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| 4. |
- 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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- Ip, H. F., et al.
(författare)
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Genetic association study of childhood aggression across raters, instruments, and age
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGG(overall). The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from r(g)= 0.46 between self- and teacher-assessment to r(g)d= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range r(g): 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r(g)=-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |r(g)| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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| 8. |
- Neumann, A, et al.
(författare)
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A genome-wide association study of total child psychiatric problems scores
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:8, s. e0273116-
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Tidskriftsartikel (refereegranskat)abstract
- Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.
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| 10. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)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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| 15. |
- Axelson, Olav, 1937-, et al.
(författare)
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Regulatory toxicology and pharmacology.
- 2003
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Ingår i: International journal of occupational and environmental health. - 1077-3525 .- 2049-3967. ; 9, s. 386-389
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Tidskriftsartikel (refereegranskat)
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| 16. |
- Fischer, Alexander W., et al.
(författare)
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Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation
- 2021
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Ingår i: Cell Metabolism. - : Elsevier. - 1550-4131 .- 1932-7420. ; 33:3, s. 547-564.e7
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Tidskriftsartikel (refereegranskat)abstract
- In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.
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| 17. |
- Håkanson, Ulf, et al.
(författare)
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Photon mapping of single quantum dots by scanning tunneling microscopy induced luminescence spectroscopy
- 2002
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Ingår i: 7th International Conference on Nanometer-Scale Science and Technology and 21st European Conference on Surface Science.
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Konferensbidrag (refereegranskat)abstract
- Scanning tunneling microscopy induced luminescence (STML) has been used to investigate individual self-assembled InP quantum dots overgrown with GaInP. We will present results correlating the surface morphology with the optical properties of single dots. In particular, the strain induced energy-shift of the dot emission with increasing cap layer thickness and its relation to the overgrowth will be discussed. Effects of the dots on the properties of the overgrown GaInP will also be treated. STML spectra and monochromatic photon maps are compared with results from photoluminescence and transmission electron microscopy measurements. Furthermore, a comparison with theoretical calculations is made
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| 18. |
- Sass, K, et al.
(författare)
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Electrocochleographic signal analysis : condensation and rarefaction click stimulation contributes to diagnosis in Menière's disorder
- 1998
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Ingår i: Audiology. - 0020-6091. ; 37:4, s. 198-206
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Tidskriftsartikel (refereegranskat)abstract
- Thirty patients with Menière's disorder, 11 patients with cochlear hearing loss of other aetiologies and 10 normally-hearing subjects, were investigated using transtympanic electrocochleography (TT ECochG). Alternating polarity clicks, condensation and rarefaction clicks and long tone-bursts of 1 kHz were used for stimulation. The latencies of the AP responses to click stimulation were evaluated. It was found that the latency differences between the condensation and rarefaction click-evoked responses were significantly larger in patients with Menière's disorder as compared to normal subjects and to patients with other cochlear hearing losses. It was found that the sensitivity of TT ECochG, obtained by using measurements of SP-AP ratios and the SP amplitude at 1 kHz burst stimulation, increased from 83 per cent to 87 per cent by addition of the con-rar shift measurement. The specificity of TT ECochG obtained by this combination of variables was 100 per cent in our material. The results of the study indicate that the latency shift found in responses evoked by clicks of opposite polarities in TT ECochG, can be a useful parameter in the detection of suspected endolymphatic hydrops.
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| 21. |
- Strupinski, W., et al.
(författare)
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MOVPE strain layers - growth and application
- 2000
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Ingår i: Journal of Crystal Growth. ; 221, s. 20-25
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Tidskriftsartikel (refereegranskat)abstract
- The critical thickness, characteristic for the lattice-mismatch parameter, plays a key role in the growth of strain layers. The driving force for the 2D-3D transition can be minimized by slowing the relaxation of misfit strain. As a result the relatively smooth layer is deposited at lower temperature for the optimal growth rate. The quality of the InGaAs- and AlAs-strained layers deposited on InP substrate have been examined by the XRD, AFM and SIMS methods. Atomic force microscopy allows to observe 3D growth mode even for very thin layers. Relatively strong relaxation effects are recognized by surface roughness. Two-dimensional di!raction measurement is a much more sensitive tool for the estimation of relaxation degree. The observations results were applied in the heterostructure barrier varactor (HBV) diode. In order to minimize the conduction current through HBV two materials with different design of the barriers were studied: one heterostructure with three homogeneous lattice matched barriers consisting of 20nm Al0.48In0.52As and another one with strained step-like barriers consisting of 5 nm Al0.48In0.52As, 3 nm AlAs and 5 nm Al0.48In0.52As. We found that the use of strained step-like barriers results in a much lower conduction current. For current density
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| 22. |
- Thomsen, J., et al.
(författare)
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Local overpressure treatment reduces vestibular symptoms in patients with Ménière's disease : A clinical, randomized, multicenter, double-blind, placebo-controlled study
- 2005
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Ingår i: Otology and Neurotology. - : Ovid Technologies (Wolters Kluwer Health). - 1531-7129 .- 1537-4505. ; 26:1, s. 68-73
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the efficacy of a new device, the Meniett, in the treatment of Ménière's disease. The device delivers pressure pulses to the middle ear through a ventilating tube in the tympanic membrane at a frequency of 6 Hz for 0.6 second. After rising to a pressure level of 1.2 kPa, the pressure oscillates between 0.4 and 1.2 kPa. It is believed that the pressure changes are conveyed to the inner ear, inducing a transport of fluids via the pressure outlets and thus reducing the endolymphatic hydrops. Study Design: A clinical, randomized, multicenter, double-blind, placebo-controlled study. A total of 40 patients were included that had active Méniè re's disease according to American Academy of Otolaryngology-Head and Neck Surgery criteria, aged between 20 and 65 years, with a history of at least eight attacks during the past year. After insertion of the ventilation tube, the patients should have had attacks of vertigo for 2 months before entering the study. Outcome Measures: Primary study endpoints were change in frequency of vertigo, change of functionality profile, and change in patient perception of vertigo (visual analogue scale), secondary endpoints were perception of tinnitus, aural pressure, and hearing, as well as an audiologic evaluation of hearing before and after the treatment period. Results: The functionality level improved statistically significantly in the active group compared with the placebo group (p = 0.0014), as did the visual analogue scale evaluation of vertigo (p = 0.005). There was a trend toward a reduction of the frequency of vertiginous attacks that was not significant (p = 0.090). With regard to the secondary endpoints, there was no statistical difference between active and placebo groups. Conclusion: Local overpressure treatment is a novel treatment that is noninvasive, nondestructive, and safe. It significantly reduces vestibular symptoms in patients with Ménière's disease. The Meniett was cleared by the Food and Drug Administration in 2000.
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| 23. |
- van Kuilenburg, André B P, et al.
(författare)
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Dihydropyrimidinase deficiency : Phenotype, genotype and structural consequences in 17 patients
- 2010
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Ingår i: Biochimica et Biophysica Acta - Molecular Basis of Disease. - : Elsevier BV. - 0925-4439 .- 1879-260X. ; 1802:7-8, s. 639-648
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Tidskriftsartikel (refereegranskat)abstract
- Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 11 individuals have been reported suffering from a complete DHP deficiency. Here, we report on the clinical, biochemical and molecular findings of 17 newly identified DHP deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. Analysis of DPYS, encoding DHP, showed nine missense mutations, two nonsense mutations, two deletions and one splice-site mutation. Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence. Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity. Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively. The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme. In contrast, p.M70T, p.D81G, p.L337P and p.T343A affect regions near the di-zinc centre and the substrate binding site. The p.S379R and p.L7V mutations were likely to cause structural destabilization and protein misfolding. Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated.
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