| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
- Baigent, Colin, et al.
(författare)
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The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection) : a randomised placebo-controlled trial
- 2011
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 377:9784, s. 2181-2192
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Tidskriftsartikel (refereegranskat)abstract
- Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and I SRCTN54137607. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/L (SE 0.02; with about two-thirds compliance) during a median follow-up of 4.9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs 619 [13.4%] placebo; rate ratio [RR] 0.83, 95% CI 0.74-0.94; log-rank p=0.0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs 230 [5.0%]; RR 0.92,95% CI 0.76-1.11; p=0.37) and there were significant reductions in non-haemorrhagic stroke (131 [2.8%] vs 174 [3.8%]; RR 0.75,95% CI 0.60-0.94; p=0.01) and arterial revascularisation procedures (284 [6.1%] vs 352 [7.6%]; RR 0.79, 95% CI 0.68-0.93; p=0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0.2%] vs 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs 18 [0.4%]), gallstones (106 [2.3%] vs 106 [2.3%]), or cancer (438 [9.4%] vs 439 [9.5%], p=0.89) and there was no significant excess of death from any non-vascular cause (668 [14.4%] vs 612 [13.2%], p=0.13). Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
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| 3. |
- Dong, Jianbo, et al.
(författare)
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Venice: Exploring Server Architectures for Effective Resource Sharing
- 2016
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Ingår i: Proceedings - International Symposium on High-Performance Computer Architecture. - 1530-0897. - 9781467392112 ; 2016-April, s. 507-518
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Konferensbidrag (refereegranskat)abstract
- Consolidated server racks are quickly becoming the backbone of IT infrastructure for science, engineering, and business, alike. These servers are still largely built and organized as when they were distributed, individual entities. Given that many fields increasingly rely on analytics of huge datasets, it makes sense to support flexible resource utilization across servers to improve cost-effectiveness and performance. We introduce Venice, a family of data-center server architectures that builds a strong communication substrate as a first-class resource for server chips. Venice provides a diverse set of resource-joining mechanisms that enables user programs to efficiently leverage non-local resources.To better understand the implications of design decisionsabout system support for resource sharing we have constructed a hardware prototype that allows us to more accurately measure end-to-end performance of at-scale applications and to explore tradeoffs among performance, power, and resource-sharing transparency. We present results from our initial studies analyzing these tradeoffs when sharing memory, accelerators, or NICs. We find that it is particularly important to reduce or hide latency, that data-sharing access patterns should match the features of the communication channels employed, and that inter-channel collaboration can be exploited for better performance.
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| 4. |
- Gao, Chan, et al.
(författare)
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Defect evolution behaviors from single sulfur point vacancies to line vacancies in monolayer molybdenum disulfide
- 2021
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 23:35, s. 19525-19536
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Tidskriftsartikel (refereegranskat)abstract
- Two-dimensional monolayer transition metal dichalcogenides (TMDs) are promising candidates for many novel nanoelectronic and optoelectronic applications due to their exceptional electronic, optical, chemical and mechanical properties. Experimentally, single chalcogen point vacancies caused by electron beam irradiation are found to agglomerate into line vacancy defects in monolayer TMDs. Herein, the corresponding defect evolution behaviors from single sulfur point vacancies to line vacancies in the monolayer molybdenum disulfide (MoS2) have been systematically studied using molecular dynamics and first principles calculations. The experimental observations of the defect evolution from single sulfur point vacancies to line vacancies are reproduced at the atomic level. The results indicate that the di-vacancy line defect and a point vacancy separated by a sulfur atom in a line evolve into tri-vacancy line defects, and the di-vacancy line defects can rotate 60 degrees clockwise or counterclockwise. Moreover, two adjacent di-vacancy line defects with an angle of 120 degrees can evolve into tri-vacancy line defects. High temperature and large vacancy concentrations promote the defect evolution from point vacancies to line vacancies. Intriguingly, compared with the randomly distributed point vacancy defects, the line vacancy defects formed after the defect evolution significantly decrease the mechanical properties, such as the ultimate strength, ultimate strain and Young's modulus of monolayer MoS2. In addition, the mechanical properties decrease with increasing vacancy concentration and temperature for the final configurations after defect evolution in monolayer MoS2 with different vacancy concentrations at different temperatures. The band gaps of monolayer MoS2 with line vacancy defects are smaller than those with randomly distributed point vacancy defects. Therefore, our study clarifies the defect evolution behaviors from single sulfur point vacancies to line vacancies in monolayer MoS2 and opens an opportunity for the novel nanoelectronic and optoelectronic applications of monolayer TMDs.
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| 5. |
- Gao, Chan, et al.
(författare)
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Synergistic vacancy defects and mechanical strain for the modulation of the mechanical, electronic and optical properties of monolayer tungsten disulfide
- 2021
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 23:10, s. 6298-6308
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Tidskriftsartikel (refereegranskat)abstract
- Monolayer transition metal dichalcogenides (TMDs) are the potential candidate materials in nanoelectronic and optoelectronic applications due to their unique physical and chemical properties. Although both defect and strain greatly alter the structural, physical and chemical properties of monolayer TMDs, the defective monolayer TMDs under applied strain have not been adequately studied. In this paper, the synergistic effects of sulfur vacancy defects and mechanical strain on the mechanical, electronic and optical properties of monolayer tungsten disulfide (WS2) have been systematically studied using first principles density functional theory. The results indicate that the sulfur vacancy formation energy increases linearly with increasing sulfur vacancy concentration under different strains. The strain energy and stress of monolayer WS2 with different sulfur vacancy concentrations increase with increasing applied strain in the strain range of -10% to 10%. The band gap of monolayer WS2 decreases with increasing sulfur vacancy concentration under different strains. Moreover, compared with unstrained conditions, 5% compressive strain increases the band gap at a larger vacancy concentration and the case is just opposite at a smaller vacancy concentration, while 5% tensile strain decreases the band gap. The band gap of monolayer WS2 with different sulfur vacancy concentrations firstly increases and then shrinks with increasing applied strain under compressive strain, whereas it decreases monotonically under tensile strain in the strain range of -10% to 10%. In the visible-light wavelength region, the out-of-plane absorption coefficient under different strains increases with increasing sulfur vacancy concentration. Furthermore, 5% compressive strain enhances the absorption coefficient and 5% tensile strain decreases the absorption coefficient. Hence, the synergistic effects of sulfur vacancy defects and mechanical strain in monolayer TMDs can open new avenues for their applications in nanoelectronic and optoelectronic devices.
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| 6. |
- Griep, Yannick, et al.
(författare)
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The chicken or the egg : The reciprocal relationship between job insecurity and mental health complaints
- 2021
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Ingår i: Journal of Business Research. - : Elsevier BV. - 0148-2963 .- 1873-7978. ; 126, s. 170-186
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Tidskriftsartikel (refereegranskat)abstract
- To push the job insecurity literature forward, we bring together and simultaneously examine multiple theoretical frameworks to explain the direct job insecurity-mental health relationship and the reciprocal mental health-job insecurity relationship. Using 3-wave survey data, with a six-month time lag, from 1994 employees, we found that the stability of job insecurity from Time 1 to Time 2 was positively related to stress and social exchange mechanisms, as well as mental health complaints at Time 3. We also found that the stability of mental health complaints from Time 1 to Time 2 was positively related to the conservation of resources mechanism of absenteeism, as well as to perceptions of job insecurity at Time 3. Moreover, the stability of absenteeism over time was positively related to perceptions of job insecurity at Time 3. We discuss implications for the job insecurity literature, as well as make suggestions for future research and practical implications.
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| 7. |
- Held, Claes, et al.
(författare)
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Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: : results from the TRACER trial
- 2014
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 3:3, s. 246-256
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo.Methods: In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization.Results: Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83–1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74–1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99–2.15).Conclusions: NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.
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| 8. |
- Jiang, Lan, et al.
(författare)
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Heparin mimetics as potential intervention for COVID-19 and their bio-manufacturing
- 2023
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Ingår i: SYNTHETIC AND SYSTEMS BIOTECHNOLOGY. - : KEAI PUBLISHING LTD. - 2405-805X. ; 8:1, s. 11-19
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Forskningsöversikt (refereegranskat)abstract
- The COVID-19 pandemic has caused severe health problems worldwide and unprecedented decimation of the global economy. Moreover, after more than 2 years, many populations are still under pressure of infection. Thus, a broader perspective in developing antiviral strategies is still of great importance. Inspired by the observed multiple benefits of heparin in the treatment of thrombosis, the potential of low molecular weight heparin (LMWH) for the treatment of COVID-19 have been explored. Clinical applications found that LMWH decreased the level of inflammatory cytokines in COVID-19 patients, accordingly reducing lethality. Furthermore, several in vitro studies have demonstrated the important roles of heparan sulfate in SARS-CoV-2 infection and the inhibitory effects of heparin and heparin mimetics in viral infection. These clinical observations and designed studies argue for the potential to develop heparin mimetics as anti-SARS-CoV-2 drug candidates. In this review, we summarize the properties of heparin as an anticoagulant and the pharmaceutical possibilities for the treatment of virus infection, focusing on the perspectives of developing heparin mimetics via chemical synthesis, chemoenzymatic synthesis, and bioengineered production by microbial cell factories. The ultimate goal is to pave the eminent need for exploring novel compounds to treat coronavirus infection-caused diseases.
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| 9. |
- Li, Longkun, et al.
(författare)
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Changes in T-type calcium channel and its subtypes in overactive detrusor of the rats with partial bladder outflow obstruction
- 2007
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Ingår i: Neurourology and Urodynamics. - : Wiley. - 0733-2467 .- 1520-6777. ; 26:6, s. 870-878
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Tidskriftsartikel (refereegranskat)abstract
- AimsTo investigate the activity of the T-type calcium channel (TCC) and the expression of its subtypes in overactive detrusor (OD) myocytes in rats after partial bladder outflow obstruction (PBOO).MethodsThirteen male Wistar rats with OD after PBOO (OD group) and eight sham-operated rats (control group) were studied. The two groups were compared regarding the expression of TCC subtype genes by reverse transcription-polymerase chain reaction (RT-PCR) and the TCC kinetics and cell action potential by whole-cell patch-clamp.ResultsThe time course and density of the current were significantly higher in the OD cells than those in the control detrusor. Whole-cell patch-clamp analysis showed that the activation of TCCs in detrusor myocytes in the OD group was faster than the control group, but inactivation was almost the same in both groups, suggesting a significant enhancement of the Ca2+ window current in the OD group. Patch-clamp recording of action potentials in the OD cells indicated an increase in excitability and a decrease in the repolarization interval. RT-PCR assay showed an abnormal expression of 1G subtype in the OD cells.ConclusionsTCCs could be one of the crucial factors for the abnormal excitation in OD cells. The development of OD after PBOO presumably relates to the increase in TCC current in the bladder cells, the enhancement of the Ca2+ window current for Ca2+ inflow, the prolongation of the intracellular calcium oscillations, and the acceleration of the cell depolarization.
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| 10. |
- Mafham, Marion M, et al.
(författare)
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Prognostic utility of estimated albumin excretion rate in chronic kidney disease : results from the Study of Heart and Renal Protection
- 2018
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 33:2, s. 257-264
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Tidskriftsartikel (refereegranskat)abstract
- Background: Estimated albumin excretion rate (eAER) provides a better estimate of 24-h albuminuria than albumin:creatinine ratio (ACR). However, whether eAER is superior to ACR in predicting end-stage renal disease (ESRD), vascular events (VEs) or death is uncertain.Methods: The prognostic utility of ACR and eAER (estimated from ACR, sex, age and race) to predict mortality, ESRD and VEs was compared using Cox proportional hazards regression among 5552 participants with chronic kidney disease in the Study of Heart and Renal Protection, who were not on dialysis at baseline.Results: During a median follow-up of 4.8 years, 1959 participants developed ESRD, 1204 had a VE and 1130 died (641 from a non-vascular, 369 from a vascular and 120 from an unknown cause). After adjustment for age, sex and eGFR, both ACR and eAER were strongly and similarly associated with ESRD risk. The average relative risk (RR) per 10-fold higher level was 2.70 (95% confidence interval 2.45-2.98) for ACR and 2.67 (2.43-2.94) for eAER. Neither ACR nor eAER provided any additional prognostic information for ESRD risk over and above the other. For VEs, there were modest positive associations between both ACR and eAER and risk [adjusted RR per 10-fold higher level 1.37 (1.22-1.53) for ACR and 1.36 (1.22-1.52) for eAER]. Again, neither measure added prognostic information over and above the other. Similar results were observed when ACR and eAER were related to vascular mortality [RR per 10-fold higher level: 1.64 (1.33-2.03) and 1.62 (1.32-2.00), respectively] or to non-vascular mortality [1.53 (1.31-1.79) and 1.50 (1.29-1.76), respectively].Conclusions: In this study, eAER did not improve risk prediction of ESRD, VEs or mortality.
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