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Background: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.
Results: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.
Conclusions: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
Highly efficient single-photon sources (SPS) can increase the secure key rate of quantum key distribution (QKD) systems compared to conventional attenuated laser systems. Here we report on a free space QKD test using an electrically driven quantum dot single-photon source (QD SPS) that does not require a separate laser setup for optical pumping and thus allows for a simple and compact SPS QKD system. We describe its implementation in our 500 m free space QKD system in downtown Munich. Emulating a BB84 protocol operating at a repetition rate of 125 MHz, we could achieve sifted key rates of 5-17 kHz with error ratios of 6-9% and g((2))(0)-values of 0.39-0.76.
Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Met\(^{high}\)-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.
Charcot-Marie-Tooth 1B (CMT1B) is a progressive inherited demyelinating disease of human peripheral nervous system leading to sensory and/or motor function disability and is caused by mutations in the P0 gene. Mice heterozygously deficient for P0 (P0+/-) are an adequate model of this human disorder showing myelin degeneration, formation of onion bulbs, remyelination and a reduced motor conduction velocity of around 30m/s similar to patients. Previously, it had been shown that T-lymphocytes and macrophages play a crucial role during pathogenesis in peripheral nerves of P0+/- mice. Both, T-lymphocytes and macrophages increase in number in the endoneurium and deletion of T-lymphocytes or deletion of a macrophage-directed cytokine ameliorates the disease. In this study the monocyte chemoattractant protein-1 (MCP-1) was identified as an early regulated cytokine before onset of disease is visible at the age of six months. MCP-1 mRNA and protein expression could be detected in femoral quadriceps and sciatic nerves of P0+/- mice already at the age of one month but not in cutaneous saphenous nerves which are never affected by the disease. MCP-1 was shown to be expressed by Schwann cells and to mediate the immigration of immune cells into peripheral nerves. Deletion of MCP-1 in P0+/- mice accomplished by crossbreeding P0 and MCP-1 deficient mice revealed a substantial reduction of immune cells in peripheral nerves of P0+/-/MCP-1+/- and P0+/-/MCP-1-/- mice at the age of six months. In twelve months old mice reduction of immune cells in peripheral nerves is accompanied by amelioration of demyelinating disease in P0+/-/MCP-1+/- and aggravation of demyelinating disease in lumbar ventral roots of P0+/ /MCP-1-/- mice in comparison to P0+/ /MCP 1+/+ mice. Furthermore, activation of the MEK1/2-ERK1/2 signalling cascade could be demonstrated to take place in Schwann cells of affected peripheral nerves of P0+/- mice overlapping temporarily and spatially with MCP-1 expression. An animal experiment using a MEK1/2-inhibitor in vivo, CI-1040, revealed that upon reduction of ERK1/2 phosphorylation MCP-1 mRNA expression is diminished suggesting that the activation of the MEK1/2-ERK1/2 signalling cascade is necessary for MCP-1 expression. Additionally, peripheral nerves of P0+/- mice showing reduced ERK1/2 phosphorylation and MCP-1 mRNA expression also show reduced numbers of macrophages in the endoneurium. This study shows a molecular link between a Schwann cell based mutation and immune cell function. Inhibition of the identified signalling cascade might be a putative target for therapeutic approaches.
Optimal open-loop control, i.e. the application of an analytically derived control rule, is demonstrated for nanooptical excitations using polarization-shaped laser pulses. Optimal spatial near-field localization in gold nanoprisms and excitation switching is realized by applying a shift to the relative phase of the two polarization components. The achieved near-field switching confirms theoretical predictions, proves the applicability of predefined control rules in nanooptical light–matter interaction and reveals local mode interference to be an important control mechanism.
Various biomaterial combinations have been studied focusing on their ability to stabilize blood clots and maintain space under soft tissue to support new bone formation. A popular combination is Deproteinized Bovine Bone Mineral (DBBM) placed with a native collagen membrane (NCM) tacked to native bone. In this study, we compared the outcome of this treatment option to those achieved with three different graft/membrane combinations with respect to total newly occupied area and the mineralized compound inside. After bi-lateral extraction of two mandibular premolars in five adult beagles L-shaped alveolar defects were created. A total of 20 defects healed for 6 weeks resulting in chronic type bone defects. At baseline, four options were randomly allocated to five defects each: a. DBBM + NCM with a four-pin fixation across the ridge; b. DBBM + RCLC (ribose cross-linked collagen membrane); c. DBBM + NPPM (native porcine pericardium membrane); and d. Ca-sulfate (CS) + RCLC membrane. Membranes in b/c/d were not fixed; complete tensionless wound closure was achieved by CAF. Termination after 3 months and sampling followed, and non-decalcified processing and toluidine blue staining were applied. Microscopic images obtained at standardized magnification were histomorphometrically assessed by ImageJ software (NIH). An ANOVA post hoc test was applied; histomorphometric data are presented in this paper as medians and interquartile ranges (IRs). All sites healed uneventfully, all sites were sampled and block separation followed before Technovit embedding. Two central sections per block for each group were included. Two of five specimen were lost due to processing error and were excluded from group b. New bone area was significantly greater for option b. compared to a. (p = 0.001), c. (p = 0.002), and d. (p = 0.046). Residual non-bone graft area was significantly less for option d. compared to a. (p = 0.026) or c. (p = 0.021). We conclude that collagen membranes with a prolonged resorption/barrier profile combined with bone substitutes featuring different degradation profiles sufficiently support new bone formation. Tacking strategy/membrane fixation appears redundant when using these biomaterials.
The factors determining gradients of biodiversity are a fundamental yet unresolved topic in ecology. While diversity gradients have been analysed for numerous single taxa, progress towards general explanatory models has been hampered by limitations in the phylogenetic coverage of past studies. By parallel sampling of 25 major plant and animal taxa along a 3.7 km elevational gradient on Mt. Kilimanjaro, we quantify cross-taxon consensus in diversity gradients and evaluate predictors of diversity from single taxa to a multi-taxa community level. While single taxa show complex distribution patterns and respond to different environmental factors, scaling up diversity to the community level leads to an unambiguous support for temperature as the main predictor of species richness in both plants and animals. Our findings illuminate the influence of taxonomic coverage for models of diversity gradients and point to the importance of temperature for diversification and species coexistence in plant and animal communities.
Analysis of a multi-component multi-stage malaria vaccine candidate—tackling the cocktail challenge
(2015)
Combining key antigens from the different stages of the P. falciparum life cycle in the context of a multi-stage-specific cocktail offers a promising approach towards the development of a malaria vaccine ideally capable of preventing initial infection, the clinical manifestation as well as the transmission of the disease. To investigate the potential of such an approach we combined proteins and domains (11 in total) from the pre-erythrocytic, blood and sexual stages of P. falciparum into a cocktail of four different components recombinantly produced in plants. After immunization of rabbits we determined the domain-specific antibody titers as well as component-specific antibody concentrations and correlated them with stage specific in vitro efficacy. Using purified rabbit immune IgG we observed strong inhibition in functional in vitro assays addressing the pre-erythrocytic (up to 80%), blood (up to 90%) and sexual parasite stages (100%). Based on the component-specific antibody concentrations we calculated the IC50 values for the pre-erythrocytic stage (17–25 μg/ml), the blood stage (40–60 μg/ml) and the sexual stage (1.75 μg/ml). While the results underline the feasibility of a multi-stage vaccine cocktail, the analysis of component-specific efficacy indicates significant differences in IC50 requirements for stage-specific antibody concentrations providing valuable insights into this complex scenario and will thereby improve future approaches towards malaria vaccine cocktail development regarding the selection of suitable antigens and the ratios of components, to fine tune overall and stage-specific efficacy.
Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
The monitoring of species and functional diversity is of increasing relevance for the development of strategies for the conservation and management of biodiversity. Therefore, reliable estimates of the performance of monitoring techniques across taxa become important. Using a unique dataset, this study investigates the potential of airborne LiDAR-derived variables characterizing vegetation structure as predictors for animal species richness at the southern slopes of Mount Kilimanjaro. To disentangle the structural LiDAR information from co-factors related to elevational vegetation zones, LiDAR-based models were compared to the predictive power of elevation models. 17 taxa and 4 feeding guilds were modeled and the standardized study design allowed for a comparison across the assemblages. Results show that most taxa (14) and feeding guilds (3) can be predicted best by elevation with normalized RMSE values but only for three of those taxa and two of those feeding guilds the difference to other models is significant. Generally, modeling performances between different models vary only slightly for each assemblage. For the remaining, structural information at most showed little additional contribution to the performance. In summary, LiDAR observations can be used for animal species prediction. However, the effort and cost of aerial surveys are not always in proportion with the prediction quality, especially when the species distribution follows zonal patterns, and elevation information yields similar results.