. In both study areas, significant differences between understorey plant communities in the preharvest forests and those in large, medium-sized, and small residual patches were observed. In addition, large and medium-sized residual patches had understorey plant communities that differed from those in the cutover matrix. If forest managers expect to maintain preharvest understorey plant communities within cutblock boundaries, residual patches need to be larger than those tested.