bluuebunny/crossref_metadata_2025 huggingface dataset:
Self‐assessed health, sadness and happiness in relation to the total burden of symptoms from the lower urinary tract
Authors: Engström Gabriella , Henningsohn Lars , Steineck Gunnar , Leppert Jerzy
Published: March 2005

OBJECTIVES

To evaluate the effect of lower urinary tract symptoms (LUTS) on self‐assessed health, sadness and happiness of men.

SUBJECTS AND METHODS

The study included 504 men (aged 40–80 years) in the rural community of Surahammar, Sweden, who a year earlier had reported stress incontinence, urgency or postvoid dribbling in answer to a postal questionnaire, and 504 age‐matched control men from the same community. The occurrence of 12 specific LUTS was rated using the Danish Prostatic Symptom Score. Health, sadness and happiness were measured by three questions from the Medical Outcomes Study Short‐Form 36 health survey questionnaire.

RESULTS

Completed questionnaires were returned by 74.2% of men (748/1008). A low score for health was reported by 34% of men with one to four LUTS, by 67% with five to eight, and by 75% with nine or more LUTS. The total LUTS burden correlated with lower scores for happiness and with higher scores for sadness. For each of the 12 specific LUTS, men with the symptom had lower scores for health and happiness, and higher scores for sadness, than men without the symptom. Comparing men with the symptom of ‘other incontinence’ to men with no ‘other incontinence’, the relative risk (95% confidence interval) of impaired health was 2.2 (1.8–2.8), while that of a high score for happiness was 0.5 (0.3–0.7) and that of greater sadness was 2.3 (1.7–3.3). Social status, marital status, education, smoking, physical activity and urinary tract infection all affected the impact of LUTS.

CONCLUSIONS

The total burden of LUTS is related to self‐assessed health, sadness and happiness.
Nocturia in relation to somatic health, mental health and pain in adult men and women
Authors: Asplund Ragnar , Marnetoft Sven‐Uno , Selander John , Åkerström Bengt
Published: March 2005

OBJECTIVE

To assess the relationship of nocturia to somatic health, mental health and bodily pain.

SUBJECTS AND METHODS

A randomly selected group of men and women aged 20–64 years, living in three small municipalities in northern Sweden, or in the city of Östersund or in Stockholm, were sent a postal questionnaire containing questions on somatic and mental health, satisfaction with life, pain, nocturnal voiding, work and sick‐listing from work.

RESULTS

Reports (from 1948 respondents) on poor somatic and mental health and on pain all increased in parallel with increasing frequency of nocturnal voids. In a multiple logistic regression analysis with sex, age, somatic health, mental health and bodily pain as the independent variables, significant independent correlates (odds ratios, confidence intervals) of nocturnal micturition (two or more episodes vs none or one) were: age 45–59 vs 20–44 years, 1.9 (1.3–2.7), ≥60 vs 20–44 years, 3.8 (2.4–6.0); somatic health, poor vs good, 2.3 (1.4–3.7); mental health, poor vs good, 1.9 (1.2–3.0); pain, rather mild vs very mild or none, 1.5 (1.0–2.3); rather severe vs very mild or none, 1.9 (1.1–3.2); and very severe vs very mild or none, 6.0 (2.5–14.0). Gender was deleted by the logistic model. Sick‐listing for ≥ 60 days during the past year was reported by 4.9%, 10.6%, 5.6% and 38.9% of the men with none, one, two or ≥ three nocturnal voids, respectively, and by 10%, 12.4%, 23% and 46.7% (both P < 0.001) of the corresponding women, respectively. Life satisfaction decreased in parallel with increased nocturia.

CONCLUSION

The impairment of both somatic and mental health was associated with increased nocturnal voiding. Pain was associated with a substantial increase in nocturia after adjusting for age and somatic and mental health. Sick‐leave was more common in association with more nocturnal voids.
Gene transfer of vasoactive intestinal polypeptide into the penis improves erectile response in the diabetic rat
Authors: Shen Zhou‐Jun , Wang Hua , Lu Ying‐Li , Zhou Xie‐Lai , Chen Shan‐Wen , Chen Zhao‐Dian
Published: March 2005

OBJECTIVES

To determine the feasibility of transfecting penile corpora cavernosa with pcDNA3/vasoactive intestinal polypeptide (VIP) cDNA, which encodes for VIP in streptozotocin (STZ)‐diabetic rats, to clarify whether transfection of VIP cDNA into the cavernosum affects the physiological response to cavernosal nerve stimulation, and whether this process would affect other organs in the diabetic rat model in vivo.

MATERIALS AND METHODS

pcDNA3/VIP cDNA was injected into the corpus cavernosum of STZ‐induced diabetic Sprague‐Dawley rats. The intracavernosal pressure (ICP) and response to electrical stimulation of the cavernosal nerve (15 Hz, 1.5 ms, 20 V, 1 min) were measured in subsamples of rats at 1, 3, 7 and 14 days after injection; after measuring the ICP the animals were killed, and penile, hepatic, renal artery and abdominal aorta tissue samples were frozen in liquid nitrogen and stored at −80° C. The gene expression of VIP in all samples, assessed as the expression of VIP mRNA, was estimated using a semiquantitative reverse‐transcription polymerase chain reaction.

RESULTS

The mean amplitude of ICP and expression of VIP mRNA in the cavernosa of the VIP‐treated rats was greater at 1, 3, 7 and 14 days after injection (P < 0.05) than in the control animals. There were no changes in the expression of VIP mRNA in hepatic, renal and abdominal aorta samples after injection (P > 0.05).

CONCLUSIONS

VIP cDNA is easily incorporated into corpus cavernosum, and the expression is sustained for ≥ 2 weeks in the penis in vivo. The transfer of VIP is capable of altering the physiologically relevant erectile response, as measured by an increase in the ICP after stimulating the cavernosal nerve. The intracorporal micro‐injection of pcDNA3/VIP cDNA had little effect on the expression of VIP mRNA in other important organs.
Exogenous melatonin enhances bile flow and ATP levels after cold storage and reperfusion in rat liver: implications for liver transplantation
Authors: Vairetti Mariapia , Ferrigno Andrea , Bertone Roberta , Rizzo Vittoria , Richelmi Plinio , Bertè Francantonio , Reiter Russel J. , Freitas Isabel
Published: March 2005

Abstract:   Although the use of melatonin in the transplantation field has been suggested, it has not been previously tested in a liver cold‐storage model. We used a rat liver model to study (a) the dose‐dependent effect of melatonin on bile production, and (b) the potential of melatonin to improve liver function after cold‐storage. Male Wistar rats were perfused with Krebs–Henseleit bicarbonate buffer (KHB) at 37°C without or with 25, 50, 100 and 200 μm melatonin. Each dose of melatonin stimulated bile production. For cold‐storage studies, livers were flushed with either University of Wisconsin (UW) or Celsior solution and stored for 20 hr at 4°C. Reperfusion (120 min) was performed with KHB at 37°C. In subsequent studies, 100 μm melatonin were added to the perfusate during the reperfusion period. ATP and melatonin levels in the tissue were measured. Bile analysis was performed by measuring melatonin, bilirubin and gamma‐glutamyl transpeptidase (γ‐GT) levels in the fluid. A dose‐dependent increase in bile secretion, associated with an enhanced melatonin and bilirubin levels in the bile were observed. Also, tissue levels of melatonin increased in a dose‐dependent manner. When melatonin was added during the reperfusion period, bile production and bile bilirubin levels increased both with UW and Celsior solutions. The analysis of γ‐GT in the bile showed an increase in the Celsior‐preserved liver and the addition of melatonin to the perfusate reduced this effect. Tissue ATP levels were higher when melatonin was added to the perfusion medium. Higher levels of melatonin in bile than in tissue were found. In conclusion, we demonstrate that melatonin improves significantly the restoration of liver function after cold‐storage and reperfusion.
First insights into regiospecific transnitrosation reactions between tryptophan derivatives: melatonin as an effective target
Authors: Kirsch Michael , De Groot Herbert
Published: March 2005

Abstract:  Melatonin, a derivative of the essential amino acid tryptophan, has been portrayed as a hormone, a tissue factor, an autocoid, a paracoid, and a vitamin with antioxidative capabilities. In the present study a novel reaction which cannot be attributed to any of these suggested features, i.e. the transfer of the nitroso‐function from N‐nitrosotryptophan derivatives to melatonin, is unequivocally demonstrated. In the lipophilic buffer dimethylsulfoxide reaction of N‐acetyl‐N‐nitrosotryptophan (NANT) with melatonin was very slow (k = 1.5 × 10−6/m/s), but reversible as shown by 15N‐NMR spectrometry. These measurements demonstrated also that the thermodynamical equilibrium lies on the side of N‐nitrosomelatonin (NOMela). Quantum‐chemical calculations performed with the third‐generation density functional B97‐2 additionally predicted that this is also the case in an aqueous environment. In fact, reaction of melatonin with either NANT or N‐nitrosotryptophan located at the endothelin‐1 fragment 16–21 yielded NOMela with a rate constant of 1.7 ± 0.5/m/s as shown by capillary zone electrophoresis. Interestingly, the known reactive nitrogen oxide species scavenger, piperazine, did not inhibit the NANT‐dependent nitrosation of melatonin, thus very strongly indicating a direct transnitrosation reaction. All of these capabilities are known from the reaction of S‐nitrosothiols with thiolate anions and are believed to be highly important in the transport and targeting of nitric oxide.
Tryptophan affects both gastrointestinal melatonin production and interrenal activity in stressed and nonstressed rainbow trout
Authors: Lepage Olivier , Larson Earl T. , Mayer Ian , Winberg Svante
Published: March 2005

Abstract:  The present experiments were designed to test the hypothesis that elevated dietary levels of l‐tryptophan (Trp) result in elevated plasma levels of melatonin and that this increase in plasma melatonin concentration is caused by elevated melatonin production and secretion by the gastro‐intestinal‐tract (GIT). Feeding juvenile rainbow trout (Oncorhynchus mykiss) Trp‐supplemented feed for 7 days resulted in elevated daytime plasma levels of melatonin and reduced poststress plasma cortisol concentrations. Nighttime plasma melatonin concentrations were, however, not affected by elevated dietary Trp. Moreover, stress caused a reduction in daytime plasma levels of melatonin in fish fed Trp‐supplemented feed, an effect that was counteracted by treatment with an α‐receptor antagonist. These results clearly suggest that elevated dietary intake of Trp results in an increase in the GIT production of melatonin in rainbow trout. A suggestion that was further supported by the results from an in vitro experiment demonstrating that addition of Trp to the incubation medium stimulates melatonin production and release by incubated rainbow trout GIT. The results from this study led us to suggest a possible mechanism for melatonin in mediating the effects of elevated dietary Trp on poststress plasma cortisol concentrations and aggressive behavior in rainbow trout.
Melatonin–estrogen interactions in breast cancer
Authors: Sánchez‐Barceló Emilio J. , Cos Samuel , Mediavilla Dolores , Martínez‐Campa Carlos , González Alicia , Alonso‐González Carolina
Published: March 2005

Abstract:  In this article, we review the experimental data supporting an oncostatic role of melatonin on hormone‐dependent mammary tumors. Beginning with the evidence on the role of estrogens in breast cancer etiology and mammary tumor growth, we summarize the actual therapeutic strategies with estrogens as a target. Additionally, we demonstrate that melatonin fulfills all the requirements to be considered as an antiestrogenic drug which shares properties with drugs of the two main pharmacological groups of substances which interact with the estrogen‐signaling pathways such as: (i) drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens; and (ii) drugs that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors. Furthermore, melatonin decreases circulating levels of estradiol. These three antiestrogenic mechanisms suggest that melatonin may have an important role in the prevention and treatment of hormone‐dependent mammary cancer.
Local anaesthetic infiltration increases the accuracy of assessment of ulnar collateral ligament injuries
Authors: Cooper Jamie G , Johnstone Alan J , Hider Phil , Ardagh Michael W
Published: March 2005

Objective:  To assess the effectiveness of a systematic examination of the ulnar collateral ligament (UCL) of the thumb metacarpophalangeal joint (MCPJ) prior to and post infiltration of local anaesthetic.

Methods:  During the study period from 24 October 2001 to 22 February 2002, 51 patients with clinical signs suggestive of UCL injuries were identified prospectively from initial ED attendances and attendances at a subsequent review clinic. Patients were formally assessed a mean of 6.6 days post injury. A single ED Senior House Officer carried out examination before and after direct infiltration of local anaesthetic around the site of injury. Stress radiography was also performed as the ‘gold standard’ diagnostic test of UCL instability.

Results:  Forty‐seven patients were enrolled in the study. When reviewed by the single observer, examination prior to and post local anaesthetic infiltration revealed a degree of joint stability in 28% (95% CI 16–43%) and 98% (95% CI 88–100%) cases, respectively, compared to the gold standard. Post infiltration, this technique had a specificity of 100% (95% CI 94–100%) and a sensitivity of 87.5% (95% CI 74–95%) (P < 0.001). Stress radiography offered additional information in one patient. A total of eight patients previously underdiagnosed in the ED were found to have unstable thumb MCPJs.

Conclusion:  This simple technique improves assessment of suspected UCL injuries approximately 1 week post injury. Further studies are indicated to determine its effectiveness in the ED immediately post injury.
Management of chronic heart failure: An old disease with a new face
Authors: Prendergast Heather M , Bunney E Bradshaw
Published: March 2005

Heart failure is a leading cause of morbidity and mortality. It affects over 5 million patients annually. There are an estimated 400 000–700 000 new cases diagnosed each year. The management of heart failure has changed significantly over the last decade. This review focuses on the pharmacologic management of systolic heart failure, and provides current recommendations for the practicing acute care provider.
Death by oral ingestion of iodine
Authors: Edwards Nicholas A , Quigley Paul , Hackett L Peter , James Ross
Published: March 2005

We report the clinical and toxicological features of a case of fatal iodine ingestion, and summarize the physiology, clinical characteristics and management of iodine ingestion. Physicians are likely to have little experience in managing such patients, particularly with the advent of less toxic preparations, and therefore need ready access to management guidelines. This case also highlights the potential for substances to retain their toxicity over long periods of time.
A Robust Structural Stress Method for Fatigue Analysis of Offshore/Marine Structures
Authors: Dong P.
Published: March 2005

Recent rapid advances in developing mesh-insensitive structural stress methods are summarized in this paper. The new structural stress methods have been demonstrated to be effective in reliably calculating structural stresses that can be correlated with fatigue behavior from simple weld details to complex structures. As a result, a master S–N curve approach has been developed and validated by a large amount of weld S–N data in the literature. The applications of the present structural stress methods in a number of joint types in offshore/marine structures will be illustrated in this paper. The implications on future applications in drastically simplifying fatigue design and evaluation for offshore/marine structures will also be discussed, particularly for using very coarse finite element mesh designs in ship structures.
The Interaction Between Steep Waves and a Vertical, Surface-Piercing Column
Authors: Sheikh Rizwan , Swan Chris
Published: March 2005

This paper describes new laboratory observations concerning the interaction between a series of steep incident waves and a vertical, surface-piercing, column. The motivation for the study arose as a result of wave impact damage sustained to the undersides of several concrete gravity-based structures in the northern North Sea. Earlier work, [Swan et al. Appl. Ocean. Res. 19, pp. 309–327 (1997)], demonstrated that in the case of multiple column structures, the individual diameters of which lie outside the typical (linear) diffraction regime, there exists a new and previously unexpected mechanism leading to the scattering of high-frequency waves. Although the implications of this effect was carefully documented, not least because it explained the occurrence of wave impacts in relatively moderate seas, its physical origins remained unclear. In particular, it was uncertain whether this type of scattering would be observed in the case of a single column, or whether it results from the transmission of wave modes trapped between the legs of a multiple column structure. In the case of a single column, if the diameter, D, is such that the flow lies within the drag-inertia regime, D/λ<0.2, where λ is the corresponding wavelength, linear diffraction theory suggests there will be little or no scattered wave energy. The present laboratory observations demonstrate that this is not, in fact, the case. If the incident waves are steep, a strong and apparently localized interaction is clearly observed at the water surface. This, in turn, leads to the scattering of high-frequency waves. Although these waves are relatively small in amplitude, their subsequent interaction with other steep incident waves takes the form of a classic long-wave short-wave interaction and can produce a significant increase in the maximum crest elevation relative to those recorded in the absence of the structure. The present paper will demonstrate that the scattering of these high-frequency waves, and their subsequent nonlinear interaction with other incident waves, has significant implications for the specification of an effective air-gap and hence for the setting of deck elevations.
Coupled Analysis of a Spar Structure: Monte Carlo and Statistical Linearization Solutions
Authors: Spanos Pol D. , Ghosh Rupak , Finn Lyle D. , Halkyard John
Published: March 2005

The response of a combined dynamic system consisting of a Spar, a mooring line system, and top tension risers is presented. The top tension of a riser is provided by a buoyancy-can that is laterally supported by a preloaded compliant guide. The overall system is nonlinear due to the mooring line restoring force, the friction between the buoyancy-cans and the compliant guides, and the friction between the risers and the guides at the Spar keel. The friction between the Spar and the riser system is captured by a Coulomb model, whereas the stiffness of the mooring line system is accounted for by using a nonlinear regression analysis of pertinent load versus displacement data. The combined model is numerically integrated using input time histories of force and moment that are compatible with a random representation (Jonswap spectrum) of a typical extreme environmental loading in the Gulf of Mexico. The input time histories of the force and the moment for the combined model are obtained at the center of gravity of the Spar by using a standard motion analysis program (MLTSIM). The numerical results of the time domain analysis of the combined model, in conjunction with ergodicity, are used for an associated Monte Carlo study. The Monte Carlo study provides useful information regarding the probability densities and the power spectra of various response components of the combined system. These results serve as a benchmark for additional analytical studies that call attention to the potential usefulness of the technique of statistical linearization for efficient dynamic analyses of preliminary design decisions regarding the combined Spar–Risers–Mooring lines system.
Report on the 14th Annual Meeting of the German Society for Geriatric Research
Authors: Scheckhuber Christian
Published: March 2005

Members of the German Society for Geriatric Research (Deutsche Gesellschaft für Alternsforschung) and various invited speakers met in Karlsruhe, Germany, in November 2004 to discuss new findings and exchange views on intriguing problems in the broad field of aging research. This report summarizes some of the diverse topics that arose at the meeting, including diapause in insects, mitochondrial morphology in fungi, the production of reactive oxygen species, neurogenesis, and age-dependent changes of the cardiac system in mammals.
Outrunning Alzheimer's Disease
Authors: Leslie Mitch
Published: March 2005

A mile or two a day might keep plaques at bay, if the results of a new rodent study hold true for humans. The research reveals that mice that got off their furry little duffs amassed fewer of the brain-clogging globs seen in Alzheimer's disease patients. Activity apparently rouses an enzyme that destroys the plaque protein and spurs other salutary molecular changes in the brain.
Diabetes and Stem Cell Researchers Turn to the Lowly Spleen
Authors: Kodama Shohta , Davis Miriam , Faustman Denise L.
Published: March 2005

The spleen gets no respect. Long seen as superfluous, the adult spleen of the mouse has recently been shown to hold stem cells that, in diabetic mice or genetically altered mice that lack a pancreas, effectively regenerate insulin-producing islet cells of the pancreas. Stem cells of the spleen express Hox11, a highly conserved transcription factor that plays a major role in the development of organs in vertebrate and invertebrate embryos.Hox11and other members of the Hox family of genes may give stem cells of the spleen the capacity to mature into cell types other than islet cells, including neurons and bone cells. Multilineage splenic stem cells may trace to the embryogenesis and possible persistence into adulthood of a fetal stem cell region called the aorta-gonad-mesonephros (AGM). This Perspective calls for reappraisal of the lowly spleen for treating diabetes and other diseases of aging.
Led Astray
Authors: Leslie Mitch
Published: March 2005

Cells that have lost the ability to divide are like those bad kids your mother warned you to avoid. They corrupt young cells, disrupting the growth and specialization of fresh tissue, according to new research. Rising numbers of these stagnant cells might explain why our bodies don't work as well in our golden years.
The Better to See You With
Authors: Leslie Mitch
Published: March 2005

Wisdom may increase with age, but vision typically deteriorates. However, new work suggests that one visual ability improves: detecting the movement of certain types of patterns. The counterintuitive outcome might stem from a communication breakdown between visual neurons.
Drug Discovery in Neurodegenerative Diseases
Authors: Geerts Hugo , Trojanowski John Q. , Lee Virginia M.-Y.
Published: March 2005

This meeting report documents the exciting ongoing research aimed at developing new therapeutic agents for neurodegenerative diseases at the interface between academia and industry, and illustrates the direction the NIH "roadmap" for medical research is taking. Some of the projects have resulted in very promising drugs, identified and developed by academic centers, entering clinical trials.
Now Hear This
Authors: Leslie Mitch
Published: March 2005

Like the understudy who backs up the veteran star of a Broadway musical, some ear cells are ready to replace the sound-sensing cells that falter with age. All they need is the right stimulation, a new study suggests. The work shows that gene therapy induces deaf animals to spawn new sound-sensitive cells. The technique could eventually lead to remedies for age-related hearing loss.
Short Circuit, Long Life
Authors: Davenport R. John
Published: March 2005

Dimming the lights can extend a bulb's life. Similarly, a protein that turns down the current running through cellular power plants prolongs fly survival, new results reveal. The protein works by squelching the production of noxious oxidants.
Gene Regulation at the Single-Cell Level
Authors: Rosenfeld Nitzan , Young Jonathan W. , Alon Uri , Swain Peter S. , Elowitz Michael B.
Published: March 2005

The quantitative relation between transcription factor concentrations and the rate of protein production from downstream genes is central to the function of genetic networks. Here we show that this relation, which we call the gene regulation function (GRF), fluctuates dynamically in individual living cells, thereby limiting the accuracy with which transcriptional genetic circuits can transfer signals. Using fluorescent reporter genes and fusion proteins, we characterized the bacteriophage lambda promoter P
R
in
Escherichia coli
. A novel technique based on binomial errors in protein partitioning enabled calibration of in vivo biochemical parameters in molecular units. We found that protein production rates fluctuate over a time scale of about one cell cycle, while intrinsic noise decays rapidly. Thus, biochemical parameters, noise, and slowly varying cellular states together determine the effective single-cell GRF. These results can form a basis for quantitative modeling of natural gene circuits and for design of synthetic ones.
Introduced Predators Transform Subarctic Islands from Grassland to Tundra
Authors: Croll D. A. , Maron J. L. , Estes J. A. , Danner E. M. , Byrd G. V.
Published: March 2005

Top predators often have powerful direct effects on prey populations, but whether these direct effects propagate to the base of terrestrial food webs is debated. There are few examples of trophic cascades strong enough to alter the abundance and composition of entire plant communities. We show that the introduction of arctic foxes (
Alopex lagopus
) to the Aleutian archipelago induced strong shifts in plant productivity and community structure via a previously unknown pathway. By preying on seabirds, foxes reduced nutrient transport from ocean to land, affecting soil fertility and transforming grasslands to dwarf shrub/forb-dominated ecosystems.
A New Population of Very High Energy Gamma-Ray Sources in the Milky Way
Authors: Aharonian F. , Akhperjanian A. G. , Aye K.-M. , Bazer-Bachi A. R. , Beilicke M. , Benbow W. , Berge D. , Berghaus P. , Bernlöhr K. , Boisson C. , Bolz O. , Borgmeier C. , Braun I. , Breitling F. , Brown A. M. , Gordo J. Bussons , Chadwick P. M. , Chounet L.-M. , Cornils R. , Costamante L. , Degrange B. , Djannati-Ataï A. , Drury L. O'C. , Dubus G. , Ergin T. , Espigat P. , Feinstein F. , Fleury P. , Fontaine G. , Funk S. , Gallant Y. A. , Giebels B. , Gillessen S. , Goret P. , Hadjichristidis C. , Hauser M. , Heinzelmann G. , Henri G. , Hermann G. , Hinton J. A. , Hofmann W. , Holleran M. , Horns D. , de Jager O. C. , Jung I. , Khélifi B. , Komin Nu. , Konopelko A. , Latham I. J. , Le Gallou R. , Lemière A. , Lemoine M. , Leroy N. , Lohse T. , Marcowith A. , Masterson C. , McComb T. J. L. , de Naurois M. , Nolan S. J. , Noutsos A. , Orford K. J. , Osborne J. L. , Ouchrif M. , Panter M. , Pelletier G. , Pita S. , Pühlhofer G. , Punch M. , Raubenheimer B. C. , Raue M. , Raux J. , Rayner S. M. , Redondo I. , Reimer A. , Reimer O. , Ripken J. , Rob L. , Rolland L. , Rowell G. , Sahakian V. , Saugé L. , Schlenker S. , Schlickeiser R. , Schuster C. , Schwanke U. , Siewert M. , Sol H. , Steenkamp R. , Stegmann C. , Tavernet J.-P. , Terrier R. , Théoret C. G. , Tluczykont M. , van der Walt D. J. , Vasileiadis G. , Venter C. , Vincent P. , Visser B. , Völk H. J. , Wagner S. J.
Published: March 2005

Very high energy γ-rays probe the long-standing mystery of the origin of cosmic rays. Produced in the interactions of accelerated particles in astrophysical objects, they can be used to image cosmic particle accelerators. A first sensitive survey of the inner part of the Milky Way with the High Energy Stereoscopic System (HESS) reveals a population of eight previously unknown firmly detected sources of very high energy γ-rays. At least two have no known radio or x-ray counterpart and may be representative of a new class of “dark” nucleonic cosmic ray sources.
Light Scattering to Determine the Relative Phase of Two Bose-Einstein Condensates
Authors: Saba M. , Pasquini T. A. , Sanner C. , Shin Y. , Ketterle W. , Pritchard D. E.
Published: March 2005

We demonstrated an experimental technique based on stimulated light scattering to continuously sample the relative phase of two spatially separated Bose-Einstein condensates of atoms. The phase measurement process created a relative phase between two condensates with no initial phase relation, read out the phase, and monitored the phase evolution. This technique was used to realize interferometry between two trapped Bose-Einstein condensates without need for splitting or recombining the atom cloud.
Glycan Foraging in Vivo by an Intestine-Adapted Bacterial Symbiont
Authors: Sonnenburg Justin L. , Xu Jian , Leip Douglas D. , Chen Chien-Huan , Westover Benjamin P. , Weatherford Jeremy , Buhler Jeremy D. , Gordon Jeffrey I.
Published: March 2005

Germ-free mice were maintained on polysaccharide-rich or simple-sugar diets and colonized for 10 days with an organism also found in human guts,
Bacteroides thetaiotaomicron
, followed by whole-genome transcriptional profiling of bacteria and mass spectrometry of cecal glycans. We found that these bacteria assembled on food particles and mucus, selectively induced outer-membrane polysaccharide-binding proteins and glycoside hydrolases, prioritized the consumption of liberated hexose sugars, and revealed a capacity to turn to host mucus glycans when polysaccharides were absent from the diet. This flexible foraging behavior should contribute to ecosystem stability and functional diversity.
Noise Propagation in Gene Networks
Authors: Pedraza Juan M. , van Oudenaarden Alexander
Published: March 2005

Accurately predicting noise propagation in gene networks is crucial for understanding signal fidelity in natural networks and designing noise-tolerant gene circuits. To quantify how noise propagates through gene networks, we measured expression correlations between genes in single cells. We found that noise in a gene was determined by its intrinsic fluctuations, transmitted noise from upstream genes, and global noise affecting all genes. A model was developed that explains the complex behavior exhibited by the correlations and reveals the dominant noise sources. The model successfully predicts the correlations as the network is systematically perturbed. This approach provides a step toward understanding and manipulating noise propagation in more complex gene networks.
The Gut and Energy Balance: Visceral Allies in the Obesity Wars
Authors: Badman Michael K. , Flier Jeffrey S.
Published: March 2005

In addition to digesting and assimilating nutrients, the intestine and associated visceral organs play a key sensing and signaling role in the physiology of energy homeostasis. The gut, the pancreatic islets of Langerhans, elements in the portal vasculature, and even visceral adipose tissue communicate with the controllers of energy balance in the brain by means of neural and endocrine pathways. Signals reflecting energy stores, recent nutritional state, and other parameters are integrated in the central nervous system, particularly in the hypothalamus, to coordinate energy intake and expenditure. Our understanding of regulatory neural circuits and the signaling molecules that influence them has progressed rapidly, particularly after the discovery of the adipocyte hormone leptin. These discoveries have led to exploration of novel routes for obesity control, some of which involve gut-derived pathways.
Place Matters
Authors: Sarkar Sahotra
Published: March 2005

Frontiers of Biogeography
New Directions in the Geography of Nature.
Mark V. Lomolino and Lawrence R. Heaney, Eds.
. Sinauer Associates, Sunderland, MA, 2004. 448 pp. $79.95, £51.99. ISBN 0-87893-479-0. Paper, $49.95, £31.99. ISBN 0-87893-478-2.

Besides reviewing developments in historical, island, and marine biogeography, the contributors explore newly emerged fields such as phylogeography, macroecology, and the applications of biogeography in conservation biology.
Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) for Studying Dynamics of Protein Abundance and Posttranslational Modifications
Authors: Amanchy Ramars , Kalume Dario Eluan , Pandey Akhilesh
Published: March 2005

Stable isotope labeling with amino acids in cell culture (SILAC) is a simple and straightforward approach for in vivo incorporation of a tag into proteins for relative quantitation by mass spectrometry. SILAC is a simple, yet powerful, method for investigating the dynamics of protein abundance and posttranslational modifications. Here, we provide detailed instructions for using this method to study protein complexes, protein-protein interactions, and the dynamics of protein abundance and posttranslational modifications. We expect that SILAC will become a routine technique because of its applicability to most areas of cell biology. We have also developed a Web site (
http://www.silac.org
) to provide researchers with updated information about this method and related resources.
Calcium-Triggered Exocytosis and Clathrin-Mediated Endocytosis of Synaptic Vesicles
Authors: Galli Thierry , Haucke Volker
Published: March 2005

The animation illustrates the recruitment, calcium-triggered exocytosis, and clathrin-mediated endocytosis of synaptic vesicles. The animation shows not only the proteins involved in synaptic vesicle fusion and recycling, but also changes in the lipid composition that are important for targeting of proteins to sites of membrane internalization. The animation would be useful in both neurobiology courses, but also any cell biology course that explores clathrin-mediated endocytic and calcium-regulated secretion events.
Diabetes Outfoxed by GLP-1?
Authors: Holz George G. , Chepurny Oleg G.
Published: March 2005

Foxo1, a member of the Fox0 subfamily of winged-helix forkhead transcription factors, is a target of insulin and insulin-like growth factor–1 (IGF-1) signal transduction pathways that activate protein kinase B (PKB) in pancreatic β cells. Foxo1 is a substrate for PKB, and its phosphorylation results in nuclear exclusion with concomitant alterations in gene expression that are important to cellular growth and differentiation. Because activation of PKB can require insulin receptor substrate proteins (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase (PI3K), it is of interest to determine whether the activity of Foxo1 is also regulated by heterotrimeric G protein–coupled receptors (GPCRs) with IRS-1 or -2, PI3K, or PKB signaling potential. Indeed, studies of β cells have demonstrated that activation of a GPCR for the blood glucose–lowering hormone GLP-1 leads to major alterations of IRS-2, PI3K, and PKB activity. By promoting nuclear exclusion of Foxo1 in a PKB-mediated manner, GLP-1 may up-regulate the expression of a homeodomain transcription factor (PDX-1) that serves as a master regulator of β-cell growth and differentiation. This STKE Perspective summarizes signaling properties of GLP-1 that may explain its ability to increase β-cell mass, to increase pancreatic insulin secretory capacity, and to lower levels of blood glucose in type 2 diabetic subjects.
Alpha Subunit Position and GABA Receptor Function
Authors: Burt David R.
Published: March 2005

GABA
A
(γ-aminobutyric acid type A) receptors are ligand-gated ion channels composed of five subunits, generally two αs, two βs, and a γ2. Recent research in which sets of subunits containing α1 or α6 subunits were artificially linked has revealed the importance of subunit position in determining GABA
A
receptor function. Sensitivity to benzodiazepines depended on juxtaposition of an α1 subunit with the γ2 subunit, whereas sensitivity to furosemide depended only on the presence of an α6 subunit and not on its specific location. The major utility of the linked subunit approach is to provide a mechanism for discovering the functional signatures of defined subunit arrangements, and thus a route to identifying such arrangements in vivo.
Xenopus
Egg Wnt/β-Catenin Pathway
Authors: Moon Randall T.
Published: March 2005

In embryonic development in vertebrates, β-catenin signaling promotes polarization of the embryo to establish the dorsoventral axis, and it is this process that is highlighted by the
Xenopus
Egg Wnt/β-Catenin Pathway. In the amphibian
Xenopus
, fertilization of the egg results in the establishment of a parallel array of microtubules with the plus end pointing away from the sperm entry point. Concurrent with a process of cortical rotation, in which the cortex of the egg utilizes these microtubules to rotate relative to the inner cytoplasm, there is a movement of small vesicles toward the plus end of the microtubules. Cells inheriting these vesicles are destined to give rise to dorsal and anterior structures of the embryo. Three components of the Wnt/β-catenin pathway—Dishevelled, glycogen synthase kinase 3 (GSK-3)-binding protein (GBP), and β-catenin—accumulate on the side of the egg and early embryo that receive these small vesicles. It is likely that Dishevelled and GBP are associated with the vesicles that move along the microtubules and that they promote the stabilization and dorsal accumulation of β-catenin. Although Wnts and Frizzled are present in the egg, their roles in axis specification remain unclear. Dorsal β-catenin then activates direct target genes, including the homeobox genes
siamois
and
twinned
. Activation of these genes on the prospective dorsal side is necessary and sufficient for formation of the gastrula organizer, which organizes the embryonic germ layers and axes.
Ras-MAPK Pathways
Authors: Chan Andrew
Published: March 2005

This Teaching Resource provides lecture notes and slides for a class covering three kinase-mediated signaling pathways and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The focus is three major signaling cascades that are implicated in cell proliferation, survival, and stress response. They are, respectively, the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and Jun N-terminal kinase (JNK) cascades. The aim of this lecture is to review the major players of these intracellular signaling cascades in mammalian cells. In addition, emphasis is placed on understanding the dynamic, rather than linear, nature of signal transduction in determining cellular responses to external stimuli.
TRAF2: A Double-Edged Sword?
Authors: Xia Zong-Ping , Chen Zhijian J.
Published: March 2005

Ubiquitination is best known for its role in targeting proteins for degradation by the proteasome, but evidence of the nonproteolytic functions of ubiquitin is also rapidly accumulating. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor–associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K
63
)–linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism. Some TRAF proteins, such as TRAF2 and TRAF3, have recently been shown to have a positive role in the canonical pathway that activates nuclear factor κB (NF-κB) through IκB kinase β (IKKβ), but a negative role in the noncanonical pathway that activates NF-κB through IKKα. These opposing roles of TRAF proteins may be linked to their ability to synthesize distinct forms of polyubiquitin chains. Indeed, the TRAF2-interacting protein RIP can mediate IKK activation when it is modified by K
63
polyubiquitin chains, but is targeted to degradation by the proteasome when it is K
48
-polyubiquitinted by the NF-κB inhibitor A20. Thus, ubiquitin chains are dynamic switches that can influence signaling outputs in dramatically different ways.
Growth Factor and Receptor Tyrosine Kinases
Authors: Aaronson Stuart
Published: March 2005

This Teaching Resource provides lecture notes and slides for a graduate-level class on ligand regulation of signaling by receptor tyrosine kinases and receptors involved in the Wnt canonical pathway. It is part of a series of lectures that constitute the Cell Signaling Systems course. A description of the lecture, along with a set of slides used to present this information, is provided.
Swapping Molecules During Cell-Cell Interactions
Authors: Sprent Jonathan
Published: March 2005

Interactions between cells of the immune system can lead to intercellular exchange of cell-surface molecules. Recent studies indicate that such exchange can be bidirectional when natural killer cells interact with their target cells. Sprent reviews the mechanisms involved in cell-cell molecular transfer and the receptor-ligand interactions involved.
Progress from the Postsynaptic Side: Signaling in Synaptic Differentiation
Authors: Biederer Thomas
Published: March 2005

The signals mediating synaptic differentiation are critical for our understanding of synapse formation and nervous system development. Recent progress highlights the roles of membrane-bound and soluble signaling pathways in this process. The postsynaptic adhesion molecules neuroligin-1, neuroligin-2, and SynCAM1 provide target-derived signals leading to the assembly of presynaptic terminals. In the reverse direction, neuroligins also relay signals into postsynaptic sites through interactions with their presynaptic partners, the β-neurexins. This adhesion-based system helps to determine the neurotransmitter specificity of postsynaptic specializations. In addition, soluble molecules are released from target neurons and initiate presynaptic differentiation, as demonstrated for the fibroblast growth factor FGF-22. This Perspective summarizes new insights into early synaptic differentiation signals and discusses underlying principles.
Protein Domains that Interact with Receptor Tyrosine Kinases: Structural Aspects
Authors: Zhou Ming-Ming
Published: March 2005

This Teaching Resource provides lecture notes and slides for a class covering insights gained from structural analysis of the regulation of receptor tyrosine kinases and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with an overview of the many protein domains thus far implicated in cell signaling and then describes in detail the phosphotyrosine-binding domain (PTB). The application of structural information to rational drug design by targeting protein interaction domains is also covered.
Utilizing the Split-Ubiquitin Membrane Yeast Two-Hybrid System to Identify Protein-Protein Interactions of Integral Membrane Proteins
Authors: Iyer Kavitha , Bürkle Lukas , Auerbach Daniel , Thaminy Safia , Dinkel Martin , Engels Kim , Stagljar Igor
Published: March 2005

Various modifications of the conventional yeast two-hybrid system have played an essential role in confirming or detecting protein-protein interactions among nuclear and cytoplasmic proteins. These approaches have permitted the identification of novel interaction partners, as well as provided hints as to their function. However, membrane proteins, such as receptor tyrosine kinases, G protein–coupled receptors, membrane-bound phosphatases, and transporters, which represent important classes of signaling molecules, are difficult to study using classical protein interaction assays because of their hydrophobic nature. Here, we describe a genetic system that allows the identification of integral membrane-interacting proteins. This so-called "split-ubiquitin membrane-based yeast two-hybrid assay" involves fusing the halves of ubiquitin to two interacting proteins, at least one of which is membrane bound. Upon interaction of these two proteins, the halves of ubiquitin are brought together, and the transcription factor that is fused to a membrane protein of interest is cleaved and released. The free transcription factor then enters the nucleus and activates transcription of reporter genes. We also describe how this technology is used to screen complementary DNA libraries to identify novel binding partners of a membrane protein of interest.
Ethylene Signaling Pathway
Authors: Stepanova Anna N. , Alonso Jose M.
Published: March 2005

The structural simplicity of the plant hormone ethylene contrasts with its dramatic effects in various developmental processes, as well as in the cellular processes that ethylene initiates in response to a diversity of environmental signals. A single well-conserved signaling cascade mediates this broad spectrum of responses. Ethylene is perceived by a family of two-component histidine kinase receptors that become inactivated upon ethylene binding. In the absence of the hormone, the receptors activate CTR1, a negative regulator of ethylene responses. Sequence similarity between CTR1 and the Raf protein kinases implies involvement of a mitogen-activated protein kinase cascade in this signaling pathway. The protein EIN2 acts downstream of CTR1 and the possible kinase cascade. Although the biochemical function of EIN2 is not understood, its critical role is manifested by the complete ethylene insensitivity of
EIN2
loss-of-function mutants. Downstream of EIN2, a family of plant-specific EIN3-like transcription factors mediate ethylene responses. The regulation of EIN3 stability by ethylene is accomplished by F-box–containing proteins that participate in the formation of a SKP1/cullin/F-box complex that targets proteins for degradation by the proteasome. A large number of ethylene-regulated genes have been identified, including the APETALA2 domain–containing transcription factor genes
ERF1
and
EDF1
to
4
, which suggests the participation of a transcriptional cascade in the ethylene response. The differential regulation of some components of this complex nuclear cascade by other signaling pathways provides a possible mechanism for interaction and signal integration. As new points of intersection with other pathways and additional participants in the pathway are identified, the Connections Map will be updated to include this new information.