ORCID Profile
0000-0002-0214-6498
Current Organisation
University of South Australia
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Publisher: Oxford University Press (OUP)
Date: 13-06-2007
DOI: 10.1093/HMG/DDM138
Abstract: Huntington's disease (HD) is one of nine neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine in their respective, otherwise apparently unrelated proteins. Despite these proteins having widespread and overlapping expression patterns in the brain, a specific and unique subset of neurons exhibits particular vulnerability in each disease. It has been hypothesized that perturbation of normal protein function contributes to the specificity of neuronal vulnerability however, the normal biological functions of many of these proteins including the HD gene product, Huntingtin (Htt), are unclear. To explore the roles of Htt, we have used antisense morpholino oligonucleotides to observe the effects of Htt deficiency in early zebrafish development. Knockdown of Htt expression resulted in a variety of developmental defects. Most notably, Htt-deficient zebrafish had hypochromic blood due to decreased hemoglobin production, despite the presence of iron within blood cells. Furthermore, transferrin receptor 1 transcripts were increased, suggesting cellular iron starvation. Provision of iron to the cytoplasm in a bio-available form restored hemoglobin production in Htt-deficient embryos. Since erythroid cells acquire iron via receptor-mediated endocytosis of transferrin, these results suggest a role for Htt in making endocytosed iron accessible for cellular utilization. Iron is required for oxidative energy production, and defects in iron homeostasis and energy metabolism are features of HD pathogenesis that are most pronounced in the major region of neurodegeneration. It is therefore plausible that perturbation of Htt's normal role in the iron pathway (by polyglutamine tract expansion) contributes to HD pathology, and particularly to its neuronal specificity.
Publisher: Cold Spring Harbor Laboratory
Date: 09-02-2018
DOI: 10.1101/262162
Abstract: Alzheimer’s disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN ( PSEN1 and PSEN2 ) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2 , K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional ‘inversion’ into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of Aβ. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.
Publisher: Springer Science and Business Media LLC
Date: 03-2018
DOI: 10.1038/S41366-018-0047-8
Abstract: Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity. We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4 kcal/min for 30 min) in non-diabetic obese (BMI 44 ± 4 kg/m Plasma 5-HT was twofold higher in obese than control responders prior to (P = 0.025), and during (iAUC, P = 0.009), intraduodenal glucose infusion, and related positively to BMI (R Human obesity is characterized by an increased capacity to produce and release 5-HT from the proximal small intestine, which is strongly linked to higher body mass, and glycemic control. Gut-derived 5-HT is likely to be an important driver of pathogenesis in human obesity and dysglycemia.
Publisher: Wiley
Date: 11-06-2023
DOI: 10.1111/ECI.14037
Abstract: Cancer is a leading cause of morbidity and mortality worldwide, and better understanding of the risk factors could enhance prevention. We conducted a hypothesis‐free analysis combining machine learning and statistical approaches to identify cancer risk factors from 2828 potential predictors captured at baseline. There were 459,169 UK Biobank participants free from cancer at baseline and 48,671 new cancer cases during the 10‐year follow‐up. Logistic regression models adjusted for age, sex, ethnicity, education, material deprivation, smoking, alcohol intake, body mass index and skin colour (as a proxy for sun sensitivity) were used for obtaining adjusted odds ratios, with continuous predictors presented using quintiles (Q). In addition to smoking, older age and male sex, positively associating features included several anthropometric characteristics, whole body water mass, pulse, hypertension and biomarkers such as urinary microalbumin (Q5 vs. Q1 OR 1.16, 95% CI = 1.13–1.19), C‐reactive protein (Q5 vs. Q1 OR 1.20, 95% CI = 1.16–1.24) and red blood cell distribution width (Q5 vs. Q1 OR 1.18, 95% CI = 1.14–1.21), among others. High‐density lipoprotein cholesterol (Q5 vs. Q1 OR 0.84, 95% CI = 0.81–0.87) and albumin (Q5 vs. Q1 OR 0.84, 95% CI = 0.81–0.87) were inversely associated with cancer. In sex‐stratified analyses, higher testosterone increased the risk in females but not in males (Q5 vs. Q1 OR females 1.23, 95% CI = 1.17–1.30). Phosphate was associated with a lower risk in females but a higher risk in males (Q5 vs. Q1 OR females 0.94, 95% CI = 0.90–0.99 vs. OR males 1.09, 95% CI 1.04–1.15). This hypothesis‐free analysis suggests personal characteristics, metabolic biomarkers, physical measures and smoking as important predictors of cancer risk, with further studies needed to confirm causality and clinical relevance.
Publisher: MDPI AG
Date: 22-01-2019
DOI: 10.3390/NU11020234
Abstract: Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and α-glucoside (αMG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and αMG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females (p 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females (p 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.
Publisher: Wiley
Date: 18-07-2016
DOI: 10.1111/JNC.13703
Abstract: Huntingtin-associated protein-1 (HAP1) is involved in intracellular trafficking, vesicle transport, and membrane receptor endocytosis. However, despite such erse functions, the role of HAP1 in the synaptic vesicle (SV) cycle in nerve terminals remains unclear. Here, we report that HAP1 functions in SV exocytosis, controls total SV turnover and the speed of vesicle fusion in nerve terminals and regulates glutamate release in cortical brain slices. We found that HAP1 interacts with synapsin I, an abundant neuronal phosphoprotein that associates with SVs during neurotransmitter release and regulates synaptic plasticity and neuronal development. The interaction between HAP1 with synapsin I was confirmed by reciprocal co-immunoprecipitation of the endogenous proteins. Furthermore, HAP1 co-localizes with synapsin I in cortical neurons as discrete puncta. Interestingly, we find that synapsin I localization is specifically altered in Hap1(-/-) cortical neurons without an effect on the localization of other SV proteins. This effect on synapsin I localization was not because of changes in the levels of synapsin I or its phosphorylation status in Hap1(-/-) brains. Furthermore, fluorescence recovery after photobleaching in transfected neurons expressing enhanced green fluorescent protein-synapsin Ia demonstrates that loss of HAP1 protein inhibits synapsin I transport. Thus, we demonstrate that HAP1 regulates SV exocytosis and may do so through binding to synapsin I. The Proposed mechanism of synapsin I transport mediated by HAP1 in neurons. HAP1 interacts with synapsin I, regulating the trafficking of synapsin I containing vesicles and/or transport packets, possibly through its engagement of microtubule motors. The absence of HAP1 reduces synapsin I transport and neuronal exocytosis. These findings provide insights into the processes of neuronal trafficking and synaptic signaling.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2000
Abstract: We recently published the precise chromosomal localization on chromosome 16p13.1 of the genetic defect underlying pseudoxanthoma elasticum (PXE), an inherited disorder characterized by progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Here we report the identification of mutations in the gene encoding the transmembrane transporter protein, ABC-C6 (also known as MRP-6), one of the four genes located in the region of linkage, as cause of the disease. Sequence analysis in four independent consanguineous families from Switzerland, Mexico, and South Africa and in one non-consanguineous family from the United States demonstrated several different mis-sense mutations to cosegregate with the disease phenotype. These findings are consistent with the conclusion that PXE is a recessive disorder that displays allelic heterogeneity, which may explain the considerable phenotypic variance characteristic of the disorder.
Publisher: Wiley
Date: 02-03-2017
DOI: 10.1111/NMO.13046
Abstract: Enterochromaffin (EC) cells within the gastrointestinal (GI) tract provide almost all body serotonin (5-hydroxytryptamine [5-HT]). Peripheral 5-HT, released from EC cells lining the gut wall, serves erse physiological roles. These include modulating GI motility, bone formation, hepatic gluconeogenesis, thermogenesis, insulin resistance, and regulation of fat mass. Enterochromaffin cells are nutrient sensors, but which nutrients they are responsive to and how this changes in different parts of the GI tract are poorly understood. To accurately undertake such an examination, we undertook the first isolation and purification of primary mouse EC cells from both the duodenum and colon in the same animal. This allowed us to compare, in an internally controlled manner, regional differences in the expression of nutrient sensors in EC cells using real-time PCR. Both colonic and duodenal EC cells expressed G protein-coupled receptors and facilitative transporters for sugars, free fatty acids, amino acids, and lipid amides. We find differential expression of nutrient receptor and transporters in EC cells obtained from duodenal and colonic EC cells. Duodenal EC cells have higher expression of tryptophan hydroxylase-1, sugar transporters GLUT2, GLUT5, and free fatty acid receptors 1 and 3 (FFAR1 and FFAR3). Colonic EC cells express higher levels of GLUT1, FFAR2, and FFAR4. We highlight the ersity of EC cell physiology and identify differences in the regional sensing repertoire of EC cells to an assortment of nutrients. These data indicate that not all EC cells are similar and that differences in their physiological responses are likely dependent on their location within the GI tract.
Publisher: Hindawi Limited
Date: 09-2005
DOI: 10.1002/HUMU.20206
Abstract: Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder that affects the elastic tissue in the skin, eye, and cardiovascular system. Mutations in the ABCC6 gene cause PXE. We performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. This screen consisted of 170 PXE chromosomes in 81 families, and detected 59 distinct mutations (32 missense, eight nonsense, and six likely splice-site point mutations one small insertion and seven small and five large deletions). Forty-three of these mutations are novel variants, which increases the total number of PXE mutations to 121. While most mutations are rare, three nonsense mutations, a splice donor site mutation, and the large deletion comprising exons 23-29 (c.2996_4208del) were identified as relatively frequent PXE mutations at 26%, 5%, 3.5%, 3%, and 11%, respectively. Chromosomal haplotyping with two proximal and two distal polymorphic markers flanking ABCC6 demonstrated that most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, which suggests that these chromosomes originate from single founder mutations. The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype. In 76 of the 81 families, the affected in iduals were either homozygous for the same mutation or compound heterozygous for two mutations. In the remaining five families with one uncovered mutation, affected showed allelic compound heterozygosity for the cosegregating PXE haplotype. This demonstrates pseudo-dominance as the relevant inheritance mechanism, since disease transmission to the next generation always requires one mutant allelic variant from each parent. In contrast to other previous clinical and molecular claims, our results show evidence only for recessive PXE. This has profound consequences for the genetic counseling of families with PXE.
Publisher: Oxford University Press (OUP)
Date: 29-09-2009
DOI: 10.1093/HMG/DDP455
Publisher: Wiley
Date: 03-2017
DOI: 10.14814/PHY2.13199
Publisher: Elsevier BV
Date: 2022
Publisher: Wiley
Date: 17-11-2022
DOI: 10.1002/ACR.24884
Abstract: In this Mendelian randomization (MR) study, the objective was to investigate the causal effect of metabolically different adiposity subtypes on osteoarthritis. We performed 2‐s le MR using summary‐level data for osteoarthritis (10,083 cases and 40,425 controls) from a genome‐wide association using the UK Biobank, and for site‐specific osteoarthritis from the Arthritis Research UK Osteoarthritis Genetics consortium. We used 3 classes of genetic instruments, which all increase body mass index but are associated with different metabolic profiles (unfavorable, neutral, and favorable). Primary analysis was performed using inverse variance weight (IVW), with additional sensitivity analysis from different MR methods. We further applied a nonlinear MR using UK Biobank data to understand the nature of the adiposity–osteoarthritis relationship. Greater metabolically unfavorable and metabolically neutral adiposity were associated with higher odds of osteoarthritis (IVW odds ratio [OR] 1.56 [95% confidence interval (95% CI) 1.31, 1.85] and OR 1.60 [95% CI 1.15, 2.23], respectively). The estimate for the association between metabolically favorable adiposity and osteoarthritis was similar, although with notable imprecision (OR 1.55 [95% CI 0.70, 3.41]). Using site‐specific osteoarthritis, metabolically unfavorable, neutral, and favorable adiposity were all associated with higher odds of knee osteoarthritis (OR 1.44 [95% CI 1.04, 1.98], OR 2.28 [95% CI 1.04, 4.99], and OR 6.80 [95% CI 2.08, 22.19], respectively). We found generally consistent estimates with a wider confidence interval crossing the null from other MR methods. The nonlinear MR analyses suggested a nonlinear relationship between metabolically unfavorable adiposity and osteoarthritis ( P nonlinear = 0.003). Metabolic abnormalities did not explain the association between greater adiposity and the risk of osteoarthritis, which might suggest that the association is largely due to a mechanical effect on the joints.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-04-2022
DOI: 10.1097/J.PAIN.0000000000002314
Abstract: Abdominal pain is a key symptom of inflammatory bowel disease and irritable bowel syndrome, for which there are inadequate therapeutic options. We tested whether olorinab—a highly selective, full agonist of the cannabinoid receptor 2 (CB 2 )—reduced visceral hypersensitivity in models of colitis and chronic visceral hypersensitivity (CVH). In rodents, colitis was induced by intrarectal administration of nitrobenzene sulfonic acid derivatives. Control or colitis animals were administered vehicle or olorinab (3 or 30 mg/kg) twice daily by oral gavage for 5 days, starting 1 day before colitis induction. Chronic visceral hypersensitivity mice were administered olorinab (1, 3, 10, or 30 mg/kg) twice daily by oral gavage for 5 days, starting 24 days after colitis induction. Visceral mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs) to colorectal distension. Ex vivo afferent recordings determined colonic nociceptor firing evoked by mechanical stimuli. Colitis and CVH animals displayed significantly elevated VMRs to colorectal distension and colonic nociceptor hypersensitivity. Olorinab treatment significantly reduced VMRs to control levels in colitis and CVH animals. In addition, olorinab reduced nociceptor hypersensitivity in colitis and CVH states in a concentration- and CB 2 -dependent manner. By contrast, olorinab did not alter VMRs nor nociceptor responsiveness in control animals. Cannabinoid receptor 2 mRNA was detected in colonic tissue, particularly within epithelial cells, and dorsal root ganglia, with no significant differences between healthy, colitis, and CVH states. These results demonstrate that olorinab reduces visceral hypersensitivity through CB 2 agonism in animal models, suggesting that olorinab may provide a novel therapy for inflammatory bowel disease– and irritable bowel syndrome–associated abdominal pain.
Publisher: MDPI AG
Date: 21-09-2022
DOI: 10.3390/NU14193907
Abstract: Genetic susceptibility and lifestyle affect the risk of dementia but there is little direct evidence for their associations with preclinical changes in brain structure. We investigated the association of genetic dementia risk and healthy lifestyle with brain morphometry, and whether effects from elevated genetic risk are modified by lifestyle changes. We used prospective data from up to 25,894 UK Biobank participants (median follow-up of 8.8 years), and defined healthy lifestyle according to American Heart Association criteria as BMI 30, no smoking, healthy diet and regular physical activity). Higher genetic risk was associated with lower hippoc al volume (beta −0.16 cm3, 95% CI −0.22, −0.11) and total brain volume (−4.34 cm3, 95% CI −7.68, −1.01) in participants aged ≥60 years but not years. Healthy lifestyle was associated with higher total brain, grey matter and hippoc al volumes, and lower volume of white matter hyperintensities, with no effect modification by age or genetic risk. In conclusion, adverse effects of high genetic risk on brain health were only found in older participants, while adhering to healthy lifestyle recommendations is beneficial regardless of age or genetic risk.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2001
Abstract: Pseudoxanthoma elasticum (PXE) is an inherited disorder of the elastic tissue with characteristic progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Recently mutations in the ABCC6 gene, encoding a transmembrane transporter protein, were identified as cause of the disease. Surprisingly, sequence and RFLP analysis for exon 9 with primers corresponding to flanking intronic sequence in diseased and haplotype negative members from all of our families and in a control population revealed either a homozygous or heterozygous state for the Q378X (1132C-->T) nonsense mutation in all in iduals. With the publication of the genomic structure of the PXE locus we had identified the starting point of a large genomic segmental duplication within the locus in the cytogenetic interval defined by the Cy19 and Cy185 somatic cell hybrid breakpoints on chromosome 16p13.1. By means of somatic cell hybrid mapping we located this starting point telomeric to exon 10 of ABCC6. The duplication, however, does not include exon 10, but exons 1-9. These findings suggest that one or several copies of an ABCC6 pseudogene (psiABCC6) lie within this large segmental duplication. At least one copy contains exons 1-9 and maps to the chromosomal interval defined by the Cy163 and Cy11 breakpoints. Either this copy and/or an additional copy of psiABCC6 within Cy19-Cy183 carries the Q378X mutation that masks the correct identification of this nonsense mutation as being causative in pseudoxanthoma elasticum. Long-range PCR of exon 9 starting from sequence outside the genomic replication circumvents interference from the psiABCC6 DNA sequences and demonstrates that the Q378X mutation in the ABCC6 gene is associated with PXE in some families. These findings lead us to propose that gene conversion mechanisms from psiABCC6 to ABCC6 play a functional role in mutations causing PXE.
Publisher: MDPI AG
Date: 30-12-2020
DOI: 10.3390/NU13010109
Abstract: The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.
Publisher: MDPI AG
Date: 28-01-2022
DOI: 10.3390/MICROORGANISMS10020310
Abstract: Prevalence of dengue retinopathy varies across epidemics, with the disease linked to circulation of dengue virus serotype 1 (DENV-1). The retinal pigment epithelium has been implicated in the pathology. We investigated infectivity, molecular response, and barrier function of epithelial cells inoculated with DENV strains from different outbreaks in Singapore. Monolayers of human retinal pigment epithelial cells (multiple primary cell isolates and the ARPE-19 cell line) were inoculated with six DENV strains, at multiplicity of infection of 10 uninfected and recombinant strain-infected controls were included where relevant. Infectivity and cell response were assessed primarily by RT-qPCR on total cellular RNA, and barrier function was evaluated as electrical resistance across monolayers. Higher viral RNA loads were measured in human retinal pigment epithelial cells infected with DENV-1 strains from the 2005 Singapore epidemic, when retinopathy was prevalent, versus DENV-1 strains from the 2007 Singapore epidemic, when retinopathy was not observed. Type I interferon (IFN) transcripts (IFN-β and multiple IFN-stimulated genes) were up-regulated, and impact on barrier function was more pronounced, for cells infected with DENV-1 strains from the 2005 versus the 2007 Singapore epidemics. Aside from serotype, strain of DENV may determine the potential to induce retinal pathology. Identification of molecular markers of disease-associated DENV strains may provide insights into the pathogenesis of dengue retinopathy.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Wiley
Date: 06-06-2023
DOI: 10.1111/BCP.15793
Abstract: Lipid‐lowering medications are widely used to control blood cholesterol levels and manage a range of cardiovascular and lipid disorders. We aimed to explore the possible associations between LDL lowering and multiple disease outcomes or biomarkers. We performed a Mendelian randomization phenome‐wide association study (MR‐PheWAS) in 337 475 UK Biobank participants to test for associations between four proposed LDL‐C‐lowering genetic risk scores ( PCSK9 , HMGCR , NPC1L1 and LDLR ) and 1135 disease outcomes, with follow‐up MR analyses in 52 serum, urine, imaging and clinical biomarkers. We used inverse‐variance weighted MR in the main analyses and complementary MR methods (weighted median, weighted mode, MR‐Egger and MR‐PRESSO) as sensitivity analyses. We accounted for multiple testing with false discovery rate correction ( P 2.0 × 10 −4 for phecodes, P 1.3 × 10 −2 for biomarkers). We found evidence for an association between genetically instrumented LDL lowering and 10 distinct disease outcomes, suggesting potential causality. All genetic instruments were associated with hyperlipidaemias and cardiovascular diseases in the expected directions. Biomarker analyses supported an effect of LDL‐C lowering through PCSK9 on lung function (FEV [beta per 1 mg/dL lower LDL‐C −1.49, 95% CI −2.21, −0.78] FVC [−1.42, 95% CI −2.29, −0.54]) and through HMGCR on hippoc al volume (beta per 1 mg/dL lower LDL‐C 6.09, 95% CI 1.74, 10.44). We found genetic evidence to support both positive and negative effects of LDL‐C lowering through all four LDL‐C‐lowering pathways. Future studies should further explore the effects of LDL‐C lowering on lung function and changes in brain volume.
Publisher: American Society for Clinical Investigation
Date: 17-10-2019
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.NEUROBIOLAGING.2021.02.010
Abstract: To establish causal evidence for the association of adiposity-related metabolic abnormalities with brain volumes, and the risks of dementia and stroke, we applied 1- and 2-s le Mendelian randomization (MR) analyses using up to 336,309 UK Biobank participants. We used 3 classes of genetic instruments, which all increase body mass index but are associated with different metabolic profiles (unfavorable, neutral and favorable). We validated the instruments using anthropometric and cardio-metabolic traits. Both metabolically unfavorable and metabolically neutral adiposity associated with lower gray matter volume (GMV, -9.28 cm
Publisher: Frontiers Media SA
Date: 13-08-2018
Publisher: Wiley
Date: 21-09-2023
DOI: 10.1111/DOM.14853
Abstract: To evaluate associations of metabolic profiles and biomarkers with brain atrophy, lesions, and iron deposition to understand the early risk factors associated with dementia. Using data from 26 239 UK Biobank participants free from dementia and stroke, we assessed the associations of metabolic subgroups, derived using an artificial neural network approach (self‐organizing map), and 39 in idual biomarkers with brain MRI measures: total brain volume (TBV), grey matter volume (GMV), white matter volume (WMV), hippoc al volume (HV), white matter hyperintensity (WMH) volume, and caudate iron deposition. In metabolic subgroup analyses, participants characterized by high triglycerides and liver enzymes showed the most adverse brain outcomes compared to the healthy reference subgroup with high‐density lipoprotein cholesterol and low body mass index (BMI) including associations with GMV ( β standardized −0.20, 95% confidence interval [CI] −0.24 to −0.16), HV ( β standardized −0.09, 95% CI −0.13 to −0.04), WMH volume ( β standardized 0.22, 95% CI 0.18 to 0.26), and caudate iron deposition ( β standardized 0.30, 95% CI 0.25 to 0.34), with similar adverse associations for the subgroup with high BMI, C‐reactive protein and cystatin C, and the subgroup with high blood pressure (BP) and apolipoprotein B. Among the biomarkers, striking associations were seen between basal metabolic rate (BMR) and caudate iron deposition ( β standardized 0.23, 95% CI 0.22 to 0.24 per 1 SD increase), GMV ( β standardized −0.15, 95% CI −0.16 to −0.14) and HV ( β standardized −0.11, 95% CI −0.12 to −0.10), and between BP and WMH volume ( β standardized 0.13, 95% CI 0.12 to 0.14 for diastolic BP). Metabolic profiles were associated differentially with brain neuroimaging characteristics. Associations of BMR, BP and other in idual biomarkers may provide insights into actionable mechanisms driving these brain associations.
Publisher: Cold Spring Harbor Laboratory
Date: 02-01-2018
DOI: 10.1101/241927
Abstract: The HIGH MOBILITY GROUP AT-HOOK 1 (HMGA1) family of chromatin-binding proteins plays important roles in cellular responses to low oxygen. HMGA1 proteins regulate gene activity both in the nucleus and within mitochondria. They are expressed mainly during embryogenesis and their upregulation in cancerous cells indicates poor prognosis. The human HMGA1a isoform is upregulated under hypoxia via oxidative stress-dependent signalling and can then bind nascent transcripts of the familial Alzheimer’s disease gene PSEN2 to regulate alternative splicing to produce the truncated PSEN2 protein isoform PS2V. Zebrafish where hmga1a expression is induced by hypoxia to control splicing of the psen1 gene to produce the PS2V-equivalent isoform PS1IV. Zebrafish possess a second gene with apparent HMGA1 orthology, hmga1b. Here we investigate the predicted structure of Hmga1b protein and demonstrate it to be co-orthologous to human HMGA1 and most similar in structure to human isoform HMGA1c. We show that forced over-expression of either hmga1a or hmga1b mRNA can suppress the action of the cytotoxin hydroxyurea in stimulating cell death and transcription of the genes mdm2 and cdkn1a that, in humans, are controlled by p53. Our experimental data support an important role for HMGA1 proteins in modulation of p53-dependent responses and illuminate the evolutionary subfunctionalisation.
Publisher: Public Library of Science (PLoS)
Date: 28-04-2011
Publisher: Springer Science and Business Media LLC
Date: 13-10-2016
Publisher: Springer Science and Business Media LLC
Date: 09-05-2018
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.METABOL.2022.155342
Abstract: Analyses to predict the risk of cancer typically focus on single biomarkers, which do not capture their complex interrelations. We hypothesized that the use of metabolic profiles may provide new insights into cancer prediction. We used information from 290,888 UK Biobank participants aged 37 to 73 years at baseline. Metabolic subgroups were defined based on clustering of biochemical data using an artificial neural network approach and examined for their association with incident cancers identified through linkage to cancer registry. In addition, we evaluated associations between 38 in idual biomarkers and cancer risk. In total, 21,973 in iduals developed cancer during the follow-up (median 3.87 years, interquartile range [IQR] = 2.03-5.58). Compared to the metabolically favorable subgroup (IV), subgroup III (defined as "high BMI, C-reactive protein & cystatin C") was associated with a higher risk of obesity-related cancers (hazard ratio [HR] = 1.26, 95 % CI = 1.21 to 1.32) and hematologic-malignancies (e.g., lymphoid leukemia: HR = 1.83, 95%CI = 1.44 to 2.33). Subgroup II ("high triglycerides & liver enzymes") was strongly associated with liver cancer risk (HR = 5.70, 95%CI = 3.57 to 9.11). Analysis of in idual biomarkers showed a positive association between testosterone and greater risks of hormone-sensitive cancers (HR per SD higher = 1.32, 95%CI = 1.23 to 1.44), and liver cancer (HR = 2.49, 95%CI =1.47 to 4.24). Many liver tests were in idually associated with a greater risk of liver cancer with the strongest association observed for gamma-glutamyl transferase (HR = 2.40, 95%CI = 2.19 to 2.65). Metabolic profile in middle-to-older age can predict cancer incidence, in particular risk of obesity-related cancer, hematologic malignancies, and liver cancer. Elevated values from liver tests are strong predictors for later risk of liver cancer.
Publisher: Wiley
Date: 10-12-2016
DOI: 10.1002/JCP.25256
Abstract: Enterochromaffin cells are the major site of serotonin (5-HT) synthesis and secretion providing ∼95% of the body's total 5-HT. 5-HT can act as a neurotransmitter or hormone and has several important endocrine and paracrine roles. We have previously demonstrated that EC cells release small amounts of 5-HT per exocytosis event compared to other endocrine cells. We utilized a recently developed method to purify EC cells to demonstrate the mechanisms underlying 5-HT packaging and release. Using the fluorescent probe FFN511, we demonstrate that EC cells express VMAT and that VMAT plays a functional role in 5-HT loading into vesicles. Carbon fiber erometry studies illustrate that the amount of 5-HT released per exocytosis event from EC cells is dependent on both VMAT and the H(+)-ATPase pump, as demonstrated with reserpine or bafilomycin, respectively. We also demonstrate that increasing the amount of 5-HT loaded into EC cell vesicles does not result in an increase in quantal release. As this indicates that fusion pore size may be a limiting factor involved, we compared pore diameter in EC and chromaffin cells by assessing the vesicle capture of different-sized fluorescent probes to measure the extent of fusion pore dilation. This identified that EC cells have a reduced fusion pore expansion that does not exceed 9 nm in diameter. These results demonstrate that the small amounts of 5-HT released per fusion event in EC cells can be explained by a smaller fusion pore that limits 5-HT release capacity from in idual vesicles.
Publisher: Elsevier BV
Date: 12-2023
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1053/J.GASTRO.2021.04.014
Abstract: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. GLP-1 and PYY levels were assessed in body mass index-matched in iduals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: Frontiers Media SA
Date: 23-10-2020
No related grants have been discovered for Amanda Lumsden.