Complexity of childhood sexual abuse: predictors of current post-traumatic stress disorder, mood disorders, substance use, and sexual risk behavior among adult men who have sex with men

Men who have sex with men (MSM) are the group most at risk for HIV and represent the majority of new infections in the United States. Rates of childhood sexual abuse (CSA) among MSM have been estimated as high as 46 %. CSA is associated with increased risk of HIV and greater likelihood of HIV sexual risk behavior. The purpose of this study was to identify the relationships between CSA complexity indicators and mental health, substance use, sexually transmitted infections, and HIV sexual risk among MSM. MSM with CSA histories (n = 162) who were screened for an HIV prevention efficacy trial completed comprehensive psychosocial assessments. Five indicators of complex CSA experiences were created: CSA by family member, CSA with penetration, CSA with physical injury, CSA with intense fear, and first CSA in adolescence. Adjusted regression models were used to identify relationships between CSA complexity and outcomes. Participants reporting CSA by family member were at 2.6 odds of current alcohol use disorder (OR 2.64: CI 1.24–5.63), two times higher odds of substance use disorder (OR 2.1: CI 1.02–2.36), and 2.7 times higher odds of reporting an STI in the past year (OR 2.7: CI 1.04–7.1). CSA with penetration was associated with increased likelihood of current PTSD (OR 3.17: CI 1.56–6.43), recent HIV sexual risk behavior (OR 2.7: CI 1.16–6.36), and a greater number of casual sexual partners (p = 0.02). Both CSA with Physical Injury (OR 4.05: CI 1.9–8.7) and CSA with Intense Fear (OR 5.16: CI 2.5–10.7) were related to increased odds for current PTSD. First CSA in adolescence was related to increased odds of major depressive disorder. These findings suggest that CSA, with one or more complexities, creates patterns of vulnerabilities for MSM, including post-traumatic stress disorder, substance use, and sexual risk taking, and suggests the need for detailed assessment of CSA and the development of integrated HIV prevention programs that address mental health and substance use comorbidities.This study was supported by a Grant from the NIMH (R01 MH095624) PI: O'Cleirigh; Author time (Safren) was supported, in part, by Grant 5K24MH094214. (R01 MH095624 - NIMH; 5K24MH094214)Accepted manuscrip

Rhyolitic volcanism of the central Snake River Plain: a review

The central Snake River Plain (CSRP) of southern Idaho and northern Nevada, USA, forms part of the Columbia River-Yellowstone large igneous province. Volcanic rocks of the province are compositionally bimodal (basalt-rhyolite), and the rhyolites produce a broadly time-transgressive record of a hotspot which is currently located under Yellowstone. Snake River Plain rhyolites represent hot (>850°C), dry magmas and have field characteristics consistent with high emplacement temperatures. Individual ignimbrite sheets reach 1,000km3 and exhibit little to no compositional zonation on a large scale but reveal considerable complexity on a crystal scale, particularly with regard to pyroxene compositions. Multiple pyroxene compositions may exist in a single ignimbrite which, along with multiple glass compositions in widely dispersed fallout tephra, suggests complex storage of rhyolite prior to eruption. Unlike most igneous rocks, the mineral cargo of the CSRP rhyolites exhibits little isotopic variability, with unimodal 87Sr/86Sr values returned from plagioclase grains inferred to represent the combination of strong crystal-melt coupling and rapid diffusional re-equilibriation. All the rhyolites within the CSRP have a characteristic low-δ 18O signature; with >20,000km3 of rhyolite exhibiting this depletion, the CSRP represents the largest low-δ 18O province on Earth. The low-18O nature of the rhyolites requires assimilation of hydrothermally altered materials which may be from altered Eocene batholithic rocks or from down-dropped intra-caldera tuffs. The wide range of crustal assimilants, with highly variable radiogenic isotope characteristics, available in the CSRP is permissive of a variety of petrogenetic models based on radiogenic isotopic dat

Oxidation of Alpha-Ketoglutarate Is Required for Reductive Carboxylation in Cancer Cells with Mitochondrial Defects

SummaryMammalian cells generate citrate by decarboxylating pyruvate in the mitochondria to supply the tricarboxylic acid (TCA) cycle. In contrast, hypoxia and other impairments of mitochondrial function induce an alternative pathway that produces citrate by reductively carboxylating α-ketoglutarate (AKG) via NADPH-dependent isocitrate dehydrogenase (IDH). It is unknown how cells generate reducing equivalents necessary to supply reductive carboxylation in the setting of mitochondrial impairment. Here, we identified shared metabolic features in cells using reductive carboxylation. Paradoxically, reductive carboxylation was accompanied by concomitant AKG oxidation in the TCA cycle. Inhibiting AKG oxidation decreased reducing equivalent availability and suppressed reductive carboxylation. Interrupting transfer of reducing equivalents from NADH to NADPH by nicotinamide nucleotide transhydrogenase increased NADH abundance and decreased NADPH abundance while suppressing reductive carboxylation. The data demonstrate that reductive carboxylation requires bidirectional AKG metabolism along oxidative and reductive pathways, with the oxidative pathway producing reducing equivalents used to operate IDH in reverse

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase

An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic 2 reprogramming and mammary tumourigenesis

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis