Discovery and characterization of novel TRPML1 agonists.

Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated and profiled in vitro and in vivo. Their selectivity, ready availability and CNS penetration should enable them to serve as the tool compounds of choice in future TRPML1 channel activation studies.

Evaluating the frequency of crisis pregnancy center visits among a population of patients seeking abortions in Los Angeles.

Objectives: Studies have illustrated crisis pregnancy centers' (CPC) disingenuous practices regarding abortion services. We evaluated the proportion of patients who visited a CPC before their abortion in Los Angeles.

Study Design: Patients attending one of two abortion clinics between July 2019 and March 2020 were recruited for a survey that examined patient characteristics and locations of care.

Discovery of quinuclidine modulators of cellular progranulin.

Phenotypic screening of an annotated small molecule library identified the quinuclidine tetrahydroisoquinoline solifenacin (1) as a robust enhancer of progranulin secretion with single digit micromolar potency in a murine microglial (BV-2) cell line. Subsequent SAR development led to the identification of 29 with a 38-fold decrease in muscarinic receptor antagonist activity and a 10-fold improvement in BV-2 potency.

Comparison of complications associated with induction by misoprostol versus dilation and evacuation for second-trimester abortion.

Objective: To compare the frequency of complications between medical induction with misoprostol and dilation and evacuation (D&E) for second-trimester uterine evacuation.

Methods: In a retrospective cohort study, records were reviewed from all women who underwent second-trimester uterine evacuation between 14 and 24 weeks of pregnancy at an academic hospital in the USA from January 2007 to December 2008. Total complications and serious complications were compared between medical induction and D&E, and clinical covariates associated with complications were assessed.

Reproductive healthcare experiences of women with cerebral palsy.

Background: Little is known about pregnancy rates in women with disabilities in general and even less is known about women with child-onset disabilities such as cerebral palsy (CP).

Hypothesis: We hypothesized that discussions about pregnancy with healthcare providers and pregnancy rates for woman with CP would be related to their functional levels.

Methods: Survey methodology was used to gather information about demographics, function, whether women were asked about their desire for children, pregnancy outcomes, and services offered during pregnancy and postpartum.

Medical Compared With Surgical Abortion for Effective Pregnancy Termination in the First Trimester.

Objective: To compare efficacy between medical and surgical abortion at 9 weeks of gestation or less.

Methods: We performed a retrospective cohort study comparing efficacy of medical compared with surgical abortion before 64 days of gestation at Planned Parenthood, Los Angeles, from November 2010 to August 2013. Electronic medical records were reviewed for ongoing pregnancies after the initial abortion procedure.

Cleavage and reduced CD36 ectodomain density on heart and spleen macrophages in the spontaneously hypertensive rat.

Metabolic disease is accompanied by a range of cellular defects ("comorbidities") whose origin is uncertain. To investigate this pathophysiological phenomenon we used the Spontaneously Hypertensive Rat (SHR), which besides an elevated arterial blood pressure also has many other comorbidities, including a defective glucose and lipid metabolism. We have shown that this model of metabolic disease has elevated plasma matrix metalloproteinase (MMP) activity, which cleaves the extracellular domain of membrane receptors.

Receptor cleavage and P-selectin-dependent reduction of leukocyte adhesion in the spontaneously hypertensive rat.

The SHR, a genetic model for hypertension and the metabolic syndrome, has attenuated leukocyte adhesion to the postcapillary endothelium by an unknown mechanism. Based on recent evidence of elevated levels of MMPs in plasma and on microvascular endothelium of the SHR with cleavage of several receptor types, we hypothesize that the reduced leukocyte-endothelial interaction is a result of enhanced proteolytic cleavage of P-selectin on the postcapillary endothelium and PSGL-1 on leukocytes. The attenuated rolling interactions of SHR leukocytes with the endothelium were restored by chronic treatment with a broad-spectrum MMP inhibitor (CGS) for 24 weeks.

mTORC1 signaling and regulation of pancreatic β-cell mass.

The capacity of β cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of β cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for β-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids.

Proteolytic Cleavage of the Red Blood Cell Glycocalyx in a Genetic Form of Hypertension.

Recent evidence suggests that the spontaneously hypertensive rat (SHR) has an elevated level of proteases, including matrix metalloproteinases (MMPs), involved in cell membrane receptor cleavage. We hypothesize that SHR red blood cells (RBCs) may be subject to an enhanced glycocalyx cleavage compared to the RBCs of the normotensive Wistar-Kyoto (WKY) rats. By direct observation of RBC rouleaux, we found no significant difference in RBC aggregation for unseparated SHR and WKY RBCs.

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat.

Physiological fluid shear stress evokes pseudopod retraction in normal leukocytes by a mechanism that involves the formyl peptide receptor (FPR) as mechanosensor. In hypertensives, such as the spontaneously hypertensive rat (SHR), leukocytes lack the normal fluid shear response. The increased activity of matrix metalloproteinases (MMPs, including MMP-9) in SHR plasma is associated with cleavage of several cell membrane receptors.

Microfabricated arrays of cylindrical wells facilitate single-molecule enzymology of alpha-chymotrypsin.

Single-molecule enzymology allows scientists to examine the distributions of kinetic rates among members of a population. We describe a simple method for the analysis of single-molecule enzymatic kinetics and provide comparisons to ensemble-averaged kinetics. To isolate our model enzyme, alpha-chymotrypsin, into single molecules, we use an array of cylindrical poly(dimethylsiloxane) wells 2 microm in diameter and 1.

Bleeding after medication-induced termination of pregnancy with two dosing schedules of mifepristone and misoprostol.

Objective: This study examines bleeding pattern following medication-induced termination of pregnancy, comparing two different dosing schedules of mifepristone and misoprostol.

Study Design: Diary information was analyzed from a randomized, multicenter trial in which women used vaginal misoprostol 800 mug either 6-8 or 24 h following 200 mg of oral mifepristone.

Participants And Methods: One thousand eighty women with pregnancies up to 63 days' gestation were recruited for the study; 540 were randomized to the 6- to 8-h dosing schedule, and 540 were randomized to the 24-h dosing schedule.

A randomized clinical trial of the addition of laminaria to misoprostol and hypertonic saline for second-trimester induction abortion.

Objective: To compare the outcomes of second-trimester induction abortion with misoprostol and hypertonic saline, with and without use of laminaria.

Method: Fifty-eight women, between 17.5 and 22.

Circulating cell-free fetal nucleic acid analysis may be a novel marker of fetomaternal hemorrhage after elective first-trimester termination of pregnancy.

Analysis of cell-free fetal DNA (fDNA) and RNA in maternal plasma could be useful in the diagnosis and management of complications of pregnancy. In this review, we discuss our studies to investigate the potential of fetal nucleic acid measurement in maternal plasma as a marker of fetomaternal hemorrhage (FMH) after elective first-trimester termination of pregnancy (TOP). Using quantitative real-time PCR amplification of the DYS1 sequence, elevation of plasma fDNA levels after TOP was observed, especially in the late first trimester.

Plasma gamma-globin gene expression suggests that fetal hematopoietic cells contribute to the pool of circulating cell-free fetal nucleic acids during pregnancy.

Background: Reports of placental mRNA sequences in the plasma of pregnant women suggest that the placenta is the predominant source of cell-free fetal nucleic acids in maternal plasma during pregnancy. We developed an assay for gamma-globin mRNA concentrations to determine whether hematopoietic cells also contribute to the pool of fetal mRNA in maternal plasma.

Methods: Frozen paired plasma samples obtained from 40 women before and within 20 min after elective first-trimester termination of pregnancy (TOP) were analyzed.

Cell-free fetal DNA levels in maternal plasma after elective first-trimester termination of pregnancy.

Objective: To determine if first-trimester elective termination of pregnancy affects cell-free fetal DNA (fDNA) levels in maternal plasma.

Design: Prospective cohort study.

Setting: Clinical and academic research centers.