bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the β1 Subunit in Large-Conductance Ca2+-Activated K+ Channel Gating Energetics
Authors: Cox D.H. , Aldrich R.W.
Published: July 2002

Over the past few years, it has become clear that an important mechanism by which large-conductance Ca2+-activated K+ channel (BKCa) activity is regulated is the tissue-specific expression of auxiliary β subunits. The first of these to be identified, β1, is expressed predominately in smooth muscle and causes dramatic effects, increasing the apparent affinity of the channel for Ca2+ 10-fold at 0 mV, and shifting the range of voltages over which the channel activates −80 mV at 9.1 μM Ca2+. With this study, we address the question: which aspects of BKCa gating are altered by β1 to bring about these effects: Ca2+ binding, voltage sensing, or the intrinsic energetics of channel opening? The approach we have taken is to express the β1 subunit together with the BKCa α subunit in Xenopus oocytes, and then to compare β1's steady state effects over a wide range of Ca2+ concentrations and membrane voltages to those predicted by allosteric models whose parameters have been altered to mimic changes in the aspects of gating listed above. The results of our analysis suggest that much of β1's steady state effects can be accounted for by a reduction in the intrinsic energy the channel must overcome to open and a decrease in its voltage sensitivity, with little change in the affinity of the channel for Ca2+ when it is either open or closed. Interestingly, however, the small changes in Ca2+ binding affinity suggested by our analysis (Kc 7.4 μM → 9.6 μM; Ko = 0.80 μM → 0.65 μM) do appear to be functionally important. We also show that β1 affects the mSlo conductance–voltage relation in the essential absence of Ca2+, shifting it +20 mV and reducing its apparent gating charge 38%, and we develop methods for distinguishing between alterations in Ca2+ binding and other aspects of BKCa channel gating that may be of general use.
Regulation by Ca2+ and Inositol 1,4,5-Trisphosphate (Insp3) of Single Recombinant Type 3 Insp3 Receptor Channels
Authors: Mak Don-On Daniel , McBride Sean , Foskett J. Kevin
Published: July 2002

The inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) is an endoplasmic reticulum–localized Ca2+-release channel that controls complex cytoplasmic Ca2+ signaling in many cell types. At least three InsP3Rs encoded by different genes have been identified in mammalian cells, with different primary sequences, subcellular locations, variable ratios of expression, and heteromultimer formation. To examine regulation of channel gating of the type 3 isoform, recombinant rat type 3 InsP3R (r-InsP3R-3) was expressed in Xenopus oocytes, and single-channel recordings were obtained by patch-clamp electrophysiology of the outer nuclear membrane. Gating of the r-InsP3R-3 exhibited a biphasic dependence on cytoplasmic free Ca2+ concentration ([Ca2+]i). In the presence of 0.5 mM cytoplasmic free ATP, r-InsP3R-3 gating was inhibited by high [Ca2+]i with features similar to those of the endogenous Xenopus type 1 InsP3R (X-InsP3R-1). Ca2+ inhibition of channel gating had an inhibitory Hill coefficient of ∼3 and half-maximal inhibiting [Ca2+]i (Kinh) = 39 μM under saturating (10 μM) cytoplasmic InsP3 concentrations ([InsP3]). At [InsP3] < 100 nM, the r-InsP3R-3 became more sensitive to Ca2+ inhibition, with the InsP3 concentration dependence of Kinh described by a half-maximal [InsP3] of 55 nM and a Hill coefficient of ∼4. InsP3 activated the type 3 channel by tuning the efficacy of Ca2+ to inhibit it, by a mechanism similar to that observed for the type 1 isoform. In contrast, the r-InsP3R-3 channel was uniquely distinguished from the X-InsP3R-1 channel by its enhanced Ca2+ sensitivity of activation (half-maximal activating [Ca2+]i of 77 nM instead of 190 nM) and lack of cooperativity between Ca2+ activation sites (activating Hill coefficient of 1 instead of 2). These differences endow the InsP3R-3 with high gain InsP3–induced Ca2+ release and low gain Ca2+–induced Ca2+ release properties complementary to those of InsP3R-1. Thus, distinct Ca2+ signals may be conferred by complementary Ca2+ activation properties of different InsP3R isoforms.
Open State Destabilization by Atp Occupancy Is Mechanism Speeding Burst Exit Underlying KATP Channel Inhibition by Atp
Authors: Li Lehong , Geng Xuehui , Drain Peter
Published: July 2002

The ATP-sensitive potassium (KATP) channel is named after its characteristic inhibition by intracellular ATP. The inhibition is a centerpiece of how the KATP channel sets electrical signaling to the energy state of the cell. In the β cell of the endocrine pancreas, for example, ATP inhibition results from high blood glucose levels and turns on electrical activity leading to insulin release. The underlying gating mechanism (ATP inhibition gating) includes ATP stabilization of closed states, but the action of ATP on the open state of the channel is disputed. The original models of ATP inhibition gating proposed that ATP directly binds the open state, whereas recent models indicate a prerequisite transition from the open to a closed state before ATP binds and inhibits activity. We tested these two classes of models by using kinetic analysis of single-channel currents from the cloned mouse pancreatic KATP channel expressed in Xenopus oocytes. In particular, we combined gating models based on fundamental rate law and burst gating kinetic considerations. The results demonstrate open-state ATP dependence as the major mechanism by which ATP speeds exit from the active burst state underlying inhibition of the KATP channel by ATP.
Single Channel Analysis of Conductance and Rectification in Cation-selective, Mutant Glycine Receptor Channels
Authors: Moorhouse Andrew J. , Keramidas Angelo , Zaykin Andrey , Schofield Peter R. , Barry Peter H.
Published: July 2002

Members of the ligand-gated ion channel superfamily mediate fast synaptic transmission in the nervous system. In this study, we investigate the molecular determinants and mechanisms of ion permeation and ion charge selectivity in this family of channels by characterizing the single channel conductance and rectification of α1 homomeric human glycine receptor channels (GlyRs) containing pore mutations that impart cation selectivity. The A-1'E mutant GlyR and the selectivity double mutant ([SDM], A-1'E, P-2'Δ) GlyR, had mean inward chord conductances (at −60 mV) of 7 pS and mean outward conductances of 11 and 12 pS (60 mV), respectively. This indicates that the mutations have not simply reduced anion permeability, but have replaced the previous anion conductance with a cation one. An additional mutation to neutralize the ring of positive charge at the extracellular mouth of the channel (SDM+R19'A GlyR) made the conductance–voltage relationship linear (14 pS at both 60 and −60 mV). When this external charged ring was made negative (SDM+R19'E GlyR), the inward conductance was further increased (to 22 pS) and now became sensitive to external divalent cations (being 32 pS in their absence). The effects of the mutations to the external ring of charge on conductance and rectification could be fit to a model where only the main external energy barrier height for permeation was changed. Mean outward conductances in the SDM+R19'A and SDM+R19'E GlyRs were increased when internal divalent cations were absent, consistent with the intracellular end of the pore being flanked by fixed negative charges. This supports our hypothesis that the ion charge selectivity mutations have inverted the electrostatic profile of the pore by introducing a negatively charged ring at the putative selectivity filter. These results also further confirm the role of external pore vestibule electrostatics in determining the conductance and rectification properties of the ligand-gated ion channels.
On sums of seven cubes
Authors: Bertault F. , Ramaré O. , Zimmermann P.
Published: July 2002

We show that every integer between 1290741 and

3.375
×

10

12

3.375\times 10^{12}

is a sum of 5 nonnegative cubes, from which we deduce that every integer which is a cubic residue modulo 9 and an invertible cubic residue modulo 37 is a sum of 7 nonnegative cubes.
Relatively and inner uniform domains
Authors: Väisälä Jussi
Published: July 2002

We generalize the concept of a uniform domain in Banach spaces into two directions. (1) The ordinary metric

d
d

of a domain is replaced by a metric

e
≥
d

e\ge d

, in particular, by the inner metric of the domain. (2) The uniformity condition is supposed to hold only for certain pairs of points of the domain. We consider neargeodesics and solid arcs in these domains. Applications to the boundary behavior of quasiconformal maps are given. In particular, we study maps between domains of the form

E
×
B

E\times B

, where

E
E

is a Banach space and

B
B

is a ball.
Daughter Cell Assembly in the Protozoan ParasiteToxoplasma gondii
Authors: Hu Ke , Mann Tara , Striepen Boris , Beckers Con J. M. , Roos David S. , Murray John M.
Published: July 2002

The phylum Apicomplexa includes thousands of species of obligate intracellular parasites, many of which are significant human and/or animal pathogens. Parasites in this phylum replicate by assembling daughters within the mother, using a cytoskeletal and membranous scaffolding termed the inner membrane complex. Most apicomplexan parasites, including Plasmodium sp. (which cause malaria), package many daughters within a single mother during mitosis, whereas Toxoplasma gondii typically packages only two. The comparatively simple pattern of T. gondii cell division, combined with its molecular genetic and cell biological accessibility, makes this an ideal system to study parasite cell division. A recombinant fusion between the fluorescent protein reporter YFP and the inner membrane complex protein IMC1 has been exploited to examine daughter scaffold formation in T. gondii.Time-lapse video microscopy permits the entire cell cycle of these parasites to be visualized in vivo. In addition to replication via endodyogeny (packaging two parasites at a time), T. gondii is also capable of forming multiple daughters, suggesting fundamental similarities between cell division in T. gondii and other apicomplexan parasites.
Genetic Basis of Mitochondrial Function and Morphology inSaccharomyces cerevisiae
Authors: Dimmer Kai Stefan , Fritz Stefan , Fuchs Florian , Messerschmitt Marlies , Weinbach Nadja , Neupert Walter , Westermann Benedikt
Published: July 2002

The understanding of the processes underlying organellar function and inheritance requires the identification and characterization of the molecular components involved. We pursued a genomic approach to define the complements of genes required for respiratory growth and inheritance of mitochondria with normal morphology in yeast. With the systematic screening of a deletion mutant library covering the nonessential genes of Saccharomyces cerevisiae the numbers of genes known to be required for respiratory function and establishment of wild-type-like mitochondrial structure have been more than doubled. In addition to the identification of novel components, the systematic screen revealed unprecedented mitochondrial phenotypes that have never been observed by conventional screens. These data provide a comprehensive picture of the cellular processes and molecular components required for mitochondrial function and structure in a simple eukaryotic cell.
Comparative Model-based Analysis of Screening Programs for Chlamydia trachomatis Infections
Authors: Kretzschmar Mirjam , Welte Robert , van den Hoek Anneke , Postma Maarten J.
Published: July 2002

The design of a screening program for asymptomatic genital infections with Chlamydia trachomatis, requires decisions about which sex or age group should be targeted and whether partner referral should be included in the program. To investigate the effects of various screening programs on the prevalence and incidence of asymptomatic C. trachomatis infections in women, in May 1996 to April 1997 in Bilthoven, the Netherlands, the authors used a stochastic simulation model for C. trachomatis transmission in an age-structured, heterosexual population with a sexually highly active core group. Different screening scenarios were implemented over a time period of 10 years. Prevalence, incidence, and the fraction of infected persons found by partner referral were computed. Through screening of men and women between ages 15 and 24 years (baseline scenario), the prevalence of asymptomatic infections in women could be reduced from 4.2% to 1.4% in 10 years. Increasing the age range of screening up to ages 29 or 34 years led to prevalences of 0.4% and 0.06%, respectively, after 10 years. About 28% of all infected persons were found via partner referral. There are considerable indirect positive effects of screening on those population groups that are not included in the screening because of the reduced risk of becoming infected. Partner referral contributes substantially to prevalence reduction.
Effect of Body Mass on the Association between Estrogen Replacement Therapy and Mortality among Elderly US Women
Authors: Rodriguez Carmen , Calle Eugenia E. , Patel Alpa V. , Tatham Lilith M. , Jacobs Eric J. , Thun Michael J.
Published: July 2002

In observational studies, estrogen replacement therapy is associated with decreased cardiovascular disease rates and increased breast cancer rates. Recent evidence suggests that the impact of estrogen use on disease outcomes may vary by body mass. In a prospective study of 290,827 postmenopausal US women with no history of cancer or cardiovascular disease at enrollment in 1982, the authors examined the association between postmenopausal estrogen use and all-cause, coronary heart disease, stroke, all-cancer, and breast cancer death rates and whether these associations differed by body mass. After 12 years of follow-up, results from Cox proportional hazards models showed that all-cause death rates were lower among baseline estrogen users than never users (rate ratio (RR) = 0.82, 95% confidence interval (CI): 0.78, 0.87). The lowest relative risk was found for coronary heart disease (RR = 0.66, 95% CI: 0.58, 0.77). The inverse association between estrogen use and coronary heart disease mortality was strongest for thin women (body mass index <22 kg/m2) (RR = 0.49, p for interaction = 0.02). Breast cancer mortality did not increase with estrogen use overall, and no increased risk was observed for thin or heavy women. In this population, the reduction in coronary heart disease mortality among estrogen users was greatest for thinner women. Additional studies are needed to confirm or refute these results.
Bone Lead and Blood Lead Levels in Relation to Baseline Blood Pressure and the Prospective Development of Hypertension The Normative Aging Study
Authors: Cheng Yawen , Schwartz Joel , Sparrow David , Aro Antonio , Weiss Scott T. , Hu Howard
Published: July 2002

Between 1991 and 1997, the authors studied 833 participants of the Normative Aging Study in a substudy of bone lead levels (measured by K-shell x-ray fluorescence), blood lead levels, and hypertension. Among these subjects, 337 were classified as normotensive, and 182 and 314 were classified as having borderline and definite hypertension, respectively, at baseline. These bone and blood lead levels were typical of those of community-exposed men. Among the 519 subjects with no history of definite hypertension at baseline, cross-sectional analyses revealed positive associations between systolic blood pressure and bone lead levels. Of the 474 subjects who were free from definite hypertension at baseline and had follow-up data, 74 new cases of definite hypertension were reported. Baseline bone lead levels were positively associated with incidence of hypertension. In proportional hazards models that controlled for age, age squared, body mass index, and family history of hypertension, an increase in patella (trabecular) lead from the midpoint of the lowest quintile to that of the highest quintile was associated with a rate ratio of definite hypertension of 1.71 (95% confidence interval: 1.08, 2.70). No association was found with blood lead level. These results support the hypothesis that cumulative exposure to lead, even at low levels sustained by the general population, may increase the risk of hypertension.
Being Breastfed in Infancy and Breast Cancer Incidence in Adult Life: Results from the Two Nurses' Health Studies
Authors: Michels Karin B. , Trichopoulos Dimitrios , Rosner Bernard A. , Hunter David J. , Colditz Graham A. , Hankinson Susan E. , Speizer Frank E. , Willett Walter C.
Published: July 2002

Events during perinatal and early life may influence the incidence of breast cancer in adult life, and some case-control studies suggest that having been breastfed may reduce breast cancer risk. The authors studied this association among premenopausal and postmenopausal women by using data from the two Nurses' Health Studies, the Nurses' Health Study (using data from 1992 to 1996) and the Nurses' Health Study II (using data from 1991 to 1997). A history of being breastfed was self-reported by the study participants. During a total of 695,655 person-years, 1,073 cases of invasive breast cancer were diagnosed. The authors did not observe any important overall association between having been breastfed and the development of breast cancer later in life among premenopausal women (covariate-adjusted relative risk = 0.97, 95% confidence interval (CI): 0.78, 1.20) or postmenopausal women (covariate-adjusted relative risk = 1.12, 95% CI: 0.92, 1.37). No significant trend was observed with increasing duration of breastfeeding. The authors also used data on breastfeeding retrospectively collected from 2,103 mothers of participants of the two Nurses' Health Studies. With the mothers' reports, the covariate-adjusted odds ratio of breast cancer was 1.11 (95% CI: 0.88, 1.39) for women who were breastfed compared with those who were not. Data from these two large cohorts do not support the hypothesis that being breastfed confers protection against subsequent breast cancer.
Validity of Self-reported Cancer History: A Comparison of Health Interview Data and Cancer Registry Records
Authors: Desai Mayur M. , Bruce Martha Livingston , Desai Rani A. , Druss Benjamin G.
Published: July 2002

Few studies have addressed the accuracy of self-reported cancer history, although epidemiologic studies routinely use self-reported information as the sole source of exposure or outcome data or as a criterion for exclusion from study participation. In this paper, false-negative reporting of cancer history is examined in a community-based sample by comparing interview data with tumor registry records. Subjects were participants in the 1980 New Haven Epidemiologic Catchment Area study; in 1995, cancer records (from 1935 onward) were obtained by linking the sample to the Connecticut Tumor Registry. Analyses focused on 263 individuals who had at least one tumor reported to the Connecticut Tumor Registry prior to participation in the Epidemiologic Catchment Area study. The overall rate of false-negative reporting was 39.2%. Logistic regression analysis revealed that false-negative reporting was significantly associated with non-White race, older age, increased time since cancer diagnosis, number of previous tumors, and type of cancer treatment received. In addition, false-negative reporting varied widely by cancer site, ranging from 0% for melanoma skin cancer to 83.3% for central nervous system cancers. The false-negative rate for breast cancer was 20.8%, that for colon and prostate cancers was 42.1%, and that for bladder cancer was 61.5%. Implications of these findings for prevalence estimation and future epidemiologic studies are discussed.
Early Therapy for Latent Tuberculosis Infection
Authors: Ziv Elad , Daley Charles L. , Blower Sally M.
Published: July 2002

The risk of developing active tuberculosis is highest within the first 2 years of infection. Therefore, an intervention that targets persons with recent infection, such as identifying contacts of active cases, could be particularly effective as an epidemic control measure. A mathematical model of a tuberculosis epidemic is formulated and used to evaluate the strategy of targeting therapy to persons with recently acquired latent tuberculosis infection. The model is used to quantify the effectiveness of therapy for early latent tuberculosis infection in reducing the prevalence of active tuberculosis. The model is also used to demonstrate how effective therapy for early latent tuberculosis infection has to be to eliminate tuberculosis, when used in conjunction with therapy for active tuberculosis. Analysis of the model suggests that programs such as contact investigations, which identify and treat persons recently infected with Mycobacterium tuberculosis, may have a substantial effect on controlling tuberculosis epidemics.
Lutein and Zeaxanthin in the Diet and Serum and Their Relation to Age-related Maculopathy in the Third National Health and Nutrition Examination Survey
Authors: Marse-Perlman Julie A. , Fisher Alicia I. , Klein Ronald , Palta Mari , Block Gladys , Millen Amy E. , Wright Jacqueline D.
Published: July 2002

Relations of the carotenoids lutein and zeaxanthin in the diet and serum to photographic evidence of early and late age-related maculopathy (ARM) among persons over age 40 years (n = 8,222) were examined. Inverse relations of these carotenoids in the diet or serum to any form of ARM were not observed overall. There was a direct relation of dietary levels to one type of early ARM (soft drusen). However, relations differed by age and race. In the youngest age groups who were at risk for developing early (ages 40–59 years) or late (ages 60–79 years) ARM, higher levels of lutein and zeaxanthin in the diet were related to lower odds for pigmentary abnormalities, one sign of early ARM (odds ratio among persons in high vs. low quintiles = 0.1, 95 percent confidence interval: 0.1, 0.3) and of late ARM (odds ratio = 0.1, 95 percent confidence interval: 0.0, 0.9) after adjustment for age, gender, alcohol use, hypertension, smoking, and body mass index. Relations of these carotenoids to ARM may be influenced by age and race and require further evaluation in separate populations and in prospective studies.
Air Pollution from Traffic at the Residence of Children with Cancer
Authors: Raaschou-Nielsen Ole , Hertel Ole , Thomsen Birthe L. , Olsen Jørgen H.
Published: July 2002

The hypothesis that exposure to traffic-related air pollution increases the risk of developing cancer during childhood was investigated. The authors enrolled 1,989 children reported to the Danish Cancer Registry with a diagnosis of leukemia, tumor of the central nervous system, or malignant lymphoma during 1968–1991 and 5,506 control children selected at random from the entire childhood population. The residential histories of the children were traced from 9 months before birth until the time of diagnosis of the cases and a similar period for the controls. For each of the 18,440 identified addresses, information on traffic and the configuration of streets and buildings was collected. Average concentrations of benzene and nitrogen dioxide (indicators of traffic-related air pollution) were calculated for the relevant period, and exposures to air pollution during pregnancy and during childhood were calculated separately. The risks of leukemia, central nervous system tumors, and all selected cancers combined were not linked to exposure to benzene or nitrogen dioxide during either period. The risk of lymphomas increased by 25% (p for trend = 0.06) and 51% (p for trend = 0.05) for a doubling of the concentration of benzene and nitrogen dioxide, respectively, during the pregnancy. The association was restricted to Hodgkin's disease.
Are US Populations Appropriate for Trials of Human Immunodeficiency Virus Vaccine?
Authors: Seage III George R. , Holte Sarah E. , Metzger David , Koblin Beryl A. , Gross Michael , Celum Connie , Marmor Michael , Woody George , Mayer Kenneth H. , Stevens Cladd , Judson Franklyn N. , McKirnan David , Sheon Amy , Self Steven , Buchbinder Susan P.
Published: July 2002

Questions exist about whether testing of preventive human immunodeficiency virus (HIV)-1 vaccines, which will require rapid recruitment and retention of cohorts with high HIV-1 seroincidence, is feasible in the United States. A prospective cohort study was conducted in 1995–1997 among 4,892 persons at high risk for HIV infection in nine US cities. At 18 months, with an 88% retention rate, 90 incident HIV-1 infections were observed (1.31/100 person-years (PY), 95% confidence interval (CI): 1.06, 1.61). HIV-1 seroincidence rates varied significantly by baseline eligibility criteria—1.55/100 PY among men who had sex with men, 0.38/100 PY among male intravenous drug users, 1.24/100 PY among female intravenous drug users, and 1.13/100 PY among women at heterosexual risk—and by enrollment site, from 0.48/100 PY to 2.18/100 PY. HIV-1 incidence was highest among those men who had sex with men who reported unprotected anal intercourse (2.01/100 PY, 95% CI: 1.54, 2.63), participants who were definitely willing to enroll in an HIV vaccine trial (1.96/100 PY, 95% CI: 1.41, 2.73), and women who used crack cocaine (1.62/100 PY, 95% CI: 0.92, 2.85). Therefore, cohorts with HIV-1 seroincidence rates appropriate for HIV-1 vaccine trials can be recruited, enrolled, and retained.
Low Blood Pressure During Pregnancy and Poor Perinatal Outcomes: An Obstetric Paradox
Authors: Zhang Jun , Klebanoff Mark A.
Published: July 2002

Low blood pressure during pregnancy has been associated with poor perinatal outcomes. However, whether this association is causal or is due to confounding has never been carefully assessed. The authors used data from the Collaborative Perinatal Project, a large prospective cohort study in 12 hospitals in the United States from 1959 to 1966. A total of 28,095 subjects were included. At first glance, it appeared that the lower the baseline blood pressure during pregnancy, the higher the incidence of very premature birth (<34 weeks) and severe small for gestational age (<5th percentile) in a consistent dose-response pattern. However, women with low blood pressure were generally younger, shorter, lighter, leaner, poorer, and more often a minority, and they gained less weight. After the authors controlled for these factors, low blood pressure was not associated with preterm birth (adjusted relative risks ranging from 0.86 to 0.93, p > 0.05) or small for gestational age (relative risks ranging from 0.45 to 2.0). Therefore, the association between low blood pressure during pregnancy and poor perinatal outcomes is largely due to confounding by other risk factors. Low blood pressure by itself does not increase risk of poor perinatal outcomes at a population level. However, this conclusion may not apply to individual patients who also have a compromised plasma volume expansion or pathologic homeostasis.
Frequency of Eating During Pregnancy and Its Effect on Preterm Delivery
Authors: Maria Siega-Riz Anna , Herrmann Tracy S. , Savitz David A. , Thorp John M.
Published: July 2002

Frequency of eating or meal patterns during pregnancy may be a component of maternal nutrition relevant to pregnancy outcome. To identify meal patterns of pregnant women and investigate the relation between these meal patterns and preterm delivery, the authors performed an analysis using data from the Pregnancy, Infection, and Nutrition Study (n = 2,065). Women recruited from August 1995 to December 1998 were categorized by meal patterns on the basis of their reported number of meals (breakfast, lunch, and dinner) and snacks consumed per day during the second trimester. An optimal pattern was defined according to the Institute of Medicine recommendation of three meals and two or more snacks per day. In this population, 72 percent of the women met this recommendation, and 235 delivered preterm. Women who consumed meals/snacks less frequently were slightly heavier prior to pregnancy, were older, and had a lower total energy intake. In addition, these women had a higher risk of delivering preterm (adjusted odds ratio = 1.30, 95 percent confidence interval: 0.96, 1.76). There was no meaningful difference in the risk by early versus late preterm delivery, but those who delivered after premature rupture of the membranes (adjusted odds ratio = 1.87, 95 percent confidence interval: 1.02, 3.43) had a higher risk than those who delivered after preterm labor (adjusted odds ratio = 1.11, 95 percent confidence interval: 0.64, 1.89). This study supports previous animal model work of an association between decreased frequency of eating and preterm delivery.
Methylenetetrahydrofolate Reductase 677 C/T Genotype and Cardiovascular Disease Mortality in Postmenopausal Women
Authors: Roest Mark , van der Schouw Yvonne T. , Grobbee Diederick E. , Tempelman Mariëlle J. , de Groot Philip G. , Sixma Jan J. , Banga Jan Dirk
Published: July 2002

Methylenetetrahydrofolate reductase (MTHFR) is involved in the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. A 677 C/T single nucleotide polymorphism localized in the MTHFR gene is associated with both thermolability and reduced activity of the enzyme and is associated with increased homocysteine levels. The authors investigated the relation between the MTHFR 677 C/T polymorphism and risk of cardiovascular disease mortality in a cohort study of 12,239 women initially aged 52–67 years with a maximum follow-up time of 18 years (1976–1995; 153,732 woman-years of follow-up). The cardiovascular disease mortality rate was highest among women with the MTHFR 677 CC wild-type genotype and lowest among MTHFR 677 TT homozygotes. In comparison with women with the 677 CC wild-type genotype, age-adjusted rate ratios were 0.7 (95% confidence interval: 0.5, 0.9) for 677 CT heterozygotes and 0.6 (95% confidence interval: 0.4, 1.0) for 677 TT homozygotes. The possibility that this relation is a chance finding must be considered, because the relation is weak and of borderline significance. However, it provides an important argument against the view that increased levels of homocysteine directly raise cardiovascular disease risk.
Dietary and Other Methyl-Group Availability Factors and Pancreatic Cancer Risk in a Cohort of Male Smokers
Authors: Stolzenberg-Solomon Rachael Z. , Pietinen Pirjo , Barrett Michael J. , Taylor Philip R. , Virtamo Jarmo , Albanes Demetrius
Published: July 2002

The authors examined prospectively whether dietary folate and other factors known to influence methyl-group availability were associated with the development of exocrine pancreatic cancer within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Of the 27,101 healthy male smokers aged 50–69 years who completed a self-administered dietary questionnaire at baseline, 157 developed pancreatic cancer during up to 13 years of follow-up from 1985 to 1997. Cox proportional hazards models were used to estimate the hazards ratios and 95% confidence intervals. The adjusted hazards ratio comparing the highest with the lowest quintile of dietary folate intake was 0.52 (95% confidence interval: 0.31, 0.87; p-trend = 0.05). Dietary methionine, alcohol intake, and smoking history did not modify this relation. No significant associations were observed between dietary methionine, vitamins B6 and B12, or alcohol intake and pancreatic cancer risk. Consistent with prior studies, this study shows that cigarette smoking was associated with an increased risk (highest compared with lowest quintile, cigarettes per day: hazards ratio = 1.82; 95% confidence interval: 1.10, 3.03; p-trend = 0.05). These results support the hypothesis that dietary folate intake is inversely associated with the risk of pancreatic cancer and confirm the risk associated with greater cigarette smoking.
Imagene: an integrated computer environment for sequence annotation and analysis.
Authors: M√©digue C , Rechenmann F , Danchin A , Viari A
Published: July 2002

MOTIVATION: To be fully and efficiently exploited, data coming from sequencing projects together with specific sequence analysis tools need to be integrated within reliable data management systems. Systems designed to manage genome data and analysis tend to give a greater importance either to the data storage or to the methodological aspect, but lack a complete integration of both components. RESULTS: This paper presents a co-operative computer environment (called Imagenetrade mark) dedicated to genomic sequence analysis and annotation. Imagene has been developed by using an object-based model. Thanks to this representation, the user can directly manipulate familiar data objects through icons or lists. Imagene also incorporates a solving engine in order to manage analysis tasks. A global task is solved by successive divisions into smaller sub-tasks. During program execution, these sub-tasks are graphically displayed to the user and may be further re-started at any point after task completion. In this sense, Imagene is more transparent to the user than a traditional menu-driven package. Imagene also provides a user interface to display, on the same screen, the results produced by several tasks, together with the capability to annotate these results easily. In its current form, Imagene has been designed particularly for use in microbial sequencing projects. AVAILABILITY: Imagene best runs on SGI (Irix 6.3 or higher) workstations. It is distributed free of charge on a CD-ROM, but requires some Ilog licensed software to run. Some modules also require separate license agreements. Please contact the authors for specific academic conditions and other Unix platforms. CONTACT: imagene home page: http://wwwabi.snv.jussieu.fr/imagene
Identification of novel multi-transmembrane proteins from
genomic databases using quasi-periodic structural properties
Authors: Kim Junhyong , Moriyama Etsuko N. , Warr Coral G. , Clyne Peter J. , Carlson John R.
Published: July 2002

Motivation: Identification of novel G protein-coupled receptors and other multi-transmembrane proteins from genomic databases using structural features.

Results: Here we describe a new algorithm for identifying multi-transmembrane proteins from genomic databases with a specific application to identifying G protein-coupled receptors (GPCRs) that we call quasi-periodic feature classifier (QFC). The QFC algorithm uses concise statistical variables as the ‘feature space’ to characterize the quasi-periodic physico-chemical properties of multi-transmembrane proteins. For the case of identifying GPCRs, the variables are then used in a non-parametric linear discriminant function to separate GPCRs from non-GPCRs. The algorithm runs in time linearly proportional to the number of sequences, and performance on a test dataset shows 96% positive identification of known GPCRs. The QFC algorithm also works well with short random segments of proteins and it positively identified GPCRs at a level greater than 90% even with segments as short as 100 amino acids. The primary advantage of the algorithm is that it does not directly use primary sequence patterns which may be subject to sampling bias. The utility of the new algorithm has been demonstrated by the isolation from the Drosophila genome project database of a novel class of seven-transmembrane proteins which were shown to be the elusive olfactory receptor genes of Drosophila.

Availability: C++/Perl available from http://jkim.eeb.yale.edu/index.html

Contact: Junhyong Kim, Dept. of Ecology and Evolutionary Biology, Yale University, P.O. Box 208106, New Haven, CT 06520-8106; junhyong.kim@yale.edu

Supplementary information: Test dataset and training dataset are available from http://jkim.eeb.yale.edu/index.html

**** To whom correspondence should be addressed.
BALL—rapid software prototyping in computational

molecular biology
Authors: Kohlbacher Oliver , Lenhof Hans-Peter
Published: July 2002

Motivation: Rapid software prototyping can significantly reduce development times in the field of computational molecular biology and molecular modeling. Biochemical Algorithms Library (BALL) is an application framework in C++that has been specifically designed for this purpose.

Results: BALL provides an extensive set of data structures as well as classes for molecular mechanics, advanced solvation methods, comparison and analysis of protein structures, file import/export, and visualization. BALL has been carefully designed to be robust, easy to use, and open to extensions. Especially its extensibility which results from an object-oriented and generic programming approach distinguishes it from other software packages. BALL is well suited to serve as a public repository for reliable data structures and algorithms. We show in an example that the implementation of complex methods is greatly simplified when using the data structures and functionality provided by BALL.

Availability: BALL is available via internet from http://www.mpi-sb.mpg.de/BALL/. It may be used free of charge for research and teaching. Commercial licenses are available upon request.

Contact: O.Kohlbacher, oliver@mpi-sb.mpg.de

To whom correspondence should be addressed.
Protein disulfide isomerases exploit synergy between catalytic and specific binding domains
Authors: Freedman Robert B. , Klappa Peter , Ruddock Lloyd W.
Published: July 2002

Protein disulfide isomerases (PDIs) catalyse the formation of native disulfide bonds in protein folding pathways. The key steps involve disulfide formation and isomerization in compact folding intermediates. The high‐resolution structures of the a and b domains of PDI are now known, and the overall domain architecture of PDI and its homologues can be inferred. The isolated a and a′ domains of PDI are good catalysts of simple thiol–disulfide interchange reactions but require additional domains to be effective as catalysts of the rate‐limiting disulfide isomerizations in protein folding pathways. The b′ domain of PDI has a specific binding site for peptides and its binding properties differ in specificity between members of the PDI family. A model of PDI function can be deduced in which the domains function synergically: the b′ domain binds unstructured regions of polypeptide, while the a and a′ domains catalyse the chemical isomerization steps.
The Drosophila homolog of NTF‐2, the nuclear transport factor‐2, is essential for immune response
Authors: Bhattacharya Ananya , Steward Ruth
Published: July 2002

Nuclear transport factor‐2 (NTF‐2) functions in yeast and mammalian cell culture in targeting proteins into the nucleus. The Drosophila homolog, DNTF‐2, is an essential component of the nuclear import machinery, since ntf mutants are lethal. Interestingly, hypomorphic alleles show specific phenotypes. Some are viable, but the number of omatidia in the eye is severely reduced. The immune response in the Drosophila larval fat body is also affected; the three NF‐κB/Rel proteins Dorsal, Dif and Relish do not target to the nucleus after infection, and, consequently, the expression of the anti‐microbial peptide genes drosomycin, attacin and drosocin is severely impaired. Hence, in spite of its general requirement in many developmental processes, DNTF‐2 has a higher specific requirement in the development of the eye and in the immune response. We also found that DNTF‐2 interacts directly with Mbo/DNup88, which does not contain phenylalanine‐glycine‐rich repeats, but has been shown to function in the import of Rel proteins.
Maintenance of a Smoking Cessation Program in Public Health Clinics beyond the Experimental Evaluation Period
Authors: Manfredi Clara , Crittenden Kathleen , Cho Young Ik , Engler Julie , Warnecke Richard
Published: July 2002

Objectives.

As phase 3 of a study to evaluate a smoking cessation program in public health practice, the authors assess the maintenance and impact of the It's Time smoking cessation program in seven public maternal and child health clinics in Chicago.

Methods.

The authors interviewed 404 clinic patients in the study's baseline phase (prior to introduction of the It's Time intervention program), and 610 in the program maintenance phase (in the year after experimental evaluation had ended) to assess exposure to smoking cessation interventions offered at the clinic, and smoking cessation outcomes (quit, actions toward quitting, scores on action, motivation, readiness, and confidence scales). The authors controlled for clustering of smokers within clinics, smokers' characteristics prior to clinic visit, and type of clinic service. They compared outcomes by study group (control or intervention) to which each clinic had been assigned in the earlier experimental phase.

Results.

Compared to baseline, smokers in the maintenance phase had greater exposure to posters, provider advice and booklet, and better outcomes on seven of eight smoking cessation measures, including quitting. These improvements were larger for clinics with prior experience implementing It's Time.

Conclusion.

Participation in the experimental evaluation of the It's Time program prepared and possibly motivated the clinics to continue the program. Continuing the program resulted in greater delivery of interventions and improved smoking cessation outcomes for smokers in the clinics.
Pregnancy Feelings among Adolescents Awaiting Pregnancy Test Results
Authors: Hellerstedt Wendy L. , Fee Rebecca M. , McNeely Clea A. , Sieving Renee E. , Shew Marcia L. , Resnick Michael D.
Published: July 2002

Objective.

The authors surveyed adolescent girls about their feelings regarding pregnancy.

Methods.

A survey was administered to 117 13- to 18-year-olds who obtained pregnancy tests at nine clinics in Minneapolis and St. Paul, Minnesota, in 1998. The survey included four measures of pregnancy feelings. The authors used bivariate and multivariate logistic regression analyses to examine the associations of these measures with engagement with school, future expectations, social and environmental characteristics, and perceived partner desire for pregnancy.

Results.

The four measures of pregnancy feelings were highly correlated ( P = 0.0001). Participants reported a range of positive, negative, and ambivalent feelings on all measures. Perceived partner desire for pregnancy, limited future expectations, and lack of school engagement were significantly associated with positive pregnancy feelings for the four measures.

Conclusions.

Successful adolescent pregnancy prevention interventions may include the involvement of partners and key adults as well as strategies to enhance the educational or employment aspirations of girls and adolescents.
A Computerized Tool for Evaluating the Effectiveness of Preventive Interventions
Authors: Daumit Gail , Boulware L.E. , Powe N.R. , Minkovitz C.S. , Frick K.D. , Anderson L.A. , Janes G.R. , Lawrence R.S.
Published: July 2002

In identifying appropriate strategies for effective use of preventive services for particular settings or populations, public health practitioners employ a systematic approach to evaluating the literature. Behavioral intervention studies that focus on prevention, however, pose special challenges for these traditional methods. Tools for synthesizing evidence on preventive interventions can improve public health practice.

The authors developed a literature abstraction tool and a classification for preventive interventions. They incorporated the tool into a PC-based relational database and user-friendly evidence reporting system, then tested the system by reviewing behavioral interventions for hypertension management. They performed a structured literature search and reviewed 100 studies on behavioral interventions for hypertension management. They abstracted information using the abstraction tool and classified important elements of interventions for comparison across studies.

The authors found that many studies in their pilot project did not report sufficient information to allow for complete evaluation, comparison across studies, or replication of the intervention. They propose that studies reporting on preventive interventions should ( a) categorize interventions into discrete components; ( b) report sufficient participant information; and ( c) report characteristics such as intervention leaders, timing, and setting so that public health professionals can compare and select the most appropriate interventions.
Disruption of lens fiber cell architecture in mice expressing a chimeric AQP0‐LTR protein
Authors: Shiels Alan , Mackay Donna , Bassnett Steven , Al‐Ghoul Kristin , Kuszak Jer
Published: July 2002

Aquaporin‐0 (AQP0) is the major intrinsic protein of lens fiber cells and the founder member of the water channel gene family. Here we show that disruption of the AQP0 gene by an early transposon (ETn) element results in expression of a chimeric protein, comprised of ∼75% AQP0 and ~25% ETn long terminal repeat (LTR) sequence, in the cataract Fraser (CatFr) mouse lens. Immunoblot analysis showed that mutant AQP0‐LTR was similar in mass to wild‐type AQP0. However, immunofluorescence microscopy revealed that AQP0‐LTR was localized to intracellular membranes rather than to plasma membranes of lens fiber cells. Heterozygous CatFr lenses were similar in size to wild‐type but displayed abnormal regions of translucence and light scattering. Scanning electron microscopy further revealed that mature fiber cells within the core of the heterozygous Cat Fr lens failed to stratify into uniform, concentric growth shells, suggesting that the AQP0 water channel facilitates the development of the unique cellular architecture of the crystalline lens.—Shiels, A., Mackay, D., Bassnett, S., Al‐Ghoul, K., Kuszak, J. Disruption of lens fiber cell architecture in mice expressing a chimeric AQP0‐LTR protein. FASEB J. 14, 2207–2212 (2000)
Growth and survivorship of dipterocarp seedlings: differences in shade persistence create a special case of dispersal limitation
Authors: Brown Nick , Press Malcolm , Bebber Dan
Published: July 2002

A series of growth experiments and observations on natural populations have been carried out on dipterocarp species of contrasting ecology growing in artificial gaps and the forest understorey. These studies have demonstrated that although differences exist between species in photosynthetic and growth responses to the high–light environment, competition for light in canopy gaps is highly asymmetrical and tends to reinforce any pre–existing dominance hierarchy. We propose that differences in seedling persistence in forest canopy shade are highly influenced by species–specific biotic and abiotic interactions. Our experiments suggest that as seedlings, dipterocarp species trade off traits which enhance persistence and growth in shade against those that enhance their ability to exploit gaps. Less competitive species survive for progressively longer periods of time after a gregarious fruiting event. This leads to significant shifts with time in the number of species present in the seedling bank and hence in the importance of interspecific competition in determining which species dominates regrowth in gaps. We propose that this special case of dispersal limitation is more likely to account for coexistence of dipterocarp species than differences in growth responses to gaps of different size, with stochastic and environmental variables interacting to determine species distribution and abundance.