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1دورية أكاديمية
المؤلفون: Gaia Pasqualetto, Andrew Mack, Emily Lewis, Ryan Cooper, Alistair Holland, Ufuk Borucu, Judith Mantell, Tom Davies, Miriam Weckener, Dan Clare, Tom Green, Pete Kille, Alex Muhlhozl, Mark T. Young
المصدر: PLoS ONE, Vol 18, Iss 6 (2023)
الوصف: Hemocyanins are multimeric oxygen transport proteins present in the blood of arthropods and molluscs, containing up to 8 oxygen-binding functional units per monomer. In molluscs, hemocyanins are assembled in decamer ‘building blocks’ formed of 5 dimer ‘plates’, routinely forming didecamer or higher-order assemblies with d5 or c5 symmetry. Here we describe the cryoEM structures of the didecamer (20-mer) and tridecamer (30-mer) forms of a novel hemocyanin from the slipper limpet Crepidula fornicata (SLH) at 7.0 and 4.7 Å resolution respectively. We show that two decamers assemble in a ‘tail-tail’ configuration, forming a partially capped cylinder, with an additional decamer adding on in ‘head-tail’ configuration to make the tridecamer. Analysis of SLH samples shows substantial heterogeneity, suggesting the presence of many higher-order multimers including tetra- and pentadecamers, formed by successive addition of decamers in head-tail configuration. Retrieval of sequence data for a full-length isoform of SLH enabled the use of Alphafold to produce a molecular model of SLH, which indicated the formation of dimer slabs with high similarity to those found in keyhole limpet hemocyanin. The fit of the molecular model to the cryoEM density was excellent, showing an overall structure where the final two functional units of the subunit (FU-g and FU-h) form the partial cap at one end of the decamer, and permitting analysis of the subunit interfaces governing the assembly of tail-tail and head-tail decamer interactions as well as potential sites for N-glycosylation. Our work contributes to the understanding of higher-order oligomer formation in molluscan hemocyanins and demonstrates the utility of Alphafold for building accurate structural models of large oligomeric proteins.
وصف الملف: electronic resource
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2دورية أكاديمية
المؤلفون: Gaia Pasqualetto, Andrew Mack, Emily Lewis, Ryan Cooper, Alistair Holland, Ufuk Borucu, Judith Mantell, Tom Davies, Miriam Weckener, Dan Clare, Tom Green, Pete Kille, Alex Muhlhozl, Mark T Young
المصدر: PLoS ONE, Vol 18, Iss 6, p e0287294 (2023)
الوصف: Hemocyanins are multimeric oxygen transport proteins present in the blood of arthropods and molluscs, containing up to 8 oxygen-binding functional units per monomer. In molluscs, hemocyanins are assembled in decamer 'building blocks' formed of 5 dimer 'plates', routinely forming didecamer or higher-order assemblies with d5 or c5 symmetry. Here we describe the cryoEM structures of the didecamer (20-mer) and tridecamer (30-mer) forms of a novel hemocyanin from the slipper limpet Crepidula fornicata (SLH) at 7.0 and 4.7 Å resolution respectively. We show that two decamers assemble in a 'tail-tail' configuration, forming a partially capped cylinder, with an additional decamer adding on in 'head-tail' configuration to make the tridecamer. Analysis of SLH samples shows substantial heterogeneity, suggesting the presence of many higher-order multimers including tetra- and pentadecamers, formed by successive addition of decamers in head-tail configuration. Retrieval of sequence data for a full-length isoform of SLH enabled the use of Alphafold to produce a molecular model of SLH, which indicated the formation of dimer slabs with high similarity to those found in keyhole limpet hemocyanin. The fit of the molecular model to the cryoEM density was excellent, showing an overall structure where the final two functional units of the subunit (FU-g and FU-h) form the partial cap at one end of the decamer, and permitting analysis of the subunit interfaces governing the assembly of tail-tail and head-tail decamer interactions as well as potential sites for N-glycosylation. Our work contributes to the understanding of higher-order oligomer formation in molluscan hemocyanins and demonstrates the utility of Alphafold for building accurate structural models of large oligomeric proteins.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1932-6203Test
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3دورية أكاديمية
المؤلفون: Ethan Emberley, Alison Pan, Jason Chen, Rosalyn Dang, Matt Gross, Tony Huang, Weiqun Li, Andrew MacKinnon, Devansh Singh, Natalija Sotirovska, Susanne M. Steggerda, Tracy Wang, Francesco Parlati
المصدر: PLoS ONE, Vol 16, Iss 11 (2021)
الوصف: Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.
وصف الملف: electronic resource
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4دورية أكاديمية
المؤلفون: Ethan Emberley, Alison Pan, Jason Chen, Rosalyn Dang, Matt Gross, Tony Huang, Weiqun Li, Andrew MacKinnon, Devansh Singh, Natalija Sotirovska, Susanne M Steggerda, Tracy Wang, Francesco Parlati
المصدر: PLoS ONE, Vol 16, Iss 11, p e0259241 (2021)
الوصف: Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1932-6203Test
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5دورية أكاديمية
المؤلفون: Michelle Dey, Raquel Paz Castro, Anthony Francis Jorm, Laurent Marti, Michael Patrick Schaub, Andrew Mackinnon
المصدر: PLoS ONE, Vol 15, Iss 7, p e0235034 (2020)
الوصف: BackgroundPrevious research on public stigma towards people with mental disorders has mostly targeted adult samples and focused on depression, schizophrenia or mental disorders in general. Hence, the present study aimed to investigate predictors of stigmatizing attitudes towards different mental disorders (including less researched ones) in a representative sample of adolescents and young adults.MethodsData from the Swiss Youth Mental Health Literacy and Stigma Survey were used (analytical sample: n = 4,932). Each participant was randomly presented with one of five vignettes (depression; alcohol abuse; depression and alcohol abuse combined; schizophrenia; social anxiety). The structure of stigmatizing attitudes was assessed using confirmatory factor analysis. Regression models, implemented within a structural equation framework, were used to study predictors for the identified latent variables.ResultsA three-factor model for stigmatizing attitudes-consisting of 'dangerous/unpredictable', 'weak-no-sick', and 'social distance' factors-best fitted the data. Female gender was associated with less stigmatizing attitudes. Associations in opposite directions with different latent factors were found for educational and migration background. Exposure to mental disorders (being personally affected, personally having received professional help or knowing someone close who has received treatment for a mental disorder) was either not or was negatively associated with stigmatizing attitudes. In contrast, current mental health symptoms (heightened levels of psychological distress, problematic alcohol use) were generally not or were positively associated with stigmatizing attitudes. Even though the included predictors had some predictive value, the variance explained by the models was rather small (the adjusted R2 varied between 0.03 and 0.26).ConclusionsThe current study indicates that contact with someone who has received treatment for a mental disorder might be an important component of programs aiming to decrease stigmatizing attitudes towards people with mental disorders, since this exposure variable predicted lower levels of stigmatizing attitudes. Furthermore, the findings suggest that target-group interventions for specific subgroups need to be considered, as the process leading to stigmatizing attitudes towards people with mental disorders appears to differ between specific sociodemographic subgroups.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1932-6203Test
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6دورية أكاديمية
المؤلفون: Gregory Armstrong, Georgina Sutherland, Eliza Pross, Andrew Mackinnon, Nicola Reavley, Anthony F Jorm
المصدر: PLoS ONE, Vol 15, Iss 12, p e0244091 (2020)
الوصف: ObjectiveSuicide is a leading cause of death among Aboriginal and Torres Strait Islander people. Friends, family and frontline workers (for example, teachers, youth workers) are often best positioned to provide initial assistance if someone is at risk of suicide. We developed culturally appropriate expert consensus guidelines on how to provide mental health first aid to Australian Aboriginal and Torres Strait Islander people experiencing suicidal thoughts or behaviour and used this as the basis for a 5-hour suicide gatekeeper training course called Talking About Suicide. This paper describes the outcomes for participants in an uncontrolled trial of this training course.MethodsWe undertook an uncontrolled trial of the Talking About Suicide course, delivered by Aboriginal and Torres Strait Islander Mental Health First Aid instructors to 192 adult (i.e. 18 years of age or older) Aboriginal and Torres Strait Islander (n = 110) and non-Indigenous (n = 82) participants. Questionnaires capturing self-report outcomes were self-administered immediately before (n = 192) and after attending the training course (n = 188), and at four-months follow-up (n = 98). Outcome measures were beliefs about suicide, stigmatising attitudes, confidence in ability to assist, and intended and actual actions to assist a suicidal person.ResultsDespite a high level of suicide literacy among participants at pre-course measurement, improvements at post-course were observed in beliefs about suicide, stigmatising attitudes, confidence in ability to assist and intended assisting actions. While attrition at follow-up decreased statistical power, some improvements in beliefs about suicide, stigmatising attitudes and intended assisting actions remained statistically significant at follow-up. Importantly, actual assisting actions taken showed dramatic improvements between pre-course and follow-up. Participants reported feeling more confident to assist a suicidal person after the course and this was maintained at follow-up. The course was judged to be culturally appropriate by those participants who identified as Aboriginal and/or Torres Strait Islanders.ImplicationsThe results of this uncontrolled trial were encouraging, suggesting that the Talking About Suicide course was able to improve participants' knowledge, attitudes, and intended assisting actions as well as actual actions taken.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1932-6203Test
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7دورية أكاديمية
المؤلفون: Nicholas Glozier, Helen Christensen, Sharon Naismith, Nicole Cockayne, Liesje Donkin, Bruce Neal, Andrew Mackinnon, Ian Hickie
المصدر: PLoS ONE, Vol 8, Iss 3, p e59139 (2013)
الوصف: Background and aimMild to moderate depression is common in those with cardiovascular disease and undertreated. We aimed to evaluate the effectiveness of internet-delivered Cognitive Behaviour Therapy (iCBT) on depressive symptom severity and adherence to medical advice and lifestyle interventions in adults with mild to moderate depression and high cardiovascular disease (CVD) risks.MethodsRandomised double-blind, 12 week attention-controlled trial comparing an iCBT programme (E-couch) with an internet-delivered attention control health information package (HealthWatch, n = 282). The primary outcome was depression symptom level on the nine-item Patient Health Questionnaire (PHQ-9) (trial registration: ACTRN12610000085077).Results487/562 (88%) participants completed the endpoint assessment. 383/562 (70%) were currently treated for cardiovascular disease and 314/562 (56%) had at least one other comorbid condition. In ITT analysis of 562 participants iCBT produced a greater decline in the mean PHQ-9 score compared to the attention control of 1.06 (95% CI: 0.23-1.89) points, with differences between the two arms increasing over the intervention period (time by treatment effect interaction p = .012). There were also larger improvements in adherence (2.16 points; 95% CI: 0.33-3.99), reductions in anxiety (0.96 points; 95% CI: 0.19-1.73), and a greater proportion engaging in beneficial physical activity (Odds Ratio 1.91, 95%CI: 1.01-3.61) in the iCBT participants but no effect upon disability, or walking time/day. There were no withdrawals due to study related adverse events.ConclusionsIn people with mild to moderate depression and high levels of CVD risk factors, a freely accessible iCBT programme (http://www.ecouch.anu.edu.auTest) produced a small, but robust, improvement in depressive symptoms, adherence and some health behaviours.Trial registrationAustralian and New Zealand Clinical Trials Registry ACTRN12610000085077.
وصف الملف: electronic resource
العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23555624/pdf/?tool=EBITest; https://doaj.org/toc/1932-6203Test
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8دورية أكاديمية
المؤلفون: Debra L Foley, Andrew Mackinnon, Gerald F Watts, Jonathan E Shaw, Dianna J Magliano, David J Castle, John J McGrath, Anna Waterreus, Vera A Morgan, Cherrie A Galletly
المصدر: PLoS ONE, Vol 8, Iss 12, p e82606 (2013)
الوصف: Individuals with psychosis are more likely than the general community to develop obesity and to die prematurely from heart disease. Interventions to improve cardiovascular outcomes are best targeted at the earliest indicators of risk, at the age they first emerge. We investigated which cardiometabolic risk indicators distinguished those with psychosis from the general population, by age by gender, and whether obesity explained the pattern of observed differences. Data was analyzed from an epidemiologically representative sample of 1,642 Australians with psychosis aged 18-64 years and a national comparator sample of 8,866 controls aged 25-64 years from the general population. Cubic b-splines were used to compare cross sectional age trends by gender for mean waist circumference, body mass index [BMI], blood pressure, fasting blood glucose, triglycerides, LDL, HDL, and total cholesterol in our psychosis and control samples. At age 25 individuals with psychosis had a significantly higher mean BMI, waist circumference, triglycerides, glucose [women only], and diastolic blood pressure and significantly lower HDL-cholesterol than controls. With the exception of triglycerides at age 60+ in men, and glucose in women at various ages, these differences were present at every age. Differences in BMI and waist circumference between samples, although dramatic, could not explain all differences in diastolic blood pressure, HDL-cholesterol or triglycerides but did explain differences in glucose. Psychosis has the hallmarks of insulin resistance by at least age 25. The entire syndrome, not just weight, should be a focus of intervention to reduce mortality from cardiovascular disease.
وصف الملف: electronic resource
العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24367528/?tool=EBITest; https://doaj.org/toc/1932-6203Test
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9دورية أكاديمية
المصدر: PLoS ONE, Vol 6, Iss 11, p e28099 (2011)
الوصف: BACKGROUND: Telephone helplines are frequently and repeatedly used by individuals with chronic mental health problems and web interventions may be an effective tool for reducing depression in this population. AIM: To evaluate the effectiveness of a 6 week, web-based cognitive behaviour therapy (CBT) intervention with and without proactive weekly telephone tracking in the reduction of depression in callers to a helpline service. METHOD: 155 callers to a national helpline service with moderate to high psychological distress were recruited and randomised to receive either Internet CBT plus weekly telephone follow-up; Internet CBT only; weekly telephone follow-up only; or treatment as usual. RESULTS: Depression was lower in participants in the web intervention conditions both with and without telephone tracking compared to the treatment as usual condition both at post intervention and at 6 month follow-up. Telephone tracking provided by a lay telephone counsellor did not confer any additional advantage in terms of symptom reduction or adherence. CONCLUSIONS: A web-based CBT program is effective both with and without telephone tracking for reducing depression in callers to a national helpline. TRIAL REGISTRATION: Controlled-Trials.comISRCTN93903959.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC3227639?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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