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Summary: Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.

While many digital technologies provide opportunities for creating business models that impact sustainability, some technologies, especially blockchain applications, are often criticized for harming the environment, e.g. due to high energy demand. In our study, we present a novel approach to identifying sustainability-focused blockchain companies and relate their level of engagement to location factors and entrepreneurial ecosystem embeddedness. For this, we use a large-scale web scraping approach to analyze the textual content and hyperlink networks of all US companies from their websites. Our results show that blockchain remains a niche technology, with its use communicated by about 0.6% of US companies. However, the proportion of blockchain companies that are committed to sustainability is significantly higher than in the overall firm population. Additionally, we find that such sustainability-engaged blockchain companies have, at least quantitatively, a more intensive embedding in entrepreneurial ecosystems, while infrastructural and socio-economic location factors hardly play a role.

A key pathological feature of Parkinson’s Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn’t interfere with neuronal differentiation and generation of tyrosine hydroxylase positive (TH+) neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.

Summary: Background: Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) improves multiple clinical outcomes in people with cystic fibrosis (pwCF) with at least one F508del allele. This study evaluated the real-world impact of ETI on lung function, nutritional status, pulmonary exacerbation frequency, and sweat chloride concentrations in a large group of pwCF. Methods: This observational cohort study used data from the German CF Registry for pwCF who received ETI therapy and were followed up for a period of 12 months. Findings: The study included 2645 pwCF from 67 centres in Germany (mean age 28.0 ± 11.5 years). Over the first year after ETI was initiated, percent predicted forced expiratory volume in 1 s (ppFEV1) increased by 11.3% (95% confidence interval [CI] 10.8–11.8, p

In many rural East African areas, anti-malarial plants are commonly used as first-line treatment against malaria. However, spatially explicit information about the future availability of anti-malarial plant species and its relation to future suitable habitat for malaria vectors is limited. In this study we (1) model the distribution of anti-malarial plant and malaria vector species and assess the drivers of their distributions taking the example of the Samburu dryland in Kenya, (2) map the modeled overlap in this area, (3) assess the impact of future climate change on anti-malarial plant and malaria vector species and (4) report their future overlaps. Our results show that mean temperature of warmest quarter, precipitation of wettest quarter and mean temperature of coldest quarter were the most important environmental variables that affected the distribution of anti-malarial species. The effects of climate change will vary, with some areas characterized by huge losses in anti-malarial species habitat while others gained or remained stable under both SSP2-4.5 and SSP5-8.5 climate change scenarios by 2050s and 2070s. According to most of our scenarios, more than half of the anti-malarial species will become vulnerable or threatened by 2050s and 2070s. A comparison between distribution patterns of future anti-malarial species richness and malaria vector species suitable habitat suggests that the former will decrease considerably while the later will increase. Because the availability of anti-malarial species will decrease in the areas affected by malaria vectors, geographically targeted conservation strategies and further control measures against malaria vectors are all the more important.

Imaging skeletal muscle function and metabolism, as reported by local hemodynamics and oxygen kinetics, can elucidate muscle performance, severity of an underlying disease or outcome of a treatment. Herein, we used multispectral optoacoustic tomography (MSOT) to image hemodynamics and oxygen kinetics within muscle during exercise. Four healthy volunteers underwent three different hand-grip exercise challenges (60s isometric, 120s intermittent isometric and 60s isotonic). During isometric contraction, MSOT showed a decrease of HbO2, Hb and total blood volume (TBV), followed by a prominent increase after the end of contraction. Corresponding hemodynamic behaviors were recorded during the intermittent isometric and isotonic exercises. A more detailed analysis of MSOT readouts revealed insights into arteriovenous oxygen differences and muscle oxygen consumption during all exercise schemes. These results demonstrate an excellent capability of visualizing both circulatory function and oxygen metabolism within skeletal muscle under exercise, with great potential implications for muscle research, including relevant disease diagnostics.

The durability of prestressed concrete structures built between the 1950s and 1980s is becoming a growing problem. One reason is the sensitivity to stress corrosion cracking of the prestressing steel. Failure of prestressing wires can result in collapse of the entire structure without premature indication by transverse bending cracks or considerable deformation. The response of a structure to significant number of prestressing wire breaks was studied on a bridge in Brandenburg, Germany. Two thirds of the prestressing wires in concentrated tendons of two girders were cut before the bridge was demolished. Acoustic Emission Analysis was used to detect the wire breaks. Thus, the number of wire breaks was correlated with results of other measurement techniques, in particular strain measurements on the girders. In preparation of the measurements, the acoustic properties of the bridge were determined and the suitability of Schmidt hammer impacts as an acoustic reference source was validated.

Increasing tree mortality due to climate change has been observed globally. Remote sensing is a suitable means for detecting tree mortality and has been proven effective for the assessment of abrupt and large-scale stand-replacing disturbances, such as those caused by windthrow, clear-cut harvesting, or wildfire. Non-stand replacing tree mortality events (e.g., due to drought) are more difficult to detect with satellite data – especially across regions and forest types. A common limitation for this is the availability of spatially explicit reference data. To address this issue, we propose an automated generation of reference data using uncrewed aerial vehicles (UAV) and deep learning-based pattern recognition. In this study, we used convolutional neural networks (CNN) to semantically segment crowns of standing dead trees from 176 UAV-based very high-resolution (

The Bioconcentration Factor (BCF) is an important parameter in the environmental risk assessment of chemicals, relevant for industrial and academic research as well as required in many regulatory contexts. It represents the potential of a substance to accumulate in organic tissues or whole animals and is most frequently measured in fish. However, animal welfare reasons, throughput limitations, and costs push the need for alternative methods that allow accurate and reliable estimations of BCF in silico. We present a new deep learning model to predict BCF values from chemical structures, that outperforms currently available models (R2 of 0.68 and RMSE of 0.59 log units on an external test set; R2 of 0.70 and RMSE of 0.74 log units in a demanding cluster split validation). The model is based on molecular representations encoded as CDDD descriptors and exploits a large in-house dataset with measured logD values as an auxiliary task.Additionally, we developed a post-hoc explainability method based on SMILES character substitutions to accompany our predictions with atom-level interpretations. These sensitivity scores highlight the most influential moieties in the molecule and can help to understand the predictions better and design new molecules.

Supply of medicinal plants from African landscapes is crucial because of their widespread use. Rapid climate change and land use change are potential threats to this resource but knowledge about the ecological needs of many of these plants is still rather limited. More knowledge about potential threats to medicinal plants supply and options to prevent future losses are desirable. Therefore, the objectives of the study were to examine (1) the effects of environmental drivers on the occurrence of medicinal plant species, (2) how different vegetation formations contribute to the provision of plants used for the treatment of diseases and (3) how these contributions are secured by redundancy. The analysis was based on a sample of 130 sampling plots in Samburu County, Kenya. We identified patterns in medicinal plants co-occurrences using classification and ordination analyses and analyzed these pattern in terms of environmental drivers, service diversity and service security. The pattern in medicinal plants co-occurrences reflected the distribution of broad formations (bushed grassland, forest, wooded grassland, savanna) driven by differences in grazing pressure, drought, slope and fraction of sand in soils. Each of the formations brought with it its own characteristic endowment with medicinal plants. The formations differed in the diversity and security of medicinal services provided. All resulted as fulfilling unique services with diseases treated by plants occurring exclusively in one or another formation. Forests featured the highest diversity of medicinal services, with medicinal plants used against 67 diseases. The supply security in forests, resulting from redundancy in supply provision, was moderate. In contrast to this, savanna grasslands featured plants with uses against 49 diseases, some of them were treated exclusively by plants from savanna grasslands. This formation also showed the highest redundancy. Wooded grasslands showed very little redundancy and is likely to be adversely affected by climate change. Whereas savannas feature the largest pool of medicinal plants and should receive due attention, urgent and highest conservation priority should, presently and in future, go towards the wooded grassland that had the lowest supply redundancy for traditional medicine.

Plant functional traits play a key role in the assessment of ecosystem processes and properties. Optical remote sensing is ascribed a high potential in capturing those traits and their spatiotemporal patterns. In vegetation remote sensing, reflectance-based retrieval methods are either statistical (relying on empirical observations) or physically-based (based on inversions of a radiative transfer model, RTM). Both trait retrieval approaches remain poorly investigated regarding phenology. However, within the phenology of a plant, its leaf constituents, canopy structure, and the presence of phenology-related organs (i.e., flowers or inflorescence) vary considerably – and so does its reflectance. We, therefore, addressed the question of how plant phenology affects the predictive performance of both statistical and RTM-based methods and how this effect differs between traits. For a complete growing season, we weekly measured traits of 45 herbaceous plant species together with hyperspectral canopy reflectance (ASD FieldSpec III). Plants were grown in an experimental setup. The investigated traits comprised Leaf Area Index (LAI) and the leaf traits chlorophyll, anthocyanins, carotenoids, equivalent water thickness, and leaf mass per area. We compared the predictive performances of PLSR models and three variants of PROSAIL inversions based on (1) all observations and based on (2) a phenological subset where flowering plants were excluded and only those observations most suitable for modeling were kept. Our results show that both statistical and RTM-based trait retrievals were largely affected by phenology. For carotenoids for example, R2 decreased from 0.58 at non-flowering canopies to 0.25 at 100% flowering canopies. Temporal trends were diverse. LAI and equivalent water thickness were best estimated earlier in the growing season; chlorophyll and carotenoids towards senescence. PLSR models showed generally higher bias than the PROSAIL-based retrieval approaches. Lookup-table inversion of PROSAIL in combination with a continuous wavelet transformation of reflectance showed highest accuracies. We found RTM-based retrieval not to be as accurate and transferable as previously indicated. Our results suggest that phenology is essential for accurate retrieval of plant functional traits and varies depending on the studied species and functional traits, respectively.

Study region: Lower Jordan River. Study focus: The main aim of this study was to identify differences in catchment runoff reactions across a variety of scales and a strong climatic gradient and to correlate them to physical catchment properties. For this purpose we observed rainfall and runoff responses on a hillslope (1000 m2) and in several nested catchments (3.2–129 km2) over a period of five years. Catchment characteristics and surface cover types were derived from high-resolution aerial images. To gain process understanding a single high magnitude event was analysed in detail using information from soil moisture plots. New hydrological insights for the region: Our results show that runoff in the semi-arid headwater area is strongly related to long lasting rainfall events of high amounts and is predominantly generated by saturation excess overland flow (SOF). Observations from the arid runoff plot indicated a strongly contrasting behaviour with dominating Hortonian overland flow (HOF). At catchment scale we found an accentuated runoff response when we compared arid with semi-arid conditions, which can be attributed to different geological substrate, more abundant rock surfaces, shallower soil and sparser vegetation cover. Identified strong correlations between event rainfall and runoff volumes may provide promising options for the assessment and management of surface runoff as a water resource.

Background. Intestinal intussusception in adults is associated with chronic inflammatory bowel disease, coeliac disease, abdominal tumors or previous abdominal surgery but most often of unknown origin.Aim. The aim of our study was to evaluate circumstances and identify risk factors for intussusceptions.Methods. All 65,928 abdominal ultrasound examinations performed at our tertiary medical center between January 2001 and June 2008 were analyzed retrospectively for the diagnosis “intussusception”. After identifying individuals with sonographically proven intussusception we analyzed various patients’ characteristics including age, gender and underlying disease as well as sonographic findings such as localization of the intussusception, absence or presence of ascites and lymph nodes.Results. We identified 32 cases of intussusceptions [mean age 45 years (range 18 to 88); 18 patients were male]. Twelve patients (38%) had a history of abdominal surgery including 8 patients who had undergone liver transplantation (2 patients with primary sclerosing cholangitis, 1 patient with cystic fibrosis, 1 patient with sarcoidosis, 1 patient with hepatocellular carcinoma and HCV infection, 1 patient with autoimmune hepatitis, 1 patient with Crigler-Najar-syndrome and one patient with echinococcus). A hepaticojejunostomy had been performed in 4 of the patients after liver transplantation. Liver transplanted patients were significantly overrepresented in the intussusception group compared with the overall cohort of patients undergoing abdominal ultrasound examination (25% vs. 8%, Chi-Square-test, p = 0.0023).Conclusion. In our retrospective study liver transplantation, in particular with hepaticojejunostomy, was identified as a new major risk factor for intestinal intussusceptions.