Marked variability in intrapartum electronic fetal heart rate patterns: association with neonatal morbidity and abnormal arterial cord gas.

OBJECTIVE: Investigate marked variability in fetal heart rate (FHR) patterns before delivery and its association with neonatal morbidity and abnormal arterial cord gases. STUDY DESIGN: Prospective cohort of laboring patients at term. Composite neonatal morbidity (respiratory distress, mechanical ventilation, suspected sepsis, meconium aspiration syndrome, therapeutic hypothermia, hypoxic-ischemic encephalopathy, seizure, and death) and abnormal arterial cord gases (pH < 7.10, lactate ≥ 4 mmol/L, base deficit < -12 mEq/L) were assessed with multivariable logistic regression. RESULT: Three hundred and ninety (4.5%) neonates had marked variability in FHR patterns before delivery. There was no difference in composite neonatal morbidity (aRR 1.22; 95% CI 0.91-1.63), though neonates with marked variability in FHR patterns were more likely to have a respiratory distress (aRR 1.85; 95% CI 1.25-2.70). There was an increased risk of composite abnormal arterial cord gases (aRR 1.66; 95% CI 1.47-1.88). CONCLUSION: Marked variability in FHR patterns was not associated with composite neonatal morbidity but was associated with abnormal arterial cord gases.

Functional Characterization of LIPA (Lysosomal Acid Lipase) Variants Associated With Coronary Artery Disease.

OBJECTIVE: LIPA (lysosomal acid lipase) mediates cholesteryl ester hydrolysis, and patients with rare loss-of-function mutations develop hypercholesterolemia and severe disease. Genome-wide association studies of coronary artery disease have identified several tightly linked, common intronic risk variants in LIPA which unexpectedly associate with increased mRNA expression. However, an exonic variant (rs1051338 resulting in T16P) in linkage with intronic variants lies in the signal peptide region and putatively disrupts trafficking. We sought to functionally investigate the net impact of this locus on LIPA and whether rs1051338 could disrupt LIPA processing and function to explain coronary artery disease risk. Approach and Results: In monocytes isolated from a large cohort of healthy individuals, we demonstrate both exonic and intronic risk variants are associated with increased LIPA enzyme activity coincident with the increased transcript levels. To functionally isolate the impact of rs1051338, we studied several in vitro overexpression systems and consistently observed no differences in LIPA expression, processing, activity, or secretion. Further, we characterized a second common exonic coding variant (rs1051339), which is predicted to alter LIPA signal peptide cleavage similarly to rs1051338, yet is not linked to intronic variants. rs1051339 also does not impact LIPA function in vitro and confers no coronary artery disease risk. CONCLUSIONS: Our findings show that common LIPA exonic variants in the signal peptide are of minimal functional significance and suggest coronary artery disease risk is instead associated with increased LIPA function linked to intronic variants. Understanding the mechanisms and cell-specific contexts of LIPA function in the plaque is necessary to understand its association with cardiovascular risk.

A structural model of flagellar filament switching across multiple bacterial species.

The bacterial flagellar filament has long been studied to understand how a polymer composed of a single protein can switch between different supercoiled states with high cooperativity. Here we present near-atomic resolution cryo-EM structures for flagellar filaments from both Gram-positive Bacillus subtilis and Gram-negative Pseudomonas aeruginosa. Seven mutant flagellar filaments in B. subtilis and two in P. aeruginosa capture two different states of the filament. These reliable atomic models of both states reveal conserved molecular interactions in the interior of the filament among B. subtilis, P. aeruginosa and Salmonella enterica. Using the detailed information about the molecular interactions in two filament states, we successfully predict point mutations that shift the equilibrium between those two states. Further, we observe the dimerization of P. aeruginosa outer domains without any perturbation of the conserved interior of the filament. Our results give new insights into how the flagellin sequence has been "tuned" over evolution.Bacterial flagellar filaments are composed almost entirely of a single protein-flagellin-which can switch between different supercoiled states in a highly cooperative manner. Here the authors present near-atomic resolution cryo-EM structures of nine flagellar filaments, and begin to shed light on the molecular basis of filament switching.