Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth

Growth hormone (GH)-transgenic mice with permanently elevated systemic levels of GH and insulin-like growth factor 1 (IGF1) reproducibly develop renal and glomerular hypertrophy and subsequent progressive glomerulosclerosis, finally leading to terminal renal failure. To dissociate IGF1-dependent and -independent effects of GH excess on renal growth and lesion development in vivo, the kidneys of 75 days old IGF1-deficient (I-/-) and of IGF1-deficient GH-transgenic mice (I-/-/G), as well as of GH-transgenic (G) and nontransgenic wild-type control mice (I+/+) were examined by quantitative stereological and functional analyses. Both G and I-/-/G mice developed glomerular hypertrophy, hyperplasia of glomerular mesangial and endothelial cells, podocyte hypertrophy and foot process effacement, albuminuria, and glomerulosclerosis. However, I-/-/G mice exhibited less severe glomerular alterations, as compared to G mice. Compared to I+/+ mice, G mice exhibited renal hypertrophy with a significant increase in the number without a change in the size of proximal tubular epithelial (PTE) cells. In contrast, I-/-/G mice did not display significant PTE cell hyperplasia, as compared to I-/- mice. These findings indicate that GH excess stimulates glomerular growth and induces lesions progressing to glomerulosclerosis in the absence of IGF1. In contrast, IGF1 represents an important mediator of GH-dependent proximal tubular growth in GH-transgenic mice

Trends in Tanning Bed Use, Motivation, and Risk Awareness in Germany: Findings from Four Waves of the National Cancer Aid Monitoring (NCAM)

Indoor tanning is an important risk factor for the development of melanoma and non-melanoma skin cancer. With our nationally representative monitoring, we aimed at describing tanning bed use, user characteristics, reasons for use, and risk awareness over time. In the framework of the National Cancer Aid Monitoring (NCAM), we collected representative data on 12,000 individuals aged 14 to 45 years in annual waves of n = 3,000 participants in Germany between 2015 and 2018. We used descriptive statistics and chi²-tests to uncover group differences. To compare data from the different waves, we calculated confidence intervals. The use of tanning beds decreased from 2015 (11.0%, 95%-CI: 9.9%-12.1%) to 2018 (8.8%, 95%-CI: 7.8%-9.8%). However, this decrease did not affect all subgroups. For instance, there was an (non-significant) increase in minors and the prevalence remained stable for individuals with immigrant background and males. Attractiveness was an important reason for tanning bed use in each wave. Over time, there was an increase in medical-related reasons for use. Furthermore, monitoring showed a decrease in risk awareness regarding tanning bed use and ultraviolet (UV) radiation. While it is a positive development that the overall use of tanning beds in Germany has decreased over time, the increasing use by minors despite the legal ban is alarming. Due to the declining risk awareness it is necessary to implement prevention and education campaigns specifically targeted at this group

Determination of loads and boundary conditions causing deformations of concentrating solar mirrors using non-derivative optimization methods and finite element analysis

Mirror shape optimization is a major part of improving the performance of concentrating solar power (CSP) collectors. Loads and boundary conditions of different origin and with varying influence on shape deviation need to be understood and quantified, e.g., in order to give specifications for the design of new collector generations. Finite element analysis (FEA) has proven to be a suitable method for evaluating mirror shape. An optimization process is presented that utilizes finite element models (FEM) of mirrors and a subsequent evaluation of the slope deviation to approximate a reference, e.g., a measured mirror shape, and determine the load values causing the mirror panel to deform. In this paper, the suggested approach is proven to be feasible: Two optimization algorithms are implemented: BOBYQA and CMA-ES. A simulated reference created in ANSYS Workbench and a reference from a deflectometry measurement are investigated. The determined geometrical parameters are compared to the reference values. For BOBYQA an absolute minimum and maximum deviation of 0.02 % and 0.3 %, and for CMA-ES of 0.0001 % and 0.004 % relative to the reference values is found. With the measured mirror shape as reference, the optimization algorithm was again capable of reproducing the mirror shape in FEA. However, the geometrical load parameters found were only partially in agreement with the measured values. Yet, it is concluded that the proposed method for reproducing mirror shape works

Transplantation of selected or transgenic blood stem cells – a future treatment for HIV/AIDS?

Interaction with the chemokine receptor, CCR5, is a necessary precondition for maintaining HIV-1 infection. Individuals with the CCR5-delta32 deletion who lack this receptor are highly resistant to infection by the most common forms of HIV-1. We recently reported on the successful transplantation in an HIV-1-positive patient of allogeneic stem cells homozygous for the CCR5-delta32 allele, which stopped viral replication for more than 27 months without antiretroviral therapy

Electrical Bearing Damage, A Problem in the Nano- and Macro-Range

Rolling bearings face different damaging effects: Besides mechanical effects, current-induced bearing damage occurs in electrical drive systems. Therefore, it is of increasing interest to understand the differences leading to known electrical damage patterns. It is of utmost importance not to consider the harmful current passage in the machine element as an isolated phenomenon but to take into account the whole drive system consisting of the machine elements, the electric motor and the connected power electronics. This publication works toward providing an overview of the state-of-the-art of research regarding electrical bearing currents

What can go wrong will go wrong: Birthday effects and early tracking in the German school system

At the age of ten German pupils are given a secondary school track recommendation which largely determines the actual track choice. Track choice has major effects on the life course, mainly through labor market outcomes. Using data from the German PISA extension study, we analyze the effect of month of birth and thus relative age on such recommendations. We find that younger pupils are less often recommended to and actually attend Gymnasium, the most attractive track in terms of later life outcomes. Flexible enrolment and grade retention partly offset these inequalities and the relative age effect dissipates as students age

Electrical Bearing Damage, A Problem in the Nano- and Macro-Range

Rolling bearings face different damaging effects: Besides mechanical effects, current-induced bearing damage occurs in electrical drive systems. Therefore, it is of increasing interest to understand the differences leading to known electrical damage patterns. It is of utmost importance not to consider the harmful current passage in the machine element as an isolated phenomenon but to take into account the whole drive system consisting of the machine elements, the electric motor and the connected power electronics. This publication works toward providing an overview of the state-of-the-art of research regarding electrical bearing currents

The release and trans-synaptic transmission of Tau via exosomes

BACKGROUND Tau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages ("Braak stages"). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes. METHODS Exosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau. RESULTS We show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans-neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells. CONCLUSION Our study demonstrates that exosomes contribute to trans-synaptic Tau transmission, and thus offer new approches to control the spreading of pathology in AD and other tauopathies

Bioassays to Monitor Taspase1 Function for the Identification of Pharmacogenetic Inhibitors

Background: Threonine Aspartase 1 (Taspase1) mediates cleavage of the mixed lineage leukemia (MLL) protein and leukemia provoking MLL-fusions. In contrast to other proteases, the understanding of Taspase1's (patho)biological relevance and function is limited, since neither small molecule inhibitors nor cell based functional assays for Taspase1 are currently available. Methodology/Findings: Efficient cell-based assays to probe Taspase1 function in vivo are presented here. These are composed of glutathione S-transferase, autofluorescent protein variants, Taspase1 cleavage sites and rational combinations of nuclear import and export signals. The biosensors localize predominantly to the cytoplasm, whereas expression of biologically active Taspase1 but not of inactive Taspase1 mutants or of the protease Caspase3 triggers their proteolytic cleavage and nuclear accumulation. Compared to in vitro assays using recombinant components the in vivo assay was highly efficient. Employing an optimized nuclear translocation algorithm, the triple-color assay could be adapted to a high-throughput microscopy platform (Z'factor = 0.63). Automated high-content data analysis was used to screen a focused compound library, selected by an in silico pharmacophor screening approach, as well as a collection of fungal extracts. Screening identified two compounds, N-[2-[(4-amino-6-oxo-3H-pyrimidin-2-yl)sulfanyl]ethyl]benzenesulfonamideand 2-benzyltriazole-4,5-dicarboxylic acid, which partially inhibited Taspase1 cleavage in living cells. Additionally, the assay was exploited to probe endogenous Taspase1 in solid tumor cell models and to identify an improved consensus sequence for efficient Taspase1 cleavage. This allowed the in silico identification of novel putative Taspase1 targets. Those include the FERM Domain-Containing Protein 4B, the Tyrosine-Protein Phosphatase Zeta, and DNA Polymerase Zeta. Cleavage site recognition and proteolytic processing of these substrates were verified in the context of the biosensor. Conclusions: The assay not only allows to genetically probe Taspase1 structure function in vivo, but is also applicable for high-content screening to identify Taspase1 inhibitors. Such tools will provide novel insights into Taspase1's function and its potential therapeutic relevance