Dual client binding sites in the ATP-independent chaperone SurA.

The ATP-independent chaperone SurA protects unfolded outer membrane proteins (OMPs) from aggregation in the periplasm of Gram-negative bacteria, and delivers them to the β-barrel assembly machinery (BAM) for folding into the outer membrane (OM). Precisely how SurA recognises and binds its different OMP clients remains unclear. Escherichia coli SurA comprises three domains: a core and two PPIase domains (P1 and P2).

Outer membrane protein assembly mediated by BAM-SurA complexes.

The outer membrane is a formidable barrier that protects Gram-negative bacteria against environmental threats. Its integrity requires the correct folding and insertion of outer membrane proteins (OMPs) by the membrane-embedded β-barrel assembly machinery (BAM). Unfolded OMPs are delivered to BAM by the periplasmic chaperone SurA, but how SurA and BAM work together to ensure successful OMP delivery and folding remains unclear.

Residues 2 to 7 of α-synuclein regulate amyloid formation via lipid-dependent and lipid-independent pathways.

Amyloid formation by α-synuclein (αSyn) occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate αSyn amyloid fibril formation will not only provide mechanistic insight but may also reveal targets to prevent and treat disease. Previous investigations have identified several regions of αSyn to be important in the regulation of amyloid formation, including the non-amyloid-β component (NAC), P1 region (residues 36 to 42), and residues in the C-terminal domain.

Dynamic coupling of fast channel gating with slow ATP-turnover underpins protein transport through the Sec translocon.

The Sec translocon is a highly conserved membrane assembly for polypeptide transport across, or into, lipid bilayers. In bacteria, secretion through the core channel complex-SecYEG in the inner membrane-is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the conformational state of SecYEG throughout the ATP hydrolysis cycle of SecA.

Structural and biochemical characterization of the novel serpin Iripin-5 from Ixodes ricinus.

Iripin-5 is the main Ixodes ricinus salivary serpin, which acts as a modulator of host defence mechanisms by impairing neutrophil migration, suppressing nitric oxide production by macrophages and altering complement functions. Iripin-5 influences host immunity and shows high expression in the salivary glands. Here, the crystal structure of Iripin-5 in the most thermodynamically stable state of serpins is described.

Dynamics of Membrane Proteins Monitored by Single-Molecule Fluorescence Across Multiple Timescales.

Single-molecule techniques provide insights into the heterogeneity and dynamics of ensembles and enable the extraction of mechanistic information that is complementary to high-resolution structural techniques. Here, we describe the application of single-molecule Förster resonance energy transfer to study the dynamics of integral membrane protein complexes on timescales spanning sub-milliseconds to minutes (10-10 s).

An alkynyliodide cycloaddition strategy for the construction of iodoisoxazoles.

The thermally promoted cycloaddition between alkynyliodides and nitrile oxides is reported. The process offers excellent regioselectivity and a broad scope with respect to both the iodoalkynes and chloro-oximes. Further functionalization of the highly decorated iodoisoxazole motifs can be achieved via Suzuki cross-coupling.

Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study.

Objective: To determine what impact reliance on self reported smoking status during pregnancy has on both the accuracy of smoking prevalence figures and access to smoking cessation services for pregnant women in Scotland.

Design: Retrospective, cross sectional study of cotinine measurements in stored blood samples.

Participants: Random sample (n=3475) of the 21 029 pregnant women in the West of Scotland who opted for second trimester prenatal screening over a one year period.

First-trimester contingent screening for Down syndrome can reduce the number of nuchal translucency measurements required.

Background: To assess the performance of a two-stage screening protocol for Down syndrome based on initial serum marker analysis for all women and nuchal translucency (NT) measurement only in women with intermediate risks.

Methods: Biochemical marker and NT data in 10 189 women who had had combined ultrasound and biochemical (CUB) screening, were re-analysed using the contingent model. A risk was calculated from the results of the pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (FbetahCG) measurements and maternal age.

Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth.

Objective: To estimate the relationship between maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in early pregnancy with the risk of subsequent adverse outcome.

Methods: A nested, case-control study was performed within a prospective cohort study of Down syndrome screening. Maternal serum levels of sFlt-1 and PlGF at 10-14 weeks of gestation were compared between 939 women with complicated pregnancies and 937 controls.

Maternal and biochemical predictors of antepartum stillbirth among nulliparous women in relation to gestational age of fetal death.

Objective: To determine whether maternal serum levels of alphafetoprotein (alpha-FP) and human chorionic gonadotrophin (hCG) at 15-21 weeks provided clinically useful prediction of stillbirth in first pregnancies.

Design: Retrospective study of record linkage of a regional serum screening laboratory to national registries of pregnancy outcome and perinatal death.

Setting: West of Scotland, 1992-2001.

Maternal obesity in early pregnancy and risk of spontaneous and elective preterm deliveries: a retrospective cohort study.

Objectives: We sought to determine the association between maternal body mass index and risk of preterm delivery.

Methods: We assessed 187,290 women in Scotland and estimated adjusted odds ratios for spontaneous and elective preterm deliveries among overweight, obese, and morbidly obese women relative to normal-weight women.

Results: Among nulliparous women, the risk of requiring an elective preterm delivery increased with increasing BMI, whereas the risk of spontaneous preterm labor decreased.

Maternal and biochemical predictors of spontaneous preterm birth among nulliparous women: a systematic analysis in relation to the degree of prematurity.

Background: Nulliparous women are at increased risk of spontaneous preterm birth. Other maternal and biochemical risk factors have also been described. However, it is unclear whether these associations are strong enough to offer clinically useful prediction.

Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome.

Objective: To describe the association between pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP) and adverse perinatal outcome.

Methods: We conducted a multicenter prospective cohort study of 8,483 women attending for prenatal care in southern Scotland between 1998 and 2000. The risk of delivering a small for gestational age infant, delivering preterm, and stillbirth were related to maternal serum levels of PAPP-A and AFP.

Second-trimester levels of pregnancy-associated plasma protein-A and free beta-hCG in pregnancies with trisomy 13.

Objective: To examine the levels of free beta-human chorionic gonadotrophin (free beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in second-trimester maternal serum from pregnancies affected by trisomy 13 and compare these with the known reduced levels of these markers in first-trimester cases in an attempt to better understand the pathophysiology of changes in marker levels in chromosomally abnormal pregnancies between the first and second trimester.

Methods: Using the Kryptor immunoassay system, we measured free beta-hCG and PAPP-A in 32 singleton pregnancies affected by trisomy 13 between 14 and 20 weeks of gestation. Using medians established in a previous study, these results were compared against 450 normal singleton pregnancies over the same gestational range.

First-trimester placentation and the risk of antepartum stillbirth.

Context: Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester.

Objective: To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy.

First-trimester combined ultrasound and biochemical screening for Down syndrome in routine clinical practice.

Objectives: To assess the effectiveness of combined ultrasound and biochemical (CUB) screening for chromosome abnormalities in singleton pregnancies in a routine antenatal clinic and laboratory setting.

Methods: Women whose pregnancies fell within the gestational age range of 11 to 14 weeks by ultrasound assessment were offered CUB screening on the basis of measurement of nuchal translucency (NT), maternal serum free beta-human chorionic gonadotrophin (FbetahCG) and pregnancy-associated plasma protein A (PAPP-A). NT measurements were obtained using a standardised method defined by the Fetal Medicine Foundation and FbetahCG, and PAPP-A were measured using the DELFIA immunoassay system.

Second-trimester maternal serum levels of alpha-fetoprotein and the subsequent risk of sudden infant death syndrome.

Background: Unexplained stillbirth and the sudden infant death syndrome (SIDS) share some features. A raised maternal serum level of alpha-fetoprotein during the second trimester of pregnancy is a marker of placental dysfunction and a strong predictor of the risk of unexplained stillbirth. It is unknown whether alpha-fetoprotein levels also predict the risk of SIDS.

The effect of temporal variation in biochemical markers of trisomy 21 across the first and second trimesters of pregnancy on the estimation of individual patient-specific risks and detection rates for Down's syndrome.

Background: In a previous study we examined the changes in the median multiple of the median (MoM) with gestation of free beta human chorionic gonadotrophin (F beta-hCG), total human chorionic gonadotrophin (ThCG), alpha-fetoprotein (AFP) and pregnancy-associated plasma protein A (PAPP-A) in a large series of Down's syndrome pregnancies. Results showed that there was a significant temporal variation of the MoM for each marker. In this paper, we assess the impact of this temporal shift on the estimation of patient-specific risks and the detection rates (DRs) for Down's syndrome pregnancies.

Temporal changes in maternal serum biochemical markers of trisomy 21 across the first and second trimester of pregnancy.

Background: Many maternal serum markers show concentration changes in Down's syndrome pregnancies but the magnitude of the change in median marker levels varies with gestation. To date these changes have not been accurately specified.

Methods: The trends in marker median levels between 6 and 20 weeks of gestation were examined for alphafetoprotein (AFP), free beta human chorionic gonadotrophin (Fbeta-hCG), total human chorionic gonadotrophin (ThCG) and pregnancy-associated plasma protein A (PAPP-A) by a meta-analysis of data obtained from our collaborative studies and routine screening programmes for Down's syndrome over a 10-year period.

Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicentre study.

Objective: To evaluate the use of ultrasound measurements of fetal nuchal translucency (NT) obtained in a routine antenatal clinic setting in combination with appropriate biochemical markers as a first trimester screening test for Down's Syndrome.

Design: Multicentre observational study.

Setting: Fifteen Scottish maternity units.

Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth.

The risk of adverse perinatal outcome among 8839 women recruited to a multicenter, prospective cohort study was related to maternal circulating concentrations of trophoblast-derived proteins at 8-14 wk gestation. Women with a pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile at 8-14 wk gestation had an increased risk of intrauterine growth restriction [adjusted odds ratio, 2.9; 95% confidence interval (CI), 2.

Maternal smoking: age distribution, levels of alpha-fetoprotein and human chorionic gonadotrophin, and effect on detection of Down syndrome pregnancies in second-trimester screening.

Objectives: To study the levels of maternal serum alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) in the second trimester in smokers and non-smokers with unaffected and Down syndrome pregnancies; to examine the rate of smoking in different maternal age groups in a population having routine prenatal screening; and to assess the effect of smoking on the detection rates for Down syndrome and corresponding false-positive rates, both overall and in different maternal age groups.

Methods: Information on maternal smoking status, maternal age and serum marker levels was collected from case note searches and the screening programme database on 2272 unaffected singleton pregnancies, 36 unaffected twin pregnancies and 103 singleton Down syndrome pregnancies.

Results: In unaffected pregnancies the smokers had a median age 3.

Growth hormone binding protein in normal and aneuploid pregnancy: a paradoxical decrease in trisomy 18.

Objective: To explore whether abnormalities in growth hormone binding protein (GHBP) may underlie the growth restriction associated with fetal aneuploidy.

Design: A retrospective casecontrol study.

Setting: Monash Medical Centre.