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Showing 481–500 of 2058 publications.
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Tucker, Bradley; Sawant, Sonia; McDonald, Hannah; Rye, Kerry Anne; Patel, Sanjay; Ong, Kwok Leung; Cochran, Blake J.Background and aims: There is some evidence of a cross-sectional, and possibly causal, relationship of lipid levels with leukocyte counts in mice and humans. This study investigates the cross-sectional and longitudinal relationship of blood lipid and lipoprotein levels with leukocyte counts in the UK Biobank cohort. Methods: The primary cross-sectional analysis included 417,132 participants with valid data on lipid measures and leukocyte counts. A subgroup analysis was performed in 333,668 participants with valid data on lipoprotein(a). The longitudinal analysis included 9058 participants with valid baseline and follow-up data on lipid and lipoprotein levels and leukocyte counts. The association of lipid and lipoprotein levels with leukocyte counts was analysed by multivariable linear regression. Results: Several relationships were significant in both cross-sectional and longitudinal analysis. After adjustment for demographic, socioeconomic and other confounding factors, a higher eosinophil count was associated with lower HDL cholesterol and apolipoprotein A-I concentration (p < 0.001). Higher triglycerides levels were associated with higher total leukocyte, basophil, eosinophil, monocyte and neutrophil counts (all p < 0.01). A higher lymphocyte count was associated with a higher apolipoprotein B level (p < 0.001). In the longitudinal analysis, lipoprotein(a) was inversely associated with basophil count in men but not women (p < 0.001). Conclusions: Triglyceride levels demonstrate a robust positive association with total and differential leukocyte counts suggesting they may be directly involved in leukogenesis. However, unlike in murine models, the remainder of these relationships is modest, which suggests that cholesterol and lipoproteins are minimally involved in leukogenesis in humans. 2020 Elsevier B.V.
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Zhang, Yingqi; Ramasundara, Savindi De Zoysa; Preketes-Tardiani, Renee Ellen; Cheng, Vivian; Lu, Hongxu; Ju, Lining ArnoldUnderstanding how platelets can sense and respond to hemodynamic forces in disturbed blood flow and complexed vasculature is crucial to the development of more effective and safer antithrombotic therapeutics. By incorporating diverse structural and functional designs, microfluidic technologies have emerged to mimic microvascular anatomies and hemodynamic microenvironments, which open the floodgates for fascinating platelet mechanobiology investigations. The latest endothelialized microfluidics can even recapitulate the crosstalk between platelets and the circulatory system, including the vessel walls and plasma proteins such as von Willebrand factor. Hereby, we highlight these exciting microfluidic applications to platelet mechanobiology and plateletcirculatory system interplay as implicated in thrombosis. Last but not least, we discuss the need for microfluidic standardization and summarize the commercially available microfluidic platforms for researchers to obtain reproducible and consistent results in the field. 2021 Zhang, Ramasundara, Preketes-tardiani, Cheng, Lu and Ju.
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Rayner, Benjamin SaulThe release of myeloperoxidase (MPO) produced through the activation and infiltration of immune cells within sites of inflammation and damage to the vasculature is mechanistically involved in atherosclerosis. This effect of active MPO and its derived products on the endothelial lining of the blood vessels perturbs vascular function. Mechanisms involved in this perturbation include disruption to nitric oxide signaling and mediation of the endothelial cell inflammatory response, through the oxidant-induced upregulation of cell adhesion molecules. These processes result in the ongoing chronic exacerbation of immune cell recruitment and inflammation that defines this disease. Additionally, at the endothelial cell level, the exposure to MPO-derived oxidants causes loss of intracellular glutathione and protein-bound thiols, activates signaling pathways involving intracellular calcium mishandling, resulting in mitochondrial dysfunction and endothelial cell death. Together, these events directly contribute to endothelial dysfunction that precedes atherosclerotic lesion formation, highlighting MPO as one of the most attractive targets of therapeutic intervention for this debilitating condition, the underlying cause of cardiac ischemia and heart failure. 2022 selection and editorial matter, Clare Hawkins and William M. Nauseef.
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Malavasi, Vincenzo Livio; Zoccali, Cristina; Brandi, Maria Chiara; Micali, Giulia; Vitolo, Marco; Imberti, Jacopo Francesco; Mussi, Chiara E.; Schnabel, Renate B.; Freedman, Ben Ben; Boriani, GiuseppeBackground: The impact of cognitive status on outcomes of patients with atrial fibrillation (AF) is not well defined. Aims: To assess the prevalence of cognitive impairment in AF patients and evaluate its association with: i) all-cause mortality; ii) a composite endpoint of death, stroke/systemic embolism, hemorrhages, acute coronary syndrome, pulmonary embolism, new/worsening heart failure. Methods: In a cohort study, cognitive status was assessed at baseline by the Mini Mental State examination adjusted for age and education (aMMSE). aMMSE <24 was considered indicative of cognitive impairment. Results: The cohort included 437 patients (61.3% male, mean age 73.4 11.7 years). Sixty-three patients (14.4%) had cognitive impairment at baseline aMMSE. Permanent AF (odds ratio [OR] 1.750; 95%CI 1.0123.025; p =.045), haemoglobin levels (OR 0.827; 95%CI 0.7070.967; p =.017) and previous treatment with antiplatelet drugs only, without oral anticoagulation, (OR 4.352; 95%CI 1.58311.963; p =.004) were independently associated with cognitive impairment at baseline. After a median follow-up of 887 days (interquartile range 731958) 30 patients died (7.1%), and 97 (22.9%) reached the composite endpoint. After adjustment for Elixhauser Comorbidy Measure, aMMSE <24 was significantly associated with all-cause mortality (hazard ratio [HR] 2.473, 95%CI 1.0625.756, p =.036) and with the composite endpoint (HR 1.852, 95%CI 1.1063.102, p =.019). Conclusions: In patients with AF, cognitive impairment (aMMSE <24) is associated with worse outcomes, and the association of adverse outcomes with previous treatment with antiplatelet drugs only, without oral anticoagulation, highlights the potential role of appropriate antithrombotic treatment for improving patient prognosis. 2020 The Authors
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Benjamin, Emelia J.; Go, Alan S.; Desvigne-Nickens, Patrice M.; Anderson, Christopher David; Casadei, Barbara; Chen, Lin Y.; Crijns, Harry JGM; Freedman, Ben Ben; Hills, Mellanie True; Healey, Jeff S.; Kamel, Hooman; Kim, Dongyun; Link, Mark S.; Les, Renato Delcio; Lubitz, Steven A.; McManus, David D.; Noseworthy, Peter A.; Perez, Marco Valentin; Piccini, Jonathan Paul; Schnabel, Renate B.; Singer, Daniel E.; Tieleman, Robert G.; Turakhia, Minang P.; van Gelder, Isabelle C.; Cooper, Lawton S.; Al-Khatib, Sana M.Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute's virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF. 2021 Lippincott Williams and Wilkins. All rights reserved.
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Rehan, Rajan; Kotchetkova, Irina; Cordina, Rachael Louise; Celermajer, David S.Background: Although advances in congenital heart disease (CHD) management have allowed survival of children with even highly complex CHD lesions well into adult life, the burden of disease (medical, psychological and social) has not been well characterised, for those living to middle age and beyond. Methods: We assessed 121 consecutive patients from our adult CHD centre, who survived to age 50 years and who had had moderate or complex CHD lesions. Pre-specified groups included those with repaired tetralogy of Fallot (TOF) (n=56), coarctation of the aorta (CoA) (n=34), systemic right ventricle (RV) (n=9), Fontan surgery for single ventricle hearts (n=5), those with repaired Ebstein's Anomaly (n=9) and other complex CHD (n=8). Results: The overall burden of disease was very substantial. Of the TOF patients, almost half (46%) had required at least one open-heart reoperation and 41% had had a pacemaker or implantable defibrillator; 20% had had a radiofrequency ablation and 32% were on anti-arrhythmic therapy. Over 40% had ?1 admission for heart failure and 9% had had endocarditis. Only 64% were still employed. Of the CoA survivors, 50% had had a second operation (aortic valve and/or descending aortic surgery), 88% were on medications for hypertension and 62% were still employed. In the more complex groups, approximately half had been diagnosed with depression/anxiety and cerebrovascular event, heart failure and/or significant arrhythmias were common. Conclusions: Despite considerable advances, adults with CHD who survive to age 50 years have experienced high levels of physical and mental health complications. 2020
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Gwynn, Josephine Diana; Gwynne, Kylie G.; Rodrigues, Rhys; Thompson, Sandra Claire; Bolton, Graham; Dimitropoulos, Yvonne; Dulvari, Norman; Finlayson, Heather; Hamilton, Sandra J.; Lawrence, Monica; Macniven, Rona; Neubeck, Lis; Rambaldini, Boe; Taylor, Kerry A.; Wright, Darryl C.; Freedman, Ben BenBackground: Circulatory diseases continue to be the greatest cause of mortality for Australian Aboriginal and Torres Strait Islander people, and a major cause of persistently lower life expectancy compared with non-Aboriginal Australians. The limited information that exists on atrial fibrillation (AF) prevalence in Aboriginal and Torres Strait Islander communities is mostly based on hospital admission data. This shows AF as principal or additional admission diagnosis was 1.4 times higher compared to non-Aboriginal Australians, a higher incidence of AF across the adult life span after age 20 years and a significantly higher prevalence among younger patients. Our study estimates the first national community prevalence and age distribution of AF (including paroxysmal) in Australian Aboriginal people. A handheld single-lead electrocardiograph (ECG) device (iECG), known to be acceptable in this population, was used to record participant ECGs. Methods: This co-designed, descriptive cross-sectional study was conducted in partnership with 16 Aboriginal Community Controlled Health organisations at their facilities and/or with their services delivered elsewhere. The study was also conducted at one state community event. Three (3) Australian jurisdictions were involved: New South Wales, Western Australia and the Northern Territory. Study sites were located in remote, regional and urban areas. Opportunistic recruitment occurred between June 2016 and December 2017. People <45 years of age were excluded. Results: Thirty (30) of 619 Aboriginal people received a Possible AF and 81 an Unclassified result from a hand-held smartphone ECG device. A final diagnosis of AF was made in 29 participants (4.7%; 95%CI 3.06.4%), 25 with known AF (five paroxysmal), and four with previously unknown AF. Three (3) of the four with unknown AF were aged between 5564 years, consistent with a younger age of AF onset in Aboriginal people. Estimated AF prevalence increased with age and was higher in those aged >55 years than the general population (7.2% compared with 5.4%). Slightly more men than women were diagnosed with AF. Conclusions: This study is a significant contribution to the evidence which supports screening for AF in Aboriginal and Torres Strait Islander people commencing at a younger age than as recommended in the Australian guidelines (>65 years). We recommend the age of 55 years. Consideration should be given to the inclusion of AF screening in the Australian Government Department of Health annual Aboriginal and Torres Strait Islander Health Assessment. Clinical Trial Registration: ACTRN12616000459426. 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
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Koay, Yen Chin; Stanton, Kelly M.; Kienzle, Vivian J.; Li, Mengbo; Yang, Jean Yee Hwa; Celermajer, David S.; OSullivan, John F.Aims: To examine the metabolic adaptation to an 80-day exercise intervention in healthy young male adults where lifestyle factors such as diet, sleep, and physical activities are controlled. Methods and results: This study involved cross-sectional analysis before and after an 80-day aerobic and strength exercise intervention in 52 young, adult, male, newly enlisted soldiers in 2015. Plasma metabolomic analyses were performed using liquid chromatography, tandem mass spectrometry. Data analyses were performed between March and August 2019. We analysed changes in metabolomic profiles at the end of an 80-day exercise intervention compared to baseline, and the association of metabolite changes with changes in clinical parameters. Global metabolism was dramatically shifted after the exercise training programme. Fatty acids and ketone body substrates, key fuels used by exercising muscle, were dramatically decreased in plasma in response to increased aerobic fitness. There were highly significant changes across many classes of metabolic substrates including lipids, ketone bodies, arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acid oxidation, microbiome-derived metabolites, markers of redox stress, and substrates of coagulation. For statistical analyses, a paired t-test was used and Bonferroni-adjusted P-value of <0.0004 was considered to be statistically significant. The metabolite dimethylguanidino valeric acid (DMGV) (recently shown to predict lack of metabolic response to exercise) tracked maladaptive metabolic changes to exercise; those with increases in DMGV levels had increases in several cardiovascular risk factors; changes in DMGV levels were significantly positively correlated with increases in body fat (P = 0.049), total and LDL cholesterol (P = 0.003 and P = 0.007), and systolic blood pressure (P = 0.006). This study was approved by the Departments of Defence and Veterans' Affairs Human Research Ethics Committee and written informed consent was obtained from each subject. Conclusion: For the first time, the true magnitude and extent of metabolic adaptation to chronic exercise training are revealed in this carefully designed study, which can be leveraged for novel therapeutic strategies in cardiometabolic disease. Extending the recent report of DMGV's predictive utility in sedentary, overweight individuals, we found that it is also a useful marker of poor metabolic response to exercise in young, healthy, fit males. 2020 Published on behalf of the European Society of Cardiology. All rights reserved.
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Giskes, Katrina; Lowres, Nicole; Li, Jialin; Orchard, Jessica Joan; Hespe, Charlotte Mary; Freedman, Ben BenBackground: Opportunistic screening for silent atrial fibrillation (AF) is recommended to reduce stroke, but screening rates are sub-optimal in general practice. We hypothesize that patient self-screening in the waiting room may improve screening and detection of AF. Methods and analyses: This proof-of-concept study tests a purpose-designed AF self-screening station and customised software which seamlessly integrates with general practice electronic medical records and workflow. The self-screening station records a lead-1 ECG. The software automatically (1) identifies eligible patients (aged ?65 years, no AF diagnosis) from the practice appointment diary; (2) sends eligible patients an automated SMS reminder prior to their appointment; (3) creates individualised QR code to scan at self-screening station; and (4) imports the ECG and result directly into the patients electronic medical record. Between 5 and 8 general practices in New South Wales, Australia, will participate with an aim of 1500 patients undertaking self-screening. The main outcome measures will be the proportion of eligible patients that undertook self-screening, incidence of newly-diagnosed AF, and patient and staff experience of the self-screening process. De-identified data will be collected using a clinical audit tool, and qualitative interviews will determine patient and staff acceptability. Ethics and dissemination: Ethics approval was received from the University of Sydney Human Research Ethics Committee in June 2019 (Project no: 2019/382) and the University of Notre Dame Human Research Ethics Committee (Project no: 019145S) in October 2019. Results will be disseminated through various forums, including peer-reviewed publication and conference presentations. Trial registration number ACTRN12620000233921. 2020 The Authors
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Suwanwela, Nijasri Charnnarong; Chutinet, Aurauma; Autjimanon, Hathairat; Ounahachok, Tanawat; Decha-Umphai, Chumpol; Chockchai, Songkhram; Indrabhakti, Saowanin; Kijpaisalratana, Naruchorn; Akarathanawat, Wasan; Travanichakul, Suporn; Kitjavijitre, Teeraparp; Vongvasinkul, Pakkawan; Kanacharoen, Ittaporn; Bunlikitkul, Tanyaluk O.; Charnwut, Supparat; Lowres, Nicole; Freedman, Ben BenBackground: In Thailand, almost one-quarter of strokes are related to atrial fibrillation (AF), and many could be prevented if AF were diagnosed and treated prior to the stroke. Therefore, we tested a novel strategy to screen large numbers of community residents using village health volunteers and primary care nurses. Methods: Local primary care nurses and village health volunteers in Phetchaburi and Lopburi provinces, Thailand were trained to perform AF screening using a blood pressure device with AF algorithm (Microlife A200 AFib). 10% of residents aged ? 65 years were randomly selected for screening during home-visits. Participants with possible AF were given follow-up appointments for further testing, including 12-lead ECG and echocardiogram. Results: Over two-months, 9.7% (13,864/143,478) of the target population were screened: mean age 73.2 6.4 years, 32.4% male. The estimated AF prevalence (detected by Microlife A200 AFib) was 2.8% (95% CI, 2.63.1%) for age ? 65 years (i.e. 393/13,864 participants). Prevalence increased with age from 1.9% (6569 years) to 5.0% (?85 years) (p < 0.001). Only 58% (226/393) of participants with suspected AF attended the follow-up appointment (13 months after initial screen): mean CHA2DS2-VASc score 3.2 1.2; 86.3% (195/226) had Class-1 oral anticoagulation recommendation, and 33% (75/226) had AF on 12-lead ECG. Conclusions: In Thailand, large-scale AF screening in the community is feasible using trained volunteer health workers, allowing screening of large numbers in a short time-period. Further investigation of this strategy is warranted, ensuring mechanisms to obtain a timely rhythm strip or 12-lead ECG locally, and a designated pathway to treatment. 2020
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Lowres, Nicole; Giskes, Katrina; Freedman, Ben Ben[No abstract available]
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Koay, Yen Chin; Chen, Yungchih; Wali, Jibran A.; Luk, Alison W.S.; Li, Mengbo; Doma, Hemavarni; Reimark, Rosa; Zaldivia, Maria T.K.; Habtom, Habteab T.; Franks, Ashley E.; Fusco-Allison, Gabrielle; Yang, Jean Yee Hwa; Holmes, Andrew J.; Simpson, Stephen James; Peter, Karlheinz H.; OSullivan, John F.Aims: The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis. Methods and results: Plasma TMAO increased in mice on 'unhealthy' high-choline diets and notably also on 'healthy' high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE-/- and Ldlr-/- mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage. Conclusions: Dietary-induced changes in the microbiome, of both 'healthy' and 'unhealthy' diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk. 2020 Published on behalf of the European Society of Cardiology. All rights reserved.
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Misra, Ashish K.; Fisher, Edward A.[No abstract available]
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Boriani, Giuseppe; Palmisano, Pietro; Malavasi, Vincenzo Livio; Fantecchi, Elisa; Vitolo, Marco; Bonini, Niccol Imberti, Jacopo Francesco; Valenti, Anna Chiara; Schnabel, Renate B.; Freedman, Ben BenOur aim was to assess the prevalence of unknown atrial fibrillation (AF) among adults during single-time point rhythm screening performed during meetings or social recreational activities organized by patient groups or volunteers. A total of 2814 subjects (median age 68 years) underwent AF screening by a handheld single-lead ECG device (MyDiagnostick). Overall, 56 subjects (2.0%) were diagnosed with AF, as a result of 12-lead ECG following a positive/suspected recording. Screening identified AF in 2.9% of the subjects ? 65 years. None of the 265 subjects aged below 50 years was found positive at AF screening. Risk stratification for unknown AF based on a CHA2DS2VASc > 0 in males and >1 in females (or CHA2DS2VA > 0) had a high sensitivity (98.2%) and a high negative predictive value (99.8%) for AF detection. A slightly lower sensitivity (96.4%) was achieved by using age ? 65 years as a risk stratifier. Conversely, raising the threshold at ?75 years showed a low sensitivity. Within the subset of subjects aged ? 65 a CHA2DS2VASc > 1 in males and >2 in females, or a CHA2DS2VA > 1 had a high sensitivity (94.4%) and negative predictive value (99.3%), while age ? 75 was associated with a marked drop in sensitivity for AF detection. 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Stocks, B.; Ashcroft, Stephen P.; Joanisse, Sophie D.; Dansereau, Linda C.; Koay, Yen Chin; Elhassan, Yasir S.; Lavery, Gareth G.; Quek, Lake Ee; OSullivan, John F.; Philp, Ashleigh M.; Wallis, Gareth A.; Philp, Andrew M.Key points: Acute nicotinamide riboside (NR) supplementation does not alter substrate metabolism at rest, during or in recovery from endurance exercise. NR does not alter NAD+-sensitive signalling pathways in human skeletal muscle. NR supplementation and acute exercise influence the NAD+ metabolome. Abstract: Oral supplementation of the NAD+ precursor nicotinamide riboside (NR) has been reported to alter metabolism alongside increasing sirtuin (SIRT) signalling and mitochondrial biogenesis in rodent skeletal muscle. However, whether NR supplementation can elicit a similar response in human skeletal muscle is unclear. This study assessed the effect of 7-day NR supplementation on whole-body metabolism and exercise-induced mitochondrial biogenic signalling in skeletal muscle. Eight male participants (age: 234years, (Formula presented.) 46.54.4mlkg1min1) received 1week of NR or cellulose placebo (PLA) supplementation (1000mgday1). Muscle biopsies were collected from the medial vastus lateralis prior to supplementation and pre-, immediately post- and 3h post-exercise (1h of 60% W<inf>max</inf> cycling) performed following the supplementation period. There was no effect of NR supplementation on substrate utilisation at rest or during exercise or on skeletal muscle mitochondrial respiration. Global acetylation, auto-PARylation of poly ADP-ribose polymerase 1 (PARP1), acetylation of Tumour protein 53 (p53)Lys382 and Manganese superoxide dismutase (MnSOD)Lys122 were also unaffected by NR supplementation or exercise. NR supplementation did not increase skeletal muscle NAD+ concentration, but it did increase the concentration of deaminated NAD+ precursors nicotinic acid riboside (NAR) and nicotinic acid mononucleotide (NAM) and methylated nicotinamide breakdown products (Me2PY and Me4PY), demonstrating the skeletal muscle bioavailability of NR supplementation. In summary, 1week of NR supplementation does not alter whole-body metabolism or skeletal muscle signal transduction pathways implicated in the mitochondrial adaptation to endurance exercise. 2021 The Authors. The Journal of Physiology 2021 The Physiological Society
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Agten, Stijn M.; Watson, Emma E.; Ripoll-Rozada, Jorge; Dowman, Luke J.; Wu, Mike C.L.; Alwis, Imala D.; Jackson, Shaun P.; Pereira, Pedro JosBarbosa; Payne, Richard J.Blood feeding arthropods, such as leeches, ticks, flies and mosquitoes, provide a privileged source of peptidic anticoagulant molecules. These primarily operate through inhibition of the central coagulation protease thrombin by binding to the active site and either exosite I or exosite II. Herein, we describe the rational design of a novel class of trivalent thrombin inhibitors that simultaneously block both exosites as well as the active site. These engineered hybrids were synthesized using tandem diselenide-selenoester ligation (DSL) and native chemical ligation (NCL) reactions in one-pot. The most potent trivalent inhibitors possessed femtomolar inhibition constants against ?-thrombin and were selective over related coagulation proteases. A lead hybrid inhibitor possessed potent anticoagulant activity, blockade of both thrombin generation and platelet aggregation in vitro and efficacy in a murine thrombosis model at 1 mg kg?1. The rational engineering approach described here lays the foundation for the development of potent and selective inhibitors for a range of other enzymatic targets that possess multiple sites for the disruption of proteinprotein interactions, in addition to an active site. 2020 Wiley-VCH GmbH
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Stanley, Christopher P.; Stocker, RolandPurpose of review The principle aim of this review is to prompt vascular researchers interested in vascular inflammation and oxidative stress to consider singlet molecular oxygen (1O<inf>2</inf>) as a potentially relevant contributor. A secondary goal is to propose novel treatment strategies to address haemodynamic complications associated with septic shock. Recent findings Increased inflammation and oxidative stress are hallmarks of a range of vascular diseases. We recently showed that in systemic inflammation and oxidative stress associated with models of inflammation including sepsis, the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase-1 (Ido1) contributes to hypotension and decreased blood pressure through production of singlet molecular oxygen (1O<inf>2</inf>). Once formed,1O<inf>2</inf> converts tryptophan bound to Ido1 to a vasoactive hydroperoxide which decreases arterial tone and blood pressure via oxidation of a specific cysteine residue of protein kinase G1a. Summary These works show, for the first time, that1O<inf>2</inf> contributes to arterial redox signalling and that Ido1 contributes to the regulation of blood pressure through production of a novel tryptophan-derived hydroperoxide, thus presenting a new signalling pathway as novel target in the treatment of blood pressure disorders such as sepsis. 2021 Lippincott Williams and Wilkins. All rights reserved.
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Lin, Alexander; Peiris, Niridu Jude; Dhaliwal, Harkirat; Hakim, Maria; Li, Weizhen; Ganesh, Subramaniam; Ramaswamy, Yogambha; Patel, Sanjay; Misra, Ashish K.Mural cells collectively refer to the smooth muscle cells and pericytes of the vasculature. This heterogenous population of cells play a crucial role in the regulation of blood pressure, distribution, and the structural integrity of the vascular wall. As such, dysfunction of mural cells can lead to the pathogenesis and progression of a number of diseases pertaining to the vascular system. Cardiovascular diseases, particularly atherosclerosis, are perhaps the most well?described mural cell?centric case. For instance, atherosclerotic plaques are most often described as being composed of a proliferative smooth muscle cap accompanied by a necrotic core. More recently, the role of dysfunctional mural cells in neurodegenerative diseases, such as Alzheimers and Parkinsons disease, is being recognized. In this review, we begin with an exploration of the mechanisms underlying atherosclerosis and neurodegenerative diseases, such as mural cell plasticity. Next, we highlight a selection of signaling pathways (PDGF, Notch and inflammatory signaling) that are conserved across both diseases. We propose that conserved mural cell signaling mechanisms can be exploited for the identification or development of dual?pronged therapeutics that impart both cardio? and neuroprotective qualities. 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Nedoboy, Polina E.; Houlahan, Callum B.; Farnham, M. M. J.A key feature of sleep disordered breathing syndromes, such as obstructive sleep apnea is intermittent hypoxia. Intermittent hypoxia is well accepted to drive the sympathoexcitation that is frequently associated with hypertension and diabetes, with measurable effects after just 1 h. The aim of this study was to directly measure the glucose response to 1 h of acute intermittent hypoxia in pentobarbital anesthetized rats, compared to conscious rats. However, we found that while a glucose response is measurable in conscious rats exposed to intermittent hypoxia, it is suppressed in anesthetized rats. Intermittent hypoxia for 1, 2, or 8 h increased blood glucose by 0.7 0.1 mmol/L in conscious rats but had no effect in anesthetized rats (?0.1 0.2 mmol/L). These results were independent of the frequency of the hypoxia challenges, fasting state, vagotomy, or paralytic agents. A supraphysiological challenge of 3 min of hypoxia was able to induce a glycemic response indicating that the reflex response is not abolished under pentobarbital anesthesia. We conclude that pentobarbital anesthesia is unsuitable for investigations into glycemic response pathways in response to intermittent hypoxia in rats. Copyright 2021 Nedoboy, Houlahan and Farnham.
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Shen, Bo; Tasdogan, Alpaslan; Ubellacker, Jessalyn M.; Zhang, Jingzhu; Nosyreva, Elena D.; Du, Liming; Murphy, Malea M.; Hu, Shuiqing; Yi, Yating; Kara, Nergis; Liu, Xin; Guela, Shay; Jia, Yuemeng; Ramesh, Vijayashree; Embree, Claire; Mitchell, Evann C.; Zhao, Yunduo Charles; Ju, Lining Arnold; Hu, Zhao; Crane, Genevieve M.; Zhao, Zhiyu; Syeda, Ruhma; Morrison, Sean J.Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors16. LEPR+ cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors712, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin13,14, distinguishes peri-arteriolar LEPR+ cells poised to undergo osteogenesis from peri-sinusoidal LEPR+ cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPR+osteolectin+ cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin+ cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin+ cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin+ cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin+ cells depleted osteolectin+ cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing. 2021, The Author(s), under exclusive licence to Springer Nature Limited.
