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  • 1
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    Operation and performance of the ATLAS semiconductor tracker in LHC Run 2
    IOP Publishing ; 2022
    In:  Journal of Instrumentation Vol. 17, No. 01 ( 2022-01-01), p. P01013-
    Details
    In: Journal of Instrumentation, IOP Publishing, Vol. 17, No. 01 ( 2022-01-01), p. P01013-
    Abstract: The semiconductor tracker (SCT) is one of the tracking systems for charged particles in the ATLAS detector. It consists of 4088 silicon strip sensor modules. During Run 2 (2015–2018) the Large Hadron Collider delivered an integrated luminosity of 156 fb -1 to the ATLAS experiment at a centre-of-mass proton-proton collision energy of 13 TeV. The instantaneous luminosity and pile-up conditions were far in excess of those assumed in the original design of the SCT detector. Due to improvements to the data acquisition system, the SCT operated stably throughout Run 2. It was available for 99.9% of the integrated luminosity and achieved a data-quality efficiency of 99.85%. Detailed studies have been made of the leakage current in SCT modules and the evolution of the full depletion voltage, which are used to study the impact of radiation damage to the modules.
    Type of Medium: Online Resource
    ISSN: 1748-0221
    URL: Article
    DOI: 10.1088/1748-0221/17/01/P01013
    Language: Unknown
    Publisher: IOP Publishing
    Publication Date: 2022
    detail.hit.zdb_id: 2235672-1
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  • 2
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    Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr−/− Mice
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 11 ( 2022-05-30), p. 1795-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 11 ( 2022-05-30), p. 1795-
    Abstract: Background: Hypertriglyceridemia (HTG) increases the risk for atherosclerotic cardiovascular disease, but underlying mechanisms are incompletely understood. Circulating monocytes play an important role in atherogenesis by infiltrating arterial walls, where they differentiate into macrophages. We tested the hypothesis that HTG is mechanistically linked to atherogenesis by altering the monocyte phenotype and infiltration into atherosclerotic lesions in a model of diet-induced atherogenesis in Ldlr−/− mice. Methods: HTG was induced in male Ldlr−/− mice, fed a Western, high-fat high-cholesterol diet, by daily injection of poloxamer 407 (P407), a lipoprotein lipase inhibitor, for seven weeks. Atherosclerosis, monocyte phenotypes, and monocyte migration into atherosclerotic lesions were determined by well-validated methods. Results: Compared with the saline control, P407 injection in Ldlr−/− mice rapidly induced profound and persistent HTG, modestly elevated plasma cholesterol levels, and increased levels of triglyceride and cholesterol carried in very-low-density lipoprotein and low-density lipoprotein. Unexpectedly, mice receiving P407 versus saline control showed less atherosclerosis. Following induction of HTG by P407, CD36+ (also CD11c+), but not CD36− (CD11c−), monocytes showed early increases in lipid accumulation, but the number of CD36+ (not CD36−) monocytes was dramatically decreased afterwards in the circulation until the end of the test. Concurrently, CD36+ (CD11c+) monocyte migration into atherosclerotic lesions was also reduced in mice receiving P407 versus controls. Conclusions: P407 induced severe HTG, but reduced atherosclerosis, in Ldlr−/− mice, possibly because of profound reductions of circulating CD36+ (CD11c+) monocytes, leading to decreased monocyte migration into atherosclerotic lesions.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11111795
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 3
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    Abstract 499: Serum Opacity Factor Therapy Alters Plasma, Erythrocyte And Tissue Cholesterol Content In The Dysfunctional High Density Lipoprotein Scarb1 -/- Mouse Model
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. Suppl_1 ( 2022-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. Suppl_1 ( 2022-05)
    Abstract: Aim: In humans, very high plasma HDL-cholesterol concentrations are associated with increased all cause- and atherosclerotic cardiovascular disease (ASCVD)-mortality. The HDL receptor-deficient mouse (Scarb1 -/- ) is a robust model of this phenotype having high free cholesterol (FC) bioavailability due to too many FC-rich HDL particles. Clinically, plasma LDL and HDL are quantified according to total cholesterol = FC + cholesteryl esters (CE), which likely contribute to ASCVD pathophysiology differently. Despite higher HDL, Scarb1 -/- mice have more ASCVD on a Western diet, and increased mol% FC in ovaries, erythrocytes, heart, lung, female liver and macrophages, tissues that are associated with female infertility, impaired cell maturation, cardiac dysfunction and atherosclerosis. Bacterial serum opacity factor (SOF) reduces plasma cholesterol ~ 40% by diverting HDL-cholesterol to the hepatic LDLR. Hypothesis: Adeno-associated virus delivery of SOF (AAV SOF ) normalizes plasma and tissue FC accretion and reverses the pathologies associated with Scarb1 -/- mice. Methods: The lipid compositions of plasma, HDL, erythrocytes, and tissues of Scarb1 -/- mice treated with AAV SOF at 12-13 weeks of age for three weeks were compared with age- and sex-matched wild type (WT) C57BL6 and Scarb1 -/- mice. Results: As hypothesized, AAV SOF reduced plasma and HDL-FC and CE, as well as mol% FC in Scarb1 -/- mice towards WT levels. Erythrocyte FC levels also fell, but mol% FC remained elevated. Some changes were sex-specific: AAV SOF reduced the elevated FC only in female livers to WT levels. AAV SOF reduced FC and CE in lungs of females to WT levels, but not among males; the mol% FC remained high in both sexes. In steroidogenic tissues, adrenals, ovaries and testis, AAV SOF treatment increased FC. Unexpectedly, in Scarb1 -/- mice, AAV SOF increased mol% FC and FC in heart beyond already elevated levels. Conclusions: These findings support the hypothesis that plasma and HDL cholesterol levels determine tissue cholesterol levels that drive the pathologies specific to Scarb1 -/- mice. This evolving model of the role of HDL-FC in RCT provides a rationale for human studies to determine the utility of HDL-FC bioavailability as a risk factor for ASCVD and other pathologies.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.42.suppl_1.499
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1494427-3
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  • 4
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    Abstract MP30: Excess HDL Free Cholesterol Bioavailability Drives Free Cholesterol Accretion Into Macrophages And Erythrocytes In Scarb1 -/- Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 41, No. Suppl_1 ( 2021-09)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. Suppl_1 ( 2021-09)
    Abstract: Aim: In humans, very high plasma HDL-cholesterol concentrations are associated with increased all cause- and atherosclerotic cardiovascular disease (ASCVD)-mortality. The HDL receptor-deficient mouse (Scarb1 -/- ), a robust model of this phenotype, is characterized by high free cholesterol (FC) bioavailability due to too many HDL particles that are FC-rich. Clinically, plasma LDL and HDL are quantified according to total cholesterol content, the sum of FC and esterified cholesterol, which likely contribute to ASCVD pathophysiology differently. A Western diet induces ASCVD in Scarb1 -/- mice, despite an attendant increase in HDL. We tested the hypothesis that high HDL-FC bioavailability contributes to ASCVD in Scarb1 -/- mice by increasing FC flux into macrophage cells, erythrocytes and other major tissues. Methods: Influx of HDL-FC and efflux of macrophage FC were determined between WT and Scarb1 -/- HDL and J774 macrophage cells. HDL of both genotypes were radiolabelled with [ 3 H]FC, injected into autologous mice, and the rates of plasma clearance and erythrocyte uptake were determined. Results: The magnitude of FC transfer from Scarb1 -/- HDL to LDL is greater than that from WT HDL; APOB-containing lipoproteins from Scarb1 -/- vs. WT mice are FC-enriched due likely to greater HDL-FC transfer. While macrophage efflux to HDL of Scarb1 -/- vs. WT HDL was not different, FC influx from Scarb1 -/- vs. WT HDL to macrophages was three-fold greater, a net effect that increased the FC burden of macrophages. In vivo studies showed that compared to WT mice, in Scarb1 -/- mice, autologous HDL-FC cleared more slowly and more FC transferred to erythrocytes. We compared the FC, CE, PL, and TG contents of all major tissues and determined that FC accretion by some tissues is higher among Scarb1 -/- vs. WT mice whereas in other tissues FC homeostasis is maintained. Lastly, we determined that the tissue compositions and plasma FC clearance kinetics varied according to sex, particularly among Scarb1 -/- mice. Conclusions: These findings are relevant to pathologies specific to Scarb1 -/- mice and to the evolving model of the role of HDL-FC in RCT. They provide a rationale for human studies to determine the utility of HDL-FC bioavailability as a risk factor for ASCVD and other pathologies.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.41.suppl_1.MP30
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1494427-3
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  • 5
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    Abstract 406: Normalization Of Erythrocyte Morphology In Scarb1 -/- Mice By Bacterial Serum Opacity Factor Is Dependent On HDL-free Cholesterol
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 43, No. Suppl_1 ( 2023-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. Suppl_1 ( 2023-05)
    Abstract: Compared to wild-type mice, HDL-receptor-deficient (Scarb1 -/- ) mice have higher plasma levels of free cholesterol (FC)-rich HDL and exhibit multiple pathologies—female infertility and deranged platelet and erythrocyte morphology and function. These pathologies are associated with a low mol% FC in ovaries, platelets, and erythrocytes, effects that are reversed by the HDL-lowering drug probucol. Some strains of Streptococcus pyogenes secrete a protein, serum opacity factor (SOF), which catalyzes the clouding i.e., opacification, of plasma. SOF specifically targets and quantitatively converts HDL into three products, that include a cholesteryl ester-rich microemulsion containing all the cholesterol content of 〉 100,000 HDL particles as well as APOE and its heterodimer with APOA2 as its sole apolipoproteins. Delivery of SOF with an adeno-associated virus (AAV SOF ) constitutively lowers plasma HDL-FC and reverses female infertility in Scarb1 -/- mice. Thus, we tested the hypothesis—AAV SOF delivery to Scarb1 -/- mice will normalize erythrocyte morphology in an HDL-FC dependent way. The erythrocyte morphology and FC content expressed as mol% FC of three groups of mice—WT, untreated Scarb1 -/- mice (control) and Scarb1 -/- mice receiving AAV SOF —were compared and correlated with their respective HDL-mol% FC. Among Scarb1 -/- mice, AAV SOF treatment normalized reticulocyte number, erythrocyte morphology and erythrocyte mol% FC. Plasma- and HDL-mol% FC positively correlated (p 〈 0.0001) across all three groups of mice. HDL-mol% FC also positively correlated with erythrocyte mol% FC (p 〈 0.0001). Finally, the erythrocyte mol% FC positively correlated with both the number of reticulocytes (p = 0.006) and abnormal erythrocytes (p 〈 0.0001). Although less profound, AAV SOF treatment also reduced the FC contents of some extravascular tissues. HDL-FC spontaneously transfers from plasma lipoproteins to cell membranes in multiple tissues sites on a time scale of minutes to a few hours. FC-enrichment of erythrocytes, which are in contact with plasma HDL, was more profound than FC enrichment in tissues. AAV SOF treatment lowers both plasma HDL-FC and erythrocyte-FC and normalizes erythrocyte morphology and lipid composition in an HDL-FC dependent way.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.43.suppl_1.406
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1494427-3
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  • 6
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    Free Cholesterol Bioavailability and Atherosclerosis
    Springer Science and Business Media LLC ; 2022
    In:  Current Atherosclerosis Reports Vol. 24, No. 5 ( 2022-05), p. 323-336
    Details
    In: Current Atherosclerosis Reports, Springer Science and Business Media LLC, Vol. 24, No. 5 ( 2022-05), p. 323-336
    Abstract: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection. Recent Findings Recent findings have established a complex relationship between HDL-c concentration and atherosclerosis. Systemic scavenger receptor class B type 1 (SR-B1) knock out (KO) mice exhibit with increased diet-induced atherosclerosis despite having an elevated plasma HDL-c concentration compared to wild type (WT) mice. The greater bioavailability of HDL-FC in SR-B1 vs. WT mice is associated with a higher FC content in multiple cell types and tissue sites. These results suggest that dysfunctional HDL with high FC bioavailability is atheroprone despite high HDL-c concentration. Summary Past oversimplification of HDL-c involvement in cholesterol transport has led to the failures in HDL targeted therapy. Evidence suggests that FC-mediated functionality of HDL is of higher importance than its quantity; as a result, deciphering the regulatory mechanisms by which HDL-FC bioavailability can induce atherosclerosis can have far-reaching clinical implications.
    Type of Medium: Online Resource
    ISSN: 1523-3804 , 1534-6242
    URL: Article
    DOI: 10.1007/s11883-022-01011-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2094154-7
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  • 7
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    Weight Change During the Postintervention Follow-up of Look AHEAD
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 6 ( 2022-06-02), p. 1306-1314
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 6 ( 2022-06-02), p. 1306-1314
    Abstract: Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P & lt; 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-1990
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
    detail.hit.zdb_id: 1490520-6
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  • 8
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    Intensive Weight Loss Intervention and Cancer Risk in Adults with Type 2 Diabetes: Analysis of the Look AHEAD Randomized Clinical Trial
    Wiley ; 2020
    In:  Obesity Vol. 28, No. 9 ( 2020-09), p. 1678-1686
    Details
    In: Obesity, Wiley, Vol. 28, No. 9 ( 2020-09), p. 1678-1686
    Abstract: This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality. Methods Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity‐related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer. Results After a median follow‐up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity‐related cancers were 6.1 and 7.3 per 1,000 person‐years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95% CI: 0.68‐1.04). There was no significant difference between the two groups in total cancer incidence (HR, 0.93; 95% CI: 0.80‐1.08), incidence of nonobesity‐related cancers (HR, 1.02; 95% CI: 0.83‐1.27), or total cancer mortality (HR, 0.92; 95% CI: 0.68‐1.25). Conclusions An ILI aimed at weight loss lowered incidence of obesity‐related cancers by 16% in adults with overweight or obesity and type 2 diabetes. The study sample size likely lacked power to determine effect sizes of this magnitude and smaller.
    Type of Medium: Online Resource
    ISSN: 1930-7381 , 1930-739X
    URL: Article
    DOI: 10.1002/oby.22936
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2027211-X
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  • 9
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    Highly conserved amino acid residues in apolipoprotein A1 discordantly induce high density lipoprotein assembly in vitro and in vivo
    Elsevier BV ; 2020
    In:  Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids Vol. 1865, No. 12 ( 2020-12), p. 158794-
    Details
    In: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Elsevier BV, Vol. 1865, No. 12 ( 2020-12), p. 158794-
    Type of Medium: Online Resource
    ISSN: 1388-1981
    URL: Article
    DOI: 10.1016/j.bbalip.2020.158794
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2209502-0
    SSG: 12
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  • 10
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    Within-Trial Cost-Effectiveness of a Structured Lifestyle Intervention in Adults With Overweight/Obesity and Type 2 Diabetes: Results From the Action for Health in Diabetes (Look AHEAD) Study
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 1 ( 2021-01-01), p. 67-74
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 1 ( 2021-01-01), p. 67-74
    Abstract: To assess the cost-effectiveness (CE) of an intensive lifestyle intervention (ILI) compared with standard diabetes support and education (DSE) in adults with overweight/obesity and type 2 diabetes, as implemented in the Action for Health in Diabetes study. RESEARCH DESIGN AND METHODS Data were from 4,827 participants during their first 9 years of study participation from 2001 to 2012. Information on Health Utilities Index Mark 2 (HUI-2) and HUI-3, Short-Form 6D (SF-6D), and Feeling Thermometer (FT), cost of delivering the interventions, and health expenditures was collected during the study. CE was measured by incremental CE ratios (ICERs) in costs per quality-adjusted life year (QALY). Future costs and QALYs were discounted at 3% annually. Costs were in 2012 U.S. dollars. RESULTS Over the 9 years studied, the mean cumulative intervention costs and mean cumulative health care expenditures were $11,275 and $64,453 per person for ILI and $887 and $68,174 for DSE. Thus, ILI cost $6,666 more per person than DSE. Additional QALYs gained by ILI were not statistically significant measured by the HUIs and were 0.07 and 0.15, respectively, measured by SF-6D and FT. The ICERs ranged from no health benefit with a higher cost based on HUIs to $96,458/QALY and $43,169/QALY, respectively, based on SF-6D and FT. CONCLUSIONS Whether ILI was cost-effective over the 9-year period is unclear because different health utility measures led to different conclusions.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-0358
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
    detail.hit.zdb_id: 1490520-6
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