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- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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In: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Research review (peer-reviewed)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is 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 verify an autophagic response.
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- Olsen, Michael Hecht, et al.
(author)
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Effects of losartan compared with atenolol on lipids in patients with hypertension and left ventricular hypertrophy : the losartan intervention for endpoint reduction in hypertension (LIFE) study
- 2009
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In: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 27:3, s. 567-574
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Journal article (peer-reviewed)abstract
- Objective: Beta-blockers and angiotensin II receptor blockers have different effects on lipids. Methods: We examined lipid levels in the Losartan Intervention For Endpoint reduction in hypertension study and their impact on the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke. We measured total and high-density lipoprotein cholesterol at baseline and annually during 4.8 years of losartan-based compared with atenolol-based treatment in 8611 patients with hypertension and left ventricular hypertrophy. Results: Patients randomized to losartan-based or atenolol-based treatment had similar baseline total (6.04 ± 1.12 vs. 6.05 ± 1.13 mmol/l, NS) and high-density lipoprotein (HDL) cholesterol (1.50 ± 0.44 vs. 1.49 ± 0.44 mmol/l, NS). Total cholesterol decreased significantly but equally (-0.37 ± 1.05 vs. -0.34 ± 1.09 mmol/l, NS), whereas HDL cholesterol decreased less during the first 2 years in patients randomized to losartan compared with atenolol (-0.13 ± 0.24 vs. -0.19 ± 0.25 mmol/l) and remained higher each year (1.38, 1.37, 1.42, 1.47, and 1.48 mmol/l vs. 1.32, 1.30, 1.36, 1.40, and 1.42 mmol/l, all P < 0.001) independent of hydrochlorothiazide or statin treatment. In Cox regression analysis, baseline total cholesterol [hazard ratio (HR) = 1.08 (1.02–1.14) per mmol/l, P < 0.01], HDL cholesterol [HR = 0.56 (0.48–0.66) per mmol/l, P < 0.001], and treatment allocation [HR = 0.86 (0.76–0.98), P < 0.05] predicted composite endpoint independently. Using time-varying analyses, the predictive strength of HDL cholesterol was increased [HR = 0.36 (0.30–0.44) per mmol/l, P < 0.001], whereas that of total cholesterol [HR = 1.03 (0.97–1.09) per mmol/l, NS] and treatment allocation [HR = 0.91 (0.80–1.03), NS] were reduced. Conclusion: Losartan blunted the decrease in HDL cholesterol during antihypertensive treatment in the LIFE study. Higher intreatment HDL cholesterol was associated with fewer composite endpoints and may partly explain the better outcome of losartan-based treatment.
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| 8. |
- Olsen, Rikke K J, et al.
(author)
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ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.
- 2007
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 130:Pt 8, s. 2045-54
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Journal article (peer-reviewed)abstract
- Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.
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| 9. |
- Olsen, Sarah H., et al.
(author)
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Control of self-heating in thin virtual substrate strained Si MOSFETs
- 2006
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In: IEEE Transactions on Electron Devices. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9383 .- 1557-9646. ; 53:9, s. 2296-2305
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Journal article (peer-reviewed)abstract
- This paper presents the first results and analysis of strained Si n-channel MOSFETs fabricated on thin SiGe virtual substrates. Significant improvements in electrical performance are demonstrated compared with Si control devices. The impact of SiGe device self-heating is compared for strained Si MOSFETs fabricated on thin and thick virtual substrates. This paper demonstrates that by using high-quality thin virtual substrates,,the compromised performance enhancements commonly observed in short-gate-length MOSFETs and high-bias conditions due to self-heating in conventional thick virtual substrate devices are eradicated. The devices were fabricated with a 2.8-nm gate oxide and included NiSi to reduce the parasitic series resistance. The strained layers grown on the novel substrates comprising 20% Ge did not relax during fabrication. Good ON-state performance, OFF-state performance, and cross-wafer uniformity are demonstrated. The results show that thin virtual substrates have the potential to circumvent the major issues associated with conventional virtual substrate technology. A promising solution for realizing high-performance strained Si devices suitable for a wide range of applications is thus presented.
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| 10. |
- Varzgar, John B., et al.
(author)
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Reliability study of ultra-thin gate oxides on strained-Si/SiGe MOS structures
- 2006
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In: Materials Science & Engineering. - : Elsevier BV. - 0921-5107 .- 1873-4944. ; 135:3, s. 203-206
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Journal article (peer-reviewed)abstract
- The reliability of gate oxides on bulk Si and strained Si (s-Si) has been evaluated using constant voltage stressing (CVS) to investigate their breakdown characteristics. The s-Si architectures exhibit a shorter life time compared to that of bulk Si, which is attributed to higher bulk oxide charges (Q(ox)) and increased surface roughness in the s-Si structures. The gate oxide in the s-Si structure exhibits a hard breakdown (HBD) at 1.9 x 10(4) s, whereas HBD is not observed in bulk Si up to a measurement period of 1.44 x 10(5) s. The shorter lifetime of the s-Si gate oxide is attributed to a larger injected charge (Q(inj)) compared to Q(inj) in bulk Si. Current-voltage (I-V) measurements for bulk Si samples at different stress intervals show an increase in stress induced leakage current (SILC) of two orders in the low voltage regime from zero stress time to up to 5 x 10(4) s. In contrast, superior performance enhancements in terms of drain current, maximum transconductance and effective channel mobility are observed in s-Si MOSFET devices compared to bulk Si. The results from this study indicate that further improvement in gate oxide reliability is needed to exploit the sustained performance enhancement of s-Si devices over bulk Si.
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