Natural and synthetic 2-oxoglutarate derivatives are substrates for oncogenic variants of human isocitrate dehydrogenase 1 and 2

Variants of isocitrate dehydrogenase (IDH) 1 and 2 (IDH1/2) alter metabolism in cancer cells by catalyzing the NADPH-dependent reduction of 2-oxoglutarate (2OG) to (2R)-hydroxyglutarate. However, it is unclear how derivatives of 2OG can affect cancer cell metabolism. Here, we used synthetic C3- and C4-alkylated 2OG derivatives to investigate the substrate selectivities of the most common cancer-associated IDH1 variant (R132H IDH1), of two cancer-associated IDH2 variants (R172K IDH2, R140Q IDH2), and of WT IDH1/2. Absorbance-based, NMR, and electrochemical assays were employed to monitor WT IDH1/2 and IDH1/2 variant-catalyzed 2OG derivative turnover in the presence and absence of 2OG. Our results reveal that 2OG derivatives can serve as substrates of the investigated IDH1/2 variants, but not of WT IDH1/2, and have the potential to act as 2OG-competitive inhibitors. Kinetic parameters reveal that some 2OG derivatives, including the natural product 3-methyl-2OG, are equally or even more efficient IDH1/2 variant substrates than 2OG. Furthermore, NMR and mass spectrometry studies confirmed IDH1/2 variant-catalyzed production of alcohols in the cases of the 3-methyl–, 3-butyl–, and 3-benzyl–substituted 2OG derivatives; a crystal structure of 3-butyl-2OG with an IDH1 variant (R132C/S280F IDH1) reveals active site binding. The combined results highlight the potential for (i) IDH1/2 variant-catalyzed reduction of 2-oxoacids other than 2OG in cells, (ii) modulation of IDH1/2 variant activity by 2-oxoacid natural products, including some present in common foods, (iii) inhibition of IDH1/2 variants via active site binding rather than the established allosteric mode of inhibition, and (iv) possible use of IDH1/2 variants as biocatalysts

Cross-Cultural Validation of the Perceptions of Stigmatization by Others for Seeking Help (PSOSH) Scale

Social network stigma refers to the perceived negative views about seeking help for mental health problems that are held by those closest to an individual, such as family and friends. This form of stigma predicts help-seeking attitudes and intentions beyond other forms of stigma, and is predominantly measured using the Perceptions of Stigmatization by Others for Seeking Help scale (PSOSH; Vogel, Wade, & Ascheman, 2009). However, the PSOSH was normed using samples from the United States and, until the cross-cultural validity of this measure is established, it cannot reliably be used within other countries (Miller & Sheu, 2008). As such, the current study (N = 3,440) examined the cross-cultural measurement invariance of the PSOSH using the sequential constraint imposition approach across 11 countries/regions: Australia, Brazil, Canada, Hong Kong, Portugal, Romania, Taiwan, Turkey, the United Arab Emirates (UAE), the United Kingdom (U.K.), and the United States (U.S.). Overall, findings indicate that the PSOSH measures a meaningful construct (i.e., configural and metric invariance) across the 11 countries/regions and that future cross-cultural research could use the PSOSH to examine relationships between social network stigma and other variables. Scalar invariance results also supported the examination of mean differences in Australia, Brazil, Canada, Portugal, Turkey, the U.K., and the U.S., but not in Hong Kong, Romania, Taiwan, and UAE. Implications for future cross-cultural research are discussed

Stigma of Seeking Psychological Services: Examining College Students Across Ten Countries/Regions

© Division of Counseling Psychology of the American Psychological Association. Stigma is an important barrier to seeking psychological services worldwide. Two types of stigma exist: public stigma and self-stigma. Scholars have argued that public stigma leads to self-stigma, and then self-stigma is the primary predictor of attitudes toward seeking psychological services. However, this assertion is largely limited to U.S. samples. The goal of this research was to provide a first step in understanding the relationship between public stigma, self-stigma, and attitudes toward seeking psychological services in international contexts (N = 3,276; Australia, Brazil, Canada, Hong Kong, Portugal, Romania, Taiwan, Turkey, United Arab Emirates, and United States). Using structural equation modeling, we found that self-stigma mediated the relationship between public stigma and attitudes toward seeking services among college students in each country and region. However, differences in path strengths emphasize the need to pay attention to the role of public and self-stigma on attitudes toward seeking psychological services throughout the world

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

Malaria in pregnant women in an area with sustained high coverage of insecticide-treated bed nets

BACKGROUND\ud \ud Since 2000, the World Health Organization has recommended a package of interventions to prevent malaria during pregnancy and its sequelae that includes the promotion of insecticide-treated bed nets (ITNs), intermittent preventive treatment in pregnancy (IPTp), and effective case management of malarial illness. It is recommended that pregnant women in malaria-endemic areas receive at least two doses of sulphadoxine-pyrimethamine in the second and third trimesters of pregnancy. This study assessed the prevalence of placental malaria at delivery in women during 1st or 2nd pregnancy, who did not receive intermittent preventive treatment for malaria (IPTp) in a malaria-endemic area with high bed net coverage.\ud \ud METHODS\ud \ud A hospital-based cross-sectional study was done in Ifakara, Tanzania, where bed net coverage is high. Primi- and secundigravid women, who presented to the labour ward and who reported not using IPTp were included in the study. Self-report data were collected by questionnaire; whereas neonatal birth weight and placenta parasitaemia were measured directly at the time of delivery.\ud \ud RESULTS\ud \ud Overall, 413 pregnant women were enrolled of which 91% reported to have slept under a bed net at home the previous night, 43% reported history of fever and 62% were primigravid. Malaria parasites were detected in 8% of the placenta samples; the geometric mean (95%CI) placental parasite density was 3,457 (1,060-11,271) parasites/mul in primigravid women and 2,178 (881-5,383) parasites/mul in secundigravid women. Fifteen percent of newborns weighed <2,500 g at delivery. Self-reported bed net use was statistically associated with lower risk for low birth weight [OR 0.34 (95% CI: 0.16-0.74) and OR 0.22 (95% CI: 0.08-0.59) for untreated and treated bed nets, respectively], but was not associated with placental parasitaemia [OR 0.74 (0.21-2.68) and OR 1.64 (0.44-6.19) for untreated and treated bed nets, respectively].\ud \ud CONCLUSION\ud \ud The observed incidence of LBW and prevalence of placental parasitaemia at delivery suggests that malaria remains a problem in pregnancy in this area with high bed net coverage when eligible women do not receive IPTp. Delivery of IPTp should be emphasized at all levels of implementation to achieve maximum community coverage

What's in a message? Delivering sexual health promotion to young people in Australia via text messaging

<p>Abstract</p> <p>Background</p> <p>Advances in communication technologies have dramatically changed how individuals access information and communicate. Recent studies have found that mobile phone text messages (SMS) can be used successfully for short-term behaviour change. However there is no published information examining the acceptability, utility and efficacy of different characteristics of health promotion SMS. This paper presents the results of evaluation focus groups among participants who received twelve sexual health related SMS as part of a study examining the impact of text messaging for sexual health promotion to on young people in Victoria, Australia.</p> <p>Methods</p> <p>Eight gender-segregated focus groups were held with 21 males and 22 females in August 2008. Transcripts of audio recordings were analysed using thematic analysis. Data were coded under one or more themes.</p> <p>Results</p> <p>Text messages were viewed as an acceptable and 'personal' means of health promotion, with participants particularly valuing the informal language. There was a preference for messages that were positive, relevant and short and for messages to cover a variety of topics. Participants were more likely to remember and share messages that were funny, rhymed and/or tied into particular annual events. The message broadcasting, generally fortnightly on Friday afternoons, was viewed as appropriate. Participants said the messages provided new information, a reminder of existing information and reduced apprehension about testing for sexually transmitted infections.</p> <p>Conclusions</p> <p>Mobile phones, in particular SMS, offer health promoters an exciting opportunity to engage personally with a huge number of individuals for low cost. The key elements emerging from this evaluation, such as message style, language and broadcast schedule are directly relevant to future studies using SMS for health promotion, as well as for future health promotion interventions in other mediums that require short formats, such as social networking sites.</p

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition