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Frames are a central concept in communication research. Based on our literature review, we propose that frame identification is an act of identifying selected reality and communicative intention. We then highlight the conceptual and methodological issues of frame identification using computational methods. To avoid the correlation between topics and frames, we provide a synthetic dataset for evaluating frames found in multi-topical news content, using the detection of generic frames as a test case. With this dataset, for the first time, we benchmark manual coding and various automatic and semi-supervised methods. Based on the preliminary benchmark results, this study provides evidence that generic frame identification using both manual coding and automatic methods might not be accurate.

Nanomaterial properties and functionalities are influenced by their shape, size, and chemical composition. The importance of these parameters highlights the need for a statistically robust analysis of a large particle population, necessitating automation. This study introduces a neural network‐empowered smart scan technique that achieves a relative increase in speed compared to traditional energy‐dispersive X‐ray spectroscopy (EDX) mapping. The main advantage is that it reduces the required dose, decreasing potential damage to the sample by avoiding unnecessary exposure. It holds potential use in other multimodal scanning transmission electron microscopy or scanning‐based imaging approaches. In the first example, identifying particles in a matrix with a trained neural network reduces the acquisition time by two orders of magnitude. This acceleration enables a statistical compositional analysis of thousands of particles in less than 1 h. Similar improvements are observed for atomic resolution. The discrete positions of atoms identified by the trained network allow for selective EDX sampling at these centers, thereby identifying the atomic species of the column with much‐reduced sampling. Consequently, a lower sampling dose is required, enabling mapping of more delicate materials with high lateral resolution and at a high statistical confidence interval. Even though manual training is still required, this approach greatly benefits repetitive quality control tasks.

Abstract This paper addresses the question whether and to what extent the experience of online hate speech affects victims’ sense of security. Studies on hate crime in general show that such crimes are associated with a significantly higher feeling of insecurity, but there is little evidence concerning feeling of insecurity due to online hate speech. Based on a secondary data analysis of a representative population survey in Lower Saxony, Germany, on the topic of cybercrime in 2020 (N = 4,102), we tested three hypotheses regarding the effect of offline and online hate speech on feelings of insecurity. As a result, compared to non-victims, victims of online hate speech exhibit a more pronounced feeling of insecurity outside the Internet, while victims of other forms of cybercrime do not differ in this regard from non-victims. We found no effect for offline hate speech when relevant control variables were included in the statistical model. Possible reasons for this finding are assumed to lie in the characteristics of the phenomenon of online hate speech, for example, because the hateful content spreads uncontrollably on the Internet and reaches its victims even in protected private spheres.

PurposeNeuroglial tumors are frequently associated with pharmacorefractory epilepsies. However, comprehensive knowledge about long-term outcomes after epilepsy surgery and the main prognostic factors for outcome is still limited. We sought to evaluate long-term outcomes and potential influencing factors in a large cohort of patients who underwent surgery for neuroglial tumors in a single-center setting.MethodsThe study analyzed the outcomes of 107 patients who underwent epilepsy surgery for neuroglial tumors between 2001 and 2020 at the Department of Epileptology, University Hospital Bonn, in Germany. The outcomes were evaluated using Engel classification. Differences in outcome related to potential prognostic factors were examined using the Chi2-test, Fisher’s exact test and sign test. Additionally, stepwise logistic regression analysis was employed to identify independent prognostic factors.ResultsComplete seizure freedom (Engel Class IA) was achieved in 75% of the operated patients at 12 months, and 56% at the last follow-up visit (70.4 ± 6.2 months, median: 40 months). Completeness of resection was a crucial factor for both 12-month follow-up outcomes and the longest available outcomes, whereas lobar tumor localization, histology (ganglioglioma vs. dysembryoplastic neuroepithelial tumor), history of bilateral tonic–clonic seizures prior to surgery, invasive diagnostics, side of surgery (dominant vs. non-dominant hemisphere), age at epilepsy onset, age at surgery, and epilepsy duration did not consistently impact postsurgical outcomes. Among temporal lobe surgeries, patients who underwent lesionectomy and lesionectomy, including hippocampal resection, demonstrated similar outcomes.ConclusionNeuroglial tumors present as excellent surgical substrates in treating structural epilepsy. To achieve an optimal postsurgical outcome, a complete lesion resection should be pursued whenever possible.

Background The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.Methods HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.Results We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.Conclusion The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.

Summary: Eosinophils play a crucial role in host defense while also contributing to immunopathology through the release of inflammatory mediators. Characterized by distinctive cytoplasmic granules, eosinophils securely store and rapidly release various proteins exhibiting high toxicity upon extracellular release. Among these, major basic protein 1 (MBP-1) emerges as an important mediator in eosinophil function against pathogens and in eosinophil-associated diseases. While MBP-1 targets both microorganisms and host cells, its precise mechanism remains elusive. We demonstrate that formation of small pores by MBP-1 in lipid bilayers induces membrane permeabilization and disrupts potassium balance. Additionally, we reveal that mitochondrial DNA (mtDNA) present in eosinophil extracellular traps (EETs) amplifies MBP-1 toxic effects, underscoring the pivotal role of mtDNA in EETs. Furthermore, we present evidence indicating that absence of CpG methylation in mtDNA contributes to the regulation of MBP-1-mediated toxicity. Taken together, our data suggest that the mtDNA scaffold within extracellular traps promotes MBP-1 toxicity.

Gangliogliomas (GGs) represent the most frequent glioneuronal tumor entity associated with chronic recurrent seizures; rare anaplastic GGs variants retain the glioneuronal character. So far, key mechanisms triggering chronic hyperexcitability in the peritumoral area are unresolved. Based on a recent mouse model for anaplastic GG (BRAFV600E, mTOR activation and Trp53KO) we here assessed the influence of GG-secreted factors on non-neoplastic cells in-vitro. We generated conditioned medium (CM) from primary GG cell cultures to developing primary cortical neurons cultured on multielectrode-arrays and assessed their electrical activity in comparison to neurons incubated with naïve and neuronal CMs. Our results showed that the GG CM, while not affecting the mean firing rates of networks, strongly accelerated the formation of functional networks as indicated increased synchrony of firing and burst activity. Washing out the GG CM did not reverse these effects indicating an irreversible effect on the neuronal network. Mass spectrometry analysis of GG CM detected several enriched proteins associated with neurogenesis as well as gliogenesis, including Gap43, App, Apoe, S100a8, Tnc and Sod1. Concomitantly, immunocytochemical analysis of the neuronal cultures exposed to GG CM revealed abundant astrocytes suggesting that the GG-secreted factors induce astroglial proliferation. Pharmacological inhibition of astrocyte proliferation only partially reversed the accelerated network maturation in neuronal cultures exposed to GG CM indicating that the GG CM exerts a direct effect on the neuronal component. Taken together, we demonstrate that GG-derived paracrine signaling alone is sufficient to induce accelerated neuronal network development accompanied by astrocytic proliferation. Perspectively, a deeper understanding of factors involved may serve as the basis for future therapeutic approaches.

The aim was to investigate how the congruence of odors and visual objects in virtual reality (VR) affects later memory recall of the objects. Participants (N = 30) interacted with 12 objects in VR. The interaction was varied by odor congruency (i.e., the odor matched the object’s visual appearance, the odor did not match the object’s visual appearance, or the object had no odor); odor quality (i.e., an authentic or a synthetic odor); and interaction type (i.e., participants could look and manipulate or could only look at objects). After interacting with the 12 objects, incidental memory performance was measured with a free recall task. In addition, the participants rated the pleasantness and arousal of the interaction with each object. The results showed that the participants remembered significantly more objects with congruent odors than objects with incongruent odors or odorless objects. Furthermore, interaction with congruent objects was rated significantly more pleasant and relaxed than interaction with incongruent objects. Odor quality and interaction type did not have significant effects on recall or emotional ratings. These results can be utilized in the development of multisensory VR applications.

Loss of the Y chromosome (LoY) is frequently observed in somatic cells of elderly men. However, LoY is highly increased in tumor tissue and correlates with an overall worse prognosis. The underlying causes and downstream effects of LoY are widely unknown. Therefore, we analyzed genomic and transcriptomic data of 13 cancer types (2375 patients) and classified tumors of male patients according to loss or retain of the Y chromosome (LoY or RoY, average LoY fraction: 0.46). The frequencies of LoY ranged from almost absence (glioblastoma, glioma, thyroid carcinoma) to 77% (kidney renal papillary cell carcinoma). Genomic instability, aneuploidy, and mutation burden were enriched in LoY tumors. In addition, we found more frequently in LoY tumors the gate keeping tumor suppressor gene TP53 mutated in three cancer types (colon adenocarcinoma, head and neck squamous carcinoma, lung adenocarcinoma) and oncogenes MET, CDK6, KRAS, and EGFR amplified in multiple cancer types. On the transcriptomic level, we observed MMP13, known to be involved in invasion, to be up-regulated in LoY of three adenocarcinomas and down-regulation of the tumor suppressor gene GPC5 in LoY of three cancer types. Furthermore, we found enrichment of a smoking-related mutation signature in LoY tumors of head and neck and lung cancer. Strikingly, we observed a correlation between cancer type-specific sex bias in incidence rates and frequencies of LoY, in line with the hypothesis that LoY increases cancer risk in males. Overall, LoY is a frequent phenomenon in cancer that is enriched in genomically unstable tumors. It correlates with genomic features beyond the Y chromosome and might contribute to higher incidence rates in males.

In the aviation industry, a large number of processes are not digitalised. Simultaneously, many special processes are used in production, such as incremental bending. In order to model and efficiently design multi-stage processes with methods such as FEM, automation and linking of the individual simulations are necessary. This paper therefore presents a method for automatically simulating and evaluating a complete incremental bending process with 24 strokes in LS-Dyna using a Python framework with cfiles. The final validation of the force–displacement relationships and inner radii of the generated scaled fuselage shell show high prediction accuracies of about 90%. Thus, the presented methodology enables a FEM-based process design of incremental bending in the aviation industry.

BackgroundMajor depressive episode (MDE) is a common clinical syndrome. It can be found in different pathologies such as major depressive disorder (MDD), bipolar disorder (BD), posttraumatic stress disorder (PTSD), or even occur in the context of psychological trauma. However, only 1 syndrome is described in international classifications (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5]/International Classification of Diseases 11th Revision [ICD-11]), which do not take into account the underlying pathology at the origin of the MDE. Clinical interviews are currently the best source of information to obtain the etiological diagnosis of MDE. Nevertheless, it does not allow an early diagnosis and there are no objective measures of extracted clinical information. To remedy this, the use of digital tools and their correlation with clinical symptomatology could be useful. ObjectiveWe aimed to review the current application of digital tools for MDE diagnosis while highlighting shortcomings for further research. In addition, our work was focused on digital devices easy to use during clinical interview and mental health issues where depression is common. MethodsWe conducted a narrative review of the use of digital tools during clinical interviews for MDE by searching papers published in PubMed/MEDLINE, Web of Science, and Google Scholar databases since February 2010. The search was conducted from June to September 2021. Potentially relevant papers were then compared against a checklist for relevance and reviewed independently for inclusion, with focus on 4 allocated topics of (1) automated voice analysis, behavior analysis by (2) video and physiological measures, (3) heart rate variability (HRV), and (4) electrodermal activity (EDA). For this purpose, we were interested in 4 frequently found clinical conditions in which MDE can occur: (1) MDD, (2) BD, (3) PTSD, and (4) psychological trauma. ResultsA total of 74 relevant papers on the subject were qualitatively analyzed and the information was synthesized. Thus, a digital phenotype of MDE seems to emerge consisting of modifications in speech features (namely, temporal, prosodic, spectral, source, and formants) and in speech content, modifications in nonverbal behavior (head, hand, body and eyes movement, facial expressivity, and gaze), and a decrease in physiological measurements (HRV and EDA). We not only found similarities but also differences when MDE occurs in MDD, BD, PTSD, or psychological trauma. However, comparative studies were rare in BD or PTSD conditions, which does not allow us to identify clear and distinct digital phenotypes. ConclusionsOur search identified markers from several modalities that hold promise for helping with a more objective diagnosis of MDE. To validate their potential, further longitudinal and prospective studies are needed.

NHA2, also known as SLC9B2, is an orphan intracellular Na+/H+ exchanger (NHE) that has been associated with arterial hypertension and diabetes mellitus in humans. The objective of this NCCR TransCure project was to define the physiological and molecular function of NHA2, to develop a high resolution kinetic transport assay for NHA2 and to identify specific and potent compounds targeting NHA2. In this review, we summarize the results of this highly interdisciplinary and interfaculty effort, led by the groups of Proffs. Jean-Louis Reymond, Christoph von Ballmoos and Daniel Fuster.

Abstract Membrane bound nicotinamide nucleotide transhydrogenase (TH) catalyses the hydride transfer from NADH to NADP+. Under physiological conditions, this reaction is endergonic and must be energized by the pmf, coupled to transmembrane proton transport. Recent structures of transhydrogenase holoenzymes suggest new mechanistic details, how the long-distance coupling between hydride transfer in the peripheral nucleotide binding sites and the membrane-localized proton transfer occurs that now must be tested experimentally. Here, we provide protocols for the efficient expression and purification of the Escherichia coli transhydrogenase and its reconstitution into liposomes, alone or together with the Escherichia coli F1F0 ATP synthase. We show that E. coli transhydrogenase is a reversible enzyme that can also work as a NADPH-driven proton pump. In liposomes containing both enzymes, NADPH driven H+-transport by TH is sufficient to instantly fuel ATP synthesis, which adds TH to the pool of pmf generating enzymes. If the same liposomes are energized with ATP, NADPH production by TH is stimulated > sixfold both by a pH gradient or a membrane potential. The presented protocols and results reinforce the tight coupling between hydride transfer in the peripheral nucleotide binding sites and transmembrane proton transport and provide powerful tools to investigate their coupling mechanism.

When on-site classification of volatile organic compounds (VOCs) is required, a portable ion mobility spectrometer (IMS) is a suitable choice. However, the IMS readings often show transient phases before they stabilize. Even so the importance of transient phase and features extracted from it has been highlighted in the literature, it has not, to our knowledge, been used for IMS-based classification so far. This paper analyzes whether change point detection algorithms with low computational complexity can separate transient and stable phases in IMS readings. The algorithms were tested on IMS data from different types of mushrooms. All algorithms successfully detected switches from transient to stable phase. The most accurate results were provided by the previously proposed multivariate max-CUSUM algorithm and the matrix form CUSUM algorithm, which is developed in this paper.

The new recommended definition of a nanomaterial, 2022/C 229/01, adopted by the European Commission in 2022, will have a considerable impact on European Union legislation addressing chemicals, and therefore tools to implement this new definition are urgently needed. The updated NanoDefiner framework and its e-tool implementation presented here are such instruments, which help stakeholders to find out in a straightforward way whether a material is a nanomaterial or not. They are two major outcomes of the NanoDefine project, which is explicitly referred to in the new definition. This work revisits the framework and e-tool, and elaborates necessary adjustments to make these outcomes applicable for the updated recommendation. A broad set of case studies on representative materials confirms the validity of these adjustments. To further foster the sustainability and applicability of the framework and e-tool, measures for the FAIRification of expert knowledge within the e-tool’s knowledge base are elaborated as well. The updated framework and e-tool are now ready to be used in line with the updated recommendation. The presented approach may serve as an example for reviewing existing guidance and tools developed for the previous definition 2011/696/EU, particularly those adopting NanoDefine project outcomes.

Abstract Background FES (Functional Electrical Stimulation) neuroprostheses have long been a permanent feature in the rehabilitation and gait support of people who had a stroke or have a Spinal Cord Injury (SCI). Over time the well-known foot switch triggered drop foot neuroprosthesis, was extended to a multichannel full-leg support neuroprosthesis enabling improved support and rehabilitation. However, these neuroprostheses had to be manually tuned and could not adapt to the persons’ individual needs. In recent research, a learning controller was added to the drop foot neuroprosthesis, so that the full stimulation pattern during the swing phase could be adapted by measuring the joint angles of previous steps. Methods The aim of this research is to begin developing a learning full-leg supporting neuroprosthesis, which controls the antagonistic muscle pairs for knee flexion and extension, as well as for ankle joint dorsi- and plantarflexion during all gait phases. A method was established that allows a continuous assessment of knee and foot joint angles with every step. This method can warp the physiological joint angles of healthy subjects to match the individual pathological gait of the subject and thus allows a direct comparison of the two. A new kind of Iterative Learning Controller (ILC) is proposed which works independent of the step duration of the individual and uses physiological joint angle reference bands. Results In a first test with four people with an incomplete SCI, the results showed that the proposed neuroprosthesis was able to generate individually fitted stimulation patterns for three of the participants. The other participant was more severely affected and had to be excluded due to the resulting false triggering of the gait phase detection. For two of the three remaining participants, a slight improvement in the average foot angles could be observed, for one participant slight improvements in the averaged knee angles. These improvements where in the range of 4 c i r c at the times of peak dorsiflexion, peak plantarflexion, or peak knee flexion. Conclusions Direct adaptation to the current gait of the participants could be achieved with the proposed method. The preliminary first test with people with a SCI showed that the neuroprosthesis can generate individual stimulation patterns. The sensitivity to the knee angle reset, timing problems in participants with significant gait fluctuations, and the automatic ILC gain tuning are remaining issues that need be addressed. Subsequently, future studies should compare the improved, long-term rehabilitation effects of the here presented neuroprosthesis, with conventional multichannel FES neuroprostheses.

Maximal oxygen uptake (VO2 max) is the maximum amount of oxygen attainable by a person during exercise. VO2 max is used in different domains including sports and medical sciences and is usually measured during an incremental treadmill or cycle ergometer test. The drawback of directly measuring VO2 max using the maximal test is that it is expensive and requires a fixed and controlled protocol. During the last decade, various machine learning models have been developed for VO2 max prediction and numerous studies have attempted to predict VO2 max using data from submaximal and non-exercise tests. This article gives an overview of the machine learning models developed over the past five years (2016–2021) for the prediction of VO2 max. Multiple linear regression, support vector machine, artificial neural network and multilayer perceptron are some of the techniques that have been used to build predictive models using different combinations of predictor variables. Model performance is generally assessed using correlation coefficient (R-value), standard error of estimate (SEE) and root mean squared error (RMSE), computed between ground truth and predicted values. The findings of this review indicate that models using ANN typically outperform other machine learning techniques. Moreover, the predictor variables used to build the model have a large influence on the model's predictive performance.

ObjectiveInflammation of brain structures, in particular the hippocampal formation, can induce neuronal degeneration and be associated with increased excitability manifesting as propensity for repetitive seizures. An increase in the abundance of individual proinflammatory molecules including interleukin 1 beta has been observed in brain tissue samples of patients with pharmacoresistant temporal lobe epilepsy (TLE) and corresponding animal models. The NLRP3-inflammasome, a cytosolic protein complex, acts as a key regulator in proinflammatory innate immune signalling. Upon activation, it leads to the release of interleukin 1 beta and inflammation-mediated neurodegeneration. Transient brain insults, like status epilepticus (SE), can render hippocampi chronically hyperexcitable and induce segmental neurodegeneration. The underlying mechanisms are referred to as epileptogenesis. Here, we have tested the hypothesis that distinct NLRP3-dependent transcript and protein signalling dynamics are induced by SE and whether they differ between two classical SE models. We further correlated the association of NLRP3-related transcript abundance with convulsive activity in human TLE hippocampi of patients with and without associated neurodegenerative damage.MethodsHippocampal mRNA- and protein-expression of NLRP3 and associated signalling molecules were analysed longitudinally in pilocarpine- and kainic acid-induced SE TLE mouse models. Complementarily, we studied NLRP3 inflammasome-associated transcript patterns in epileptogenic hippocampi with different damage patterns of pharmacoresistant TLE patients that had undergone epilepsy surgery for seizure relief.ResultsPilocarpine- and kainic acid-induced SE elicit distinct hippocampal Nlrp3-associated molecular signalling. Transcriptional activation of NLRP3 pathway elements is associated with seizure activity but independent of the particular neuronal damage phenotype in KA-induced and in human TLE hippocampi.SignificanceThese data suggest highly dynamic inflammasome signalling in SE-induced TLE and highlight a vicious cycle associated with seizure activity. Our results provide promising perspectives for the inflammasome signalling pathway as a target for anti-epileptogenic and -convulsive therapeutic strategies. The latter may even applicable to a particularly broad spectrum of TLE patients with currently pharmacoresistant disease.

Oxygen uptake (V˙O2) is an important metric in any exercise test including walking and running. It can be measured using portable spirometers or metabolic analyzers. Those devices are, however, not suitable for constant use by consumers due to their costs, difficulty of operation and their intervening in the physical integrity of their users. Therefore, it is important to develop approaches for the indirect estimation of V˙O2-based measurements of motion parameters, heart rate data and application-specific measurements from consumer-grade sensors. Typically, these approaches are based on linear regression models or neural networks. This study investigates how motion data contribute to V˙O2 estimation accuracy during unconstrained running and walking. The results suggest that a long short term memory (LSTM) neural network can predict oxygen consumption with an accuracy of 2.49 mL/min/kg (95% limits of agreement) based only on speed, speed change, cadence and vertical oscillation measurements from an inertial navigation system combined with a Global Positioning System (INS/GPS) device developed by our group, worn on the torso. Combining motion data and heart rate data can significantly improve the V˙O2 estimation resulting in approximately 1.7–1.9 times smaller prediction errors than using only motion or heart rate data.

Research suggests that Facebook’s reputation as a news source is in decline. One reason for this development might be found in how users perceive their own exposure to alleged ‘fake news’ - a phenomenon which has been strongly linked to Facebook in public debate. Using a quota survey of German Internet users (n = 743) we investigate how users’ self-perceived exposure to ‘fake news’ and the ‘fake news’ debate are related to their evaluation and verification of political information on Facebook. Results indicate that the evaluation of Facebook as a news source is independent of users’ perceptions of their total amount of exposure to ‘fake news’ or the ‘fake news’ debate. However, individuals who feel they encounter many ‘fake news’ from traditional news sources evaluate Facebook more positively. Contrary to that, those who believe that the ‘fake news’ they are exposed to originate in alternative sources evaluate Facebook less positively and also engage in verification behaviors more frequently. Moreover, verification is predicted by the overall level of perceived ‘fake news’ exposure and, most strongly, by exposure to the ‘fake news’ debate. Findings are discussed in light of recent research on news audience polarization.

The deep-drawability of a sheet metal blank is strongly influenced by the tribological conditions prevailing in a deep-drawing process. Therefore, new methods to influence the tribology represent an important research topic. In this work, the application of a process-integrated lubrication in a deep-drawing process is investigated. Most promising geometries of the lubrication channels and outlet openings are first identified by means of numerical simulation at the example of a demonstrator process. Cylindrical test specimens with the specified channel geometries are additively manufactured and installed in a strip drawing test stand. Additive manufacturing enables the possibility of manufacturing complex channel geometries which cannot be manufactured by conventional methods. A hydraulic metering device for conveying lubricant is connected to the cylindrical test specimens. Thus, hydraulically lubricated strip drawing tests are performed. The tests are evaluated according to the force curves and the fluid mechanical buildup of pressure cushion. The performance of process-integrated lubrication is thus analyzed and evaluated. By means of a coupled forming and SPH simulation, the lubrication channels could be optimally designed. From the practical tests, it could be achieved that the drawing force decreases up to 27% with pressure cushion build up. In this research, a hydraulic lubrication in the area of highest contact normal stresses is the most optimal process parameter regarding friction reduction.

One important prerequisite for developing a therapeutic monoclonal antibody is to evaluate its in vivo efficacy. We tested the therapeutic potential of an anti-CD96 antibody alone or in combination with an anti-PD-1 antibody in a mouse colon cancer model. Early anti-PD-1 treatment significantly decreased tumor growth and the combination with anti-CD96 further increased the therapeutic benefit, while anti-CD96 treatment alone had no effect. In late therapeutic settings, the treatment combination resulted in enhanced CD8+ T cell infiltration of tumors and an increased CD8/Treg ratio. Measured anti-PD-1 concentrations were as expected in animals treated with anti-PD-1 alone, but lower at later time points in animals receiving combination treatment. Moreover, anti-CD96 concentrations dropped dramatically after 10 days and were undetectable thereafter in most animals due to the occurrence of anti-drug antibodies that were increasing antibody clearance. Comparison of the anti-PD-1 concentrations with tumor growth showed that higher antibody concentrations in plasma correlated with better therapeutic efficacy. The therapeutic effect of anti-CD96 treatment could not be evaluated, because plasma concentrations were too low. Our findings strongly support the notion of measuring both plasma concentration and anti-drug antibody formation throughout in vivo studies, in order to interpret pharmacodynamic data correctly.

Abstract Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCRβ clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as α-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies.

Der vorliegende Beitrag diskutiert die Entwicklung von Kriminalität unter der aktuellen Corona-Krise bezogen auf fünf ausgewählte Deliktbereiche. Im Rahmen einer wissenschaftlichen Auseinandersetzung zeigt sich, dass die derzeitige Situation Menschen vor besondere Herausforderungen stellt, die das Risiko mitunter erhöhen können, Täter*in oder Opfer zu werden. So verzeichnet der Beitrag auf den verschiedenen Deliktebenen einen überwiegend verstärkenden Einfluss, auch wenn sich dieser in einigen Fällen voraussichtlich erst nach Beendigung der Maßnahmen zeigen wird. Diese Dynamik wird begründet mit einer Veränderung der Alltagsroutinen, einer psychischen Belastung sowie einem erschwerten Zugang zu Hilfs- und Unterstützungsangeboten während der Krise.

Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.

For ion-mobility spectrometry (IMS)-based electronic noses (eNose) samples of scents are markedly time-dependent, with a transient phase and a highly volatile stable phase in certain conditions. At the same time, the samples depend on various environmental factors, such as temperature and humidity. This makes fast classification of scents challenging. The present aim was to develop and test an algorithm for online scent classification that mitigates these dependencies by using both baseline measurements and sequences of samples for classification. A classifier based on the K nearest neighbors approach was derived. The classifier is able to use measurements from both transient and stable phase, yields a label for the analyzed scent, and information on the trustworthiness of the returned label. In order to avoid the classifier being fooled by irrelevant features and to reduce the dimensionality of the feature space, principal component analysis was applied to the data. The classifier was tested with four food scents, each presented in two different ways to the IMS. By using baseline measurements, the misclassification rate was reduced from 20.0 to 13.3%. A second experiment showed that the used IMS type experiences device heterogeneity.

Tools are of strategic importance for industrial manufacturing processes. Their behaviour has a great influence on the productivity of the process and the quality of the product. A material saving and efficient technique for processing metallic workpieces is cold forging. One major challenge of this production method is the handling of high contact normal stresses in the tool contact, which can lead to severe tool wear. To investigate promising approaches for understanding wear modelling and wear reduction a demonstrator process based on the first stage of a total five-staged cold forging process for the manufacturing of a bolt anchor is considered in the scope of this research. This work aims at the further development of a numerical wear calculation based on an adapted Archard model in order to be able to realistically predict the tool wear in cold forging processes. Therefore, the material characterization of the used workpiece material as well as an investigation of the worn tool dies takes place to validate a numerical wear calculation model. Furthermore, this research addresses a reduction in wear by identifying critical areas and changing the inlet geometry of the investigated demonstrator tool die. This way, conclusions can be drawn about the wear sensitivity during numerical process design, and particularly critical areas can be geometrically modified in terms of the design.

Fringe projection profilometry in combination with other optical measuring technologies has established itself over the last decades as an essential complement to conventional, tactile measuring devices. The non-contact, holistic reconstruction of complex geometries within fractions of a second in conjunction with the lightweight and transportable sensor design open up many fields of application in production metrology. Furthermore, triangulation-based measuring principles feature good scalability, which has led to 3D scanners for various scale ranges. Innovative and modern production processes, such as sheet-bulk metal forming, thus, utilize fringe projection profilometry in many respects to monitor the process, quantify possible wear and improve production technology. Therefore, it is essential to identify the appropriate 3D scanner for each application and to properly evaluate the acquired data. Through precise knowledge of the measurement volume and the relative uncertainty with respect to the specimen and scanner position, adapted measurement strategies and integrated production concepts can be realized. Although there are extensive industrial standards and guidelines for the quantification of sensor performance, evaluation and tolerancing is mainly global and can, therefore, neither provide assistance in the correct, application-specific positioning and alignment of the sensor nor reflect the local characteristics within the measuring volume. Therefore, this article compares fringe projection systems across various scale ranges by positioning and scanning a calibrated sphere in a high resolution grid.

Vertical ground reaction force (vGRF) can be measured by force plates or instrumented treadmills, but their application is limited to indoor environments. Insoles remove this restriction but suffer from low durability (several hundred hours). Therefore, interest in the indirect estimation of vGRF using inertial measurement units and machine learning techniques has increased. This paper presents a methodology for indirectly estimating vGRF and other features used in gait analysis from measurements of a wearable GPS-aided inertial navigation system (INS/GPS) device. A set of 27 features was extracted from the INS/GPS data. Feature analysis showed that six of these features suffice to provide precise estimates of 11 different gait parameters. Bagged ensembles of regression trees were then trained and used for predicting gait parameters for a dataset from the test subject from whom the training data were collected and for a dataset from a subject for whom no training data were available. The prediction accuracies for the latter were significantly worse than for the first subject but still sufficiently good. K-nearest neighbor (KNN) and long short-term memory (LSTM) neural networks were then used for predicting vGRF and ground contact times. The KNN yielded a lower normalized root mean square error than the neural network for vGRF predictions but cannot detect new patterns in force curves.

The present aim was to compare the accuracy of several algorithms in classifying data collected from food scent samples. Measurements using an electronic nose (eNose) can be used for classification of different scents. An eNose was used to measure scent samples from seven food scent sources, both from an open plate and a sealed jar. The k-Nearest Neighbour (k-NN) classifier provides reasonable accuracy under certain conditions and uses traditionally the Euclidean distance for measuring the similarity of samples. Therefore, it was used as a baseline distance metric for the k-NN in this paper. Its classification accuracy was compared with the accuracies of the k-NN with 66 alternative distance metrics. In addition, 18 other classifiers were tested with raw eNose data. For each classifier various parameter settings were tried and compared. Overall, 304 different classifier variations were tested, which differed from each other in at least one parameter value. The results showed that Quadratic Discriminant Analysis, MLPClassifier, C-Support Vector Classification (SVC), and several different single hidden layer Neural Networks yielded lower misclassification rates applied to the raw data than k-NN with Euclidean distance. Both MLP Classifiers and SVC yielded misclassification rates of less than 3% when applied to raw data. Furthermore, when applied both to the raw data and the data preprocessed by principal component analysis that explained at least 95% or 99% of the total variance in the raw data, Quadratic Discriminant Analysis outperformed the other classifiers. The findings of this study can be used for further algorithm development. They can also be used, for example, to improve the estimation of storage times of fruit.

While there has been a broad debate on the use of theory in history in general, there are few contributions by historians of communication and the media discussing the role of theory in their particular field. We therefore review and discuss some of the main arguments pertaining to the use of theory in historiography and apply them to the field of media and communication history. Such arguments include the assumption that theories are already implicit in all types of narratives, or the idea that theory amounts to a speculative philosophy of history. We also discuss the controversial question whether deductive explanations and general laws should be applied to history. The article concludes that the use of theories is advisable, perhaps even necessary, given their multifunctionality and their different forms.

The tailored manipulation of ceramic surfaces gained recent interest to optimize the performance and lifetime of composite materials used as implants. In this work, a hierarchical surface texturing of hydroxyapatite (HAp) ceramics was developed to improve the poor adhesive bonding strength in hydroxyapatite and polycaprolactone (HAp/PCL) composites. Four different types of periodic surface morphologies (grooves, cylindric pits, linear waves and Gaussian hills) were realized by a ceramic micro-transfer molding technique in the submillimeter range. A subsequent surface roughening and functionalization on a micron to nanometer scale was obtained by two different etchings with hydrochloric and tartaric acid. An ensuing silane coupling with 3-aminopropyltriethoxysilane (APTES) enhanced the chemical adhesion between the HAp surface and PCL on the nanometer scale by the formation of dipole–dipole interactions and covalent bonds. The adhesive bonding strengths of the individual and combined surface texturings were investigated by performing single-lap compressive shear tests. All individual texturing types (macro, micro and nano) showed significantly improved HAp/PCL interface strengths compared to the non-textured HAp reference, based on an enhanced mechanical, physical and chemical adhesion. The independent effect mechanisms allow the deliberately hierarchical combination of all texturing types without negative influences. The hierarchical surface-textured HAp showed a 6.5 times higher adhesive bonding strength (7.7 ± 1.5 MPa) than the non-textured reference, proving that surface texturing is an attractive method to optimize the component adhesion in composites for potential medical implants.

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

Within the scope of the transregional collaborative research centre TCRC73, the effects of an oscillation superimposed forming process for the production of a demonstrator component are investigated. Previous studies in this field were limited to a consideration of the process-related parameters such as the influence of the plastic work and the friction or the component-related parameters such as the influence of the surface quality and the mold filling. This research concentrates on the consideration of the mechanical vibration resistance of components that were manufactured superimposed oscillated. For this purpose, Wöhler tests are conducted in which the fatigue strength of superimposed oscillation pre-stretched test samples and oscillation-free pre-stretched test samples are investigated. First, Wöhler curves are generated in the tensile threshold range for tensile samples made out of the steels DC04 and DP600. Subsequently, tensile specimens are pre-stretched superimposed oscillated and oscillation-free. These specimens are subjected to a tensile threshold load until they break. The influence of the superimposed oscillation forming on the long-term fatigue of components is derived from the comparison of the bearable load cycles. Investigations of the microstructure of the specimens are conducted in order to draw conclusions about the influence on the long-term strength.

Clinical diagnostics and disease control are fields that strongly depend on technologies for rapid, sensitive, and selective detection of biological or chemical analytes. Nanoparticles have become an integral part in various biomedical detection devices and nanotherapeutics. An increasing focus is laid on gold nanoparticles as they express less cytotoxicity, high stability, and hold unique optical properties with the ability of signal transduction of biological recognition events with enhanced analytical performance. Strong electromagnetic field enhancements can be found in close proximity to the nanoparticle that can be exploited to enhance signals for e.g., metal-enhanced fluorescence or Raman spectroscopy. Even stronger field enhancements can be achieved with sharp-edged nanoparticles, which are synthesized with the help of facet blocking agents, such as cetyltrimethylammonium bromide/chloride (CTAB/CTAC). However, chemical modification of the nanoparticle surface is necessary to reduce the particle’s cytotoxicity, stabilize it against aggregation, and to bioconjugate it with biomolecules to increase its biocompatibility and/or specificity for analytical applications. Here, a reliable two-step protocol following a ligand exchange with bis (p-sulfonatophenyl) phenyl phosphine (BSPP) as the intermediate capping-agent is demonstrated, which results in the reliable biofunctionalization of CTAC-capped gold nanocubes with thiol-modified DNA. The functionalized nanocubes have been characterized regarding their electric potential, plasmonic properties, and stability against high concentrations of NaCl and MgCl2.

A new sheet-bulk metal forming process for the production of bulk components out of a flat sheet has been developed. Superimposed oscillation has been applied to the new process. By this means, process limits regarding better mould filling were expanded, and forming forces could be reduced. In order to investigate the effects of superimposed oscillation on material behaviour, plane strain and ring compression tests were carried out. The superimposed oscillated plane strain compression test showed a reduction in biaxial flow stress and thus in plastic work. Furthermore, reduced friction and roughness were verified in ring compression tests using superimposed oscillation.

Producing complex sheet metal components in fewer process steps motivated the development of the innovative forming process called sheet-bulk metal forming (SBMF). In this process, sheet metal forming and bulk-metal forming are combined to create a unique forming process in which a component with external and internal gearing is produced in three production steps. However, the high degrees of deformation that occur using high-strength steels and the number of different process steps result in high process forces, strongly limiting the service life of tools. To reduce the forming force during SBMF processes, tool and process modifications were investigated. Therefore, plane-strain compression tests were conducted to examine the influence of a CrAlN PVD coating and tailored surfaces produced by high-feed milling (HF) of tool-active elements on the material flow of the specimens. In addition to the tool-sided modifications, the influence of an oscillation overlay during the forming process was investigated. Based on the results of the compression tests, the surfaces of the active tool elements of the SBMF process were modified in order to transfer the basic experimental results to the production of a functional component. The friction is thus adapted locally in the SBMF process.

Dieser Beitrag stellt zunächst dar, was heutige Jugendliche in Deutschland, von denen weniger als ein Drittel katholisch getauft ist, über Glaube und Kirche denken. Anschließend kommt die breite Praxis der Jugendpastoral in Deutschland zur Sprache, aber auch theoretische Konzepte, denen sie sich verpflichtet weiß. Der Beitrag schließt mit einem Plädoyer, sich als Seelsorger auf die Jugendlichen von heute und ihre existentiellen Fragen wirklich einzulassen.

The interaction of carbon-based aromatic molecules and nanostructures with metals can strongly depend on the topology of their π-electron systems. This is shown with a model system using the isomers azulene, which has a nonalternant π system with a 5-7 ring structure, and naphthalene, which has an alternant π system with a 6-6 ring structure. We found that azulene can interact much more strongly with metal surfaces. On copper (111), its zero-coverage desorption energy is 1.86 eV, compared to 1.07 eV for naphthalene. The different bond strengths are reflected in the adsorption heights, which are 2.30 Å for azulene and 3.04 Å for naphthalene, as measured by the normal incidence x-ray standing wave technique. These differences in the surface chemical bond are related to the electronic structure of the molecular π systems. Azulene has a low-lying LUMO that is close to the Fermi energy of Cu and strongly hybridizes with electronic states of the surface, as is shown by photoemission, near-edge x-ray absorption fine-structure, and scanning tunneling microscopy data in combination with theoretical analysis. According to density functional theory calculations, electron donation from the surface into the molecular LUMO leads to negative charging and deformation of the adsorbed azulene. Noncontact atomic force microscopy confirms the deformation, while Kelvin probe force microscopy maps show that adsorbed azulene partially retains its in-plane dipole. In contrast, naphthalene experiences only minor adsorption-induced changes of its electronic and geometric structure. Our results indicate that the electronic properties of metal-organic interfaces, as they occur in organic (opto)electronic devices, can be tuned through modifications of the π topology of the molecular organic semiconductor, especially by introducing 5-7 ring pairs as functional structural elements.

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From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo.

The vast majority of tumours are characterised by high frequencies of genetic and epigenetic alterations resulting in tumour-specific antigens, which may, in principle, be recognised by cytotoxic T cells. Though early clinical immunotherapy trials have yielded mixed results with ambiguous clinical benefit, cancer immunotherapy is now attracting increasing attention as a viable therapeutic option, mainly in melanoma and lung cancer, but increasingly also in other malignancies. In particular, recent therapeutic efforts targeting inhibitory receptors on T cells to overcome tumour-induced immune dysfunction have the potential to reshape current treatment standards in oncology. The clinical development has been pioneered by the antibody ipilimumab, which blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and has demonstrated survival benefit in two randomised landmark trials in melanoma. Capitalising on this success, the research on the clinical implication of T cell checkpoint inhibition has been boosted. Early clinical trials have demonstrated meaningful response rates, sustained clinical benefits with encouraging survival rates and good tolerability of next-generation checkpoint inhibitors, including programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors, across multiple cancer types. Attractive perspectives include the concurrent blockade of immunological (non-redundant) checkpoints, which has recently been demonstrated using combinations of immune checkpoint modulators themselves or with other therapies, such as chemotherapy, targeted therapy or radiotherapy. This article summarises the mechanism of action and subsequent clinical studies of immune checkpoint antibodies in oncology with a particular focus on melanoma and lung cancer.

Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic-AMP-protein kinase A-dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1-deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.

Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period.229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qbeta (47.2%) and placebo (35.1%) (P = 0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P = 0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P = 0.012).Whereas Nicotine-Qbeta did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction.Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616.