ORCID Profile
0000-0001-9309-2829
Current Organisations
Queen Mary University of London
,
Monash University
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Publisher: Public Library of Science (PLoS)
Date: 08-10-2013
Publisher: Elsevier BV
Date: 2022
Publisher: MDPI AG
Date: 22-03-2021
Abstract: There is a strong association between hepatocyte phospholipid homeostasis and non-alcoholic fatty liver disease (NAFLD). The phosphatidylcholine to phosphatidylethanolamine ratio (PC/PE) often draws special attention as genetic and dietary disruptions to this ratio can provoke steatohepatitis and other signs of NAFLD. Here we demonstrated that excessive free fatty acid (1:2 mixture of palmitic and oleic acid) alone was able to significantly lower the phosphatidylcholine to phosphatidylethanolamine ratio, along with substantial alterations to phospholipid composition in rat hepatocytes. This involved both a decrease in hepatocyte phosphatidylcholine (less prominent) and an increase in phosphatidylethanolamine, with the latter contributing more to the lowered ratio. Stable isotopic tracer phospholipidomic analysis revealed several previously unidentified changes that were triggered by excessive free fatty acid. Importantly, the enhanced cytidine diphosphate (CDP)-ethanolamine pathway activity appeared to be driven by the increased supply of preferred fatty acid substrates. By contrast, the phosphatidylethanolamine N-methyl transferase (PEMT) pathway was restricted by low endogenous methionine and consequently low S-adenosylmethionine, which resulted in a concomitant decrease in phosphatidylcholine and accumulation of phosphatidylethanolamine. Overall, our study identified several previously unreported links in the relationship between hepatocyte free fatty acid overload, phospholipid homeostasis, and the development of NAFLD.
Publisher: American Society for Clinical Investigation
Date: 11-07-2019
Publisher: American Chemical Society (ACS)
Date: 07-04-2006
DOI: 10.1021/JP056471V
Abstract: The results from an investigation of the collision-induced dissociation (CID) of the ternary complexes [Cu(II)(terpy)(AA)](2+) are presented (terpy = 2,2':6',2' '-terpyridine AA = one of the twenty common amino acids). These complexes show a rich gas-phase chemistry, which depends on the identity of the amino acid. For the histidine-, lysine- and tryptophan-containing complexes, oxidative dissociation of the amino acid is observed, yielding the amino acid radical cation. The results of further mass selection and CID of these amino acid radical cations are presented. The CID of the series [Fe(III)(salen)(AA)](+) (where salen = N,N'-ethylenebis(salicylideneaminato)) is also examined. These complexes undergo loss of the neutral amino acid in all cases, although the radical cation of arginine is also produced and its subsequent fragmentation examined. B3-LYP/6-31G(d) computations were carried out to test aspects of the proposed fragmentation mechanism of the histidine and arginine radical cations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2018
DOI: 10.1161/ATVBAHA.117.310212
Abstract: High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. Plasma s les from MetS patients (n=95) and healthy in iduals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy in iduals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy in iduals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. URL: www.clinicaltrials.gov . Unique identifier: NCT00163943
Publisher: Public Library of Science (PLoS)
Date: 24-06-2015
Publisher: American Society for Microbiology
Date: 03-09-2021
DOI: 10.1128/SPECTRUM.01023-21
Abstract: Klebsiella pneumoniae is a medically important pathogen that produces a thick protective capsule that is essential for pathogenicity. Phages are natural predators of bacteria, and many encode erse “capsule depolymerases” which specifically degrade the capsule of their hosts, an exploitable trait for potential therapies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-11-2016
DOI: 10.1161/CIRCULATIONAHA.116.023233
Abstract: Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization–tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with ≥1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework. Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678–0.682) to 0.700 (95% CI, 0.698–0.702 P .0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219–0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738–0.742) to 0.760 (95% CI, 0.757–0.762 P .0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317–0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease). The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus. URL: clinicaltrials.gov . Unique identifier: NCT00145925.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1194/JLR.P012518
Publisher: Wiley
Date: 30-08-2006
DOI: 10.1002/RCM.2671
Abstract: As a means of generating fixed-charge peptide radicals in the gas phase we have examined the collision-induced dissociation (CID) chemistry of ternary [Cu(II)(terpy)(TMPP-M)]2+ complexes, where terpy = 2,2':6'2''-terpyridine and TMPP-M represents a peptide (M) modified by conversion of the N-terminal amine to a [tris(2,4,6-trimethoxyphenyl)phosphonium]acetamide (TMPP-) fixed-charge derivative. The following modified peptides were examined: oligoglycines, (Gly)n (n = 1-5), alanylglycine, glycylalanine, dialanine, trialanine and leucine-enkephaline (YGGFL). The [Cu(II)(terpy)(TMPP-M)]2+ complexes are readily formed upon electrospray ionization (ESI) of a mixture of derivatized peptide and [Cu(II)(terpy)(NO3)2] and generally fragment to form transient peptide radical cations, TMPP-M+*, which undergo rapid decarboxylation for the simple aliphatic peptides. This is contrasted with the complexes containing the unmodified peptides, which predominantly undergo fragmentation of the coordinated peptide. These differences demonstrate the importance of proton mobility in directing fragmentation of ternary copper(II) peptide complexes. In the case of leucine-enkephaline, a sufficient yield of the radical cation was obtained to allow further CID. The TMPP-YGGFL+* ion showed a rich fragmentation chemistry, including CO2 loss, side-chain losses of an isopropyl radical, 2-methylpropene and p-quinomethide, and *a1 and *a4 sequence ion formation. In contrast, the even-electron TMPP-YGGFL+ ion fragments to form *a(n) and *b(n) sequence ions as well as the [*b4 + H2O]+ rearrangement ion.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
DOI: 10.1161/HYPERTENSIONAHA.113.01396
Abstract: Both as a component of metabolic syndrome and as an independent entity, hypertension poses a continued challenge with regard to its diagnosis, pathogenesis, and treatment. Previous studies have documented connections between hypertension and indicators of lipid metabolism. Novel technologies, such as plasma lipidomic profiling, promise a better understanding of disorders in which there is a derangement of the lipid metabolism. However, association of plasma lipidomic profiles with hypertension in a high-risk population, such as Mexican Americans, has not been evaluated before. Using the rich data and s le resource from the ongoing San Antonio Family Heart Study, we conducted plasma lipidomic profiling by combining high-performance liquid chromatography with tandem mass spectroscopy to characterize 319 lipid species in 1192 in iduals from 42 large and extended Mexican American families. Robust statistical analyses using polygenic regression models, liability threshold models, and bivariate trait analyses implemented in the SOLAR software were conducted after accounting for obesity, insulin resistance, and relative abundance of various lipoprotein fractions. Diacylglycerols, in general, and the DG 16:0/22:5 and DG 16:0/22:6 lipid species, in particular, were significantly associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), as well as liability of incident hypertension measured during 7140.17 person-years of follow-up. Four lipid species, including the DG 16:0/22:5 and DG 16:0/22:6 species, showed significant genetic correlations with the liability of hypertension in bivariate trait analyses. Our results demonstrate the value of plasma lipidomic profiling in the context of hypertension and identify disturbance of diacylglycerol metabolism as an independent biomarker of hypertension.
Publisher: Elsevier BV
Date: 09-2015
Abstract: Postprandial lipemia represents a risk factor for chronic diseases, including type 2 diabetes. Little is known about the effect of dietary fat on the plasma lipidome in the postprandial period. The objective of this study was to assess the effect of dairy fat and soy oil on circulating postprandial lipids in men. Men (40-60 y old, nonsmokers n = 16) were randomly assigned in a crossover design to consume 2 breakfast meals of dairy-based or soy oil-based foods. The changes in the plasma lipidome during the 4-h postprandial period were analyzed with electrospray ionization tandem mass spectrometry and included 316 lipid species in 23 classes and subclasses, representing sphingolipids, phospholipids, glycerolipids, and sterols. Nonparametric Friedman tests showed significant changes in multiple plasma lipid classes, subclasses, and species in the postprandial period after both dairy and soy meals. No difference was found in triglyceridemia after each meal. However, 6 endogenous lipid classes increased after dairy but decreased after soy (P < 0.05), including ether-linked phospholipids and plasmalogens and sphingomyelin (not present in soy), dihexosylceramide, and GM3 ganglioside. Phosphatidylcholine and phosphatidylinositol were not affected by the soy meal but were significantly elevated after the dairy meal (8.3% and 16%, respectively P < 0.05). The changes in postprandial plasma phospholipids in men relate to the diet composition and the relative size of the endogenous phospholipid pools. Despite similar lipemic responses as measured by changes in triglyceride concentrations, the differential responses to dairy and soy meals derived through lipidomic analysis of phospholipids suggest differences in the metabolism of soybean oil and dairy fat. The increased concentrations of plasmalogens, with potential antioxidant capacity, in the postprandial period after dairy but not soy meals may represent a further important difference in the response to these sources of fat. The trial was registered at www.anzctr.org.au as ACTRN12610000562077.
Publisher: Springer Science and Business Media LLC
Date: 08-03-2023
DOI: 10.1038/S41586-023-05781-7
Abstract: Diverse aerobic bacteria use atmospheric H 2 as an energy source for growth and survival 1 . This globally significant process regulates the composition of the atmosphere, enhances soil bio ersity and drives primary production in extreme environments 2,3 . Atmospheric H 2 oxidation is attributed to uncharacterized members of the [NiFe] hydrogenase superfamily 4,5 . However, it remains unresolved how these enzymes overcome the extraordinary catalytic challenge of oxidizing picomolar levels of H 2 amid ambient levels of the catalytic poison O 2 and how the derived electrons are transferred to the respiratory chain 1 . Here we determined the cryo-electron microscopy structure of the Mycobacterium smegmatis hydrogenase Huc and investigated its mechanism. Huc is a highly efficient oxygen-insensitive enzyme that couples oxidation of atmospheric H 2 to the hydrogenation of the respiratory electron carrier menaquinone. Huc uses narrow hydrophobic gas channels to selectively bind atmospheric H 2 at the expense of O 2 , and 3 [3Fe–4S] clusters modulate the properties of the enzyme so that atmospheric H 2 oxidation is energetically feasible. The Huc catalytic subunits form an octameric 833 kDa complex around a membrane-associated stalk, which transports and reduces menaquinone 94 Å from the membrane. These findings provide a mechanistic basis for the biogeochemically and ecologically important process of atmospheric H 2 oxidation, uncover a mode of energy coupling dependent on long-range quinone transport, and pave the way for the development of catalysts that oxidize H 2 in ambient air.
Publisher: Wiley
Date: 08-06-2020
Publisher: Springer Science and Business Media LLC
Date: 19-05-2021
Publisher: BMJ
Date: 03-2017
Publisher: eLife Sciences Publications, Ltd
Date: 09-03-2023
DOI: 10.7554/ELIFE.78877
Abstract: There are no pharmacological disease-modifying treatments with an enduring effect to mitigate the seizures and comorbidities of established chronic temporal lobe epilepsy (TLE). This study aimed to evaluate for disease modifying effects of sodium selenate treatment in the chronically epileptic rat post-status epilepticus (SE) model of drug-resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, animals received sodium selenate, levetiracetam, or vehicle subcutaneousinfusion continuously for 4 weeks. To evaluate the effects of the treatments, one week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of epilepsy disease severity in our current study. The results showed that sodium selenate treatment was associated with mitigation of measures of disease severity at 8 weeks post-treatment cessation reducing the number of spontaneous seizures (p 0.05), cognitive dysfunction (p 0.05), and sensorimotor deficits (p 0.01). Moreover, selenate treatment was associated with increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening (p 0.05). Network medicine integration of multi-omics re-clinical outcomes identified protein-metabolite modules positively correlated with TLE. Our results provide evidence that treatment with sodium selenate results in a sustained disease-modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.
Publisher: American Society for Microbiology
Date: 30-06-2020
DOI: 10.1128/MSYSTEMS.00389-20
Abstract: Mycobacteria are major environmental microorganisms and cause many significant diseases, including tuberculosis. Mycobacteria make an unusual vitamin-like compound, F 420 , and use it to both persist during stress and resist antibiotic treatment. Understanding how mycobacteria make F 420 is important, as this process can be targeted to create new drugs to combat infections like tuberculosis. In this study, we show that mycobacteria make F 420 in a way that is different from other bacteria. We studied the molecular machinery that mycobacteria use to make F 420 , determining the chemical mechanism for this process and identifying a novel chemical intermediate. These findings also have clinical relevance, given that two new prodrugs for tuberculosis treatment are activated by F 420 .
Publisher: Wiley
Date: 30-09-2010
Publisher: Elsevier BV
Date: 08-2023
Publisher: Wiley
Date: 20-09-2014
DOI: 10.1002/OBY.20598
Abstract: Waist circumference (WC), the clinical marker of central obesity, is gaining popularity as a screening tool for type 2 diabetes (T2D). While there is epidemiologic evidence favoring the WC‐T2D association, its biological substantiation is generally weak. Our objective was to determine the independent association of plasma lipid repertoire with WC. S les and data from the San Antonio Family Heart Study of 1208 Mexican Americans from 42 extended families were used. Association of plasma lipidomic profiles with the cross‐sectionally assessed WC was determined. Plasma lipidomic profiling entailed liquid chromatography with mass spectrometry. Statistical analyses included multivariable polygenic regression models and bivariate trait analyses using the SOLAR software. After adjusting for age and sex interactions, body mass index, homeostasis model of assessment—insulin resistance, total cholesterol, triglycerides, high density lipoproteins and use of lipid lowering drugs, dihydroceramides as a class were associated with WC. Dihydroceramide species 18:0, 20:0, 22:0, and 24:1 were significantly associated and genetically correlated with WC. Two sphingomyelin species (31:1 and 41:1) were also associated with WC. Plasma dihydroceramide levels independently associate with WC. Thus, high resolution plasma lipidomic studies can provide further credence to the biological underpinnings of the association of WC with T2D.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2017
Publisher: American Chemical Society (ACS)
Date: 29-03-2005
DOI: 10.1021/JA043088F
Abstract: The collision-induced dissociation (CID) of a series of gas-phase complexes [M(III)(salen)(P)](+) [where M = Cr, Mn, Fe, and Co P = hexapeptides YGGFLR, WGGFLR, and GGGFLR and salen = N,N'-ethylenebis(salicylideneaminato)] has been examined with respect to the ability of the complexes to form the corresponding cationic peptide radical ions, P(+)(*), by homolytic cleavage of the metal peptide bond. This is the first ex le of the use of gas-phase ternary metal peptide complexes to produce the corresponding cationic peptide radical for a metal other than copper(II). The fragmentation reactions competing with radical formation are highly dependent on the metal ion used. In addition, examination of modified complexes in which the periphery of the salen was substituted allowed evaluation of electronic effects on the CID process, presumably without significant change in the geometry surrounding the metal. This substitution demonstrates that the ligand can be used to tune the dissociation chemistry to favor radical formation and suppress unwanted further fragmentation of the peptide radical that is typically observed immediately following its dissociation from the complex.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1194/JLR.P035808
Publisher: Cold Spring Harbor Laboratory
Date: 30-08-2023
DOI: 10.1101/2023.08.28.555220
Abstract: Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that improves larval growth, development rate, and rescues survival. We demonstrate its use for exploring pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2016
Publisher: American Society for Microbiology
Date: 15-10-2019
DOI: 10.1128/JB.00400-19
Abstract: The World Health Organization listed Helicobacter pylori as a high-priority pathogen for antibiotic development. The potential of using peptide transporters in drug design is well recognized. We discovered that the substrate-binding protein of the ABC transporter for peptides, termed dipeptide permease, is an unusual member of its family in that it directly binds peptides of erse amino acid sequences, ranging between two and eight residues in length. We also provided a structural rationale for the observed broad specificity. Since the ability to import peptides as a source of carbon is critical for H. pylori , our findings will inform drug design strategies based on inhibition or fusion of membrane-impermeant antimicrobials with peptides.
Publisher: American Chemical Society (ACS)
Date: 24-05-2011
DOI: 10.1007/S13361-011-0165-1
Abstract: We present here a study of the collision induced dissociation (CID) of deprotonated cysteic acid containing peptides produced by MALDI. The effect of cysteic acid (C(ox)) position is interrogated by considering the positional isomers, C(ox)LVINVLSQG, LVINVLSQGC(ox), and LVINVC(ox)LSQG. Although considerable variation between the CID spectra is observed, the mechanistic picture that emerges involves charge retention at the deprotonated cysteic acid side chain. Fragmentation occurs in the proximity of the cysteic acid group by charge directed mechanisms as well as remote from this group to form ions, which may be rationalized by charge remote mechanisms. Additionally, the formation of the SO(3)(-•) ion is observed in all cases. Fragmentation of C(ox)LVINVLSQC(ox) provides both N- and C-terminal, y and b ions, respectively indicating that the negative charge may be retained at either of the cysteic acids however, there is some evidence that charge retention at the C-terminal cysteic acid may be preferred. Fragmentation of tryptic type peptides containing a C-terminal arginine or lysine residue is considered through comparison of three peptides C(ox)LVINKLSQG, C(ox)LVINVLSQK, and C(ox)LVINVLSQR. Lastly, we rationalize the formation of b(n-1)+ H(2)O and a(n-1) ions through a mechanism involving rearrangement of the C-terminal residue to form a mixed anhydride intermediate.
Publisher: Public Library of Science (PLoS)
Date: 27-09-2013
Publisher: Springer Science and Business Media LLC
Date: 09-06-2020
DOI: 10.1038/S41467-020-16568-Z
Abstract: Dietary protein dilution (DPD) promotes metabolic-remodelling and -health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.
Publisher: Frontiers Media SA
Date: 04-07-2019
Publisher: National Institute for Health and Care Research
Date: 02-2023
DOI: 10.3310/QFGT2379
Abstract: Centralising specialist cancer surgical services is an ex le of major system change. High-volume centres are recommended to improve specialist cancer surgery care and outcomes. Our aim was to use a mixed-methods approach to evaluate the centralisation of specialist surgery for prostate, bladder, renal and oesophago-gastric cancers in two areas of England [i.e. London Cancer (London, UK), which covers north-central London, north-east London and west Essex, and Greater Manchester Cancer (Manchester, UK), which covers Greater Manchester]. Stakeholder preferences for centralising specialist cancer surgery were analysed using a discrete choice experiment, surveying cancer patients ( n = 206), health-care professionals ( n = 111) and the general public ( n = 127). Quantitative analysis of impact on care, outcomes and cost-effectiveness used a controlled before-and-after design. Qualitative analysis of implementation and outcomes of change used a multisite case study design, analysing documents ( n = 873), interviews ( n = 212) and non-participant observations ( n = 182). To understand how lessons apply in other contexts, we conducted an online workshop with stakeholders from a range of settings. A theory-based framework was used to synthesise these approaches. Stakeholder preferences – patients, health-care professionals and the public had similar preferences, prioritising reduced risk of complications and death, and better access to specialist teams. Travel time was considered least important. Quantitative analysis (impact of change) – only London Cancer’s centralisations happened soon enough for analysis. These changes were associated with fewer surgeons doing more operations and reduced length of stay [prostate –0.44 (95% confidence interval –0.55 to –0.34) days bladder –0.563 (95% confidence interval –4.30 to –0.83) days renal –1.20 (95% confidence interval –1.57 to –0.82) days]. The centralisation meant that renal patients had an increased probability of receiving non-invasive surgery (0.05, 95% confidence interval 0.02 to 0.08). We found no evidence of impact on mortality or re-admissions, possibly because risk was already low pre-centralisation. London Cancer’s prostate, oesophago-gastric and bladder centralisations had medium probabilities (79%, 62% and 49%, respectively) of being cost-effective, and centralising renal services was not cost-effective (12% probability), at the £30,000/quality-adjusted life-year threshold. Qualitative analysis, implementation and outcomes – London Cancer’s provider-led network overcame local resistance by distributing leadership throughout the system. Important facilitators included consistent clinical leadership and transparent governance processes. Greater Manchester Cancer’s change leaders learned from history to deliver the oesophago-gastric centralisation. Greater Manchester Cancer’s urology centralisations were not implemented because of local concerns about the service model and local clinician disengagement. London Cancer’s network continued to develop post implementation. Consistent clinical leadership helped to build shared priorities and collaboration. Information technology difficulties had implications for interorganisational communication and how reliably data follow the patient. London Cancer’s bidding processes and hierarchical service model meant that staff reported feelings of loss and a perceived ‘us and them’ culture. Workshop – our findings resonated with workshop attendees, highlighting issues about change leadership, stakeholder collaboration and implications for future change and evaluation. The discrete choice experiment used a convenience s le, limiting generalisability. Greater Manchester Cancer implementation delays meant that we could study the impact of only London Cancer changes. We could not analyse patient experience, quality of life or functional outcomes that were important to patients (e.g. continence). Future research may focus on impact of change on care options offered, patient experience, functional outcomes and long-term sustainability. Studying other approaches to achieving high-volume services would be valuable. National Institute for Health and Care Research (NIHR) Clinical Research Network Portfolio reference 19761. This project was funded by the NIHR Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research Vol. 11, No. 2. See the NIHR Journals Library website for further project information.
Publisher: American Chemical Society (ACS)
Date: 02-2009
DOI: 10.1016/J.JASMS.2008.09.017
Abstract: Low-energy collision-induced dissociation (CID) of acetylcholine (ACh) yields only two fragment ions: the dominant C(4)H(7)O(2)(+) ion at m/z 87, arising from trimethylamine loss and protonated trimethylamine at m/z 60. Since the literature is replete with conflicting mechanisms for the loss of trimethylamine from ACh, in this article density functional theory (DFT) calculations are used to assess four competing mechanisms: (1) Path A involves a neighboring group attack to form a five-membered ring product, 2-methyl-1,3-dioxolan-2-ylium cation (2) Path B is a neighboring group attack to form a three-membered ring product, 1-methyl-oxiranium ion (3) Path C involves an intramolecular elimination reaction to form CO protonated vinylacetate and (4) Path D is a 1,2-hydride migration reaction forming CH(2)-protonated vinylacetate. At the MP2/6-311++G(2d,p)//B3-LYP/6-31+G(d,p) level of theory path A is the kinetically favored pathway, with a transition-state energy barrier of 37.7 kcal mol(-1) relative to the most stable conformer of ACh. The lowest energy pathway for the formation of protonated trimethylamine was also calculated to proceed via path A, involving proton transfer within the ion-molecule complex intermediate, with the exocylic methyl group being the proton donor. To confirm the site of proton transfer, low-energy CID of acetyl-d(3)-choline (d(3)-ACh) was carried out, which revealed loss of trimethylamine and the formation of Me(3)ND(+).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/CIRCGENETICS.114.000600
Abstract: Cardiovascular disease (CVD) is the most common cause of death in the United States and is associated with a high economic burden. Prevention of CVD focuses on controlling or improving the lipid profile of patients at risk. The human lipidome is made up of thousands of ubiquitous lipid species. By studying biologically simple canonical lipid species, we investigated whether the lipidome is genetically redundant and whether its genetic influences can provide clinically relevant clues of CVD risk. We performed a genetic study of the human lipidome in 1212 in iduals from 42 extended Mexican American families. High-throughput mass spectrometry enabled rapid capture of precise lipidomic profiles, providing 319 unique species. Using variance component–based heritability analyses and bivariate trait analyses, we detected significant genetic influences on each lipid assayed. Median heritability of the plasma lipid species was 0.37. Hierarchical clustering based on complex genetic correlation patterns identified 12 genetic clusters that characterized the plasma lipidome. These genetic clusters were differentially but consistently associated with risk factors of CVD, including central obesity, obesity, type 2 diabetes mellitus, raised serum triglycerides, and metabolic syndrome. Also, these clusters consistently predicted occurrence of cardiovascular deaths during follow-up. The human plasma lipidome is heritable. Shared genetic influences reduce the dimensionality of the human lipidome into clusters that are associated with risk factors of CVD.
Publisher: American Society for Clinical Investigation
Date: 06-09-2018
Publisher: Wiley
Date: 06-06-2022
DOI: 10.1111/JPY.13254
Abstract: Extracellular signals are reported to mediate chemical cross‐talk among pelagic microbes, including microalgal prey and predators. Water‐soluble mediator compounds play a crucial role in extracellular communication which is vital for prey recognition, attraction, capture, and predator deterrence. A range of exo‐metabolites including oxylipins and vitamins are released by prey in response to grazing stress. The temporal dynamics of such exo‐metabolites largely remains unknown, especially in large‐scale cultivation of microalgae such as closed or open ponds. In open ponds, infestation of predators is almost inevitable but highly undesirable due to the imminent threat of culture collapse. The early production of exo‐metabolites emitted by microalgal prey in response to predator attack could be leveraged as diagnostic markers of possible culture collapse. This study uses an untargeted approach for temporal profiling of Dunaliella tertiolecta ‐specific exo‐metabolites under grazing pressure from Oxyrrhis marina . We report 24 putatively identified metabolites, belonging to various classes such as short peptides, lipids, indole‐derivatives, and free amino acids, as potential markers of grazing‐mediated stress. In addition, this study outlines a clear methodology for screening of exo‐metabolites in marine algal s les, the analysis of which is frequently hindered by high salt concentrations. In future, a chemistry‐based targeted detection of these metabolites could enable a quick and on‐site screening of predators in microalgal cultures.
Publisher: MDPI AG
Date: 28-05-2022
DOI: 10.3390/IJMS23116063
Abstract: Absence epilepsy syndromes are part of the genetic generalized epilepsies, the pathogenesis of which remains poorly understood, although a polygenic architecture is presumed. Current focus on single molecule or gene identification to elucidate epileptogenic drivers is unable to fully capture the complex dysfunctional interactions occurring at a genetic roteomic/metabolomic level. Here, we employ a multi-omic, network-based approach to characterize the molecular signature associated with absence epilepsy-like phenotype seen in a well validated rat model of genetic generalized epilepsy with absence seizures. Electroencephalographic and behavioral data was collected from Genetic Absence Epilepsy Rats from Strasbourg (GAERS, n = 6) and non-epileptic controls (NEC, n = 6), followed by proteomic and metabolomic profiling of the cortical and thalamic tissue of rats from both groups. The general framework of weighted correlation network analysis (WGCNA) was used to identify groups of highly correlated proteins and metabolites, which were then functionally annotated through joint pathway enrichment analysis. In both brain regions a large protein-metabolite module was found to be highly associated with the GAERS strain, absence seizures and associated anxiety and depressive-like phenotype. Quantitative pathway analysis indicated enrichment in oxidative pathways and a downregulation of the lysine degradation pathway in both brain regions. GSTM1 and ALDH2 were identified as central regulatory hubs of the seizure-associated module in the somatosensory cortex and thalamus, respectively. These enzymes are involved in lysine degradation and play important roles in maintaining oxidative balance. We conclude that the dysregulated pathways identified in the seizure-associated module may be involved in the aetiology and maintenance of absence seizure activity. This dysregulated activity could potentially be modulated by targeting one or both central regulatory hubs.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christopher Barlow.