TMM@: a web application for the analysis of transmembrane helix mobility

Background: To understand the mechanism by which a protein transmits a signal through the cell membrane, an understanding of the flexibility of its transmembrane (TM) region is essential. Normal Mode Analysis (NMA) has become the method of choice to investigate the slowest motions in macromolecular systems. It has been widely used to study transmembrane channels and pumps. It relies on the hypothesis that the vibrational normal modes having the lowest frequencies (also named soft modes) describe the largest movements in a protein and are the ones that are functionally relevant. In particular NMA can be used to study dynamics of TM regions, but no tool making this approach available for non-experts, has been available so far. Results: We developed the web-application TMM@ (TransMembrane α-helical Mobility analyzer). It uses NMA to characterize the propensity of transmembrane α-helices to be displaced. Starting from a structure file at the PDB format, the server computes the normal modes of the protein and identifies which helices in the bundle are the most mobile. Each analysis is performed independently from the others and results can be visualized using only a web browser. No additional plug-in or software is required. For users who would like to further analyze the output data with their favourite software, raw results can also be downloaded. Conclusion: We built a novel and unique tool, TMM@, to study the mobility of transmembrane α-helices. The tool can be applied to for example membrane transporters and provides biologists studying transmembrane proteins with an approach to investigate which α-helices are likely to undergo the largest displacements, and hence which helices are most likely to be involved in the transportation of molecules in and out of the cell

Perinatal mortality by gestational week and size at birth in singleton pregnancies at and beyond term: a nationwide population-based cohort study

BACKGROUND: Whether gestational age per se increases perinatal mortality in post-term pregnancy is unclear. We aimed at assessing gestational week specific perinatal mortality in small-for-gestational-age (SGA) and non-SGA term and post-term gestations, and specifically to evaluate whether the relation between post-term gestation and perinatal mortality differed before and after ultrasound was introduced as the standard method of gestational age estimation. METHODS: A population-based cohort study, using data from the Medical Birth Registry of Norway (MBRN), 1967–2006, was designed. Singleton births at 37 through 44 gestational weeks (n = 1 855 682), excluding preeclampsia, diabetes and fetal anomalies, were included. Odds ratios (OR) with 95% confidence intervals (CI) for perinatal mortality and stillbirth in SGA and non-SGA births by gestational week were calculated. RESULTS: SGA infants judged post-term by LMP had significantly higher perinatal mortality than post-term non-SGA infants at 40 weeks, independent of time period (highest during 1999–2006 [OR 9.8, 95% CI: 5.7-17.0]). When comparing years before (1967–1986) versus after (1987–2006) ultrasound was introduced, there was no decrease in the excess mortality for post-term SGA versus non-SGA births (ORs from 6.1 [95% CI: 5.2-7.1] to 6.7 [5.2-8.5]), while mortality at 40 weeks decreased significantly (ORs from 4.6, [4.0-5.3] to 3.2 [2.5-3.9]). When assessing stillbirth risk (1999–2006), more than 40% of SGA stillbirths (11/26) judged to be ≥41 weeks by LMP were shifted to lower gestational ages using ultrasound estimation. CONCLUSIONS: Mortality risk in post-term infants was strongly associated with growth restriction. Such infants may erroneously be judged younger than they are when using ultrasound estimation, so that the routine assessment for fetal wellbeing in the prolonged gestation may be given too late

Lipid levels after childbirth and association with number of children: A population-based cohort study

Objective Low parity women are at increased risk of cardiovascular mortality. Unfavourable lipid profiles have been found in one-child mothers years before they conceive. However, it remains unclear whether unfavourable lipid profiles are evident in these women also after their first birth. The aim was to estimate post-pregnancy lipid levels in one-child mothers compared to mothers with two or more children and to assess these lipid’s associations with number of children. Methods We used data on 32 618 parous women (4 490 one-child mothers and 28 128 women with ≥2 children) examined after first childbirth as part of Cohort of Norway (1994–2003) with linked data on reproduction and number of children from the Medical Birth Registry of Norway (1967–2008). Odds ratios (ORs) with 95% confidence intervals (CIs) for one lifetime pregnancy (vs. ≥2 pregnancies) by lipid quintiles were obtained by logistic regression and adjusted for age at examination, year of first birth, body mass index, oral contraceptive use, smoking and educational level. Results Compared to women with the lowest quintiles, ORs for one lifetime pregnancy for the highest quintiles of LDL and total cholesterol were 1.30 (95%CI: 1.14–1.45) and 1.43 (95%CI: 1.27–1.61), respectively. Sensitivity analysis (women <40 years) showed no appreciable change in our results. In stratified analyses, estimates were slightly stronger in overweight/obese, physically inactive and women with self-perceived bad health. Conclusions Mean lipid levels measured after childbirth in women with one child were significantly higher compared to mothers with two or more children and were associated with higher probability of having only one child. These findings corroborate an association between serum lipid levels and one lifetime pregnancy (as a feature of subfecundity), emphasizing that these particular women may be a specific predetermined risk group for cardiovascular related disease and death.publishedVersio

Women's prepregnancy lipid levels and number of children: a Norwegian prospective population-based cohort study

Objective. To study prepregnancy serum lipid levels and the association with the number of children. Design. Prospective, population-based cohort. Setting. Linked data from the Cohort of Norway and the Medical Birth Registry of Norway. Participants. 2645 women giving birth to their first child during 1994–2003 (488 one-child mothers and 2157 women with ≥2 births) and 1677 nulliparous women. Main outcome measures. ORs for no and one lifetime pregnancy (relative to ≥2 pregnancies) obtained by multinomial logistic regression, adjusted for age at examination, education, body mass index (BMI), smoking, time since last meal and oral contraceptive use. Results. Assessed in quintiles, higher prepregnant triglyceride (TG) and TG to high-density lipoprotein (TG:HDL-c) ratio levels were associated with increased risk of one lifetime pregnancy compared with having ≥2 children. Compared with the highest quintile, women in the lowest quintile of HDL cholesterol levels had an increased risk of one lifetime pregnancy (OR 1.7, 95% CI 1.2 to 2.4), as were women with the highest low-density lipoprotein (LDL) cholesterol, TG and TG:HDL-c ratio quintiles (compared with the lowest) (OR 1.2, 95% CI 0.8 to 1.7; OR 2.2, 95% CI 1.5 to 3.2; and OR 2.2, 95% CI 1.5 to 3.2, respectively). Similar effects were found in women with BMI≥25 and the highest LDL and total cholesterol levels in risk of lifetime nulliparity. Conclusion. Women with unfavourable prepregnant lipid profile had higher risk of having no or only one child. These findings substantiate an association between prepregnant serum lipid levels and number of children. Previously observed associations between low parity and increased cardiovascular mortality may in part be due to pre-existing cardiovascular disease lipid risk factors.publishedVersio

Preeclampsia in pregnancy and later use of antihypertensive drugs

We explored the association between preeclampsia and later use of antihypertensive drugs in a population-based study with data from the Medical Birth Registry of Norway and the Norwegian Prescription Database. The study cohort consisted of 980,000 women having 2.1 million pregnancies during 1967–2012. Hazard ratios (HRs) with 95 % confidence intervals (95 % CI) were estimated in multivariate time-dependent Cox proportional hazards regression models. Overall, the HR of later use of antihypertensive drugs was 2.0 (95 % CI 2.0–2.0) in women with one preeclamptic pregnancy compared to women without preeclamptic pregnancies. The HR increased by increasing number of preeclamptic pregnancies, both term and preterm pregnancies. In women with two or more preeclamptic pregnancies, the HR was 2.8 (2.7–3.0). The overall HR after 40 years of follow-up for women with one preeclamptic pregnancy was 1.3 (1.2–1.4) and for two or more preeclamptic pregnancies the HR was 1.6 (1.1–2.1). The first 5 years after the first birth, the HR of being dispensed antihypertensive drugs was higher in preterm [8.4 (7.7–9.1)] than term preeclamptic pregnancies [4.3(4.0–4.6)]. However, after 10 years, this difference was no longer present. The HR of later use of antihypertensive drugs increased with the number of preeclamptic pregnancies, and in the first 10 years the HR was higher after a preterm than a term preeclamptic pregnancy. Although the HR decreased with time since first birth, the risk was still elevated after 40 years. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited

Molecular Dynamics Simulations

figurasGroEL is an ATP dependent molecular chaperone that promotes the folding of a large number of substrate proteins in E. coli. Large-scale conformational transitions occurring during the reaction cycle have been characterized from extensive crystallographic studies. However, the link between the observed conformations and the mechanisms involved in the allosteric response to ATP and the nucleotide-driven reaction cycle are not completely established. Here we describe extensive (in total long) unbiased molecular dynamics (MD) simulations that probe the response of GroEL subunits to ATP binding. We observe nucleotide dependent conformational transitions, and show with multiple 100 ns long simulations that the ligand-induced shift in the conformational populations are intrinsically coded in the structure-dynamics relationship of the protein subunit. Thus, these simulations reveal a stabilization of the equatorial domain upon nucleotide binding and a concomitant “opening” of the subunit, which reaches a conformation close to that observed in the crystal structure of the subunits within the ADP-bound oligomer. Moreover, we identify changes in a set of unique intrasubunit interactions potentially important for the conformational transition.The Norwegian Research Council is acknowledged for CPU resources granted through the NOTUR supercomputing program (http://www.notur.no/) and Bergen Center for Computational Science for providing powerful computer facilities (http://www.bccs.uni.no/). Work at CSIC/UPV/EHU was financed by MICINN (Grant BUF2007-64452). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Cesarean delivery in Norwegian nulliparous women with singleton cephalic term births, 1967–2020: a population-based study

Background Nulliparous women contribute to increasing cesarean delivery in the Nordic countries and advanced maternal age has been suggested as responsible for rise in cesarean delivery rates in many developed countries. The aim was to describe changes in cesarean delivery rates among nulliparous women with singleton, cephalic, term births by change in sociodemographic factors across 50 years in Norway. Methods We used data from the Medical Birth Registry of Norway and included 1 067 356 women delivering their first, singleton, cephalic, term birth between 1967 and 2020. Cesarean delivery was described by maternal age (5-year groups), onset of labor (spontaneous, induced and pre-labor CD), and time periods: 1967–1982, 1983–1998 and 1999–2020. We combined women’s age, onset of labor and time period into a compound variable, using women of 20–24 years, with spontaneous labor onset during 1967–1982 as reference. Multivariable regression models were used to estimate adjusted relative risk (ARR) of cesarean delivery with 95% confidence interval (CI). Results Overall cesarean delivery increased both in women with and without spontaneous onset of labor, with a slight decline in recent years. The increase was mainly found among women   = 35 years. In women with spontaneous onset of labor, the ARR of CD in women >  = 40 years decreased from 14.2 (95% CI 12.4–16.3) in 1967–82 to 6.7 (95% CI 6.2–7.4) in 1999–2020 and from 7.0 (95% CI 6.4–7.8) to 5.0 (95% CI 4.7–5.2) in women aged 35–39 years, compared to the reference population. Despite the rise in induced onset of labor over time, the ARR of CD declined in induced women >  = 40 years from 17.6 (95% CI 14.4–21.4) to 13.4 (95% CI 12.5–14.3) while it was stable in women 35–39 years. Conclusion Despite growing number of Norwegian women having their first birth at a higher age, the increase in cesarean delivery was found among women < 35 years, while it was stable or decreased in older women. The increase in cesarean delivery cannot be solely explained by the shift to an older population of first-time mothers.publishedVersio

Sex differences in parent–offspring recurrence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison. Methods In a generation study linking data from several population-based registries, all Norwegians born 1967–2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex. Results The absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RRmaternal 8.4, 95% confidence interval (CI) 8.2–8.6 vs. RRpaternal 6.2, 6.0–6.4) and this was also true on the absolute scale (PDmaternal 21.1% (20.5–21.7) vs. PDpaternal 14.8% (14.3–15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons. Conclusions The intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex- and diagnosis-specific intergenerational recurrence risk in parents with ADHD.publishedVersio