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The present work focuses on a detailed analysis of new and used braking friction partners (discs and pads) in order to provide a comprehensive characterization of the source of the airborne particles formed during braking. Scanning electron microscopy (SEM) combined with energy dispersive X-Ray analysis (EDX) was applied to investigate the new brake disc and new and used brake pad components of a passenger vehicle. The pads include at least 21 different substances, involving carbonaceous particles, oxides, sulfides, sulfates and silicates of Al, Si, K, Ca, Ti, Fe, Zr, Sn, less Mg, Ba, Na and, rarely, Bi and Zn, as well as K-titanate. Aramid and phenolic resin are also present, enriched toward the metal interface. The size of the pad constituents extends over a very wide range, from hundreds of µm to a few µm, and goes down to hundreds of nm and, rarely, tens of nanometers. Carbonaceous particles with sizes down to a few tens of nanometers occupy ca. 16% of the total of the pad constituents. Abundant Zr-bearing phases, as well as various other phases involving S, Ca, Mg, Si, Ti and, to a lower extent, Ba and Fe in different combinations, constitute the pad main matrix.

It has been suggested that B-cell receptor (BCRs) stimulation by specific antigens plays a pathogenic role in diffuse large B-cell lymphoma (DLBCL). Here, it was the aim to screen for specific reactivities of DLBCL-BCRs in the spectrum of autoantigens and antigens of infectious origin. Arsenite resistance protein 2 (Ars2) was identified as the BCR target of 3/5 ABC-type DLBCL cell lines and 2/11 primary DLBCL cases. Compared to controls, Ars2 was hypo-phosphorylated exclusively in cases and cell lines with Ars2-specific BCRs. In a validation cohort, hypo-phosphorylated Ars2 was found in 8/31 ABC-type, but only 1/20 germinal center B cell (GBC)-like type DLBCL. Incubation with Ars2 induced BCR-pathway activation and increased proliferation, while an Ars2/ETA-toxin conjugate induced killing of cell lines with Ars2-reactive BCRs. Ars2 appears to play a role in a subgroup of ABC-type DLBCLs. Moreover, transformed DLBCL lines with Ars2-reactive BCRs still show growth advantage after incubation with Ars2. These results provide knowledge about the pathogenic role of a specific antigen stimulating the BCR pathway in DLCBL.

Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11–17 steps, 1.5–2.9% yield). Thus, to access this compound more efficiently, we herein present a concise and significantly improved total synthesis of the natural product. Our short synthesis relies on two key cyclization steps to assemble the central scaffold: isoquinoline formation via an ethynyl-imino cyclization and an intramolecular Friedel-Crafts reaction to form the furanone.

Abstract Background and purpose New or enlarging T2‐hyperintense white matter lesions (WML) are associated with clinical disease progression in multiple sclerosis (MS). The prognostic value of WML shrinking is unclear. Assuming that waning of acute inflammation and repair processes would be the main drivers of WML shrinking, we aimed to assess the prognostic value of WML shrinking in early MS. Methods We retrospectively analyzed a cohort of 144 early MS patients with three brain MRI scans at baseline and after 1 and 3 years available. All patients were therapy naïve at baseline and 70.5% of them treated with disease modifying drugs at year 1. We determined the volume of WML shrinking between MRI scans, total WML volumes, number of gadolinium‐enhancing and new WML, white matter (WM) and gray matter volumes at each MRI scan. Clinical disability was measured by Expanded Disability Status Scale. We performed the correlation analyses of WML shrinking with other MRI parameters and clinical outcome. Results White matter lesions shrinking was highly variable between patients and correlated with the initial number of gadolinium‐enhancing WML and with WM volume decrease. WML shrinking was not associated with clinical outcome. Conclusion We found no indication of a prognostic value of WML shrinking in early MS patients. WML shrinking seems to be related to waning of acute inflammation.

From infectious diseases to brain activity, complex systems can be approximated using autoregressive models. Here, the authors show that incomplete sampling can bias estimates of the stability of such systems, and introduce a novel, unbiased metric for use in such situations.

Postcolonial theories have been applied in various contexts all over the globe. The article deals with the ways postcolonial thought, especially in combination with gender concerns, has been used in Finnish literary studies. I look at the broader problem of applying postcolonial theories in new contexts and pay close attention to the Nordic European space and its special features. I map the process through which postcolonial theories arrived in Finnish literary studies and then show how postcolonial thought has been applied, in a gender-conscious way, in two particular cases. The first one is the study of the Sámi, the indigenous population of the European North, and their literature, the second one is the study of the Finnish Roma and their literature. In conclusion, I consider the latest developments, i.e. combining postcolonial theoretical framework with multilingual, transnational and cross-border literary studies in Finland and outline some present and future tasks and challenges.

Homework is a core pedagogical tool used by schools around the world. Yet concern for heavy homework load has been raised regarding stress on students and families and how it may overshadow opportunities for non-academic development. Drawing support from Self-Determination Theory and Hope Theory, an innovative intervention project was designed to create homework-free opportunities for school children to take part in freely chosen self-directed leisure activities. The project was implemented in four primary schools in Hong Kong during the Easter holiday in 2017 and 2018. A mixed-method evaluation was conducted to appraise the experiences of student participants as well as the project's impact on holiday satisfaction, homework attitudes and self-directed outcomes. This study's sample was comprised of 1,425 students enrolled in Primary levels 1 to 6. Participants reported in interviews that engagement in self-chosen, self-directed leisure activities were exciting and appealing. Pre- and post-holiday survey results with control-group comparisons confirmed that students who undertook self-directed leisure activities over a homework-free holiday gained enhanced agency thinking and academic competence while also becoming less inclined to see homework as meeting their immediate learning needs. Implications are also discussed regarding the benefits of self-directed leisure activities as well as school-based homework policies regarding assignment load.

Profound knowledge exists about the clinical, morphologic, genomic, and transcriptomic characteristics of most lymphoma entities. However, information is currently lacking on the dynamic behavior of malignant lymphomas. This pilot study aimed to gain insight into the motility of malignant lymphomas and bystander cells in 20 human lymph nodes. Generally, B cells were faster under reactive conditions compared with B cells in malignant lymphomas. In contrast, PD1-positive T cells did not show systematic differences in velocity between reactive and neoplastic conditions in general. However, lymphomas could be divided into two groups: one with fast PD1-positive T cells (e.g., Hodgkin lymphoma and mantle cell lymphoma; means 8.4 and 7.8 µm/min) and another with slower PD1-positive T cells (e.g., mediastinal grey zone lymphoma; mean 3.5 µm/min). Although the number of contacts between lymphoma cells and PD1-positive T cells was similar in different lymphoma types, important differences were observed in the duration of these contacts. Among the lymphomas with fast PD1-positive T cells, contacts were particularly short in mantle cell lymphoma (mean 54 s), whereas nodular lymphocyte-predominant Hodgkin lymphoma presented prolonged contact times (mean 6.1 min). Short contact times in mantle cell lymphoma were associated with the largest spatial displacement of PD1-positive cells (mean 12.3 µm). Although PD1-positive T cells in nodular lymphocyte-predominant Hodgkin lymphoma were fast, they remained in close contact with the lymphoma cells, in line with a dynamic immunological synapse. This pilot study shows for the first time systematic differences in the dynamic behavior of lymphoma and bystander cells between different lymphoma types.

The copper harmonic structure, which consists of a coarse-grained “core” surrounded by a three-dimensional continuously connected fine-grained “shell,” exhibits both high ductility and high strength. In the present study, dislocation interactions at the shell–core boundary in the copper harmonic structure were directly measured using nanoindentation and microstructural observations via kernel average misorientation (KAM) to further understand the reason for its excellent mechanical properties. KAM analysis showed that the dislocation density in the vicinity of the shell–core boundary within the core region gradually increases with increasing plastic strain. The variation in the nanohardness exactly corresponds to the KAM, indicating that the higher strength is primarily caused by the higher dislocation density. The critical load for nanoindentation-induced plasticity initiation was lower at the shell–core boundary than at the core–core boundary, indicating a higher potency of dislocation emission at the shell–core boundary. Because dislocation–dislocation interactions are one of the major causes of the increase in the flow stress leading to higher strain hardening rates during deformation, the excellent balance between strength and ductility is attributed to the higher potency of dislocation emission at the shell–core boundary.

Nowadays, in the context of climate change, efficient energy management and increasing the share of renewable energy sources in the energy mix are helping to reduce greenhouse gases. In this research, we present the energy system and its management and the possibilities of its development through the example of an ecovillage. The basic goal of such a community is to be economically, socially, and ecologically sustainable, so the study of energy system of an ecovillage is especially justified. As the goal of this community is sustainability, potential technological and efficiency barriers to the use of renewable energy sources will also become visible. Our sample area is Visnyeszéplak ecovillage, where we examined the energy production and consumption habits and possibilities of the community with the help of interviews, literature, and map databases. By examining the spatial structure of the settlement, we examined the spatial structure of energy management. We formulated development proposals that can make the community’s energy management system more efficient.

Abstract While the use of bioluminescent proteins for molecular imaging is a powerful technology to further our understanding of complex processes, fluorescent labeling with visible light fluorescent proteins such as GFP and RFP suffers from poor tissue penetration and high background autofluorescence. To overcome these limitations, we generated an inducible knock-in mouse model of iRFP713. This model was used to assess Cre activity in a Rosa Cre–ER background and quantify Cre activity upon different tamoxifen treatments in several organs. We also show that iRFP can be readily detected in 3D organoid cultures, FACS analysis and in vivo tumour models. Taken together we demonstrate that iRFP713 is a progressive step in in vivo imaging and analysis that widens the optical imaging window to the near-infrared spectrum, thereby allowing deeper tissue penetration, quicker image acquisition without the need to inject substrates and a better signal to background ratio in genetically engineered mouse models (GEMMs).

Today restrictions on pollutant emissions require the use of catalyst-based after-treatment systems as a standard both in SI and in Diesel engines. The application of monolith cores with a honeycomb structure is an established practice: however, to overcome drawbacks such as weak mass transfer from the bulk flow to the catalytic walls as well as poor flow homogenization, the use of ceramic foams has been recently investigated as an alternative showing better conversion efficiencies (even accepting higher flow through losses). The scope of this paper is to analyse the effects of foam substrates characteristics on engine performance. To this purpose a 0D “crank-angle” real-time mathematical model of an I.C. Engine developed by the authors has been enhanced improving the heat exchange model of the exhaust manifold to take account of thermal transients and adding an original 0D model of the catalytic converter to describe mass flows and thermal processes. The model has been used to simulate a 1.6l turbocharged Diesel engine during a driving cycle (EUDC). Effects of honeycomb and foam substrates on fuel consumption and on variations of catalyst temperatures and pressures are compared in the paper.

Background: Fibrocystic changes are associated with an increased risk of breast cancer. Genetic alterations have been found in fibrocystic changes with or without epithelial changes, suggesting that critical oncogenic events are occurring at an early stage.Methods: We investigated a unique collective of 17 breast cancer patients who, prior to the diagnosis of invasive breast cancer, underwent open surgical biopsy showing fibrocystic changes of the breast. The time span between biopsy for fibrocystic changes and invasive carcinoma ranged from 1 to 11 years (average 5.3 years). Ten (58.8%) of the patients had an ipsilateral invasive carcinoma, and 7 (41.2%) of the patients developed an invasive carcinoma of the contralateral breast. Massive parallel sequencing targeting genes frequently mutated in breast cancer was performed on the fibrocystic breast tissue as well as the ensuing cancer tissue.Results: In 9 cases, somatic mutations were found in the tumor tissue, the most prevalent being PIK3CA mutations (n = 4), followed by TP53 mutations (n = 2). None of these mutations were present in the previously removed mastopathy tissue. In one of the cases, an ERBB3 E928G mutation was present in the mastopathy as well as in the tumor tissue, with the variant allele frequency in the mastopathy being

Background: CSF protein concentrations vary greatly among individuals. Accounting for brain volume may lower the variance and increase the diagnostic value of CSF protein concentrations.Objective: To determine the relation between CSF protein concentrations and brain volume.Methods: Brain volumes (total intracranial, gray matter, white matter volumes) derived from brain MRI and CSF protein concentrations (total protein, albumin, albumin CSF/serum ratio) of 29 control patients and 497 patients with clinically isolated syndrome or multiple sclerosis were studied.Finding: We found significant positive correlations of CSF protein concentrations with intracranial, gray matter, and white matter volumes. None of the correlations remained significant after correction for age and sex.Conclusion: Accounting for brain volume derived from brain MRI is unlikely to improve the diagnostic value of protein concentrations in CSF.

Mit Hilfe der Effektgröße Cohen’s d kann ein Effekt quantitativ und metrikfrei geschätzt werden. Dieser Effekt kann z. B. durch die Abweichung eines Mittelwertes von einem bestimmten Wert oder durch den Mittelwertsunterschied zwischen zwei Stichproben zustande kommen. Die Breite eines Konfidenzintervalls für die Effektgröße Cohen’s d gibt an, wie genau diese Schätzung ist. In diesem Beitrag soll gezeigt werden, warum nichtzentrale t-Verteilungen eine große Rolle in der präzisen Berechnung der Konfidenzintervalle für Cohen’s d spielen und wie diese berechnet werden können. Auf der Online-Plattform Open Science Framework stehen zwei Programme in R frei zur Verfügung, die ein solches Konfidenzintervall für Cohen’s d für eine bzw. für zwei Stichproben ausgehend von den folgenden Eingabeparametern berechnen: Konfidenzniveau (z. B. 95%), Stichprobengröße(n), Mittelwert(e) und Standardabweichung(en). Am Ende dieses Beitrags wird das Vorgehen an einem Beispiel illustriert.

Longitudinal analysis of white matter lesion changes on serial MRI has become an important parameter to study diseases with white-matter lesions. Here, we build on earlier work on cross-sectional lesion segmentation; we present a fully automatic pipeline for serial analysis of FLAIR-hyperintense white matter lesions. Our algorithm requires three-dimensional gradient echo T1- and FLAIR- weighted images at 3 Tesla as well as available cross-sectional lesion segmentations of both time points. Preprocessing steps include lesion filling and intrasubject registration. For segmentation of lesion changes, initial lesion maps of different time points are fused; herein changes in intensity are analyzed at the voxel level. Significance of lesion change is estimated by comparison with the difference distribution of FLAIR intensities within normal appearing white matter. The method is validated on MRI data of two time points from 40 subjects with multiple sclerosis derived from two different scanners (20 subjects per scanner). Manual segmentation of lesion increases served as gold standard. Across all lesion increases, voxel-wise Dice coefficient (0.7) as well as lesion-wise detection rate (0.8) and false-discovery rate (0.2) indicate good overall performance. Analysis of scans from a repositioning experiment in a single patient with multiple sclerosis did not yield a single false positive lesion. We also introduce the lesion change plot as a descriptive tool for the lesion change of individual patients with regard to both number and volume. An open source implementation of the algorithm is available at http://www.statistical-modeling.de/lst.html. Keywords: Magnetic resonance imaging, Multiple sclerosis, White matter lesions, Lesion segmentation

Magnetic resonance imaging (MRI) scans play a pivotal role in the evaluation of patients presenting with a clinically isolated syndrome (CIS), as these may depict brain lesions suggestive of an inflammatory cause. We hypothesized that it is possible to predict the conversion from CIS to multiple sclerosis (MS) based on the baseline MRI scan by studying image features of these lesions.We analyzed 84 patients diagnosed with CIS from a prospective observational single center cohort. The patients were followed up for at least three years. Conversion to MS was defined according to the 2010 McDonald criteria. Brain lesions were segmented based on 3D FLAIR and 3D T1 images. We generated brain lesion masks by a computer assisted manual segmentation. We also generated a set of automated segmentations using the Lesion Segmentation Toolbox for SPM to assess the influence of different segmentation methods. Shape and brightness features were automatically calculated from the segmented masks and used as input data to train an oblique random forest classifier. Prediction accuracies of the resulting model were validated through a three-fold cross-validation.Conversion from CIS to MS occurred in 66 of 84 patients (79%). The conversion or non-conversion was predicted correctly in 71 patients based on shape features derived from the computer assisted manual segmentation masks (84.5% accuracy). This predictor was more accurate than predicting conversion using dissemination in space at baseline according to the 2010 McDonald criteria (75% accuracy). While shape features strongly contributed to the accuracy of the predictor, including intensity features did not further improve performance.As patients who convert to definite MS benefit from early treatment, an early classification model is highly desirable. Our study shows that shape parameters of lesions can contribute to predicting the future course of CIS patients more accurately. Keywords: Multiple sclerosis, Clinically isolated syndrome, MRI, Machine learning

The purpose of this study is to explore the effectiveness of the parallel classroom model in comparison to a support facilitation model. Using district-level assessments in geometry, this study assessed student performance when students were taught the same content with the same rigor, where one classroom uses differentiation strategies and small-group instruction to instruct students and the other classroom uses support facilitation. By examining the success of the parallel classroom model, we hope to prove this model to be a viable curricular alternative for the needs of exceptional learners. Specifically, we see parallel classrooms as being more flexible to diverse student needs than traditional classrooms.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with presumed autoimmune origin. The development of lesions within the gray matter and white matter, which are highly variable with respect to number, total volume, morphology and spatial evolution and which only show a limited correlation with clinical disability, is a hallmark of the disease. Population-based studies indicate a distinct outcome depending on gender. Here, we studied gender-related differences in the evolution of white matter MS-lesions (MS-WML) in early MS by using geostatistical methods. Within a 3 years observation period, a female and a male MS patient group received disease modifying drugs and underwent standardized annual brain magnetic resonance imaging, accompanied by neurological examination. MS-WML were automatically extracted and the derived binary lesion masks were subject to geostatistical analysis, yielding quantitative spatial-statistics metrics on MS-WML pattern morphology and total lesion volume (TLV). Through the MS-lesion pattern discrimination plot, the following differences were disclosed: corresponding to gender and MS-WML pattern morphology at baseline, two female subgroups (F1, F2) and two male subgroups (M1, M2) are discerned that follow a distinct MS-WML pattern evolution in space and time. F1 and M1 start with medium-level MS-WML pattern smoothness and TLV, both behave longitudinally quasi-static. By contrast, F2 and M2 start with high-level MS-WML pattern smoothness and medium-level TLV. F2 and M2 longitudinal development is characterized by strongly diminishing MS-WML pattern smoothness and TLV, i.e., continued shrinking and break-up of MS-WML. As compared to the male subgroup M2, the female subgroup F2 shows continued, increased MS-WML pattern smoothness and TLV. Data from neurological examination suggest a correlation of MS-WML pattern morphology metrics and EDSS. Our results justify detailed studies on gender-related differences.

Neural circuits are able to perform computations under very diverse conditions and requirements. The required computations impose clear constraints on their fine-tuning: a rapid and maximally informative response to stimuli in general requires decorrelated baseline neural activity. Such network dynamics is known as asynchronous-irregular. In contrast, spatio-temporal integration of information requires maintenance and transfer of stimulus information over extended time periods. This can be realized at criticality, a phase transition where correlations, sensitivity and integration time diverge. Being able to flexibly switch, or even combine the above properties in a task-dependent manner would present a clear functional advantage. We propose that cortex operates in a “reverberating regime” because it is particularly favorable for ready adaptation of computational properties to context and task. This reverberating regime enables cortical networks to interpolate between the asynchronous-irregular and the critical state by small changes in effective synaptic strength or excitation-inhibition ratio. These changes directly adapt computational properties, including sensitivity, amplification, integration time and correlation length within the local network. We review recent converging evidence that cortex in vivo operates in the reverberating regime, and that various cortical areas have adapted their integration times to processing requirements. In addition, we propose that neuromodulation enables a fine-tuning of the network, so that local circuits can either decorrelate or integrate, and quench or maintain their input depending on task. We argue that this task-dependent tuning, which we call “dynamic adaptive computation,” presents a central organization principle of cortical networks and discuss first experimental evidence.

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.