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Prolonged exposure to weightlessness leads to loss of muscle and bone mass. Therefore, astronauts on board the International Space Station (ISS) currently perform mandatory daily exercises. ISS missions usually last 6 months, and future missions will become significantly longer when going, for example, to Mars. To that purpose, an exoskeleton‐based exercise device, called ATHLETIC, was developed. The functionality and relevance of this device was evaluated in this study. Ten participants performed resistance exercises (squats) and plyometric exercises (countermovement jumps, reactive hops). Results showed that all participants were technically able to perform the intended exercises on ATHLETIC, albeit with reduced loading as compared to the reference exercises. This resulted in less mechanical performance and muscle activity. Due to the unfamiliar horizontal training axis, some participants had difficulty performing the movements correctly. Follow‐up studies are required testing, whether an adequate number of practicing sessions could enable persons to approach the performances of reference measurements, and whether further improvements of the device are needed to improve the exercise performance. What is the central question of the study? A new type of training device (called ATHLETIC) was tested for functionality for complex plyometric and high‐intensive resistance exercises: are the planned exercises generally possible on the new training device and to what extent do the exercises performed on the device differ from reference exercises? What is the main finding and its importance? Squatting on the ATHLETIC device was technically possible, albeit with reduced loading as compared to reference exercises. Thus, although participants were able to jump and even hop, reactive muscle contractions were not possible as indicated, for example, by the long ground contact times.

Patients with chronic daily headaches (CDH) are often a diagnostic challenge and frequently undergo neuroimaging. One common underlying cause of CDH is idiopathic intracranial hypertension (IIH). However, certain neuroimaging abnormalities that suggest IIH, such as optic nerve sheath diameters (ONSD), pituitary gland height, and venous sinus diameter, require interpretation due to the absence of established normative values. Notably, intracranial pressure is known to varies with age, sex and weight, further complicating the determination of objectively abnormal findings within a specific patient group. This study aims to assist clinical neuroradiologists in differentiating neuroimaging results in CDH by providing weight-adjusted normative values for imaging characteristics of IIH. In addition to age and BMI we here assessed 1924 population-based T1-weighted MRI datasets of healthy participants for relevant MRI aspects of IIH. Association to BMI was analyzed using linear/logistic regression controlled for age and stratified for sex. ONSD was 4.3 mm [2.8; 5.9]/4.6 mm [3.6; 5.7] and diameter of transverse sinus was 4.67 mm [1.6; 6.5]/4.45 mm [3.0; 7.9]. Height of pituitary gland was 5.1 mm [2.2;8.1]/4.6 mm [1.9;7.1] for female and male respectively. Values generally varied with BMI with regression slopes spanning 0.0001 to 0.05 and were therefor presented as normative values stratified by BMI. Protrusion of ocular papilla, empty sella and transverse sinus occlusion were rare in total. Our data show an association between BMI and commonly used MRI features for diagnosing IIH. We provide categorized normative BMI values for ONSD, pituitary gland height, and transverse sinus diameter. This distinction helps objectively identify potential IIH indicators compared to regular population norms, enhancing diagnostic accuracy for suspected IIH patients. Notably, optic nerve head protrusion, empty sella, and transverse sinus occlusion are rare in healthy individuals, solidifying their importance as imaging markers regardless of BMI.

The synthesis of bioactive compounds with differential, and ideally enhanced, activities presents persistent and growing challenges for the field of organic synthesis. By leveraging Nature’s ability to build complex, stereochemically rich, and biologically active molecular scaffolds, site-selective modification of natural products can deliver analogs without the need for lengthy de novo syntheses. Yet, achieving selective reactivity at a single desired position is complicated by the presence of multiple iterations of similar reactive functional groups, thus precluding widespread adoption of catalyst-controlled site-selective modification. Herein we describe the development of complementary systems for the oxidation of secondary alcohols on erythromycin A, clarithromycin, and azithromycin using a newly designed azaadamantyl oxoammonium catalyst, wherein different hydroxyl groups show disparate reactivities under the same conditions. The application of this methodology has enabled the generation of a suite of oxidized macrolide antibiotics and derivatives that take advantage of the newly installed carbonyls. Antimicrobial activity testing revealed that multiple compounds retain activity against a broad range of pathogens consistent with erythromycin A coverage. Additionally, three of the compounds reported herein display antibiotic activity against CA-MRSA and MRSA­(mph(C)), for which the clinical analogs erythromycin A, clarithromycin, and azithromycin exhibit no activity at tested concentrations.

Tryptophan metabolites: kynurenine (KYN), kynurenic acid (KYNA) and 6-formylindolo[3,2-b]carbazole (FICZ) are considered aryl hydrocarbon receptor (AhR) ligands. AhR is mainly expressed in barrier tissues, including skin, and is involved in various physiological and pathological processes in skin. We studied the effect of KYN, KYNA and FICZ on melanocyte and melanoma A375 and RPMI7951 cell toxicity, proliferation and cell death. KYN and FICZ inhibited DNA synthesis in both melanoma cell lines, but RPMI7951 cells were more resistant to pharmacological treatment. Tested compounds were toxic to melanoma cells but not to normal human adult melanocytes. Changes in the protein level of cyclin D1, CDK4 and retinoblastoma tumor suppressor protein (Rb) phosphorylation revealed different mechanisms of action of individual AhR ligands. Importantly, all tryptophan metabolites induced necrosis, but only KYNA and FICZ promoted apoptosis in melanoma A375 cells. This effect was not observed in RPMI7951 cells. KYN, KYNA and FICZ in higher concentrations inhibited the protein level of AhR but did not affect the gene expression. To conclude, despite belonging to the group of AhR ligands, KYN, KYNA and FICZ exerted different effects on proliferation, toxicity and induction of cell death in melanoma cells in vitro.

Air pollution remains a significant issue, particularly in urban areas. This study explored the prediction of hourly point-based PM10 concentrations using the XGBoost algorithm to assimilate them into a geostatistical land use regression model for spatially and temporally high-resolution prediction maps. The model configuration and training incorporated meteorological data, station metadata, and time variables based on statistical values and expert knowledge. Hourly measurements from approximately 400 stations from 2009 to 2017 were used for training. The selected model performed with a mean absolute error (MAE) of 6.88 μg m−3, root mean squared error (RMSE) of 9.95 μg m−3, and an R² of 0.65, with variations depending on the siting type and surrounding area. The model achieved a high accuracy of 98.54% and a precision of 73.96% in predicting exceedances of the current EU-limit value for the daily mean of 50 μg m−3. Despite identified limitations, the model can effectively predict hourly values for assimilation into a geostatistical land use regression model.

In cases with residual-hearing (RH) loss after cochlear implantation, a safe method is needed to provide full spectral resolution and as much auditory information as possible without implant replacement. Aim of this study was to prove the feasibility of accessing a partially inserted cochlear-implant-electrode for complete insertion to its maximum length through the external ear canal using a transcanal approach. Two CI electrodes were customized with 18 stimulating channels. The electrode design enables the use of 12 active channels available for electrical stimulation inside the cochlea both after partial and full insertion. 10 CI electrodes were implanted in 10 fresh human cadaveric temporal bones. After initial partial insertion by posterior tympanotomy, the electrode was inserted to its maximum length via a transcanal approach. Radiographs and CT scans were performed to confirm the electrode position. The electrodes were investigated via x-ray after removal. X-ray and CT-scans confirmed the electrode prototypes covering an angular insertion depth between 236° to 307° after initial insertion. Accessing the electrode in the middle ear space was feasible and insertion to its full length was successful. Post-insertion CT confirmed insertion of the 28mm and 31.5mm electrode arrays covering an angular insertion depth between 360° and 540° respectively. No tip foldovers were detected. This study confirms the feasibility of extending the electrode insertion to its maximum insertion length using a transcanal approach in temporal bone specimens. This constitutes a second stage procedure on demand in EAS-surgery. This may be beneficial for EAS-patients providing electrical stimulation beyond the basal turn of the cochlea once the functional residual hearing is lost, without replacing the entire CI.

In order to assess the model uncertainty of our RANS-based tool chain for wind-resource assessment “E-Wind”, we have simulated a large number of real wind farm projects with multiple measurement locations. Using one measurement location as reference and all others as target position, we systematically evaluated and analysed the horizontal extrapolation error for the annual mean wind speed introduced by the RANS method. Similar to previous studies, we found the model error to be strongly correlated with the simulated speed-up factor between two locations. We derived a method for site-specific prediction of the model uncertainty based on terrain complexity, simulated speed-up and distance between the measurement location and the turbine.

Air pollution is a major health risk factor worldwide. Regular short- and long-time exposures to ambient particulate matter (PM) promote various diseases and can lead to premature death. Therefore, in Germany, air quality is assessed continuously at approximately 400 measurement sites. However, knowledge about this intermediate distribution is either unknown or lacks a high spatial–temporal resolution to accurately determine exposure since commonly used chemical transport models are resource intensive. In this study, we present a method that can provide information about the ambient PM concentration for all of Germany at high spatial (100 m × 100 m) and hourly resolutions based on freely available data. To do so we adopted and optimised a method that combined land use regression modelling with a geostatistical interpolation technique using ordinary kriging. The land use regression model was set up based on CORINE (Coordination of Information on the Environment) land cover data and the Germany National Emission Inventory. To test the model’s performance under different conditions, four distinct data sets were used. (1) From a total of 8760 (365 × 24) available h, 1500 were randomly selected. From those, the hourly mean concentrations at all stations (ca. 400) were used to run the model (n = 566,326). The leave-one-out cross-validation resulted in a mean absolute error (MAE) of 7.68μgm−3 and a root mean square error (RMSE) of 11.20μgm−3. (2) For a more detailed analysis of how the model performs when an above-average number of high values are modelled, we selected all hourly means from February 2011 (n = 256,606). In February, measured concentrations were much higher than in any other month, leading to a slightly higher MAE of 9.77μgm−3 and RMSE of 14.36μgm−3, respectively. (3) To enable better comparability with other studies, the annual mean concentration (n = 413) was modelled with a MAE of 4.82μgm−3 and a RMSE of 6.08μgm−3. (4) To verify the model’s capability of predicting the exceedance of the daily mean limit value, daily means were modelled for all days in February (n = 10,845). The exceedances of the daily mean limit value of 50 μgm−3 were predicted correctly in 88.67% of all cases. We show that modelling ambient PM concentrations can be performed at a high spatial–temporal resolution for large areas based on open data, land use regression modelling, and kriging, with overall convincing results. This approach offers new possibilities in the fields of exposure assessment, city planning, and governance since it allows more accurate views of ambient PM concentrations at the spatial–temporal resolution required for such assessments.

The activating receptor natural killer group 2, member D (NKG2D) represents an attractive target for immunotherapy as it exerts a crucial role in cancer immunosurveillance by regulating the activity of cytotoxic lymphocytes. In this study, a panel of novel NKG2D-specific single-chain fragments variable (scFv) were isolated from naïve human antibody gene libraries and fused to the fragment antigen binding (Fab) of rituximab to obtain [CD20×NKG2D] bibodies with the aim to recruit cytotoxic lymphocytes to lymphoma cells. All bispecific antibodies bound both antigens simultaneously. Two bibody constructs, [CD20×NKG2D#3] and [CD20×NKG2D#32], efficiently activated natural killer (NK) cells in co-cultures with CD20+ lymphoma cells. Both bibodies triggered NK cell-mediated lysis of lymphoma cells and especially enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by CD38 or CD19 specific monoclonal antibodies suggesting a synergistic effect between NKG2D and FcγRIIIA signaling pathways in NK cell activation. The [CD20×NKG2D] bibodies were not effective in redirecting CD8+ T cells as single agents, but enhanced cytotoxicity when combined with a bispecific [CD19×CD3] T cell engager, indicating that NKG2D signaling also supports CD3-mediated T cell activation. In conclusion, engagement of NKG2D with bispecific antibodies is attractive to directly activate cytotoxic lymphocytes or to support their activation by monoclonal antibodies or bispecific T cell engagers. As a perspective, co-targeting of two tumor antigens may allow fine-tuning of antibody cancer therapies. Our proposed combinatorial approach is potentially applicable for many existing immunotherapies but further testing in different preclinical models is necessary to explore the full potential.

The human thalamus relays sensory signals to the cortex and facilitates brain-wide communication. The thalamus is also more directly involved in sensorimotor and various cognitive functions but a full characterization of its functional repertoire, particularly in regard to its internal anatomical structure, is still outstanding. As a putative hub in the human connectome, the thalamus might reveal its functional profile only in conjunction with interconnected brain areas. We therefore developed a novel systems-level Bayesian reverse inference decoding that complements the traditional neuroinformatics approach towards a network account of thalamic function. The systems-level decoding considers the functional repertoire (i.e., the terms associated with a brain region) of all regions showing co-activations with a predefined seed region in a brain-wide fashion. Here, we used task-constrained meta-analytic connectivity-based parcellation (MACM-CBP) to identify thalamic subregions as seed regions and applied the systems-level decoding to these subregions in conjunction with functionally connected cortical regions. Our results confirm thalamic structure–function relationships known from animal and clinical studies and revealed further associations with language, memory, and locomotion that have not been detailed in the cognitive neuroscience literature before. The systems-level decoding further uncovered large systems engaged in autobiographical memory and nociception. We propose this novel decoding approach as a useful tool to detect previously unknown structure–function relationships at the brain network level, and to build viable starting points for future studies.