Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness

Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined the expression of sclerostin, a soluble Wnt inhibitor that represses osteoblast differentiation and bone formation. In mice with breast cancer bone metastases, pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and reducing osteoclast-dependent bone resorption. During advanced disease, NF-κB and p38 signaling was increased in muscles in a TGF-β1-dependent manner, causing muscle fiber atrophy, muscle weakness and tissue regeneration with an increase in Pax7-positive satellite cells. Scl-Ab treatment restored NF-κB and p38 signaling, the abundance of Pax7-positive cells and ultimately muscle function. These effects improved the overall health condition and expanded the life span of cancer-bearing mice. Together, these results demonstrate that pharmacological inhibition of sclerostin reduces bone metastatic burden and muscle weakness with a prolongation of the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. 

"in dem moment wo ich es dann erkenne dann ist es auch gleich wieder weg" – Salienzeffekte in der Sprachperzeption

In context of the first study on folk linguistic concepts in the German language area carried out by the Kiel DFG research project "perceptual dialectology", this article looks at how salient features could be surveyed and categorized by a stimulus-response-test. After a definition of salience, the study design including the stimulus-response-test is presented. The test was created and modified during the project as a guessing game by the Institute for German Language (IDS Mannheim). The central question in this article is which linguistic features stimulate the informants to locate a speech sample on a map with predetermined cities and hence which salient features trigger the regional identification. In a second step, the speech samples are analyzed by the variables 'pleasantness' and 'correctness' defined by Dennis R. Preston. The central question here is: Are speech samples with a high pleasure value also automatically considered correct? Finally, an interpretation of metalinguistic comments in the speech examples will give more insight into folk linguistic concepts and the role of salient features in this regard

Structural Change Identification at a Wind Turbine Blade using Model Updating

In this paper, a damage and ice accretion localization method based on finite element model updating is tested using the example of a wind turbine blade. Both eigenfrequencies in combination with mode shapes and a new comparison technique based on transmissibility functions are employed in order to define measures for a quantification of the difference between numerical and measured results. Results of these quantifications are used to define an optimization problem, minimizing the deviation between model and measurement by variations of the numerical model using a combination of a global and a local optimization method. A full-scale rotor blade was tested in a rotor blade test facility in order to test those structural health monitoring methods. During the test, additional masses were installed on the structure in order to emulate ice accretion. Afterwards, the blade was driven to damage using an edgewise fatigue test. In this test a crack occurs at the trailing edge of the rotor blade. The model updating algorithm is applied to locate and quantify both structural changes with the two different measures. Though shown to be successful in a numerical study, both measures return incorrect damage locations when applied to real measurement data. On the other hand, ice localization is successful using eigenfrequencies and mode shapes, even quantification is possible. If transmissibility functions are applied, the localization is not possible

When decisions of others matter to me: an electrophysiological analysis

Background: Actions of others may have immediate consequences for oneself. We probed the neural responses associated with the observation of another person"s action using event-related potentials in a modified gambling task. In this task a"performer" bet either a higher or lower number and could win or lose this amount. Three different groups of"observers" were also studied. The first (neutral) group simply observed the performer"s action, which had no consequences for the observers. In the second (parallel) group, wins/losses of the performer were paralleled by similar wins and losses by the observer. In the third (reverse) group, wins of the performer led to a loss of the observer and vice versa. Results: ERPs of the performers showed a mediofrontal feedback related negativity (FRN) to losses. The neutral and parallel observer groups did similarly show an FRN response to the performer"s losses with a topography indistinguishable from that seen in the performers. In the reverse group, however, the FRN occurred for wins of the performer which translated to losses for the observer. Conclusions: Taking into account previous experiments, we suggest that the FRN response in observers is driven by two evaluative processes (a) related to the benefit/loss for oneself and (b) related to the benefit/loss of another perso

Bright Room-Temperature Single Photon Emission from Defects in Gallium Nitride

Single photon emitters play a central role in many photonic quantum technologies. A promising class of single photon emitters consists of atomic color centers in wide-bandgap crystals, such as diamond silicon carbide and hexagonal boron nitride. However, it is currently not possible to grow these materials as sub-micron thick films on low-refractive index substrates, which is necessary for mature photonic integrated circuit technologies. Hence, there is great interest in identifying quantum emitters in technologically mature semiconductors that are compatible with suitable heteroepitaxies. Here, we demonstrate robust single photon emitters based on defects in gallium nitride (GaN), the most established and well understood semiconductor that can emit light over the entire visible spectrum. We show that the emitters have excellent photophysical properties including a brightness in excess of 500x10^3 counts/s. We further show that the emitters can be found in a variety of GaN wafers, thus offering reliable and scalable platform for further technological development. We propose a theoretical model to explain the origin of these emitters based on cubic inclusions in hexagonal gallium nitride. Our results constitute a feasible path to scalable, integrated on-chip quantum technologies based on GaN

Ancient DNA identification of domestic animals used for leather objects in Central Asia during the Bronze Age

The arid climate of many regions within Central Asia often leads to excellent archaeological preservation, especially in sealed funerary contexts, allowing for ancient DNA analyses. While geneticists have looked at human remains, clothes, tools, and other burial objects are often neglected. In this paper, we present the results of an ancient DNA study on Bronze Age leather objects excavated from tombs of the Wupu cemetery in the Hami Oasis and Yanghai cemetery in the Turpan Oasis, both in Xinjiang Uyghur Autonomous Region of northwestern China. In addition to species identification of goat (Capra aegagrus/hircus), sheep (Ovis orientalis/aries), and cattle (Bos primigenius/taurus), mitochondrial haplogroups were determined for several samples. Our results show that Bronze Age domesticated goats and sheep from the Hami and Turpan oases possessed identical or closely related haplotypes to modern domestic animals of this area. The absence of leather produced from wild animals emphasizes the importance of animal husbandry in the cultures of Wupu and Yanghai

Contamination of personal protective equipment during COVID-19 autopsies

Confronted with an emerging infectious disease at the beginning of the COVID-19 pandemic, the medical community faced concerns regarding the safety of autopsies on those who died of the disease. This attitude has changed, and autopsies are now recognized as indispensable tools for understanding COVID-19, but the true risk of infection to autopsy staff is nevertheless still debated. To clarify the rate of SARS-CoV-2 contamination in personal protective equipment (PPE), swabs were taken at nine points in the PPE of one physician and one assistant after each of 11 full autopsies performed at four centers. Swabs were also obtained from three minimally invasive autopsies (MIAs) conducted at a fifth center. Lung/bronchus swabs of the deceased served as positive controls, and SARS-CoV-2 RNA was detected by real-time RT-PCR. In 9 of 11 full autopsies, PPE samples tested RNA positive through PCR, accounting for 41 of the 198 PPE samples taken (21%). The main contaminated items of the PPE were gloves (64% positive), aprons (50% positive), and the tops of shoes (36% positive) while the fronts of safety goggles, for example, were positive in only 4.5% of the samples, and all the face masks were negative. In MIAs, viral RNA was observed in one sample from a glove but not in other swabs. Infectious virus isolation in cell culture was performed on RNA-positive swabs from the full autopsies. Of all the RNA-positive PPE samples, 21% of the glove samples, taken in 3 of 11 full autopsies, tested positive for infectious virus. In conclusion, PPE was contaminated with viral RNA in 82% of autopsies. In 27% of autopsies, PPE was found to be contaminated even with infectious virus, representing a potential risk of infection to autopsy staff. Adequate PPE and hygiene measures, including appropriate waste deposition, are therefore essential to ensure a safe work environment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00428-021-03263-7

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites

Suppression of p75 Neurotrophin Receptor Surface Expression with Intrabodies Influences Bcl-xL mRNA Expression and Neurite Outgrowth in PC12 Cells

Background: Although p75 neurotrophin receptor (p75NTR) is the first neurotrophin receptor isolated, its diverse physiological functions and signaling have remained elusive for many years. Loss-of-function phenotypic analyses for p75NTR were mainly focused at the genetic level; however these approaches were impacted by off-target effect, insufficient stability, unspecific stress response or alternative active splicing products. In this study, p75NTR surface expression was suppressed for the first time at the protein level by endoplasmic reticulum (ER) retained intrabodies. Results: Three monoclonal recombinant antibody fragments (scFv) with affinities in the low nanomolar range to murine p75NTR were isolated by antibody phage display. To suppress p75NTR cell surface expression, the encoding genes of these scFvs extended by the ER retention peptide KDEL were transiently transfected into the neuron-like rat pheochromocytoma cell line PC12 and the mouse neuroblastoma x mouse spinal cord hybrid cell line NSC19. The ER retained intrabody construct, SH325-G7-KDEL, mediated a downregulation of p75NTR cell surface expression as shown by flow cytometry. This effect was maintained over a period of at least eight days without activating an unfolded protein response (UPR). Moreover, the ER retention of p75NTR resulted in downregulation of mRNA levels of the anti-apoptotic protein Bcl-xL as well as in strong inhibition of NGF-induced neurite outgrowth in PC12 cells. Conclusion: The ER retained intrabody SH325-G7-KDEL not only induces phenotypic knockdown of this p75NTR but als