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Born 1906 in London as the son of an English mother and a German father, Rudolf Uhlenhaut was an engineer and designer for Daimler-Benz. He became famous for his achievements regarding the Silver Arrows, the 300 SL with the famous gull wing doors, the legendary Mercedes-Benz 300 SLR, known as the?Uhlenhaut Coupé? and the various experimental C 111 versions well-known for several speed records. -- Uhlenhaut joined Daimler-Benz in 1931 after finishing his studies of mechanical engineering in Munich. In 1936 he took over as head of the racing department and conducted the Silver Arrows and Rudolf Caracciola to their 1937 European championship. Based upon the 300 SL?Gullwing?, initially a thoroughbred racing sports car, he created the road versions W198 and the smaller open-topped W121, both launched at the International Motor Sports Show in New York 1954. Though Uhlenhaut never owned a car of his own, his official company car, a 300 SLR with a top speed of 290 km/h became famous as the Uhlenhaut Coupé? the fastest car of its day authorized for road use! -- This first ever comprehensive biography of Rudolf Uhlenhaut, illustrated with many previously unpublished photographs, depicts his life and technical achievements, presenting a complete compilation of all the patents he filed and exploring their significance. It also draws a vivid picture of the person behind the technical innovations and tries to explore his character and motivation.

Social recognition is essential for the formation of social structures. Many times, recognition comes with lesser exploration of familiar animals. This lesser exploration has led to the assumption that recognition may be a habituation memory. The underlying memory mechanisms and the thereby acquired cortical representations of familiar mice have remained largely unknown, however. Here, we introduce an approach directly examining the recognition process from volatile body odors among male mice. We show that volatile body odors emitted by mice are sufficient to identify individuals and that more salience is assigned to familiar mice. Familiarity is encoded by reinforced population responses in two olfactory cortex hubs and communicated to other brain regions. The underlying oxytocin-induced plasticity promotes the separation of the cortical representations of familiar from other mice. In summary, neuronal encoding of familiar animals is distinct and utilizes the cortical representational space more broadly, promoting storage of complex social relationships. Recognition memory for other individuals forms quickly. Here the authors show that such memories are enabled by oxytocin and can be retrieved from reinforced and more distinct neural representations even when only limited sensory information is available.

In a pilot trial, 52 patients with coronary disease and restenosis of a previously placed intracoronary stent underwent angioplasty with either a paclitaxel-coated balloon or an uncoated balloon. Late luminal loss and the incidence of restenosis at 6 months were significantly reduced with the paclitaxel-coated balloon, as was the rate of target-vessel revascularization at 1 year. The results of this small proof-of-concept study will require confirmation in larger clinical trials. Late luminal loss and the incidence of restenosis at 6 months were significantly reduced with the paclitaxel-coated balloon, as was the rate of target-vessel revascularization at 1 year. The incidence of in-stent restenosis after percutaneous coronary intervention ranges from 5 to 35% after the implantation of an uncoated stent and is somewhat lower after the implantation of a drug-eluting stent in patients who are at moderate risk. 1 Treatment of in-stent restenosis with a balloon catheter for coronary angioplasty is limited by high rates of restenosis (39 to 67%). 2 – 6 Other approaches, such as the implantation of a second, uncoated stent or mechanical debulking (e.g., rotablation), have not been associated with a significant reduction in recurrent in-stent restenosis. 2 Intracoronary irradiation (brachytherapy) has been found to be effective in this . . .

The small arginine-rich protein protamine condenses complete genomic DNA into the sperm head. Here, we applied its high RNA binding capacity for spontaneous electrostatic assembly of therapeutic nanoparticles decorated with tumour-cell-specific antibodies for efficiently targeting siRNA. Fluorescence microscopy and DLS measurements of these nanocarriers revealed the formation of a vesicular architecture that requires presence of antibody-protamine, defined excess of free SMCC-protamine, and anionic siRNA to form. Only these complex nanoparticles were efficient in the treatment of non-small-cell lung cancer (NSCLC) xenograft models, when the oncogene KRAS was targeted via EGFR-mediated delivery. To show general applicability, we used the modular platform for IGF1R-positive Ewing sarcomas. Anti-IGR1R-antibodies were integrated into an antibody-protamine nanoparticle with an siRNA specifically against the oncogenic translocation product EWS/FLI1. Using these nanoparticles, EWS/FLI1 knockdown blocked in vitro and in vivo growth of Ewing sarcoma cells. We conclude that these antibody-protamine-siRNA nanocarriers provide a novel platform technology to specifically target different cell types and yet undruggable targets in cancer therapy by RNAi.

The learning of stimulus-outcome associations allows for predictions about the environment. Ventral striatum and dopaminergic midbrain neurons form a larger network for generating reward prediction signals from sensory cues. Yet, the network plasticity mechanisms to generate predictive signals in these distributed circuits have not been entirely clarified. Also, direct evidence of the underlying interregional assembly formation and information transfer is still missing. Here we show that phasic dopamine is sufficient to reinforce the distinctness of stimulus representations in the ventral striatum even in the absence of reward. Upon such reinforcement, striatal stimulus encoding gives rise to interregional assemblies that drive dopaminergic neurons during stimulus-outcome learning. These assemblies dynamically encode the predicted reward value of conditioned stimuli. Together, our data reveal that ventral striatal and midbrain reward networks form a reinforcing loop to generate reward prediction coding. It is not entirely understood how network plasticity produces the coding of predicted value during stimulus-outcome learning. Here, the authors reveal a reinforcing loop in distributed limbic circuits, transforming sensory stimuli into reward prediction coding broadcasted by dopamine neurons to the brain.

Identifying the circuits responsible for cognition and understanding their embedded computations is a challenge for neuroscience. We establish here a hierarchical cross-scale approach, from behavioral modeling and fMRI in task-performing mice to cellular recordings, in order to disentangle local network contributions to olfactory reinforcement learning. At mesoscale, fMRI identifies a functional olfactory-striatal network interacting dynamically with higher-order cortices. While primary olfactory cortices respectively contribute only some value components, the downstream olfactory tubercle of the ventral striatum expresses comprehensively reward prediction, its dynamic updating, and prediction error components. In the tubercle, recordings reveal two underlying neuronal populations with non-redundant reward prediction coding schemes. One population collectively produces stabilized predictions as distributed activity across neurons; in the other, neurons encode value individually and dynamically integrate the recent history of uncertain outcomes. These findings validate a cross-scale approach to mechanistic investigations of higher cognitive functions in rodents. Where and how the brain learns from experience is not fully understood. Here the authors use a hierarchical approach from behavioural modelling to systems fMRI to cellular coding reveals brain mechanisms for history informed updating of future predictions.

Besides their neuronal support functions, astrocytes are active partners in neuronal information processing. The typical territorial structure of astrocytes (the volume of neuropil occupied by a single astrocyte) is pivotal for many aspects of glia-neuron interactions. Individual astrocyte territorial volumes are measured by Golgi impregnation, and astrocyte densities are determined by S100β immunolabeling. These data are compared with results from conventionally applied methods such as dye filling and determination of the density of astrocyte networks by biocytin loading. Finally, we implemented our new approach to investigate age-related changes in astrocyte territories in the cortex and hippocampus of 5- and 21-month-old mice. The data obtained by our simplified approach based on Golgi impregnation were compared to previously published dye filling experiments, and yielded remarkably comparable results regarding astrocyte territorial volumes. Moreover, we found that almost all coupled astrocytes (as indicated by biocytin loading) were immunopositive for S100β. A first application of this new experimental approach gives insight in age-dependent changes in astrocyte territorial volumes. They increased with age, while cell densities remained stable. In 5-month-old mice, the overlap factor was close to 1, revealing little or no interdigitation of astrocyte territories. However, in 21-month-old mice, the overlap factor was more than 2, suggesting that processes of adjacent astrocytes interdigitate. Here we verified the usability of a simple, versatile method for assessing astrocyte territories and the overlap factor between adjacent territories. Second, we found that there is an age-related increase in territorial volumes of astrocytes that leads to loss of the strict organization in non-overlapping territories. Future studies should elucidate the physiological relevance of this adaptive reaction of astrocytes in the aging brain and the methods presented in this study might be a powerful tool to do so.

The drug efflux transporter P-glycoprotein, encoded by the ABCB1 gene, promotes acquired chemoresistance. We explored the presence and clinical relevance of circulating cell-free ABCB1 transcripts (cfABCB1 tx ) in ovarian cancer patients (173 longitudinal serum samples from 79 cancer patients) using digital droplet PCR. cfABCB1 tx  were readily detectable at primary diagnosis (median 354 mRNA copies/20 µl serum), paralleled FIGO-stage and predicted surgical outcome ( p  = 0.023, p =0.022, respectively). Increased cfABCB1 tx levels at primary diagnosis indicated poor PFS (HR = 2.329, 95%CI:1.374–3.947, p  = 0.0017) and OS (HR = 2.074, 95%CI:1.194–3.601, p  = 0.0096). cfABCB1 tx induction under platinum-based chemotherapy was an independent predictor for poor OS (HR = 2.597, 95%CI: 1.218–5.538, p  = 0.013) and paralelled a micrometastatic phenotype, shaped by the presence of disseminated tumor cells in the bone marrow. A strong correlation was observed between cfABCB1 tx and circulating transcripts of the metastasis-inducer MACC1, which is the transcriptional activator of ABCB1. Combined assessment of cfABCB1 tx and circulating cell-free MACC1 transcripts (cfMACC1 tx ) resulted in an improved prognostic prediction, with  the cfABCB1 tx -high/cfMACC1 tx -high phenotype bearing the highest risk for relapse and death. Conclusively, we provide proof of principle, that ABCB1 transcripts are readily traceable in the liquid-biopsy of ovarian cancer patients, advancing a new dimension for systemic monitoring of ABCB1/P-glycoprotein expression dynamics.

Background Acute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells, with a worldwide 5-year survival prognosis of about 30%. Therefore, the development of more effective therapeutics with novel mode of action is urgently demanded. One common mutated gene in the AML is the DNA-methyltransferase DNMT3A whose function in the development and maintenance of AML is still unclear. To specifically target “undruggable” oncogenes, we initially invented an RNAi-based targeted therapy option that uses the internalization capacity of a colorectal cancer specific anti-EGFR-antibody bound to cationic protamine and the anionic siRNA. Here, we present a new experimental platform technology of molecular oncogene targeting in AML. Methods Our AML-targeting system consists of an internalizing anti-CD33-antibody–protamine conjugate, which together with anionic molecules such as siRNA or ibrutinib-Cy3.5 and cationic free protamine spontaneously assembles into vesicular nanocarriers in aqueous solution. These nanocarriers were analyzed concerning their physical properties and relevant characteristics in vitro in cell lines and in vivo in xenograft tumor models and patient-derived xenograft leukemia models with the aim to prepare them for translation into clinical application. Results The nanocarriers formed depend on a balanced electrostatic combination of the positively charged cationic protamine-conjugated anti-CD33 antibody, unbound cationic protamine and the anionic cargo. This nanocarrier transports its cargo safely into the AML target cells and has therapeutic activity against AML in vitro and in vivo. siRNAs directed specifically against two common mutated genes in the AML, the DNA-methyltransferase DNMT3A and FLT3-ITD lead to a reduction of clonal growth in vitro in AML cell lines and inhibit tumor growth in vivo in xenotransplanted cell lines. Moreover, oncogene knockdown of DNMT3A leads to increased survival of mice carrying leukemia patient-derived xenografts. Furthermore, an anionic derivative of the approved Bruton’s kinase (BTK) inhibitor ibrutinib, ibrutinib-Cy3.5, is also transported by this nanocarrier into AML cells and decreases colony formation. Conclusions We report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.

Background We are presenting an extension of a previously published trial on the efficacy and safety of a paclitaxel-coated balloon in coronary ISR in a larger patient population and after a complete follow-up of 2 years. Methods Hundred eight patients were enrolled in two separately randomized, double-blind multicenter trials on efficacy and safety using an identical protocol. Patients were treated by the paclitaxel-coated (3 µg/mm 2 balloon surface; Paccocath) or an uncoated balloon. The main inclusion criteria were a diameter stenosis of ≥70% and <30 mm length with a vessel diameter of 2.5–3.5 mm. The primary endpoint was angiographic late lumen loss in-segment. Secondary endpoints included binary restenosis rate and major adverse cardiovascular events (MACE). Results Quantitative coronary angiography revealed no differences in baseline parameters. After six months in-segment late lumen loss was 0.81 ± 0.79 mm in the uncoated balloon group vs. 0.11 ± 0.45 mm ( P  < 0.001) in the drug-coated balloon group resulting in a binary restenosis rate of 25/49 vs. 3/47 ( P  < 0.001). Until 12 months post procedure 20 patients in the uncoated balloon group compared to two patients in the coated balloon group required target lesion revascularization ( P  = 0.001). Between 12 and 24 only two MACE were recorded, a stroke in the uncoated and a target lesion revascularization in the coated balloon group. Conclusion Treatment of coronary ISR with paclitaxel-coated balloon catheters persistently reduces repeat restenosis up to 2 years. (ClinicalTrials.gov Identifier: NCT00106587, NCT00409981).