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Intermittent injections of parathyroid hormone (iPTH) are applied clinically to stimulate bone formation by osteoblasts, although continuous elevation of parathyroid hormone (PTH) primarily results in increased bone resorption. Here, we identifiedCalca, encoding the sepsis biomarker procalcitonin (ProCT), as a novel target gene of PTH in murine osteoblasts that inhibits osteoclast formation. During iPTH treatment, mice lacking ProCT develop increased bone resorption with excessive osteoclast formation in both the long bones and axial skeleton. Mechanistically, ProCT inhibits the expression of key mediators involved in the recruitment of macrophages, representing osteoclast precursors. Accordingly, ProCT arrests macrophage migration and causes inhibition of early but not late osteoclastogenesis. In conclusion, our results reveal a potential role of osteoblast-derived ProCT in the bone microenvironment that is required to limit bone resorption during iPTH.

Despite significant advances in surgical techniques, treatment options for impaired bone healing are still limited. Inadequate bone regeneration is not only associated with pain, prolonged immobilization and often multiple revision surgeries, but also with high socioeconomic costs, underlining the importance of a detailed understanding of the bone healing process. In this regard, we previously showed that mice lacking the calcitonin receptor (CTR) display increased bone formation mediated through the increased osteoclastic secretion of sphingosine-1-phosphate (S1P), an osteoanabolic molecule promoting osteoblast function. Although strong evidence is now available for the crucial role of osteoclast-to-osteoblast coupling in normal bone hemostasis, the relevance of this paracrine crosstalk during bone regeneration is unknown. Therefore, our study was designed to test whether increased osteoclast-to-osteoblast coupling, as observed in CTR-deficient mice, may positively affect bone repair. In a standardized femoral osteotomy model, global CTR-deficient mice displayed no alteration in radiologic callus parameters. Likewise, static histomorphometry demonstrated moderate impairment of callus microstructure and normal osseous bridging of osteotomy ends. In conclusion, bone regeneration is not accelerated in CTR-deficient mice, and contrary to its osteoanabolic action in normal bone turnover, osteoclast-to-osteoblast coupling specifically involving the CTR-S1P axis, may only be of minor relevance during bone healing.

In this chapter, we explore different discourse functions of two types of German demonstrative pronouns compared to the personal pronoun. Utilising a continuation task, we first demonstrate that personal and demonstrative pronouns refer back to different referents from previous discourse. We then show that anaphoric pronouns can also initiate a referential shift towards a previously less prominent referent in upcoming discourse, and we compare three types of pronouns in this regard. We also demonstrate that the referential shift potential is modulated by context-dependent factors. Furthermore, we present evidence that the two demonstrative pronouns differ in the duration of their discourse structuring capacity in the unfolding text.

The deep–sea sponge fauna of the NW (North–West) Pacific has been re–examined with new and previously collected specimens. In total, 555 new sponge specimens were collected in the under–explored deep Kuril Basin (Sea of Okhotsk), Bussol Strait and adjacent NW Pacific Ocean sites during the Russian–German expedition SokhoBio (Sea of Okhotsk Biodiversity Studies) in 2015. Our knowledge of Sea of Okhotsk deep–sea sponge species has nearly tripled (additional 19 spp.) as a result of this expedition, taking the total of known deep–sea species to 32 for this region. Close to half of species collected were either new to science or new to this region, and two–thirds of species were only found at one site during this study. The Sea of Okhotsk is unlikely to be a sink population, and could be considered a source population for several species due to the large numbers of individuals found. The NE Kuril Basin (Sea of Okhotsk) harboured nearly half of all sponge individuals found during this expedition, and is more species diverse than other Kuril Basin sectors, highlighting the variability in abundance and diversity found in this basin; and is also far richer than the Bussol Strait and NW Pacific sites explored. These differences are potentially due to the presence of productive currents, variable substrates, and niche differences in throughout this region. The semi–enclosed abyssal sector of the Sea of Okhotsk is partially connected with the adjacent NW Pacific abyssal plains through the Bussol and Krusenstern straits, and these straits have enabled faunal connectivity. The long–term partial isolation of the Sea of Okhotsk, low population density of deep–sea sponges, high productivity, and its unusual marine environment, could be key to understanding the exceptional levels of regional deep–sea sponge endemism and diversity.

Das Rupert Mayer Haus der Caritas steht fur eine Reihe von Einrichtungen, die im letzten Drittel des 20. Jahrhunderts im Bereich der zunachst noch kirchlichen Obdachlosenfursorge geschaffen wurden und die im Laufe der Jahrzehnte einen Prozess der fachlichen Professionalisierung und Differenzierung durchlaufen haben und auf diesem Weg zu Brennpunkten urbaner Sozialpsychiatrie geworden sind. In diesem Artikel wird speziell die Weiterentwicklung des Betreuungskonzepts fur Alkoholkranke und Wohnungslose thematisiert sowie die fachlichen Bezugnahmen (Typologie nach Lesch) und speziell die Schritte der Evaluierung (Fragebogen) dokumentiert. Paradigmatisch lasst sich in der „sozialpsychiatrischen“ Praxis die Hinwendung vom passiven Einrichtungsbewohner zum aktiven Mitarbeiter in Gesundheitsfragen mitvollziehen.

Background Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. Method Bone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies. Findings WT mice with a femoral fracture display increased CGRP serum levels. αCGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, αCGRP-deficient mice display profoundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPARγ signaling plays a central role in fracture healing. Interpretation This study demonstrates an essential role of αCGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation. Funding This work was funded by grants from the Else-Kroner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).

Here we present an approach to establish species-specific genetic markers for sex identification suitable for non-invasive samples. Such markers are not yet available for the endangered common hamster (Cricetus cricetus) because of the lack of genomic resources. Using Y chromosome conserved anchored tagged sequences (YCATS) exonic primers, we obtained Y-chromosomal sequences from hamsters and sympatric rodent species. From this, we designed hamster-specific primers targeting two short Y-chromosomal intron fragments and included them in microsatellite multiplex reactions, using autosomal loci also as amplification controls. The method yielded highly consistent results. The approach can be easily applied to development of sex markers in species for which there are no genome sequences available and thus aid conservation genetics efforts.

Sonic Hedgehog (SHH)-GLI signalling plays an important role during embryogenesis and in tumorigenesis. The survival and growth of several types of cancer depend on autonomously activated SHH-GLI signalling. A protein complex containing the ubiquitin-ligase MID1 and protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity of GLI3, a transcriptional effector molecule of SHH, in cancer cell lines with autonomously activated SHH signalling. However, the exact molecular mechanisms that mediate the interaction between MID1 and GLI3 remained unknown. Here, we show that MID1 catalyses the ubiquitination and proteasomal cleavage of the GLI3-regulator Fu. Our data suggest that Fu ubiquitination and cleavage is one of the key elements connecting the MID1/PP2A protein complex with GLI3 activity control.

Plastid RNA editing of a number of transcripts at specific sites changes genomically encoded cytidines to nucleosides, which act like uridines in RT-PCR analyses. To study plastid-editing directly at the RNA level, we established a single-strand conformational polymorphism assay for the discrimination of small RNA molecules. The electrophoretic mobility of a oligoribonucleotide resulting from a RNase T1-digested and edited plastid mRNA was shown to be identical with a control RNA molecule containing a uridine at the editing site, whereas the unedited RNA behaved like a RNA molecule containing a cytidine at the respective position.

Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments ( i ) metformin induces PP2A activity before and at lower levels than AMPK activity and ( ii ) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-α4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.

Im Zuge der Globalisierung siedeln sich immer mehr deutsche Unternehmen im Ausland an, mit dem Ziel, neue Absatzmarkte zu erschliesen. Im folgenden Beitrag wird vor diesem Hintergrand das Thema, Kultur’ aufgegriffen. Es wird die Frage diskutiert, ob die Firmenleitungen entsprechend einem Mythos eine inadaquate Vorstellung vom auslandischen Absatzmarkt haben, wenn sie ihn als eine reine Tauschbeziehung zwischen Anbieter und Nachfrager betrachten, die auf der ganzen Welt den gleichen Regeln unterliegt und somit unabhangig von kulturellen Einflussen ist. Dazu wird eine psychologische Studie vorgestellt, in der die kulturellen Unterschiede der deutschen und brasilianischen Kultur aufgedeckt wurden, indem deutsche Expatriais nach konfliktreichen Situationen bzw. nach so genannten, kritischen Interaktionssituationen’ mit Brasilianern befragt wurden.

Conventional active noise control experiments use loudspeakers to generate the secondary anti-phase sound field to be superimposed with the primary sound waves. In this study, flow induced aerodynamic sound sources are used for that purpose. This is achieved by disturbing the flow field in the blade tip region using air jets blowing through the fans casing wall. Hereby additional periodic forces are set up which in turn form the flow induced aerodynamic secondary sound sources, which are adjustable in both amplitude and phase. In this way active flow control reduces the tonal noise components of the axial fan. Experimental results are presented for steady and unsteady jets injected into the main flow at various axial positions relative to the rotor blades. The method is successful for plane wave as well as for higher-order mode sound fields. The sound pressure level at the blade passing frequency was reduced by up to 20.5 dB. To obtain a better understanding of the physical mechanisms involved in the interaction of the air jets and the rotor blades, flow visualisation experiments were carried out with a stationary two-dimensional blade cascade. The investigation revealed that the air injection produces vortex generator jets causing additional unsteady longitudinal structures in the flow. For the ANC experiments this can be interpreted as the generating mechanism of the additional aeroacoustic sources with dipole characteristics.