Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria ...from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration.
There is no well-established in vivo marker of nigral degeneration in Parkinson's disease (PD). An ideal imaging marker would directly mirror the loss of substantia nigra dopaminergic neurones, which ...is most prominent in sub-regions called nigrosomes. High-resolution, iron-sensitive, magnetic resonance imaging (MRI) at 7T allows direct nigrosome-1 visualisation in healthy people but not in PD. Here, we investigated the feasibility of nigrosome-1 detection using 3T - susceptibility-weighted (SWI) MRI and the diagnostic accuracy that can be achieved for diagnosing PD in a clinical population. 114 high-resolution 3T - SWI-scans were reviewed consisting of a prospective case-control study in 19 subjects (10 PD, 9 controls) and a retrospective cross-sectional study in 95 consecutive patients undergoing routine clinical SWI-scans (>50 years, 9 PD, 81 non-PD, 5 non-diagnostic studies excluded). Two raters independently classified subjects into PD and non-PD according to absence or presence of nigrosome-1, followed by consensus reading. Diagnostic accuracy was assessed against clinical diagnosis as gold standard. Absolute inter- and intra-rater agreement was ≥94% (kappa≥0.82, p<0.001). In the prospective study 8/9 control and 8/10 PD; and in the retrospective study 77/81 non-PD and all 9 PD subjects were correctly classified. Diagnostic accuracy of the retrospective cohort was: sensitivity 100%, specificity 95%, NPV 1, PPV 0.69 and accuracy 96% which dropped to 91% when including non-diagnostic scans ('intent to diagnose'). The healthy nigrosome-1 can be readily depicted on high-resolution 3T - SWI giving rise to a 'swallow tail' appearance of the dorsolateral substantia nigra, and this feature is lost in PD. Visual radiological assessment yielded a high diagnostic accuracy for PD vs. an unselected clinical control population. Assessing the substantia nigra on SWI for the typical 'swallow tail' appearance has potential to become a new and easy applicable 3T MRI diagnostic tool for nigral degeneration in PD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Experimental results from the literature on the evolution of deuterium retention in displacement-damaged tungsten as a function of damaging dose are presented. Except for a few outliers, ...retention is generally found to increase with the presence of displacement damage. However, total retention results scatter by three orders of magnitude for similar exposure temperatures and are difficult to compare, because they depend on experiment-specific parameters such as the irradiation energy used to produce the displacement damage or the deuterium exposure parameters such as fluence. Even local deuterium concentration measurements were found to scatter by more than one order of magnitude. An experimental methodology is proposed that allows robust conclusions about the evolution of deuterium retention with damage dose and the results are discussed in detail. Recrystallized tungsten is irradiated with 20.3 MeV self-ions at room temperature with different damage doses ranging from 0.001 to 2.3 displacements per atom. The defects are then decorated with a low flux, low-energy deuterium plasma at 450 K sample temperature.
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He Nuclear Reaction Analysis (NRA) shows that the deuterium concentration levels off from the linear increase already at very low damage dose of about 0.005 dpa. At a damage dose of 0.23 dpa a maximum deuterium concentration of about 1.4 at% is reached. Thermal Desorption Spectroscopy (TDS) shows that with damage increasing above 0.005 dpa, the overall shape of the desorption spectra does not change substantially, only their intensities increase. Total amounts derived from TDS are in quantitative agreement with results from
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He-NRA. Experimental results following this methodology also agree quantitatively with very recent parameter-free modeling of damage evolution.
Lateral ambipolar diffusion in an InGaN/GaN single quantum well (SQW) structure grown on bulk GaN is studied by microphotoluminescence (μPL) investigations. The analysis is done via pinhole scans, ...that is, by decoupling the excitation area from the detection area and scanning the latter one. Knowing the size of the excited region, conclusions about the carrier transport in the in‐plane layer of the QW can be drawn. In this study, a diffusion length
L
d
up to 12 μm is observed at room temperature. Furthermore, the energy of the spectral peak is analyzed as a function of distance, showing a pronounced blueshift at the excitation center. An increase in distance to the injection region is accompanied by a redshift. The indication of peak energy is used to relate the drop of PL intensity with increasing radius to actual diffusion of charge carriers. In addition, temperature‐dependent studies of the diffusion behavior are done, covering the range between 10 K and room temperature. No significant change of diffusion length can be seen with temperature, indicating that temperature dependencies of carrier lifetime and of mobility compensate each other.
The diffusion behavior of charge carriers in a light‐emitting diode is studied, using an advanced microphotoluminescence setup, that is, decoupling the excitation from the detection. Results show charge carrier‐dependent diffusion with a length up to 12 μm and no change with temperature. Simulations approve the experimental observations at room temperature, confirming the long‐range transport dynamics of carriers.
Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and ...excretion of rivaroxaban in rats, dogs, and humans. Single doses of (14)Crivaroxaban (3 and 1 mg/kg) were administered to rats (orally/intravenously) and dogs (orally), respectively. A single oral dose of (14)Crivaroxaban (10 mg) was administered to healthy human males (n = 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and > or = 92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans.
The canonical WNT signaling pathway is crucial for intestinal stem cell renewal and aberrant WNT signaling is an early event in colorectal cancer (CRC) development. Here, we show for the first time ...that WNT2 is one of the most significantly induced genes in CRC stroma as compared to normal stroma. The impact of stromal WNT2 on carcinoma formation or progression was not addressed so far. Canonical WNT/β-catenin signaling was assessed using a 7TGP-reporter construct. Furthermore, effects of WNT2 on fibroblast migration and invasion were determined using siRNA-mediated gene silencing. Tumor cell invasion was studied using organotypic raft cultures and in vivo significance was assessed via a xenograft mouse model. We identified cancer-associated fibroblasts (CAFs) as the main source of WNT2. CAF-derived WNT2 activated canonical signaling in adenomatous polyposis coli/β-catenin wild-type colon cancer cells in a paracrine fashion, whereas no hyperactivation was detectable in cell lines harboring mutations in the adenomatous polyposis coli/β-catenin pathway. Furthermore, WNT2 activated autocrine canonical WNT signaling in primary fibroblasts, which was associated with a pro-migratory and pro-invasive phenotype. We identified FZD8 as the putative WNT2 receptor in CAFs. Three-dimensional organotypic co-culture assays revealed that WNT2-mediated fibroblast motility and extracellular matrix remodeling enhanced cancer cell invasion of cell lines even harboring mutations in the adenomatous polyposis coli/β-catenin pathway. Thus, suggesting a tumor-promoting influence on a broad range of CRC. In line, WNT2 also promotes tumor growth, invasion and metastasis in vivo. Moreover, high WNT2 expression is associated with poor prognosis in human CRC. The identification of the pro-malignant function of stromal derived WNT2 in CRC classifies WNT2 and its receptor as promising stromal targets to confine cancer progression in combination with conventional or targeted therapies.
Dissolved organic matter (DOM) is part of the biogeochemical cycles of carbon and nutrients, carries pollutants and drives soil formation. The DOM concentration and properties along the water flow ...path through forest ecosystems depend on its sampling location and transformation processes. To improve our understanding of the effects of forest management, especially tree species selection and management intensity, on DOM concentrations and properties of samples from different ecosystem fluxes, we studied throughfall, stemflow, litter leachate and mineral soil solution at 26 forest sites in the three regions of the German Biodiversity Exploratories. We covered forest stands with three management categories (coniferous, deciduous age class and unmanaged beech forests). In water samples from these forests, we monitored DOC concentrations over 4 years and characterized the quality of DOM with UV-vis absorption, fluorescence spectroscopy combined with parallel factor analysis (PARAFAC) and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). Additionally, we performed incubation-based biodegradation assays. Multivariate statistics revealed strong significant effects of ecosystem fluxes and smaller effects of main tree species on DOM quality. Coniferous forests differed from deciduous forests by showing larger DOC concentrations, more lignin- and protein-like molecules, and fewer tannin-like molecules in throughfall, stemflow, and litter leachate. Cluster analysis of FT-ICR-MS data indicated that DOM compositions, which varied in aboveground samples depending on tree species, become aligned in mineral soil. This alignment of DOM composition along the water flow path in mineral soil is likely caused by microbial production and consumption of DOM in combination with its interaction with the solid phase, producing a characteristic pattern of organic compounds in forest mineral soils. We found similarly pronounced effects of ecosystem fluxes on the biodegradability of DOM, but surprisingly no differences between deciduous and coniferous forests. Forest management intensity, mainly determined by biomass extraction, contribution of species, which are not site-adapted, and deadwood mass, did not influence DOC concentrations, DOM composition and properties significantly.
To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and ...predictive disease severity markers.
A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included.
136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss.
Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.
Melanopic stimuli trigger diverse non-image-forming effects. However, evidence of a melanopic contribution to acute effects on alertness and performance is inconclusive, especially under common ...lighting situations. Effects on cognitive performance are likely mediated by effort-related physiological changes. We assessed the acute effects of lighting in three scenarios, at two times of day, on effort-related changes to cardiac contraction as indexed by the cardiac pre-ejection period (PEP). In a within-subject design, twenty-seven participants performed a cognitive task thrice during a morning and a late-afternoon session. We set the lighting at 500 lux in all three lighting scenarios, measured horizontally at the desk level, but with 54 lux, 128 lux, or 241 lux melanopic equivalent daylight illuminance at the eye level. Impedance cardiography and electrocardiography measurements were used to calculate PEP, for the baseline and task period. A shorter PEP during the task represents a sympathetic heart activation and therefore increased effort. Data were analysed with linear mixed-effect models. PEP changes depended on both the light scene and time of day (p = 0.01 and p = 0.002, respectively). The highest change (sympathetic activation) occurred for the medium one of the three stimuli (128 lux) during the late-afternoon session. However, effect sizes for the singular effects were small, and only for the combined effect of light and time of day middle-sized. Performance scores or self-reported scores on alertness and task demand did not change with the light scene. In conclusion, participants reached the same performance most efficiently at both the highest and lowest melanopic setting, and during the morning session. The resulting U-shaped relation between melanopic stimulus intensity and PEP is likely not dependent solely on intrinsic ipRGC stimuli, and might be moderated by extrinsic cone input. Since lighting situations were modelled according to current integrative lighting strategies and real-life indoor light intensities, the result has implications for artificial lighting in a work environment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Solar/ultraviolet (UV) radiation exerts a variety of biological effects, including suppression of the immune system. UV-induced immunosuppression is induced by suberythemogenic/physiological UV ...doses, and it affects primarily T-cell driven immune reactions. Another characteristic feature of UV-induced immunosuppression is its antigen-specificity. This is due to the induction of T cells with suppressive features, called regulatory T cells. Since UV-induced regulatory T cells may harbor therapeutic potential phenotypic and functional characterization of these cells is ongoing. Most of these studies have been performed in the murine model of contact hypersensitivity. In this protocol we describe a method for the UV-induced suppression of the induction of contact hypersensitivity and the adoptive transfer of immune response.
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