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Gestational hyperandrogenism adversely impacts offspring health. Using an ovine model, we found that prenatal testosterone (T) excess adversely affects growth and cardiometabolic outcomes in female offspring and produces sex-specific effects on fetal myocardium. Since lipids are essential to cardiometabolic function, we hypothesized that prenatal T excess leads to sex-specific disruptions in lipid metabolism at birth. Shotgun lipidomics was performed on the plasma samples collected 48 hours after birth from female (F) and male (M) lambs of control (C) and (T) sheep (CF = 4, TF = 7, CM = 5, TM = 10) and data were analyzed by univariate analysis, multivariate dimensionality reduction modeling followed by functional enrichment, and pathway analyses. Biosynthesis of phosphatidylserine was the major pathway responsible for sex differences in controls. Unsupervised and supervised models showed separation between C and T in both sexes with glycerophospholipids and glycerolipids classes being responsible for the sex differences between C and T. T excess increased cholesterol in females while decreasing phosphatidylcholine levels in male lambs. Specifically, T excess: 1) suppressed the phosphatidylethanolamine N-methyltransferase (PEMT) phosphatidylcholine synthesis pathway overall and in TM lambs as opposed to suppression of carnitine levels overall and TF lambs; and 2) activated biosynthesis of ether-linked (O-)phosphatidylethanolamine and O-phosphatidylcholine from O-diacylglycerol overall and in TF lambs. Higher cholesterol levels could underlie adverse cardiometabolic outcomes in TF lambs, whereas suppressed PEMT pathway in TM lambs could lead to endoplasmic reticulum stress and defective lipid transport. These novel findings point to sex-specific effects of prenatal T excess on lipid metabolism in newborn lambs, a precocial ovine model of translational relevance. [ABSTRACT FROM AUTHOR]

There is limited literature on emergency department (ED) use among pregnant women. In this article, we examined the associations between prenatal counseling with the use of the ED during pregnancy. In our cohort of Black women in the Metro Detroit area, we found that approximately 70.5% of the women had an ED visit at some point during pregnancy. In unadjusted models of prevalence ratios, we found women reporting receipt of prenatal counseling regarding fetal movement, what to do about baby's movement slowing down, and smoking (but not what to do about smoking) were at statistically significantly greater risk of ED utilization during pregnancy. Adjustment for confounders slightly weakened the associations for counseling about baby's movement or smoking, so that the associations were no longer statistically significant. These findings call for further research on ED utilization among this population, especially differentiating urgent versus non-urgent use of the ED during pregnancy. [ABSTRACT FROM AUTHOR]

Prenatal testosterone (T)-treated female sheep manifest peripheral insulin resistance, ectopic lipid accumulation, and insulin signaling disruption in liver and muscle. This study investigated transcriptional changes and transcriptome signature of prenatal T excess–induced hepatic and muscle-specific metabolic disruptions. Genome-wide coding and noncoding (nc) RNA expression in liver and muscle from 21-month-old prenatal T-treated (T propionate 100 mg intramuscular twice weekly from days 30-90 of gestation; term: 147 days) and control females were compared. Prenatal T (1) induced differential expression of messenger RNAs (mRNAs) in liver (15 down, 17 up) and muscle (66 down, 176 up) (false discovery rate < 0.05, absolute log2 fold change > 0.5); (2) downregulated mitochondrial pathway genes in liver and muscle; (3) downregulated hepatic lipid catabolism and peroxisome proliferator-activated receptor (PPAR) signaling gene pathways; (4) modulated noncoding RNA (ncRNA) metabolic processes gene pathway in muscle; and (5) downregulated 5 uncharacterized long noncoding RNA (lncRNA) in the muscle but no ncRNA changes in the liver. Correlation analysis showed downregulation of lncRNAs LOC114112974 and LOC105607806 was associated with decreased TPK1 , and LOC114113790 with increased ZNF470 expression. Orthogonal projections to latent structures discriminant analysis identified mRNAs HADHA and SLC25A45 , and microRNAs MIR154A , MIR25 , and MIR487B in the liver and ARIH1 and ITCH and miRNAs MIR369 , MIR10A , and MIR10B in muscle as potential biomarkers of prenatal T excess. These findings suggest downregulation of mitochondria, lipid catabolism, and PPAR signaling genes in the liver and dysregulation of mitochondrial and ncRNA gene pathways in muscle are contributors of lipotoxic and insulin-resistant hepatic and muscle phenotype. Gestational T excess programming of metabolic dysfunctions involve tissue-specific ncRNA–modulated transcriptional changes. [ABSTRACT FROM AUTHOR]

A small group of faculty, staff, and administrators, known as the Online Learning Community (OLC), were collectively interested in enriching online learning at a Jesuit university. With a culture at this Jesuit and Mercy university driven by face-to-face (F2F) learning, the first step was to assess students' perceptions of online learning from students who have taken online courses at the university. The survey, guided by best instructor practices in online learning and Jesuit philosophy, traditions, and concepts, was designed to explore students' perceptions, experiences, and practices in online learning. Students (N=484) self-enrolled in the study and included students from all the colleges in the university and across four campuses. The most notable response in the data was students' (72%) desire for more online learning opportunities at the host university. The freedom and flexibility afforded in online classes was prevalent in students' open-ended statements about online learning but students additionally emphasized the importance of instructor qualities of being organized in course delivery, availability, and effective communication skills. In this study, OLC members sought to place students' perceptions at the core of efforts to inform online learning at this Jesuit and Mercy university. The findings enrich and demonstrate linkages with core Jesuit traditions and concepts. [ABSTRACT FROM AUTHOR]

The SIN3 histone-modifying complex regulates the expression of multiple methionine catabolic genes, includingSAMsynthetase (Sam-S), as well as SAM levels. To further dissect the relationship between methionine catabolism and epigenetic regulation by SIN3, we sought to identify genes and metabolic pathways controlled by SIN3 and SAM synthetase (SAM-S) in Drosophila melanogaster. Using several approaches, including RNAi-mediated gene silencing, RNA-Seq- and quantitative RT-PCR-based transcriptomics, and ultra-high-performance LC-MS/MS- and GC/MS-based metabolomics, we found that, as a global transcriptional regulator, SIN3 impacted a wide range of genes and pathways. In contrast, SAM-S affected only a narrow range of genes and pathways. The expression and levels of additional genes and metabolites, however, were altered in Sin3A-Sam-S dual knockdown cells. This analysis revealed that SIN3 and SAM-S regulate overlapping pathways, many of which involve one-carbon and central carbon metabolisms. In some cases, the factors acted independently; in some others, redundantly; and for a third set, in opposition. Together, these results, obtained from experiments with the chromatin regulator SIN3 and the metabolic enzyme SAM-S, uncover a complex relationship between metabolism and epigenetic regulation. [ABSTRACT FROM AUTHOR]

The triple-negative breast cancer (TNBC) subtype, regardless of their BRCA1 status, has the poorest outcome compared with other breast cancer subtypes, and currently there are no approved targeted therapies for TNBC. We have previously demonstrated the importance of RAD6 -mediated translesion synthesis pathway in TNBC development/progression and chemoresistance, and the potential therapeutic benefit of targeting RAD6 with a RAD6 -selective small-molecule inhibitor, SMI#9. To overcome SMI#9 solubility limitations, we recently developed a gold nanoparticle (GNP)-based platform for conjugation and intracellular release of SMI#9, and demonstrated its in vitro cytotoxic activity toward TNBC cells. Here, we characterized the in vivo pharmacokinetic and therapeutic properties of PEGylated GNP-conjugated SMI#9 in BRCA1 wild-type and BRCA1-mutant TNBC xenograft models, and investigated the impact of RAD6 inhibition on TNBC metabolism by 1 H-NMR spectroscopy. GNP conjugation allowed the released SMI#9 to achieve higher systemic exposure and longer retention as compared with the unconjugated drug. Systemically administered SMI#9-GNP inhibited the TNBC growth as effectively as intratumorally injected unconjugated SMI#9. Inductively coupled mass spectrometry analysis showed highest GNP concentrations in tumors and liver of SMI#9-GNP and blank-GNP-treated mice; however, tumor growth inhibition occurred only in the SMI#9-GNP-treated group. SMI#9-GNP was tolerated without overt signs of toxicity. SMI#9-induced sensitization was associated with perturbation of a common set of glycolytic pathways in BRCA1 wild-type and BRCA1-mutant TNBC cells. These data reveal novel SMI#9 sensitive markers of metabolic vulnerability for TNBC management and suggest that nanotherapy-mediated RAD6 inhibition offers a promising strategy for TNBC treatment., (©2018 American Association for Cancer Research.)

Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell's enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed., (Copyright © 2014 Elsevier B.V. All rights reserved.)