The emerging role of LRRK2 in tauopathies

Parkinson's disease (PD) is conventionally described as an α-synuclein aggregation disorder, defined by Lewy bodies and neurites, and mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common autosomal dominant cause of PD. However, LRRK2 mutations may be associated with diverse pathologies in patients with Parkinson's syndrome including tau pathology resembling progressive supranuclear palsy (PSP). The recent discovery that variation at the LRRK2 locus is associated with the progression of PSP highlights the potential importance of LRRK2 in tauopathies. Here, we review the emerging evidence and discuss the potential impact of LRRK2 dysfunction on tau aggregation, lysosomal function, and endocytosis and exocytosis

Relationships between greenhouse gas production and landscape position during short-term permafrost thaw under anaerobic conditions in the Lena Delta

Soils in the permafrost region have acted as car- bon sinks for thousands of years. As a result of global warming, permafrost soils are thawing and will potentially release greenhouse gases (GHGs) such as methane (CH4) and carbon dioxide (CO2). However, small-scale spatial heterogeneities of GHG production have been neglected in previous incubation studies. Here, we used an anaerobic incubation experiment to simulate permafrost thaw along a transect from upland Yedoma to the floodplain on Kurungnakh Island. Potential CO2 and CH4 production was measured during incubation of the active layer and permafrost soils at 4 and 20 ◦C, first for 60 d (approximate length of the growing season) and then continuing for 1 year. An assessment of methanogen abundance was performed in parallel for the first 60 d. Yedoma samples from upland and slope cores remained in a lag phase during the growing season simulation, while those located in the floodplain showed high production of CH4 (6.5 × 103 μg CH4-C g−1 C) and CO2 (6.9 × 103 μg CO2-C g−1 C) at 20 ◦C. The Yedoma samples from the permafrost layer started producing CH4 after 6 months of incubation. We conclude that landscape position is a key factor triggering CH4 production during the growing season time on Kurungnakh Island

Non-destructive Evaluation of Workpiece Properties along the Hybrid Bearing Bushing Process Chain

To combine the advantages of two materials, hybrid bulk metal workpieces are attractive for subsequent processes such as metal forming. However, hybrid materials rely on the initial bond strength for the effective transfer of applied loads. Thus, a non-destructive evaluation of the bonding along the production process chain is of high interest. To evaluate to what extent non-destructive testing can be employed to monitor the bonding quality between the joining partners steel and aluminum and to characterize the age hardening condition of the aluminum component, ultrasonic testing and electrical conductivity measurements were applied. It was found that a lateral angular co-extrusion process can create homogeneous bonding although the electrical conductivity of the aluminum is altered during processing. A previous bonding before the subsequent die forging process leads to a sufficient bonding in areas with little deformation and is therefore, advantageous compared to unjoined semi-finished products, which do not form a bonding if the deformation ratio is too small. An influence of the subsequent heat treatment on the bonding is not visible in the ultrasonic testing signals though a homogenized electrical conductivity can be detected, which indicates uniform artificial aging conditions of the aluminum allo

Comprehensive analysis of beta-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/beta-catenin signaling

Background: Deregulation of Wnt/beta-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein beta-catenin. beta-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by beta-catenin in colorectal cancer cell lines, we analyzed beta-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to beta-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database. Results: Treatment of DLD1 and SW480 cells with beta-catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published beta-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed beta-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway - the steroid biosynthesis pathway - was regulated in all three cell lines. Conclusions: Based on the large number of potential beta-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed beta-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/beta-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential beta-catenin target genes are useful starting points for further studies

Photophysics, Molecular Reorientation in Solution and X-Ray Structure of a New Fluorescent Probe 1,7-Diazaperylene

A new fluorescent molecule 1,7-diazaperylene (DP) has been investigated by means of time-resolved and steady-state polarized fluorescence spectroscopy, as well as X-ray spectroscopy. Absorption and fluorescence spectra of DP in solution are similar to those of perylene. However, absorption and fluorescence spectra of 2,8-dimethoxy DP and 2,8-dipentyloxy DP in solution are red-shifted by ca. 55 nm relative to perylene. The fluorescence decay of DP is exponential with a lifetime of 5.1 ns in ethanol, 4.9 ns in glycerol and 4.3 ns in paraffin oil. The radiative lifetime in ethanol was calculated to be 6.3 ns for DP, 8.0 ns for 2,8-dimethoxy DP and 7.6 ns for 2,8-dipentyloxy DP. The calculated fluorescence quantum yields of 0.8 for DP and its alkoxy derivatives in ethanol, are in good agreement with those obtained from measurements. The calculated Förster radius is 37.2 ± 1 Å for DP and 41.9 ± 1 Å for its alkoxy derivatives in ethanol. Examining the S0 S1 transition, we obtain a limiting fluorescence anisotropy of r0 0.38 for DP and its alkoxy derivatives. The rotational rates of DP in paraffin oil and glycerol were compared to that of perylene. In paraffin oil both molecules show an almost identical biexponential decay of the fluorescence anisotropy, which is compatible with a rotational motion like an oblate ellipsoid. The fluorescence anisotropy is monoexponential for DP in glycerol, and DP appears to rotate like a spherical particle while perylene in glycerol appears to rotate like an oblate ellipsoid. Moreover, the rotational diffusion constant, corresponding to rotation about an axis in the aromatic plane (D), is the same for both DP and perylene in glycerol

Limited Effect of Dopaminergic Medication on Straight Walking and Turning in Early-to-Moderate Parkinson’s Disease during Single and Dual Tasking

Background: In Parkinson’s disease (PD), the effects of dopaminergic medication on straight walking and turning were mainly investigated under single tasking (ST) conditions. However, multitasking situations are considered more daily relevant.Methods: Thirty-nine early to moderate PD patients performed the following standarized ST and dual tasks (DT) as fast as possible for one minute during On- and Off-medication while wearing inertial sensors: straight walking and turning, checking boxes, and subtracting serial 7s. Quantitative gait parameters, as well as velocity of the secondary tasks were analyzed.Results: The following parameters improved significantly in On-medication during ST: gait velocity during straight walking (p=0.03); step duration (p=0.048) and peak velocity (p=0.04) during turning; velocity of checking boxes during ST (p=0.04) and DT (p=0.04). Velocity of checking boxes was the only parameter that also improved during DT.Conclusion: These results suggest that dopaminergic medication does not relevantly influence straight walking and turning in early to moderate PD during DT

The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Raw data have been deposited in the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE54810. Funding: This work was supported in part by grants to EMB from the MRC (G0501164) and BBSRC (BB/G009619/1), to EMB and NDR from the Wellcome Trust (WT093596MA), to MB from Imperial College London (Division of Investigative Sciences PhD Studentship), to HH from the ERA-NET PathoGenoMics project TRANSPAT, Austrian Science Foundation (FWF I282-B09), to SGF from the National Institutes of Health, USA (R01AI073829). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients

Uromodulin, released from tubular cells of the ascending limb into the blood, may be associated with kidney function. This work studies the relevance of plasma uromodulin as a biomarker for kidney function in an observational cohort of chronic kidney disease (CKD) patients and subjects without CKD (CKD stage 0). It should be further evaluated if uromodulin allows the identification of early CKD stages. Plasma uromodulin, serumcreatinine, cystatin C, blood-urea-nitrogen (BUN) concentrations, and estimated glomerular filtration rate (eGFR CKD-EPIcrea-cystatin) were assessed in 426 individuals of whom 71 were CKD stage 0 and 355 had CKD. Besides descriptive statistics, univariate correlations between uromodulin and biomarkers/eGFR were calculated using Pearson-correlation coefficient. Multiple linear regression modeling was applied to establish the association between uromodulin and eGFR adjusted for demographic parameters and pharmacologic treatment. Receiver-operating-characteristic (ROC) analysis adjusted for demographic parameters was performed to test if uromodulin allows differentiation of subjects with CKD stage 0 and CKD stage I. Mean uromodulin plasma levels were 85.7 +/- 60.5 ng/mL for all CKD stages combined. Uromodulin was correlated with all biomarkers/eGFR in univariate analysis (eGFR: r = 0.80, creatinine: r = +/- 0.76, BUN: r = +/- 0.72, and cystatin C: r = +/- 0.79). Multiple linear regression modeling showed significant association between uromodulin and eGFR (coefficient estimate beta = 0.696, 95% confidence interval [CI] 0.603-0.719, P<0.001). In ROC analysis uromodulin was the only parameter that significantly improved a model containing demographic parameters to differentiate between CKD 0 degrees and I degrees (area under the curve [AUC] 0.831, 95% CI 0.746-0.915, P = 0.008) compared to creatinine, cystatin C, BUN, and eGFR (AUC for creatinine: 0.722, P = 0.056, cystatin C: 0.668, P = 0.418, BUN: 0.653, P = 0.811, and eGFR: 0.634, P = 0.823). Plasma uromodulin serves as a robust biomarker for kidney function and uniquely allows the identification of early stages of CKD. As a marker of tubular secretion it might represent remaining nephron mass and therefore intrinsic "kidney function'' rather than just glomerular filtration, the latter only being of limited value to represent kidney function as a whole. It therefore gives substantial information on the renal situation in addition to glomerular filtration and potentially solves the problem of creatinine-blind range of CKD, in which kidney impairment often remains undetected

Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients

Uromodulin, released from tubular cells of the ascending limb into the blood, may be associated with kidney function. This work studies the relevance of plasma uromodulin as a biomarker for kidney function in an observational cohort of chronic kidney disease (CKD) patients and subjects without CKD (CKD stage 0). It should be further evaluated if uromodulin allows the identification of early CKD stages. Plasma uromodulin, serumcreatinine, cystatin C, blood-urea-nitrogen (BUN) concentrations, and estimated glomerular filtration rate (eGFR CKD-EPIcrea-cystatin) were assessed in 426 individuals of whom 71 were CKD stage 0 and 355 had CKD. Besides descriptive statistics, univariate correlations between uromodulin and biomarkers/eGFR were calculated using Pearson-correlation coefficient. Multiple linear regression modeling was applied to establish the association between uromodulin and eGFR adjusted for demographic parameters and pharmacologic treatment. Receiver-operating-characteristic (ROC) analysis adjusted for demographic parameters was performed to test if uromodulin allows differentiation of subjects with CKD stage 0 and CKD stage I. Mean uromodulin plasma levels were 85.7 +/- 60.5 ng/mL for all CKD stages combined. Uromodulin was correlated with all biomarkers/eGFR in univariate analysis (eGFR: r = 0.80, creatinine: r = +/- 0.76, BUN: r = +/- 0.72, and cystatin C: r = +/- 0.79). Multiple linear regression modeling showed significant association between uromodulin and eGFR (coefficient estimate beta = 0.696, 95% confidence interval [CI] 0.603-0.719, P<0.001). In ROC analysis uromodulin was the only parameter that significantly improved a model containing demographic parameters to differentiate between CKD 0 degrees and I degrees (area under the curve [AUC] 0.831, 95% CI 0.746-0.915, P = 0.008) compared to creatinine, cystatin C, BUN, and eGFR (AUC for creatinine: 0.722, P = 0.056, cystatin C: 0.668, P = 0.418, BUN: 0.653, P = 0.811, and eGFR: 0.634, P = 0.823). Plasma uromodulin serves as a robust biomarker for kidney function and uniquely allows the identification of early stages of CKD. As a marker of tubular secretion it might represent remaining nephron mass and therefore intrinsic "kidney function'' rather than just glomerular filtration, the latter only being of limited value to represent kidney function as a whole. It therefore gives substantial information on the renal situation in addition to glomerular filtration and potentially solves the problem of creatinine-blind range of CKD, in which kidney impairment often remains undetected