Dstac is required for normal circadian activity rhythms in Drosophila

The genetic, molecular and neuronal mechanism underlying circadian activity rhythms is well characterized in the brain of Drosophila. The small ventrolateral neurons (s-LN_Vs) and pigment dispersing factor (PDF) expressed by them are especially important for regulating circadian locomotion. Here we describe a novel gene, Dstac, which is similar to the stac genes found in vertebrates that encode adaptor proteins, which bind and regulate L-type voltage-gated Ca²⁺ channels (CaChs). We show that Dstac is coexpressed with PDF by the s-LN_Vs and regulates circadian activity. Furthermore, the L-type CaCh, Dmca1D, appears to be expressed by the s-LN_Vs. Since vertebrate Stac3 regulates an L-type CaCh we hypothesize that Dstac regulates Dmca1D in s-LN_Vs and circadian activity.     

Prepregnancy renal function and risk of preterm birth and related outcomes

BACKGROUND:Prepregnancy kidney dysfunction has been associated with preterm birth, which is the leading cause of neonatal morbidity and mortality; however, the relation is not well understood. We determined the risk of preterm birth in women with prepregnancy kidney dysfunction, defined using pregnancy-specific serum creatinine cut points.METHODS:This population-based cohort study in the province of Ontario, Canada, involved women aged 16 to 50 years who had a singleton birth between 2006 and 2016 and measurement of serum creatinine within 10 weeks preceding their estimated conception date. The exposure was abnormally elevated prepregnancy serum creatinine, defined as greater than the 95th percentile (> 77 μmol/L), a value derived from a population-based sample of women without known kidney disease who became pregnant soon after the measurement was obtained. The main outcome was any preterm birth from 23 to 36 weeks’ gestation. Secondary outcomes included provider-initiated preterm birth before 37 weeks’ gestation and spontaneous preterm birth before 37 weeks.RESULTS:Among 55 946 pregnancies, preterm birth before 37 weeks’ gestation occurred in 3956 women (7.1%). The risk of preterm birth before 37 weeks was higher among women with prepregnancy creatinine above the 95th percentile, relative to those with prepregnancy creatinine at or below the 95th percentile (9.1% v. 7.0%; adjusted relative risk [RR] 1.23, 95% confidence interval [CI] 1.09 to 1.38). The effect was significant for provider-initiated preterm birth (adjusted RR 1.30, 95% CI 1.11 to 1.52) but not for spontaneous preterm birth (adjusted RR 1.12, 95% CI 0.91 to 1.37).INTERPRETATION:Given that prepregnancy kidney dysfunction conferred an increased risk of preterm birth, measurement of serum creatinine (a relatively inexpensive blood test) may form part of the assessment of risk for preterm birth among those planning pregnancy.

Prepregnancy kidney dysfunction may perturb the normal physiologic adaptations of pregnancy, predisposing a woman and her fetus to adversity, at least partly mediated by placental and endothelial dysfunction.¹ Complications such as preeclampsia² and poor fetal growth³ may necessitate provider-initiated preterm birth. Preterm birth of any form before 37 weeks’ gestation occurs in 6% to 11% of viable pregnancies and is the leading cause of infant death.⁴Prepregnancy kidney dysfunction has been associated with preterm birth.^5–7 Prior studies of the relation between prepregnancy kidney dysfunction and preterm birth were primarily case series and thus had inadequate statistical power to differentiate between the outcomes of spontaneous versus provider-initiated preterm birth. In addition, arbitrary cut points were used in these studies to define prepregnancy kidney dysfunction, and there was no accounting for important confounders.^5,8–14In an effort to overcome the aforementioned limitations, we completed a large cohort study in a setting where prenatal and obstetric care is covered under a provincial health insurance plan. Using population-derived cut points for prepregnancy serum creatinine to define kidney dysfunction, we examined the risk of preterm birth and other related outcomes.     

Structural and Functional Characterization of the PaaI Thioesterase from Streptococcus pneumoniae Reveals a Dual Specificity for Phenylacetyl-CoA and Medium-chain Fatty Acyl-CoAs and a Novel CoA-induced Fit Mechanism

PaaI thioesterases are members of the TE13 thioesterase family that catalyze the hydrolysis of thioester bonds between coenzyme A and phenylacetyl-CoA. In this study we characterize the PaaI thioesterase from Streptococcus pneumoniae (SpPaaI), including structural analysis based on crystal diffraction data to 1.8-Å resolution, to reveal two double hotdog domains arranged in a back to back configuration. Consistent with the crystallography data, both size exclusion chromatography and small angle x-ray scattering data support a tetrameric arrangement of thioesterase domains in solution. Assessment of SpPaaI activity against a range of acyl-CoA substrates showed activity for both phenylacetyl-CoA and medium-chain fatty-acyl CoA substrates. Mutagenesis of putative active site residues reveals Asn³⁷, Asp⁵², and Thr⁶⁸ are important for catalysis, and size exclusion chromatography analysis and x-ray crystallography confirm that these mutants retain the same tertiary and quaternary structures, establishing that the reduced activity is not a result of structural perturbations. Interestingly, the structure of SpPaaI in the presence of CoA provides a structural basis for the observed substrate specificity, accommodating a 10-carbon fatty acid chain, and a large conformational change of up to 38 Å in the N terminus, and a loop region involving Tyr³⁸-Tyr³⁹. This is the first time PaaI thioesterases have displayed a dual specificity for medium-chain acyl-CoAs substrates and phenylacetyl-CoA substrates, and we provide a structural basis for this specificity, highlighting a novel induced fit mechanism that is likely to be conserved within members of this enzyme family.