bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond affect: A role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task
Authors: Canli Turhan , Omura Kazufumi , Haas Brian W. , Fallgatter Andreas , Constable R. Todd , Lesch Klaus Peter
Published: August 2005

Prior work has highlighted the role of genetic variation within the repetitive sequence in the transcriptional control region of the serotonin (5-HT) transporter gene (
5-HTT
,
SLC6A4
) in modulating amygdala and prefrontal activation to negative emotional stimuli. However, these studies have not explicitly tested the assumption that the control condition (neutral baseline) does not itself produce changes in activation as a function of
5-HTT
genotype. Using a fixation baseline condition, we show that variation in
5-HTT
genotype is associated with differential activation to negative, positive, and neutral stimuli in limbic, striatal, and cortical regions. We replicate earlier reports of increased amygdala activation to negative, relative to neutral, stimuli, but then show that these differences are driven by decreased activation to neutral stimuli, rather than increased activation to negative stimuli, in carriers of the
5-HTT
short allele. Using high-resolution structural images and automated processes to test for brain volume and gray matter density, we further report significant differences, as a function of
5-HTT
genotype, in frontal cortical regions, anterior cingulate, and cerebellum. These functional and structural differences suggest a much broader role for 5-HT transport efficiency in brain processes than previously thought.
5-HTT
genotype affects neural systems controlling affective, cognitive, and motor processes.
Atomic resolution structures of resting-state, substrate- and product-complexed Cu-nitrite reductase provide insight into catalytic mechanism
Authors: Antonyuk Svetlana V. , Strange Richard W. , Sawers Gary , Eady Robert R. , Hasnain S. Samar
Published: August 2005

Copper-containing nitrite reductases catalyze the reduction of nitrite to nitric oxide (NO), a key step in denitrification that results in the loss of terrestrial nitrogen to the atmosphere. They are found in a wide variety of denitrifying bacteria and fungi of different physiology from a range of soil and aquatic ecosystems. Structural analysis of potential intermediates in the catalytic cycle is an important goal in understanding enzyme mechanism. Using “crystal harvesting” and substrate-soaking techniques, we have determined atomic resolution structures of four forms of the green Cu-nitrite reductase, from the soil bacterium
Achromobacter cycloclastes
. These structures are the resting state of the enzyme at 0.9 Å, two species exhibiting different conformations of nitrite bound at the catalytic type 2 Cu, one of which is stable and also has NO present, at 1.10 Å and 1.15 Å, and a stable form with the product NO bound side-on to the catalytic type 2 Cu, at 1.12 Å resolution. These structures provide incisive insights into the initial binding of substrate, its repositioning before catalysis, bond breakage (O–NO), and the formation of a stable NO adduct.
Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation
Authors: Teo Jia-Ling , Ma Hong , Nguyen Cu , Lam Crystal , Kahn Michael
Published: August 2005

Wnt/β-catenin signaling has been shown to promote self-renewal in a variety of tissue stem cells, including neuronal stem cells and hematopoietic stem cells. However, activation of the Wnt/β-catenin pathway promoted and inhibition of the pathway prevented differentiation of neuronal precursor cells. A clear explanation for the differential effects of Wnt/β-catenin activation on neuronal precursors is not available at present. Presenilin-1 (PS-1) is a polytopic protein comprised of six to eight transmembrane domains. PS-1, as part of the γ-secretase complex, is required for the intramembrane proteolysis of both amyloid precursor protein (APP) and Notch. Additionally, through interactions with β-catenin, PS-1 is associated with modulation of Wnt/β-catenin signaling. A familial Alzheimer's disease-associated PS-1 mutant, PS-1(L286V), causes a dramatic increase in T cell factor (TCF)/β-catenin transcription in PC-12 cells, which prevents normal nerve growth factor (NGF)-induced neuronal differentiation and neurite outgrowth. Selective inhibition of TCF/β-catenin/cAMP-response element-binding protein (CREB)-binding protein (CBP)-mediated transcription, but not TCF/β-catenin/p300, with the recently described small molecule antagonist ICG-001 corrects these defects in neuronal differentiation, highlighting the importance of Wnt/β-catenin signaling in this process. We propose that increased TCF/β-catenin/CBP-mediated transcription, as well as a failure to switch to TCF/β-catenin/p300-mediated transcription, play an important role in decreasing neuronal differentiation.
HOXB4 enforces equivalent fates of ES-cell-derived and adult hematopoietic cells
Authors: Pilat Sandra , Carotta Sebastian , Schiedlmeier Bernhard , Kamino Kenji , Mairhofer Andreas , Will Elke , Modlich Ute , Steinlein Peter , Ostertag Wolfram , Baum Christopher , Beug Hartmut , Klump Hannes
Published: August 2005

Genetic manipulation of hematopoietic stem and progenitor cells is an important tool for experimental and clinical applied hematology. However, techniques that allow for gene targeting, subsequent
in vitro
selection, and expansion of genetically defined clones are available only for ES cells. Such molecularly defined and, hence, “safe” clones would be highly desirable for somatic gene therapy. Here, we demonstrate that
in vitro
differentiated ES cells completely recapitulate the growth and differentiation properties of adult bone marrow cells,
in vitro
and
in vivo
, when ectopically expressing HOXB4. Myeloid development was enforced and (T) lymphoid development suppressed over a wide range of expression levels, whereas only high expression levels of the transcription factor were detrimental for erythroid development. This indicates a close association between the amounts of ectopic HOXB4 present within a progenitor cell and and the decision to self renew or differentiate. Because HOXB4 mediates similar fates of ES-derived and bone marrow hematopoietic stem cells, the primitive embryonic cells can be considered a promising alternative for investigating hematopoietic reconstitution,
in vivo
, based on well defined clones. Provided that HOXB4 levels are kept within a certain therapeutic window, ES cells also carry the potential of efficient and safe somatic gene therapy.
Vitamin requirements for term infants: considerations for infant formulae
Authors: Powers Hilary J.
Published: August 2005

Objective

To provide the informed health professional with an up to date evaluation of the current thinking regarding requirements for vitamins in infant feeds.

Establishing criteria for adequacy

Vitamin adequacy in the neonate is currently defined in terms of circulating levels of a vitamin or of the activity of a vitamin dependent enzyme in the erythrocytes. Although these measurements have their value there is a need to develop biochemical, physiological or clinical markers of well defined specific function. For some vitamins there is a risk of deleterious effects of very high intakes: risk of toxicity needs to be taken into consideration when making recommendations for inclusion in infant formulae.

Breast milk as the ‘gold standard’

Breast milk concentrations of vitamins have been used as the criteria of adequate intake by neonates. This may not always be justified. Greater consideration needs to be given to differences in bioavailability of vitamins from breast milk compared with formula feeds, of the influence of season, and of stage of lactation, on the stated composition.

Experimental approaches

Animal studies have provided limited information regarding effects of different levels of intakes on current status indices in the neonatal period. There are few reports of randomized controlled studies into the effects of different levels of vitamins and these rely heavily on biochemical criteria of adequacy.

Recent developments

The inclusion of β-carotene into formula feeds for premature babies is an issue of current interest. What is the justification for this? Are there potential benefits for the term infant? Riboflavin deficiency in the period around weaning may affect the normal structural and functional development of the gastrointestinal tract; some of these effects may be permanent.

Research to be done

A greater understanding of the absorption and metabolism of vitamins during infancy is required in order to help establish dietary requirements. The relative bioavailability of vitamins in human milk and formulae needs to be investigated. Criteria for vitamin adequacy should be extended to include measures of function. Information regarding the conversion factor from tryptophan to niacin in infancy would allow us to set niacin requirements with greater confidence. There is a particular lack of information about concentrations of biotin and pantothenic acid in breast milk and the relative biochemical status of infants receiving breast milk and formulae. Benefits of including β-carotene into infant formulae need to be evaluated. The role of individual micronutrients in the structural and functional development of the gastrointestinal tract should be explored.
Health effects of breast feeding for mothers: a critical review
Authors: Heinig M. Jane , Dewey Kathryn G.
Published: August 2005

Lactation results in a number of physiological adaptations which exert direct effects on maternal health, some of which may confer both short and long term advantages for breast feeding mothers. Breast feeding in the early postpartum period promotes a more rapid return of the uterus to its prepregnant state through the actions of oxytocin. Breast feeding may also lead to a more rapid return to prepregnancy weight. Among studies that had good data on duration and intensity of lactation, the majority show a significant association between lactation and weight loss. However, there is no evidence that lactation prevents obesity. Lactation also affects glucose and lipid metabolism. The long term effects of these adaptations are unknown but may have implications for preventing subsequent development of diabetes and heart disease. Lactation delays the return of ovulation and significantly reduces fertility during the period of lactational amenorrhoea. This process is linked with feeding patterns and may therefore be affected by practices such as scheduled feedings and the timing of introduction of complementary foods. While the evidence from epidemiologic studies is mixed, several large studies have shown that extended lactation is associated with reduced risk of premenopausal breast, ovarian and endometrial cancers. Although bone mineralization declines during lactation, repletion takes place after weaning. As a result, breast feeding does not appear to cause long term depletion of bone nor does it increase risk of osteoporosis. Many of the physiological effects of lactation are dependent on the stimulation of the hypothalamic-pituitary axis and milk removal and thus may vary with infant feeding practices. Well controlled studies are needed that include detailed information regarding infant feeding practices in addition to the total duration of any breast feeding. Future feeding recommendations should reflect careful consideration of how such practices affect both infant and maternal health.
Diet and haemostatic processes
Authors: Vorster Hester H. , Cummings John H. , Jerling Johann C.
Published: August 2005

Diet plays an important role in the primary and secondary prevention of cardiovascular disease. The growing perception that abnormal haemostatic processes of coagulation, platelet aggregation and fibrinolysis contribute to cardiovascular disease aetiology motivated this review on the relationships of diet, specific foods and nutrients with haemostatic function. Functional endpoints that reflect the function and status of some of these processes and which can be measured in dietary trials are identified. The effects of energy intake and expenditure, alcohol, total fat and specific fatty acids, non-starch polysaccharides (dietary fibre), antioxidant nutrients and some foods on a variety of haemostatic markers are reviewed. The results indicate that the prudent low-fat, high-fibre diet and maintenance of ideal body weight recommended to protect against and treat hyperlipidaemia and coronary heart disease will also benefit haemostatic profiles. It is concluded that more research on specific effects is needed for improved recommendations on a population level for prevention of cardiovascular disease.
Lactose digestion and maldigestion: implications for dietary habits in developing countries
Authors: Rosado Jorge L.
Published: August 2005

Milk is an important source of high quality protein, energy, calcium, potassium, phosphorus and riboflavin. It also has good functional properties and a highly acceptable taste, making milk a good alternative for the nutrition of children and for food programmes in developing countries. However, in some instances it has been advocated that milk or milk based products might not be appropriate for nutritional support, given the high prevalence of lactose intolerance among populations in those countries. After reviewing studies in different regions of the world it is concluded that:

1. Prevalence of lactose maldigestion in children and adults is significantly reduced, to less than half in most studies, when assessed with a dose of milk similar to that normally taken in the diet, as distinct from a large dose of lactose used in the lactose tolerance test.

2. Lactose intolerance as a result of consuming a glass of milk occurs only in a small proportion (about 30% in most studies) of lactose maldigesters. Even this small group can ingest smaller amounts of milk without adverse symptoms and there is good evidence that colonic metabolism in these people adapts to the presence of lactose to reduce or eliminate adverse symptoms.

3. Lactose maldigestion and intolerance in children in developing countries is more likely to exist in association with gastrointestinal damage associated with diarrhoea, malnutrition and/or infection.

4. There is no evidence to support a reduction or elimination of milk intake for people in developing countries because of lactose maldigestion or intolerance.
A review of the physiology of the canine digestive tract related to the development ofin vitrosystems
Authors: Smeets-Peeters Marianne , Watson Tim , Minekus Mans , Havenaar Robert
Published: August 2005

Food and nutrition studies in animals and human beings often meet with technical difficulties and sometimes with ethical questions. An alternative to research in living animals is the dynamic multicompartmentalin vitromodel for the gastrointestinal tract described by Minekuset al.(1995) and Havenaar & Minekus (1996). The dynamic conditions that are simulated in this model are peristaltic movements, transit times, pH responses, secretion of enzymes and electrolytes and absorption of nutrients and water. To obtain data for anin vitromodel of the dog gastrointestinal tract, the literature was surveyed for physiological responses to different types of dog food. These included: values of enzyme activities, electrolyte concentrations, gastric emptying and intestinal transit times, pH values, secretion and composition of bile and absorption rates in different parts of the dog gastrointestinal tract. The review focuses on research carried out on healthy, adult dogs of 10–20 kg and on parameters related to the oral cavity, stomach and small intestine. This literature research gives sufficient data on the physiology of the canine digestive tract for the development of anin vitrodynamic model that adequately simulates the functions of the stomach and small intestine of the dog.
Interaction between physical activity and nutrition early in life and their impact on later development
Authors: Pařízková Jana
Published: August 2005

It has been rare to find studies of the influence of nutrition on growth that have incorporated careful measurements of physical activity. This paper reviews interactions between physical activity and nutrition in early life and finds that such interactions have a significant influence on growth and later metabolism.

Young animals are generally characterized by a high level of spontaneous motor activity that contributes to a high rate of energy turnover in early life. Such activity varies greatly between species and individuals and can be increased by reduced (but not extreme) dietary intake especially of protein, with consequent effects on growth rate (slower), body composition (leaner), eventual body size (smaller), lifespan (longer), cardiac resistance to toxic substances (increased) and changes in body lipids. Most studies have been conducted with laboratory rats but the much smaller literature concerning human beings is also reviewed here.

In rats, exercise during pregnancy results in offspring that are smaller and leaner and there are later improvements in cardiac microstructure, cardiac resistance to toxic substances and lower plasma cholesterol and triacylglycerol concentrations.

In industrialized countries in recent years, children's fitness, especially of the cardiorespiratory system has not developed at the same pace as body size, or has deteriorated, whereas average body mass index (BMI) and the overall prevalence of obesity have increased. This is partly accounted for by reduced levels of physical activity but there is some evidence that higher intakes of dietary proteins in early life are also implicated. Much recent research has focused on the influence of nutrition in the prenatal and early postnatal period on later health. This review has also underlined the importance of exercise and its interaction with diet beginning with the pregnant mother and continuing through childhood. Development and wider use of simple but reliable methods for the evaluation of physical activity and fitness in young children is now an important priority.
Dietary triggers in irritable bowel syndrome
Authors: Shaw Allan D. , Brooks Jillian L. , Dickerson John W.T. , Davies G. Jill
Published: August 2005

Irritable bowel syndrome (IBS) is a frequently occurring, benign functional gastrointestinal disorder with a complex poorly understood pathology which appears to be multifactorial in nature. There is no association with structural or biochemical abnormalities in the gastrointestinal tract. Functional variations in myoelectrical activity, visceral hypersensitivity and illness behaviours have all been observed in patients experimentally. In conjunction with environmental, psychological and alimentary factors, these mechanisms have been proposed as the major determinants of symptom genesis. Certainly, dietary factors are frequently perceived by sufferers as powerful symptom triggers, with many reporting multiple food intolerance. Physicians, however, remain divided upon the relevance of food to the disorder, with many eschewing a nutritional connection. This is unsurprising as, despite much experimental work to determine the clinical relevance of food intolerance and allergy to the aetiology of the disorder, the vast range of foodstuffs available for testing, inherent procedural problems with test foods, methodological insufficiencies and the continually evolving knowledge of the disorder, particularly the subgrouping of sufferers, have restricted the scientific validity of current findings. At the present time, it is difficult to make informed judgement upon the importance of food in IBS, and rigorously designed, large scale trials devised in the light of recent knowledge are required before conclusions can be drawn.
Functional foods and health claims: a public health policy perspective
Authors: Lawrence Mark , Rayner Mike
Published: August 2005

Objective:

To propose a policy framework for the regulation of functional foods and health claims within a public health context.

Design:

This article reviews the empirical evidence and public health principles associated with functional foods and health claims to analyse the issues, challenge the assumptions that have emerged and explore options for moving forward.

Setting:

Functional foods and health claims are among the more controversial and complex issues being debated by food regulators internationally. Proponents of functional foods and health claims state that functional foods may reduce health care expenditure and health claims are a legitimate nutrition education tool that will help them inform consumers of the health benefits of certain food products. Conversely, opponents of these developments respond that it is the total diet that is important for health, not so-called ‘magic bullets’. Moreover, they argue that health claims will enable manufacturers to indulge in marketing hyperbole and essentially blur the distinction between food and drugs. This topic provides a valuable case study of public policy in relation to food and health.

Conclusion:

The need to maintain a general prohibition on health claims while accommodating specific exemptions supported by scientific substantiation is recommended. Nutrition education and monitoring and evaluation are integral to the proposed regulatory framework. The intention of this policy position is to encourage research and development of innovative food products while avoiding an inappropriate medicalization of the general food supply.
Dietary pattern, nutrient intake and growth of adolescent school girls in urban Bangladesh
Authors: Ahmed Faruk , Zareen Momtaz , Khan Moududur Rahman , Banu Cadi Pervin , Haq Mohammed Nazmul , Jackson Alan A
Published: August 2005

Objective:

To investigate the dietary pattern and nutritional status of adolescent girls attending schools in Dhaka city and to examine the association with various social factors.

Design:

Cross-sectional study.

Setting:

Girls high schools in Dhaka city.

Subjects:

A total of 384 girls, aged from 10 to 16 years, who were students of classes VI to IX of 12 girls high schools in Dhaka city were selected by systematic random sampling. Nutrient intake was assessed using the 24-h recall method and the usual pattern of food intake was examined using a 7-day food frequency questionnaire.

Results:

The prevalence of undernutrition among the participants assessed as stunting was 10% overall with younger girls being less stunted (2%) than older girls (16%), whereas 16% were thin with relatively more of the younger girls (21%) being thin than of the older girls (12%). Based on the usual pattern of food intake, a substantial proportion of the girls did not consume eggs (26%), milk (35%) or dark green leafy vegetables (20%). By comparison, larger proportions consumed meat (50%) and fish (65%) at least four times a week. For the intake of energy and protein, only 9 and 17% of the girls, respectively, met the recommended daily allowance (RDA). For nearly 77% of the girls, the intake of fat was less than the recommendation. Intakes less than the RDA were found for iron (77% of the girls), calcium (79%), vitamin A (62%), vitamin C (67%), and riboflavin (96%). Based on the food consumption data, cereals were the major source of energy (57%), thiamin (67%), niacin (63%) and iron (37%). Animal sources supplied 50% of dietary protein. Cooking fats were the principal source of fat (67%) in the diet. Milk was the major contributor for riboflavin and preformed vitamin A (retinol). Leafy vegetables and fruits were the main sources of provitamin A (carotenes). The girls from families with less educated parents were more likely to be thin and short for their age. Those girls from families with lower incomes and less educated parents had a dietary pattern which tended to be poor with regard to egg, milk, meat and fruit, with lower intakes of protein, fat and riboflavin.

Conclusion:

The findings indicate that the diets of these girls tended to be inadequate both for macronutrients and micronutrients, with significant health implications. There was also a relationship between the family income and the education of the parents with the nutritional status of the girls.
Wernicke–Korsakoff syndrome in Sydney hospitals after 6 years of thiamin enrichment of bread
Authors: Rolland S , Truswell AS
Published: August 2005

Objective:

To estimate the incidence of Wernicke's encephalopathy (WE) and Korsakoffs psychosis (KP) before and after the introduction of thiamin enrichment of bread in Australia.

Design and subjects:

Inpatient records were examined in 17 major public general hospitals in greater Sydney for the 4 years 1993–96 (inclusive) with the International Classification of Diseases (ICD) 9 diagnoses 265.1 (WE), 291.1 and 294.0 (KP). Relevant clinical data were recorded on a specially designed form so that cases could be classified as confirmed or probable WE, confirmed or probable KP, confirmed or probable Wernicke–Korsakoff syndrome (WE + KP) or not WE or KP. The average number of cases of WE + KP was 38 acute (new) cases and 69 total (acute+chronic) cases per annum for all the hospitals combined.

Results:

This study used the same methods as our earlier retrospective examination of Wernicke–Korsakoff cases in essentially the same hospitals for 1978–93. Records for 1993 were thus pulled twice and, while individual cases (using hospital index number) did not always coincide, the total numbers for 1993 were 69 and 70.

For the 5 years after 1991 the number of acute cases of WE and KP in Sydney hospitals was 61% of the number for the 5 years before 1991 (P<0.01). There is, however, no continuing downward trend.

Conclusions:

These results are consistent with a 40% reduction of the incidence of acute WE and KP since bread has been enriched with thiamin. The disease complex has, however, not been eliminated. To achieve this, further public health action would be needed, such as addition of thiamin to beer.
It looks easy! Heuristics for combinatorial optimization problems
Authors: Chronicle Edward P. , MacGregor James N. , Ormerod Thomas C. , Burr Alistair
Published: August 2005

Human performance on instances of computationally intractable optimization problems, such as the travelling salesperson problem (TSP), can be excellent. We have proposed a boundary-following heuristic to account for this finding. We report three experiments with TSPs where the capacity to employ this heuristic was varied. In Experiment 1, participants free to use the heuristic produced solutions significantly closer to optimal than did those prevented from doing so. Experiments 2 and 3 together replicated this finding in larger problems and demonstrated that a potential confound had no effect. In all three experiments, performance was closely matched by a boundary-following model. The results implicate global rather than purely local processes. Humans may have access to simple, perceptually based, heuristics that are suited to some combinatorial optimization tasks.
Dual route for subtask order control: Evidence from the psychological refractory paradigm
Authors: Luria Roy , Meiran Nachshon
Published: August 2005

A change in subtask order in the psychological refractory period (PRP) paradigm increases the effect of stimulus onset asynchrony (SOA) on the second response. We used a paradigm with cued, randomly determined subtask order to test the hypothesis that this SOA by order switch overadditivity reflects order control, via “copying” stimulus order. In Experiments 1a and 1b, overadditivity was evident only with insufficient opportunity for cue-based order control. In Experiment 2, overadditivity was decreased by using the same set of stimuli in the two subtasks, presumably by removing the opportunity to rely on stimulus order. In Experiment 3, removing the order cue increased the overadditivity, presumably because control was based solely upon copying stimulus order. The results indicate interactive top-down and bottom-up order control. Implications to theories of the PRP paradigm are discussed.
Stimulus generalization of excitation and inhibition
Authors: Rescorla Robert A.
Published: August 2005

Five sign-tracking experiments with pigeons investigated the breadth of stimulus generalization of excitatory and inhibitory conditioning. Using a compound stimulus test procedure, these experiments found evidence for a narrower generalization of associative strength in excitation than in inhibition. They also found a narrower associative gradient with a more strongly conditioned excitatory stimulus, although this did not seem to account for the difference between exciters and inhibitors. These results confirm earlier findings comparing generalization after acquisition and extinction and raise various theoretical issues about generalization.
Orbites Nilpotentes Sphériques et Représentations unipotentes associées: Le cas 𝑆𝐿_𝑛
Authors: Sabourin Hervé
Published: August 2005

LetGGbe a real simple Lie group andg\mathfrak {g}its Lie algebra. Given a nilpotent adjointGG-orbitOO, the question is to determine the irreducible unitary representations ofGGthat we can associate toOO, according to the orbit method. P. Torasso gave a method to solve this problem ifOOis minimal. In this paper, we study the case whereOOis any spherical nilpotent orbit ofsln(R)sl_n({\mathbb R}), we construct, fromOO, a family of representations of the two-sheeted covering ofSLn(R)SL_n({\mathbb R})with Torasso’s method and, finally, we show that all these representations are associated to the corresponding orbit.
The Endogenous Ratio of Smad2 and Smad3 Influences the Cytostatic Function of Smad3
Authors: Kim Sang Gyun , Kim Hyun-Ah , Jong Hyun-Soon , Park Jung-Hyun , Kim Noe Kyeong , Hong Seung Hwan , Kim Tae-You , Bang Yung-Jue
Published: August 2005

Although Smad2 and Smad3, critical transcriptional mediators of transforming growth factor-β (TGF-β) signaling, are supposed to play a role in the TGF-β cytostatic program, it remains unclear whether TGF-β delivers cytostatic signals through both Smads equally or through either differentially. Here, we report that TGF-β cytostatic signals rely on a Smad3-, but not a Smad2-, dependent pathway and that the intensity of TGF-β cytostatic signals can be modulated by changing the endogenous ratio of Smad3 to Smad2. Depleting endogenous Smad3 by RNA interference sufficiently interfered with TGF-β cytostatic actions in various TGF-β-sensitive cell lines, whereas raising the relative endogenous ratio of Smad3 to Smad2, by depleting Smad2, markedly enhanced TGF-β cytostatic response. Consistently, Smad3 activation and its transcriptional activity upon TGF-β stimulation were facilitated in Smad2-depleted cells relative to controls. Most significantly, a single event of increasing this ratio by Smad2 depletion was sufficient to restore TGF-β cytostatic action in cells resistant to TGF-β. These findings suggest a new important determinant of sensitivity to TGF-β cytostatic signaling.
Identification of Raf-1 S471 as a Novel Phosphorylation Site Critical for Raf-1 and B-Raf Kinase Activities and for MEK Binding
Authors: Zhu Jun , Balan Vitaly , Bronisz Agnieszka , Balan Karina , Sun Hengrui , Leicht Deborah T. , Luo Zhijun , Qin Jun , Avruch Joseph , Tzivion Guri
Published: August 2005

The Ras-Raf-MAPK cascade is a key growth-signaling pathway and its uncontrolled activation results in cell transformation. Although the general features of the signal transmission along the cascade are reasonably defined, the mechanisms underlying Raf activation remain incompletely understood. Here, we show that Raf-1 dephosphorylation, primarily at epidermal growth factor (EGF)-induced sites, abolishes Raf-1 kinase activity. Using mass spectrometry, we identified five novel in vivo Raf-1 phosphorylation sites, one of which, S471, is located in subdomain VIB of Raf-1 kinase domain. Mutational analyses demonstrated that Raf-1 S471 is critical for Raf-1 kinase activity and for its interaction with mitogen-activated protein kinase kinase (MEK). Similarly, mutation of the corresponding B-Raf site, S578, resulted in an inactive kinase, suggesting that the same Raf-1 and B-Raf phosphorylation is needed for Raf kinase activation. Importantly, the naturally occurring, cancer-associated B-Raf activating mutation V599E suppressed the S578A mutation, suggesting that introducing a charged residue at this region eliminates the need for an activating phosphorylation. Our results demonstrate an essential role of specific EGF-induced Raf-1 phosphorylation sites in Raf-1 activation, identify Raf-1 S471 as a novel phosphorylation site critical for Raf-1 and B-Raf kinase activities, and point to the possibility that the V599E mutation activates B-Raf by mimicking a phosphorylation at the S578 site.
CDK Phosphorylation of a Novel NLS-NES Module Distributed between Two Subunits of the Mcm2-7 Complex Prevents Chromosomal Rereplication
Authors: Liku Muluye E. , Nguyen Van Q. , Rosales Audrey W. , Irie Kaoru , Li Joachim J.
Published: August 2005

Cyclin-dependent kinases (CDKs) use multiple mechanisms to block reassembly of prereplicative complexes (pre-RCs) at replication origins to prevent inappropriate rereplication. In Saccharomyces cerevisiae, one of these mechanisms promotes the net nuclear export of a pre-RC component, the Mcm2-7 complex, during S, G2, and M phases. Here we identify two partial nuclear localization signals (NLSs) on Mcm2 and Mcm3 that are each necessary, but not sufficient, for nuclear localization of the Mcm2-7 complex. When brought together in cis, however, the two partial signals constitute a potent NLS, sufficient for robust nuclear localization when fused to an otherwise cytoplasmic protein. We also identify a Crm1-dependent nuclear export signal (NES) adjacent to the Mcm3 NLS. Remarkably, the Mcm2-Mcm3 NLS and the Mcm3 NES are sufficient to form a transport module that recapitulates the cell cycle-regulated localization of the entire Mcm2-7 complex. Moreover, we show that CDK regulation promotes net export by phosphorylation of the Mcm3 portion of this module and that nuclear export of the Mcm2-7 complex is sufficient to disrupt replication initiation. We speculate that the distribution of partial transport signals among distinct subunits of a complex may enhance the specificity of protein localization and raises the possibility that previously undetected distributed transport signals are used by other multiprotein complexes.
Oligomerization and Dissociation of AP-1 Adaptors Are Regulated by Cargo Signals and by ArfGAP1-induced GTP Hydrolysis
Authors: Meyer Daniel M. , Crottet Pascal , Maco Bohumil , Degtyar Elena , Cassel Dan , Spiess Martin
Published: August 2005

The mechanism of AP-1/clathrin coat formation was analyzed using purified adaptor proteins and synthetic liposomes presenting tyrosine sorting signals. AP-1 adaptors recruited in the presence of Arf1·GTP and sorting signals were found to oligomerize to high-molecular-weight complexes even in the absence of clathrin. The appendage domains of the AP-1 adaptins were not required for oligomerization. On GTP hydrolysis induced by the GTPase-activating protein ArfGAP1, the complexes were disassembled and AP-1 dissociated from the membrane. AP-1 stimulated ArfGAP1 activity, suggesting a role of AP-1 in the regulation of the Arf1 “GTPase timer.” In the presence of cytosol, AP-1 could be recruited to liposomes without sorting signals, consistent with the existence of docking factors in the cytosol. Under these conditions, however, AP-1 remained monomeric, and recruitment in the presence of GTP was short-lived. Sorting signals allowed stable recruitment and oligomerization also in the presence of cytosol. These results suggest a mechanism whereby initial assembly of AP-1 with Arf1·GTP and ArfGAP1 on the membrane stimulates Arf1 GTPase activity, whereas interaction with cargo induces oligomerization and reduces the rate of GTP hydrolysis, thus contributing to efficient cargo sorting.
UNEMPLOYMENT RISK AND COMPENSATING DIFFERENTIALS IN NEW JERSEY MANUFACTURING
Authors: Averett Susan , Bodenhorn Howard , Staisiunas Justas
Published: August 2005

We present evidence that low‐skill workers received larger compensating differentials than more skilled workers when facing unanticipated unemployment in an era without unemployment insurance. Using information from surveys of New Jersey workers conducted during the 1880s, we test the theory of compensating wage differentials. We find that workers who faced a higher probability of predictable unemployment received compensating differentials and that the size of the differential differed across industries and skill levels. With few firm‐ or industry‐specific skills, unskilled workers were less subject to “informational capture” than skilled workers who had more but less easily transferable human capital. (JEL N31)
TWO TO TANGO? GENDER DIFFERENCES IN THE DECISIONS TO PUBLISH AND COAUTHOR
Authors: MCDOWELL JOHN M. , SINGELL LARRY D. , STATER MARK
Published: August 2005

The existence of old boy networks has long been postulated as a possible explanation for the presence of gender differences in market outcomes but with little empirical support because of the difficulty of measuring network access. This article exploits the unique attributes of academic labor markets and detailed data on individuals and jobs for PhD economists over nearly four decades. The results suggest that networks impact the joint decision to publish and coauthor, that these network effects differ by gender, and that gender differences in network access change over time as women become more well represented in a profession. (JEL J44, J77, J24)
The use of fetal Doppler cerebroplacental blood flow and amniotic fluid volume measurement in the surveillance of postdated pregnancies
Authors: Lam H. , Leung W. C. , Lee C. P. , Lao T. T.
Published: August 2005

Background.  This prospective observational study aims at determining the distribution of fetal cerebro‐placental Doppler indices and amniotic fluid volume in a homogenous group of uncomplicated postdated pregnancies at 41 weeks. The correlation with incidence of passage of thick meconium‐stained liquor in labor was analyzed to decide which parameter would be useful in the surveillance of postdated pregnancies.

Methods.  The amniotic fluid volume, middle cerebral artery pulsatility index, umbilical artery pulsatility index, and cerebroplacental ratio were measured and distribution determined in 118 well‐dated singleton pregnancies admitted for routine induction of labor at 41 weeks. The 10th centile and the 90th centile in each Doppler parameter and amniotic fluid volume were chosen to divide each parameter into three centile groups. The prevalence of thick meconium‐stained liquor in labor in different Doppler and amniotic fluid volume centile groups was compared using Chi‐square test for trend with P < 0.05 taken as statistically significant.

Results.  The prevalence of thick meconium‐stained liquor in labor was significantly inversely correlated with the middle cerebral artery pulsatility index (P = 0.008), with significant difference across different middle cerebral artery pulsatility index centile groups (P = 0.02). There was no significant difference in the prevalence of thick meconium‐stained liquor in labor or oligohydramnios across different umbilical artery pulsatility index centile groups. Neither was there significant difference in the prevalence of thick meconium‐stained liquor in labor and oligohydramnios across different cerebroplacental ratio and amniotic fluid volume centile groups. Logistic regression using the 10th centile of middle cerebral artery pulsatility index confirmed that it was a significant independent predicting factor for risk of thick meconium‐stained liquor in labor with adjusted odds ratio (95th CI) of 6.14 (1.6–24.1).

Conclusion.  Middle cerebral artery pulsatility index is better than amniotic fluid volume or umbilical artery pulsatility index in predicting the risk of thick meconium‐stained liquor in labor in uncomplicated postdated pregnancy at 41 weeks.
Pelvic floor dysfunction after Burch colposuspension – a comprehensive study. Part II
Authors: Kjølhede Preben , Wahlström Johan , Wingren Gun
Published: August 2005

Objective.  To evaluate the prevalence of pelvic floor dysfunction (PFD) concerning bowel function at long‐term follow‐up after Burch colposuspension (Bc) in relation to the bowel function in an age‐matched sample of women in the general population.

Methods and material.  This is a follow‐up study of a cohort of 190 patients who underwent Bc in 1980–1988 and 305 age‐matched control women without urinary anti‐incontinence surgery, randomly selected from the general population. The participants answered a postal questionnaire with detailed questions about the pelvic floor function in 1998. Univariate and multivariate analyses were performed.

Results.  The patients showed considerable signs of bowel dysfunction compared with the general population in the following aspects: they used the fingers to help emptying the bowel [odds ratio (OR) 3.25 (1.35–7.86)]; had feeling of incomplete emptying of the bowel [OR 2.29 (1.11–4.73)]; felt no warning before passing a motion [OR 3.04 (1.20–7.71)]; had gas incontinence [OR 1.98 (1.17–3.37); had loose stool incontinence [OR 3.67 (1.43–9.42)]; used protection against fecal leakage during daytime [OR 3.22 (1.30–7.95)]; and experienced that the bowel function affected the general well‐being adversely [OR 2.15 (1.30–3.56)].

Conclusion.  The patients who have undergone colposuspension for stress urinary incontinence have more symptoms of PFD concerning the bowel function than women without urinary anti‐incontinence surgery in the general population. This affects the general well‐being. A comprehensive concept of multidisciplinary assessment and treatment of PFD should be encouraged.
Approximate entropy of fetal heart rate variability as a predictor of fetal distress in women at term pregnancy
Authors: Li Xiaotian , Zheng Daan , Zhou Shufeng , Tang Dakan , Wang Caiyan , Wu Guoqiang
Published: August 2005

Background.  The aim of this study is to investigate the relationship between approximate entropy (ApEn) of fetal heart rate (FHR) with umbilical blood gas parameters and the power spectrum of FHR variability in Chinese and to test whether ApEn of FHR variability could be used as a predictor of fetal distress in women at term pregnancy.

Methods.  Sixty‐seven pregnant women with singleton, term fetus were recruited for the recording of FHR variability and the data were used for the estimate of ApEn. Blood gases after birth were measured through umbilical artery.

Results.  In all 67 neonates, there was some amount of interinfant variability in the ApEn values with a mean of 1.139 ± 0.169. The ApEn values were significantly (P < 0.05) correlated with pO2, SO2, pCO2, pH, HCO3, or base excess (BE). The 15 fetuses with low ApEn (ApEn <1.0) had higher risk of metabolic acidosis (BE less than −12 mmol/l) than those with high ApEn (ApEn ≥1) (likelihood ratio = 12.301, P < 0.001). The powers of FHR variability in all frequency ranges (0–0.256 Hz) were lower in the low‐ApEn group than those in the high‐ApEn group.

Conclusions.  The ApEn of FHR variability significantly decreased during fetal asphyxia, including hypoxia, hypercapnia, and both respiratory and metabolic acidosis; low ApEn was linked to decreased power spectrum density in all frequency domains. The ApEn values may be used as a predictor of fetal distress in women at term pregnancy.
Comparison of three‐dimensional hysterosalpingo‐contrast‐sonography and diagnostic laparoscopy with chromopertubation in the assessment of tubal patency for the investigation of subfertility
Authors: Chan Carina C. W. , Ng Ernest H. Y. , Tang Oi‐Shan , Chan Karen K. L. , Ho Pak‐Chung
Published: August 2005

Background.  Two‐dimensional hysterosalpingo‐contrast‐sonography, as a screening test for tubal patency for subfertile patients, is limited by the difficulty in visualizing the entire Fallopian tube owing to its tortuosity. This major disadvantage can be overcome by means of the three‐dimensional hysterosalpingo‐contrast‐sonography (3D‐HyCoSy). The current study compared the efficacy of 3D‐HyCoSy with diagnostic laparoscopy and its feasibility as a screening test for tubal patency.

Methods.  Twenty‐one consecutive patients scheduled to have laparoscopy were recruited to undergo the 3D‐HyCoSy 2 days before the scheduled laparoscopy. Echovist® (Schering AG, Berlin, Germany), the ultrasound contrast medium, was injected into the uterine cavity via a Foley's catheter. The flow of the medium in the Fallopian tube was captured by using three‐dimensional power Doppler mode and was stored for later analysis. The person analyzing the images, the surgeon performing the laparoscopy, and the patients were blinded to the patients' identity and the sonography findings. The sonography and the laparoscopy findings were compared. The duration for the ultrasound examination, pain score, and patient acceptability were assessed.

Results.  Thirty‐four of 42 (81%) Fallopian tubes were assessed. The sensitivity of 3D‐HyCoSy for detecting tubal patency was 100% with a specificity of 67%. The positive and negative predictive values were 89 and 100%, respectively; the concordance rate was 91%. The mean duration (± SD) for the 3D‐HyCoSy was 13.4 ± 5.5 min. Fifteen patients (71%) regarded the sonography examination as at least acceptable.

Conclusions.  This study confirmed the feasibility of using 3D‐HyCoSy as an initial investigation for tubal patency.
Quality of life in acute and maintenance treatment of non‐erosive and mild erosive gastro‐oesophageal reflux disease
Authors: PACE F. , NEGRINI C. , WIKLUND I. , ROSSI C. , SAVARINO V. ,   THE ITALIAN ONE INVESTIGATORS STUDY GROUP
Published: August 2005

Background:  Quality of life has been assessed in a large, multicentre randomized, open label study.

Aim:  To evaluate the economic and clinical consequences of two different maintenance treatment modalities, administered to 6017 gastro‐oesophageal reflux disease patients at 451 gastroenterological centres in Italy.

Methods:  Adult gastro‐oesophageal reflux disease patients received, at enrolment, an acute treatment of esomeprazole 40 mg/day for 4 weeks and, if successfully treated, were randomized into two maintenance treatment strategies: esomeprazole 20 mg/day or esomeprazole on demand for 6 months. A baseline endoscopy allowed the exclusion of grade II–IV oesophagitis according to Savary–Miller's classification. Burden of gastro‐oesophageal reflux disease was measured at baseline by the generic questionnaire Short‐Form 36 and by a disease specific instrument, quality of life in reflux and dyspepsia (QOLRAD), also administered at start and conclusion of maintenance period. Investigators were required to collect patient judgement about the degree of satisfaction with treatment effect on heartburn, with a 7‐point scale.

Results:  A comparison between Short‐Form 36 scores and the normative source of the Italian general population suggested that symptomatic gastro‐oesophageal reflux disease patients experience a worse quality of life than the general population. At the end of the 4‐week treatment with esomeprazole 40 mg all (QOLRAD) dimensions showed a statistically significant (P < 0.0001) and clinically meaningful improvement.

Satisfaction level towards treatment was reported high in the total enrolled population after acute treatment with esomeprazole 40 mg/day (96.2% satisfied and 64.4% very satisfied). A statistically significant difference in (QOLRAD) scores was registered at the end of maintenance phase in favour of the continuous regimen, nevertheless the size of this difference was very small in all dimensions; similarly, the proportion of patients very satisfied was slightly higher in the continuous treatment arm (64.5%) than in the on‐demand arm (59.7%).

Conclusions:  Gastro‐oesophageal reflux disease can significantly impair health‐related quality of life and esomeprazole therapy allows immediate relief in the acute phase of the disease. Quality of life improvement was maintained during the 6‐month follow‐up with a slight difference in term of quality of life in reflux and dyspepsia scores and patients’ satisfaction in favour of the continuous treatment strategy.