News von Jogl Brunner - Facebook und Presse. Jogl Brunner, Murau. Gefällt Mal · 4 Personen sprechen darüber. Alle News von Jogl Brunner und seiner Musik! Warum sein bereits fertig produziertes zweites Solo-Album erst im März nächsten Jahres auf den Markt kommt, erzählt Jogl Brunner seinen Fans persönlich.
Jogl BrunnerWarum sein bereits fertig produziertes zweites Solo-Album erst im März nächsten Jahres auf den Markt kommt, erzählt Jogl Brunner seinen Fans persönlich. kam dann die endgültige Bekanntgabe: Es ist aus mit dem Brüder-Duo. Heute hat Jogl Brunner Geburtstag und hat sein Glück längst solo. Jogl Brunner, Murau. Gefällt Mal · 4 Personen sprechen darüber. Alle News von Jogl Brunner und seiner Musik!
Jockel Brunner Todas as soluções em tecnologia que a sua empresa precisa VideoNur einen Blick - der Teaser zur Single Compre os livros de Brunner, no maior acervo de livros do Brasil. Encontre aqui obras novas, exemplares usados e seminovos pelos melhores preços. Resenha do livro A teoria de Ensino de Bruner. Esta resenha refere-se ao capítulo 05, constante da obra Teorias de Aprendizagem, intitulado A Teoria de Ensino de Bruner, organizada pelo professor Marco Antônio Moreira, publicada em , em São Paulo (SP), pela Editora Pedagógica e Universitária.. O referido livro texto, em seu capítulo 05 aborda a teoria de . A bíblia da Enfermagem em sua melhor ediçãoBrunner & Suddarth | Tratado de Enfermagem Médico-Cirúrgica, a obra mais conhecida e respeitada na área da arte de cuidar, foi totalmente reformulada, bastante atualizada e levada a um nível de aprimoramento jamais alcançado.O mais notável aperfeiçoamento se deu no aspecto visual: pela primeira vez, esse verdadeiro ícone . UllandT. With the exception of phosphorylated STAT6, data were Hochmoselübergang Eröffnung by two-way ANOVA; significant main effects of IL-4 treatment and Trem2 -knockdown indicated by horizontal and vertical lines respectively, no significant interactions were seen between IL-4 treatment and Trem2 knockdown. LoveM. Jeckeln in Soviet custody. Pablo Garcia-Reitboeck. Google Scholar PubMed. The co-expression analysis resulted in genetic modules correlating with the Trem2 R47H KI genotype or IL-4 treatment Supplementary Material, Fig. However anti-inflammatory signaling was not studied. A and B Total and phosphorylated STAT6 protein levels in primary microglia treated with IL-4 and Trem2 siRNA were analyzed with western blot. However, considering the Jockel Brunner expression of Trem2 under pro-inflammatory conditions, it is not surprising that further reducing Trem2 had little additional effect.
As a matter of fact, the Opel community is one big family, with the emphasis on family. The tent lawn for families is as full as all other camping spots every year.
It only took Sebastina Linner from Bad Lauterberg in Lower Saxony a little more than one and a half hours to get to Oschersleben. He presented his 5.
Mileage: just 68, kilometers. He searched for exactly this car for ten years. Then a few months ago everything finally came together: enough money and the perfect offer at the same time.
Sebastian Linner paid 5, euros for the car and then put 2, euros more and endless hours into its restoration.
Only the sunroof in still in old, unusable condition. Will he be here next year? A close community: the group around Marcel Lehmann from Brandenburg, a dedicated community of fans from Germany and Switzerland.
As expected, considering so little Trem2 remained under these conditions, knockdown of Trem2 by siRNA had little effect on LPS-induced gene expression with up-regulation of Tnf or Il1b being unchanged at the transcriptional level with Trem2 knockdown compared with control cultures Supplementary Material , Fig.
Consistent with the transcriptional results, the protein level of TNF-alpha released from the microglial cells showed that LPS strongly up-regulated TNF-alpha, but there was no significant change caused by Trem2 knockdown Supplementary Material , Fig.
Similar results were seen in microglia from the homozygous Trem2 R47H KI mice with no substantial change to Tnf expression but a decrease in Il1b expression Supplementary Material, Fig.
We next investigated the effects of this pro-inflammatory treatment on a variety of genes Supplementary Material, Figs S6 — S8. In general, the LPS-dependent effects on gene expression studied here were apparently independent of Trem2 expression whether knocked-down by siRNA or using the Trem2 R47H KI microglia.
The gene expression profiles were similar whether we normalized to the ubiquitous reference gene Rps28 or three housekeeping genes Supplementary Material, Fig.
S8 , accordingly all reference genes were stable between genotypes under the conditions tested Supplementary Material, Figs S9 and S However, considering the decreased expression of Trem2 under pro-inflammatory conditions, it is not surprising that further reducing Trem2 had little additional effect.
Next we studied the effect of acute Trem2 knockdown on the alternative anti-inflammatory activation of microglia in response to IL-4 treatment.
We first found that microglial Trem2 expression upon IL-4 treatment was maintained at a similar level to that under basal conditions Figs 4A and 5A.
We next investigated two anti-inflammatory markers Arg1 and Tgfb1 Fig. The Tgfb1 expression also showed an increase with IL-4 stimulation, however, in contrast to Arg1 the effect of Trem2 knockdown and IL-4 showed no interaction.
Our findings were similar in the microglia from the Trem2 R47H KI mice, with Arg1 showing a strong induction by IL-4 treatment and the down-regulation of Trem2 in the microglia from Trem2 R47H KI mice significantly preventing this change in a gene dose-dependent manner Fig.
The other anti-inflammatory marker Tgfb1 was significantly decreased in homozygous Trem2 R47H microglia independent of ILtreatment, and the fold-change in Tgfb1 up-regulation in response to treatment was similar for WT and homozygous Trem2 R47H cells Fig.
These findings suggest that separate mechanisms regulate basal levels of some genes like Tgfb1 which may be Trem2 -dependent at least in part , compared with mechanisms that regulate levels following induction which can be Trem2 -independent.
Trem2 knockdown impairs the ILinduced anti-inflammatory response of primary microglia. A Trem2 gene expression was not significantly influenced by IL-4 stimulation.
B Arg1 and Tgfb1 expression, as markers of the anti-inflammatory response, showed significant up-regulation with time after IL-4 application. Particularly, Trem2 knockdown greatly decreased ILinduced Arg1 expression compared with negative controls.
Gene expression levels were normalized to Rps28 and calculated as fold change relative to the negative control without IL-4 treatment in each individual culture preparation, except for Arg1.
Two-way ANOVA with significant main effect of IL-4 incubation time and Trem2 knockdown indicated as horizontal and vertical lines respectively.
C Expression of the pro-inflammatory genes Tnf and Il1b and other microglial genes. Gene expression levels were normalized to Rps28 and calculated as fold change relative to the negative control without IL-4 treatment in each individual culture preparation.
Primary microglia from Trem2 R47H KI mice show decreased Trem2 expression, and an impaired ILinduced anti-inflammatory response.
A Expression of Trem2. B Expression of anti-inflammatory markers, Arg1 and Tgf1b. C Expression of other microglial genes. Gene expression was normalized to Rps28 and calculated as fold change relative to the WT control without IL-4 treatment.
Two-way ANOVA for all genes except Arg1. Significant main effect of ILtreatment and genotype indicated as horizontal and vertical lines respectively, no significant interactions were seen between ILtreatment and Trem2 knockdown.
We went on to compare the effect of the anti-inflammatory stimulus on the gene expression levels of a variety of genes Fig. Expression of C1qa , Cd68 and Igf1 were all found to be significantly up-regulated with IL-4 treatment, which is similar to what we saw in transgenic mice in correlation with amyloid plaque load 43 , 44 www.
Expression of Csf1r , Spi1 , Aif1 and Plcg2 were unaffected by IL-4 treatment. Interestingly, the expression of all of these genes was significantly lower in cells with acute Trem2 knockdown, and was not dependent on IL-4 stimulation no significant interaction of knockdown versus IL Similarly to the Trem2 knockdown experiments, genes for which expression was increased in response to IL-4, such as Igf1, Cd68 and C1qa, also showed decreased expression in the homozygous Trem2 R47H microglia, regardless of ILtreatment Fig.
Collectively, these data suggest that the effect of TREM2 on the microglial gene expression profile pushes microglia towards an anti-inflammatory phenotype.
TREM2 promotes an anti-inflammatory response via two mechanisms: i an IL-4 independent mechanism supporting the expression of common genes, such as Igf1 , Cd68 and C1qa , which are induced by IL-4 in control cells and suppressed by Trem2 reduction, but there is lack of interaction between the effects of Trem2 and IL-4 on these genes, and so here TREM2 and IL-4 likely act via independent parallel pathways to converge onto similar endpoints; ii an ILdependent mechanism where the gene expression response to IL-4 depends on TREM2, genes such as Arg1 , where there is a significant interaction between the effects of Trem2 and IL Interestingly, the effects of IL-4 stimulation on gene expression mimic the changes seen in association with plaque development in transgenic mice 44 , where Trem2 levels are also strongly increased, whereas the pro-inflammatory effects of LPS have the opposite effect.
To discover novel gene expression profiles regulated by TREM2 and IL-4, we performed RNA-seq using cultured primary microglia from homozygous Trem2 R47H KI mice versus WT littermates under basal conditions and in response to IL-4 treatment.
As a means of validation of the RNA-seq data, the expression profile of all the test and reference genes assayed by RT-qPCR above were similar to the gene expression obtained by RNA-seq under basal conditions and in response to IL-4 Supplementary Material, Figs S10 and S11 , compare with Figs 4 and 5.
The genes differentially expressed in response to reduced Trem2 expression in the Trem2 R47H KI microglia showed a significant overlap with a network of genes expressed by amyloid-responsive microglia from bulk RNA-seq analysis of mouse hippocampus, which showed up to a 9.
More specifically, the genes down-regulated in cells carrying the Trem2 R47H KI alleles were associated with microglial activation, suggesting down-regulation of genes with reduced Trem2 expression may dampen some states of microglial activation Supplementary Material, Fig.
Whereas genes up-regulated in cells carrying the Trem2 R47H KI alleles were involved in cytoskeletal and actin processes Supplementary Material, Fig.
S12 , driving the majority of the changes seen with reduced Trem2 expression. Gene expression profile in primary microglia from Trem2 R47H KI and WT mice with IL-4 treatment by RNA-seq.
In addition, the genes responding to IL-4 treatment of the microglia were significantly enriched for biological annotations associated with immune cell activation and cytokine secretion Fig.
Specifically, the genes up-regulated by IL-4 showed enrichment of annotations associated with tyrosine phosphorylation indicating changes in cytokine and neuropeptide signaling Supplementary Material, Fig.
The genes down-regulated by IL-4 were involved in annotations associated with immune cell migration and activation Supplementary Material, Fig.
To investigate further the response of the microglia to reduced Trem2 expression and IL-4 treatment, we performed weighted gene co-expression network analyses WGCNA 46 , with an optimization for constructing more biologically meaningful co-expression networks The co-expression analysis resulted in genetic modules correlating with the Trem2 R47H KI genotype or IL-4 treatment Supplementary Material, Fig.
S13 , with associated biological annotations given in Supplementary Material, Table S5. Hub genes are those with the highest connectivity within a co-expression network, and are postulated to drive the response of the entire network.
The hub genes in the genetic network associated with Trem2 status were Nckap1l NCK associated protein 1 like , Cd53 leukocyte surface antigen 53 , Adam8 a disintegrin and metallopeptidase domain 8 and Fxyd5 FXYD domain-containing ion transport regulator 5.
The genetic network associated with IL-4 treatment was significantly enriched for biological annotations associated with vesicular and endosomal functions Supplementary Material, Fig.
We found genetic networks associated with decreased Trem2 expression and with IL-4 treatment Supplementary Material, Fig.
S13 ; Supplementary Material, Table S5 ; both manipulations displayed strong effects on gene expression. While there was an overlap of genotype and IL-4 affecting common genes such as Arg1 , we also saw that Trem2 and IL-4 had independent effects.
Thus, the strong drive of Trem2 R47H KI genotype and IL-4 meant there was no module that was significant for both genotype and IL-4 treatment.
Co-expression genetic networks associated with Trem2 expression and ILtreatment. A Co-expression network associated with Trem2 expression, using RNA-seq derived gene expression from primary microglia of Trem2 R47H KI and WT mice.
B Co-expression network associated with ILtreatment, using RNA-seq derived gene expression from primary microglia treated with IL-4 and untreated.
Network includes key genes involved in anti-inflammatory processes, such Arg1 , Retnla and Chil3. S15 ; Supplementary Material, Table S6.
This gene signature showing the strongest connectivity to Arg1 Supplementary Material, Table S6 , was enriched for biological annotations associated with vesicle function.
Thus, it suggests the release of cytokines or the response to cytokines in microglial activation and remodeling of the cytoskeleton associated with anti-inflammatory function was influenced by these genes which are induced by IL-4 and dependent on Trem2 Supplementary Material, Figs S14 and S To understand how this signature of genes associated with Arg1 was regulated, we mined for transcription factor recognition elements in the promoters of genes correlating with Arg1 expression using i- cis Target This suggests that TREM2 and IL-4 regulate an overlapping signature of genes that are controlled by transcription factors including STAT6 and SPI1.
Cluster of genes showing the highest connectivity to Arg1 from the genetic network associated with IL Selection of genes presented with expression tested by two-way ANOVA, all genes showing a significant main effect of ILtreatment and genotype, and a significant interaction.
The expression of these genes is represented in primary microglia from HO- Trem2 R47H KI versus WT mice treated with IL-4 or untreated.
Colors represent the z -score of the expression level for each gene red is high expression and blue is low expression. As up-regulation of genes such as Arg1 and Ap1b1 caused by IL-4 stimulation interacted with and was largely suppressed by reduced Trem2 expression, we next investigated whether there was an intersection between the IL-4 and TREM2 pathways.
We found an enrichment of STAT6 transcription factor recognition elements in the promoters of genes behaving like Arg1 and regulated by IL-4, and previous studies have shown that phosphorylation of STAT6 is a key step downstream in the IL-4 cascade that leads to Arg1 expression 49— We thus performed western blotting to test whether total or phosphorylated levels of STAT6 were changed in primary microglia with acute Trem2 knockdown with or without IL-4 stimulation Fig.
Trem2 knockdown also decreased the total levels of phosphorylated STAT6 but this could be explained by a decrease in the overall levels of STAT6 rather than an effect on phosphorylation per se.
The expression level of the Stat6 gene was also decreased with reduced Trem2 expression Fig. These results suggest that TREM2 deficiency leads to a smaller STAT6 pool in microglia, resulting in decreased amount of phosphorylated STAT6 upon IL-4 stimulation.
This is consistent with the decrease in ILinduced Arg1 and Ap1b1 expression caused by reduced STAT6-dependent microglial gene transcription in response to decreased Trem2 expression.
Trem2 knockdown resulted in significantly decreased total STAT6 levels and AKT phosphorylation in primary microglia in vitro. A and B Total and phosphorylated STAT6 protein levels in primary microglia treated with IL-4 and Trem2 siRNA were analyzed with western blot.
D and E Total and phosphorylated at Thr and Ser AKT protein levels analyzed by western blot. Protein levels were normalized to beta-actin and gene expression was normalized to Rps Fold change was calculated relative to the negative control without IL-4 treatment in each individual culture preparation.
Note that phosphorylated STAT6 was not detectable under control conditions and so under IL-4 conditions the effect of Trem2 knockdown was calculated as fold change relative to control cells.
With the exception of phosphorylated STAT6, data were analyzed by two-way ANOVA; significant main effects of IL-4 treatment and Trem2 -knockdown indicated by horizontal and vertical lines respectively, no significant interactions were seen between IL-4 treatment and Trem2 knockdown.
Phosphorylated STAT6 was analyzed by a one-sample t -test. Different from the decrease of total STAT6 protein levels, the total AKT protein level was not significantly affected by Trem2 knockdown, although there was a slight increase in AKT levels in response to IL-4 treatment.
This is not surprising considering that PI3K-AKT signaling is downstream of TREM2, but the unchanged total AKT level with knockdown suggests that the STAT6 change is not due to general changes in the health and metabolic status of microglia in our cultures.
Of the many genes that have been revealed in GWAS to increase the risk of AD, variants of TREM2 have high odds ratios. The most common of these is the R47H mutation.
We thus aimed to investigate the effect of this mutation in Trem2 R47H KI mice. However in the present study, we find that the primary phenotype of these mice both in primary microglial cultures and in brain tissue, is a substantial gene-dose-dependent decrease in the expression of Trem2 compared with WT mice.
This does not occur in human tissue with this mutation but appears to be a mouse specific effect related to altered splicing. Hence, we can largely consider these mice as a model of Trem2 down-regulation, validated by our siRNA data in primary microglia.
By investigating microglial density in fixed brains from the Trem2 R47H mice, we saw a decrease in the density of microglia in vivo in the hippocampus, and that the remaining microglia had dramatically reduced CD68 protein levels.
This raises the question as to whether any changes that we found in Trem2 R47H microglia are directly due to the mutation itself or downstream of its effect on decreasing Trem2 expression, and so we studied in parallel the effect of Trem2 knockdown using siRNA in primary microglia and compared this with the Trem2 R47H KI microglia phenotype.
Knockdown of Trem2 in the primary microglia transfected with siRNA showed similar effects to those seen in microglia from the Trem2 R47H KI mice.
In both preparations Csf1r expression was decreased. Pharmacological blockade of CSF1 receptors has been shown to impair microglial survival and can completely remove microglia from the mouse brain 53— These findings together with the decreased density of microglia in the hippocampus of Trem2 R47H mice and increased apoptosis of the microglia cultured from these mice, suggests that the decrease in Csf1r expression in the microglia with decreased Trem2 expression may contribute to the survival of microglia.
The knockdown of Trem2 decreasing survival and altering the metabolism of microglia is consistent with previous studies 35 , 38—40 , 56 , Interestingly no difference in Csf1r expression was seen in the remaining microglia in the brain tissue from the young adult Trem2 R47H KI mice, possibly suggesting different populations of microglia, with loss of those more vulnerable to the effects of Trem2 knockdown than others, at least in whole tissue.
Differences in gene expression profiles of different microglial populations have been recently described using single cell RNA-seq showing some microglial populations are selectively dependent on Trem2 58— Igf1 expression was also decreased when Trem2 expression was knocked-down or if the Trem2 R47H variant was carried by the primary microglial cultures.
Igf1 is abundantly expressed by microglia during postnatal development, aging or following brain injuries and plays a vital role in promoting neuronal survival 59 , 63— While this may not affect microglial survival as the IGF1 receptor is found largely on neurons, it could contribute to neurodegeneration, being an important factor in neuronal survival and lifespan across many species Our findings, in line with previous studies 59 , 68—71 , show that Igf1 expression is inhibited by pro-inflammatory stimuli and enhanced in anti-inflammatory environments.
Thus, the Igf1 expression decrease caused by Trem2 deficiency may suggest a microglial phenotype shift towards pro-inflammatory activation and away from non-inflammatory, and a decrease of the pro-survival role of IGF1 on neurons.
In this study, we have further investigated the role of TREM2 and effects on Trem2 expression in microglia polarized to anti-inflammatory or pro-inflammatory phenotypes.
Anti-inflammatory processes are associated with tissue repair, such as those mediated by IL-4, working through microglia and macrophages, and have been shown to provide benefits in models representing the early stages of neurodegenerative conditions, such as AD and amyotrophic lateral sclerosis, and other disorders related to cell death 45 , 72 , Our results suggest that there is cross-talk between the TREM2 and anti-inflammatory IL-4 signaling pathways, in that TREM2 knockdown decreases levels of the STAT6 transcription factor, which is downstream of IL-4 As the ILinduced up-regulation of a number of genes including Arg1 is critically dependent on phosphorylation of STAT6 75 , this suggests that TREM2 signaling functions in parallel to support ILinduced STAT6-gene transcription by supporting overall levels of STAT6.
Decreased Trem2 expression in both primary microglia models resulted in impaired induction of a program of anti-inflammatory genes induced by IL-4, including genes such as Arg1 , Ap1b1 and Dusp4.
ARG1 is an important anti-inflammatory marker induced upon IL-4 stimulation. ARG1 in myeloid cells mainly functions as an enzyme to hydrolyze arginine to produce ornithine as part of the urea cycle, which both promotes tissue repair through generation of polyamines and collagens, and also reduces nitric oxide production from inducible nitric oxide synthase through decreasing intracellular arginine availability 76— Other genes induced by IL-4 included Ap1bp1 , Dusp4 and Itgax.
AP1B1 is part of the clathrin-associated adaptor protein complex AP-1 and is involved in endocytosis and intracellular trafficking DUSP4 is a phosphatase for a number of mitogen-activated protein kinase MAPK family members, also known as MAPK phosphatase 2 MKP DUSP4 has not been studied well in microglia, but Dusp4 null mice show impaired T cell activation Erich Friderici Ludwig Kübler Kuno-Hans von Both Franz von Roques Karl von Roques Edwin von Rothkirch Max von Schenckendorff Joachim Witthöft.
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