Toolkit for success: The Griffith Health suite of online student support resources. A Practice Report

In the current higher education climate, never has it been more imperative to promote early and ongoing student success and retention. Transition theory suggests that taking a coherent, scalable and holistic approach to supporting the student learning experience is the best way to scaffold and enable early success and persistence. Utilising this pedagogical approach, Griffith Health has designed and implemented a range of innovative, online resources to support the needs of undergraduate and postgraduate students as they transition across the student lifecycle. This ‘toolkit for success’ includes school-specific orientation websites, a targeted writing and referencing online guide, and a ‘one-stop-shop’ resource where students can quickly and easily connect with all of the support services and resources available across the University. Analytics data show the support resources are being very well accessed and utilised, with staff and student feedback also highlighting their effectiveness and value

Nutrient Sensing by Tas1R Proteins is Required for Normal Bone Resorption

Current therapies for low bone mass consist of inhibiting osteoclast activity or increasing the PTH or Wnt signaling pathways. These approaches have significant drawbacks that limit their use in specific patient populations and/or negatively impact patient compliance with therapy. Developing improved therapies requires diversifying our understanding of the mechanisms underlying postnatal bone remodeling by examining lesser-known signaling pathways. One such pathway is the taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors, which participates in monitoring energy and nutrient status. Previous work reported that global deletion of TAS1R member 3 (TAS1R3), which is a bi-functional protein that recognizes amino acids or sweet molecules when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively, leads to increased cortical bone mass. Here, we corroborate the increased thickness of cortical bone in Tas1R3 knockout mice and confirm that Tas1R3 is expressed in the bone environment. Quantification of serum bone turnover markers indicate that this phenotype is likely due to uncoupled bone remodeling, with levels of the bone resorption marker CTx being reduced greater than 60% in Tas1R3 mutant mice; no changes were observed in levels of the bone formation marker PINP. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and RAW264.7 cells following RANKL-mediated differentiation. These findings suggest that osteoclast function and/or differentiation may be altered in the absence of Tas1R3 expression. To test this, we quantified bone-specific expression of Rankl and determined the Rankl:Opg ratio; no differences were observed between control and Tas1R3 knockout mice in these analyses. In vitro studies examining further downstream effectors of TAS1R2:3 in response to saccharin and receptor antagonist gurmarin are currently underway. Collectively, our findings provide the first demonstration that nutrient monitoring by TAS1R3 is essential for normal bone resorption in vivo

Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans

BACKGROUND: Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, while supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome and congenital anomalies. Inositol status may be influenced by diet, synthesis, transport, utilisation and catabolism. OBJECTIVES: We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites. METHODS: Gas chromatography mass spectrometry was used to determine plasma MI concentration of more than 2,000 healthy, young adults (aged 18-28 years) from the Trinity Student Study. Genotyping data was used to test association of plasma MI with SNPs in candidate genes, encoding inositol transporters and synthesising enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with D-chiro inositol, glucose and other metabolites by Spearman's rank correlation. RESULTS: Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 µM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11, encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (p < 5 × 10-8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (p < 1 × 10-5), 3 of which were located within or close to genes: MTDH, LAPTM4B and ZP2. We found significant positive correlation of plasma MI concentration with concentration of D-chiro-inositol and several other biochemicals including glucose, methionine, betaine, sarcosine and tryptophan. CONCLUSION: Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11 which is worthy of further investigation

Pax6- and Six3-Mediated Induction of Lens Cell Fate in Mouse and Human ES Cells

Embryonic stem (ES) cells provide a potentially useful in vitro model for the study of in vivo tissue differentiation. We used mouse and human ES cells to investigate whether the lens regulatory genes Pax6 and Six3 could induce lens cell fate in vitro. To help assess the onset of lens differentiation, we derived a new mES cell line (Pax6-GFP mES) that expresses a GFP reporter under the control of the Pax6 P0 promoter and lens ectoderm enhancer. Pax6 or Six3 expression vectors were introduced into mES or hES cells by transfection or lentiviral infection and the differentiating ES cells analyzed for lens marker expression. Transfection of mES cells with Pax6 or Six3 but not with other genes induced the expression of lens cell markers and up-regulated GFP reporter expression in Pax6-GFP mES cells by 3 days post-transfection. By 7 days post-transfection, mES cell cultures exhibited a>10-fold increase over controls in the number of colonies expressing γA-crystallin, a lens fiber cell differentiation marker. RT-PCR and immunostaining revealed induction of additional lens epithelial or fiber cell differentiation markers including Foxe3, Prox1, α- and β-crystallins, and Tdrd7. Moreover, γA-crystallin- or Prox1-expressing lentoid bodies formed by 30 days in culture. In hES cells, Pax6 or Six3 lentiviral vectors also induced lens marker expression. mES cells that express lens markers reside close to but are distinct from the Pax6 or Six3 transduced cells, suggesting that the latter induce nearby undifferentiated ES cells to adopt a lens fate by non-cell autonomous mechanisms. In sum, we describe a novel mES cell GFP reporter line that is useful for monitoring induction of lens fate, and demonstrate that Pax6 or Six3 is sufficient to induce ES cells to adopt a lens fate, potentially via non-cell autonomous mechanisms. These findings should facilitate investigations of lens development

Sleep EEG in young people with 22q11.2 deletion syndrome:a cross-sectional study of slow-waves, spindles and correlations with memory and neurodevelopmental symptoms

Background:: Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions. Methods:: In a cross-sectional design, we recorded high-density sleep EEG in young people (6–20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep. Results:: 22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures. Conclusions:: This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders. Funding:: This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award ‘Defining Endophenotypes From Integrated Neurosciences’ Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG. The views and opinions expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health funders

Progress in achieving quantitative classification of psychopathology

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level" dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity" by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach

Childhood Maltreatment, Stressful Life Events, and Alcohol Craving in Adult Drinkers

Background: Little is known about the relationship between stressful life events and alcohol craving in the general population, and whether a history of childhood maltreatment sensitizes individuals to crave alcohol after adult stressors. Methods: Participants were 22,147 past-year drinkers from Wave 2 (2004 to 2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. A structured, face-to-face interview assessed past-year stressful life events, alcohol craving, and history of childhood maltreatment. Logistic regression was used to generate adjusted odds ratios (aOR) to evaluate the relationship between stressful life events and craving, adjusting for demographic characteristics and parental history of alcoholism. Interaction between stressful life events and childhood maltreatment was also assessed. Results: Compared to participants with no stressful life events, those with ≥3 events had increased odds of moderate alcohol craving (aOR = 3.15 [95% CI = 2.30 to 4.33]) and severe craving (aOR = 8.47 [95% CI = 4.78 to 15.01]). Stressful life events and childhood maltreatment interacted in predicting severe craving (p = 0.017); those with ≥3 events were at higher risk of craving if they had been exposed to childhood maltreatment. Conclusions: A direct relationship between stressful life events and risk of alcohol craving was observed. Further, history of childhood maltreatment increased the salience of stressful life events in adulthood. Future studies should examine the role of psychiatric comorbidity in more complex models of stress sensitization and alcohol craving

BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair

The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by adjacent γ-H2AX accumulation and ssDNA breaks within the untranscribed strand of relevant R-loop structures. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. Strikingly, within some of these genes in BRCA1 null breast tumors, there are specific insertion/deletion mutations located close to R-loop-mediated BRCA1 binding sites within TRs. Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites

Ambient Particulate Matter Air Pollution and Venous Thromboembolism in the Women’s Health Initiative Hormone Therapy Trials

BackgroundThe putative effects of postmenopausal hormone therapy on the association between particulate matter (PM) air pollution and venous thromboembolism (VTE) have not been assessed in a randomized trial of hormone therapy, despite its widespread use among postmenopausal women.ObjectiveIn this study, we examined whether hormone therapy modifies the association of PM with VTE risk.MethodsPostmenopausal women 50–79 years of age (n = 26,450) who did not have a history of VTE and who were not taking anticoagulants were enrolled in the Women’s Health Initiative Hormone Therapy trials at 40 geographically diverse U.S. clinical centers. The women were randomized to treatment with estrogen versus placebo (E trial) or to estrogen plus progestin versus placebo (E + P trial). We used age-stratified Cox proportional hazard models to examine the association between time to incident, centrally adjudicated VTE, and daily mean PM concentrations spatially interpolated at geocoded addresses of the participants and averaged over 1, 7, 30, and 365 days.ResultsDuring the follow-up period (mean, 7.7 years), 508 participants (2.0%) had VTEs at a rate of 2.6 events per 1,000 person-years. Unadjusted and covariate-adjusted VTE risk was not associated with concentrations of PM 0.05) regardless of PM averaging period, either before or after combining data from both trials [e.g., combined trial-adjusted hazard ratios (95% confidence intervals) per 10 μg/m3 increase in annual mean PM2.5 and PM10, were 0.93 (0.54–1.60) and 1.05 (0.72–1.53), respectively]. Findings were insensitive to alternative exposure metrics, outcome definitions, time scales, analytic methods, and censoring dates.ConclusionsIn contrast to prior research, our findings provide little evidence of an association between short-term or long-term PM exposure and VTE, or clinically important modification by randomized exposure to exogenous estrogens among postmenopausal women