| 1291. |
- Dumont, Magali, et al.
(författare)
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Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:23, s. 5091-5105
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Tidskriftsartikel (refereegranskat)abstract
- Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPAR agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuroprotective effects. We studied the effects of the pan-PPAR agonist bezafibrate on tau pathology, inflammation, lipid metabolism and behavior in transgenic mice with the P301S human tau mutation, which causes familial frontotemporal lobar degeneration. Bezafibrate treatment significantly decreased tau hyperphosphorylation using AT8 staining and the number of MC1-positive neurons. Bezafibrate treatment also diminished microglial activation and expression of both inducible nitric oxide synthase and cyclooxygenase 2. Additionally, the drug differentially affected the brain and brown fat lipidome of control and P301S mice, preventing lipid vacuoles in brown fat. These effects were associated with behavioral improvement, as evidenced by reduced hyperactivity and disinhibition in the P301S mice. Bezafibrate therefore exerts neuroprotective effects in a mouse model of tauopathy, as shown by decreased tau pathology and behavioral improvement. Since bezafibrate was given to the mice before tau pathology had developed, our data suggest that bezafibrate exerts a preventive effect on both tau pathology and its behavioral consequences. Bezafibrate is therefore a promising agent for the treatment of neurodegenerative diseases associated with tau pathology.
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| 1292. |
- Duquennoy, Simon, et al.
(författare)
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Poster Abstract: A benchmark for low-power wireless networking
- 2016
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Ingår i: Proceedings of the 14th ACM Conference on Embedded Networked Sensor Systems. - New York, NY, USA : ACM. - 9781450342636 ; 14 November 2016, s. 332-333
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Konferensbidrag (refereegranskat)abstract
- Experimental research in low-power wireless networking lacks a reference benchmark. While other communities such as databases or machine learning have standardized bench-marks, our community still uses ad-hoc setups for its exper-iments and struggles to provide a fair comparison between communication protocols. Reasons for this include the di-versity of network scenarios and the stochastic nature of wireless experiments. Leveraging on the excellent testbeds and tools that have been built to support experimental val-idation, we make the case for a reference benchmark to pro-mote a fair comparison and reproducibility of results. This abstract describes early design elements and a benchmark-ing methodology with the goal to gather feedback from the community rather than propose a definite solution.
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| 1293. |
- Eckersley, Alexander, et al.
(författare)
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Peptide location fingerprinting identifies species- and tissue-conserved structural remodelling of proteins as a consequence of ageing and disease
- 2022
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Ingår i: Matrix Biology. - : Elsevier B.V.. - 0945-053X .- 1569-1802. ; 114, s. 108-137
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular matrices (ECMs) in the intervertebral disc (IVD), lung and artery are thought to undergo age-dependant accumulation of damage by chronic exposure to mechanisms such as reactive oxygen species, proteases and glycation. It is unknown whether this damage accumulation is species-dependant (via differing lifespans and hence cumulative exposures) or whether it can influence the progression of age-related diseases such as atherosclerosis. Peptide location fingerprinting (PLF) is a new proteomic analysis method, capable of the non-targeted identification of structure-associated changes within proteins. Here we applied PLF to publicly available ageing human IVD (outer annulus fibrosus), ageing mouse lung and human arterial atherosclerosis datasets and bioinformatically identified novel target proteins alongside common age-associated differences within protein structures which were conserved between three ECM-rich organs, two species, three IVD tissue regions, sexes and in an age-related disease. We identify peptide yield differences across protein structures which coincide with biological regions, potentially reflecting the functional consequences of ageing or atherosclerosis for macromolecular assemblies (collagen VI), enzyme/inhibitor activity (alpha-2 macroglobulin), activation states (complement C3) and interaction states (laminins, perlecan, fibronectin, filamin-A, collagen XIV and apolipoprotein-B). Furthermore, we show that alpha-2 macroglobulin and collagen XIV exhibit possible shared structural consequences in IVD ageing and arterial atherosclerosis, providing novel links between an age-related disease and intrinsic ageing. Crucially, we also demonstrate that fibronectin, laminin beta chains and filamin-A all exhibit conserved age-associated structural differences between mouse lung and human IVD, providing evidence that ECM, and their associating proteins, may be subjected to potentially similar mechanisms or consequences of ageing across both species, irrespective of differences in lifespan and tissue function. © 2022 The Author(s)
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| 1294. |
- Edvinsson, Lars, et al.
(författare)
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Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries.
- 2010
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 30:10, s. 1233-1240
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. MATERIALS AND METHODS: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP-induced cranial vasodilatation in human isolated cerebral and middle meningeal arteries. We also studied the expression of the CGRP receptor components in cranial arteries with immunocytochemistry. Concentration response curves to αCGRP were performed in human isolated cerebral and middle meningeal arteries in the absence or presence of telcagepant. Arterial slices were stained for RAMP1, CLR and actin in a double immunofluorescence staining. RESULTS: In both arteries, we found that: (i) telcagepant was devoid of any contractile or relaxant effects per se; (ii) pretreatment with telcagepant antagonised the αCGRP-induced relaxation in a competitive manner; and (iii) immunohistochemistry revealed expression and co-localisation of CLR and RAMP1 in the smooth muscle cells in the media layer of both arteries. CONCLUSIONS: Our findings provide morphological and functional data on the presence of CGRP receptors in cerebral and meningeal arteries, which illustrates a possible site of action of telcagepant in the treatment of migraine.
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| 1295. |
- Ersmark, Erik, et al.
(författare)
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From the Past to the Present : Wolf Phylogeography and Demographic History Based on the Mitochondrial Control Region
- 2016
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Ingår i: Frontiers in Ecology and Evolution. - : FRONTIERS MEDIA SA. - 2296-701X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The global distribution of the gray wolf (Canis lupus) is a complex assembly consisting of a large number of populations and described subspecies. How these lineages are related to one another is still not fully resolved, largely due to the fact that large geographical regions remain poorly sampled both at the core and periphery of the species' range. Analyses of ancient wolves have also suffered from uneven sampling, but have shown indications of a major turnover at some point during the Pleistocene-Holocene boundary in northern North America. Here we analyze variation in the mitochondrial control region in 122 contemporary wolves from some of the less studied populations, as well as six samples from the previously unstudied Greenland subspecies (Canis I. orlon) and two Late Pleistocene samples from Siberia. Together with the publicly available control region sequences of both modern and ancient wolves, this study examines genetic diversity on a wide geographical and temporal scale that includes both Eurasia and North America. We identify 13 new haplotypes, of which the majority is found in northern and eastern Asia. The results show that the Greenland samples are all represented by one haplotype, previously identified in North American wolves, among which this population seems to trace its maternal lineage. The phylogeny and network analyses show a wide spatial distribution of several lineages, but also some clusters with more distinct geographical affiliation. In North America, we find support for an end-Pleistocene population bottleneck through coalescent simulations under an approximate Bayesian framework in contrast to previous studies that suggested an extinction-replacement event. However, we find no support for a similar bottleneck in Eurasia. Overall, this global analysis helps to clarify our understanding of the complex history for wolves in Eurasia and North America.
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| 1296. |
- Evans, Colin E, et al.
(författare)
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Modelling pulmonary microthrombosis coupled to metastasis : Distinct effects of thrombogenesis on tumorigenesis
- 2017
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Ingår i: Biology Open. - : The Company of Biologists. - 2046-6390. ; 6:5, s. 688-697
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Tidskriftsartikel (refereegranskat)abstract
- Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular microocclusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection.We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-Angiogenic and pro-Tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the microocclusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2α in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-Associated tumorigenesis and its treatment.
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| 1297. |
- Fabritz, Larissa, et al.
(författare)
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Dynamic risk assessment to improve quality of care in patients with atrial fibrillation : the 7th AFNET/EHRA Consensus Conference
- 2021
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Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 23:3, s. 329-344
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Tidskriftsartikel (refereegranskat)abstract
- AimsThe risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes.Methods and resultsThis article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence.ConclusionThe remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.
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| 1298. |
- Fall, Katja, 1971-, et al.
(författare)
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No association between a polymorphic variant of the IRS-1 gene and prostate cancer risk
- 2008
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Ingår i: The Prostate. - Hoboken, USA : John Wiley & Sons. - 0270-4137 .- 1097-0045. ; 68:13, s. 1416-20
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Insulin receptor substrate-1 (IRS-1) acts as a docking protein between the insulin-like growth factor-1 (IGF-1) receptor and intracellular signaling molecules in the IGF-1 signaling pathway. Accumulating data support a role of IGF-1 in prostate carcinogenesis. We assessed the influence of the most common IRS-1 gene polymorphism (Gly972Arg) on prostate cancer risk, alone and in combination with IGF-1 and other components in the IGF-1 signaling pathway.Materials and methods: In a nested case-control study within the Physicians' Health Study, the IRS-1 polymorphism was assayed from prospectively collected samples from 564 incident prostate cancer cases and 758 controls matched on age and smoking. We calculated relative risks (RR) and 95% confidence intervals (CI) using conditional logistic regression.Results: Among the controls, 0.8% were homozygous (AA) and 12% were heterozygous (GA) for the polymorphic allele. There was no association between carriage of the A allele and total prostate cancer risk (RR = 1.1 95% CI = 0.8-1.5), advanced disease (stage C or D or lethal prostate cancer, RR = 1.3 95% CI = 0.8-2.3), or plasma IGF-1 levels. We explored possible interactions with body mass index and components in the IGF-1 pathway including IGFBP3, PI3k, and PTEN but none of these factors influenced the relation between IRS-1 genotype and prostate cancer risk.Conclusions: Our data do not support an association between carriage of the variant IRS-1 gene and prostate cancer risk.
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| 1299. |
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| 1300. |
- Fitzsimmons-Craft, Ellen E., et al.
(författare)
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Effectiveness of a chatbot for eating disorders prevention: A randomized clinical trial
- 2022
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Ingår i: International Journal of Eating Disorders. - : WILEY. - 0276-3478 .- 1098-108X. ; 55:3, s. 343-353
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Tidskriftsartikel (refereegranskat)abstract
- Objective Prevention of eating disorders (EDs) is of high importance. However, digital programs with human moderation are unlikely to be disseminated widely. The aim of this study was to test whether a chatbot (i.e., computer program simulating human conversation) would significantly reduce ED risk factors (i.e., weight/shape concerns, thin-ideal internalization) in women at high risk for an ED, compared to waitlist control, as well as whether it would significantly reduce overall ED psychopathology, depression, and anxiety and prevent ED onset. Method Women who screened as high risk for an ED were randomized (N = 700) to (1) chatbot based on the StudentBodies (c) program; or (2) waitlist control. Participants were followed for 6 months. Results For weight/shape concerns, there was a significantly greater reduction in intervention versus control at 3- (d = -0.20; p = .03) and 6-m-follow-up (d = -0.19; p = .04). There were no differences in change in thin-ideal internalization. The intervention was associated with significantly greater reductions than control in overall ED psychopathology at 3- (d = -0.29; p = .003) but not 6-month follow-up. There were no differences in change in depression or anxiety. The odds of remaining nonclinical for EDs were significantly higher in intervention versus control at both 3- (OR = 2.37, 95% CI [1.37, 4.11]) and 6-month follow-ups (OR = 2.13, 95% CI [1.26, 3.59]). Discussion Findings provide support for the use of a chatbot-based EDs prevention program in reducing weight/shape concerns through 6-month follow-up, as well as in reducing overall ED psychopathology, at least in the shorter-term. Results also suggest the intervention may reduce ED onset. Public Significance We found that a chatbot, or a computer program simulating human conversation, based on an established, cognitive-behavioral therapy-based eating disorders prevention program, was successful in reducing womens concerns about weight and shape through 6-month follow-up and that it may actually reduce eating disorder onset. These findings are important because this intervention, which uses a rather simple text-based approach, can easily be disseminated in order to prevent these deadly illnesses. Trial registration: OSF Registries;
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