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Abstract Hodgkin–Reed–Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA‐I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA‐I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA‐II was associated with only minor differential gene expression in the TME. In HLA‐I‐positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein–Barr virus in HRSCs. Additionally, HLA‐I‐positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA‐I‐positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA‐I‐positive compared to HLA‐I‐negative HL.

How can a conference as large and diverse as the first conference of the History and Translation Network in Tallinn in May of 2022 be adequately represented and remembered? To archive, share, and promote the multiplicity of topics and approaches that came together, we invited panel chairs and, in some cases, panelists to write short texts about their panels. These now form a conference mosaic as tiles. As is often the case with a mosaic, the tiles vary in size and style, with some leaving a blank space. From time to time, tiles in different languages remind us of the multilingual reality of the research subjects, the researchers, and also the conference. The texts have been arranged in three overarching categories: methods & approaches, actors & themes and time & space. We thank all contributors for their efforts and hope readers enjoy browsing the mosaic. Edited by Chronotopos, contributors of texts are named below each text.

Additive manufacturing processes have attracted broad attention in the last decades since the related freedom of design allows the manufacturing of parts with unique microstructures and unprecedented complexity in shape. Focusing on the properties of additively manufactured parts, major efforts are made to elaborate process-microstructure relationships. For instance, the inevitable thermal cycling within the process plays a significant role in microstructural evolution. Various driving forces contribute to the final grain size, boundary character, residual stress state, etc. In the present study, the properties of commercially pure iron processed on three different routes, i.e., hot rolling as a reference, electron powder bed fusion, and laser powder bed fusion, using different raw materials as well as process conditions, are compared. The manufacturing of the specimens led to five distinct microstructures, which differ significantly in terms of microstructural features and mechanical responses. Using optical and electron microscopy as well as transmission electron microscopy, the built specimens were explored in various states of a tensile test in order to reveal the microstructural evolution in the course of quasistatic loading. The grain size is found to be most influential in enhancing the material’s strength. Furthermore, substructures, i.e., low-angle grain boundaries, within the grains play an important role in terms of the homogeneity of strain distribution. On the contrary, high-angle grain boundaries are found to be regions of strain localization. In summary, a holistic macro-meso-micro-nano investigation is performed to evaluate the behavior of these specific microstructures.

Abstract Genetic variants in TMEM106B are a common risk factor for frontotemporal lobar degeneration and the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). TMEM106B is encoding a lysosomal transmembrane protein of unknown molecular function. How it mediates its disease-modifying function remains enigmatic. Several TMEM106B single nucleotide polymorphisms (SNPs) are significantly associated with disease risk in FTLD-GRN carriers, of which all except one are within intronic sequences of TMEM106B. Of note, the non-coding SNPs are in high linkage disequilibrium with the coding SNP rs3173615 located in exon six of TMEM106B, resulting in a threonine to serine change at amino acid 185 in the minor allele, which is protective in FTLD-GRN carriers. To investigate the functional consequences of this variant in vivo, we generated and characterized a knockin mouse model harboring the Tmem106b T186S variant. We analyzed the effect of this protective variant on FTLD pathology by crossing Tmem106b T186S mice with Grn −/− knockout mice, a model for GRN-mediated FTLD. We did not observe the amelioration of any of the investigated Grn −/− knockout phenotypes, including transcriptomic changes, lipid alterations, or microgliosis in Tmem106b T186S/T186S × Grn −/− mice, indicating that the Tmem106b T186S variant is not protective in the Grn −/− knockout mouse model. These data suggest that effects of the associated SNPs not directly linked to the amino acid exchange in TMEM106B are critical for the modifying effect.

Considering the increasing demand for Li-ion batteries, there is a need for sophisticated recycling strategies with both high recovery rates and low costs. Applying optical sensors for automating component detection is a very promising approach because of the non-contact, real-time process monitoring and the potential for complete digitization of mechanical sorting processes. In this work, mm-scale particles from shredded end-of-life Li-ion batteries are investigated by five different reflectance sensors, and a range from the visible to long-wave infrared is covered to determine the ideal detection window for major component identification as relevant input signals to sorting technologies. Based on the characterization, a spectral library including Al, Cu, separator foil, inlay foil, and plastic splinters was created, and the visible to near-infrared range (400–1000 nm) was identified as the most suitable spectral range to reliably discriminate between Al, Cu, and other battery components in the recycling material stream of interest. The evaluation of the different sensor types outlines that only imaging sensors meet the requirements of recycling stream monitoring and can deliver sufficient signal quality for subsequent mechanical sorting controls. Requirements for the setup parameters were discussed leading to the setup recommendation of a fast snapshot camera with a sufficiently high spectral resolution and signal-to-noise ratio.

Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.

Due to the growing interest in climbing, increasing importance has been given to research in the field of non-invasive, camera-based motion analysis. While existing work uses invasive technologies such as wearables or modified walls and holds, or focuses on competitive sports, we for the first time present a system that uses video analysis to automatically recognize six movement errors that are typical for novices with limited climbing experience. Climbing a complete route consists of three repetitive climbing phases. Therefore, a characteristic joint arrangement may be detected as an error in a specific climbing phase, while this exact arrangement may not considered to be an error in another climbing phase. That is why we introduced a finite state machine to determine the current phase and to check for errors that commonly occur in the current phase. The transition between the phases depends on which joints are being used. To capture joint movements, we use a fourth-generation iPad Pro with LiDAR to record climbing sequences in which we convert the climber’s 2-D skeleton provided by the Vision framework from Apple into 3-D joints using the LiDAR depth information. Thereupon, we introduced a method that derives whether a joint moves or not, determining the current phase. Finally, the 3-D joints are analyzed with respect to defined characteristic joint arrangements to identify possible motion errors. To present the feedback to the climber, we imitate a virtual mentor by realizing an application on the iPad that creates an analysis immediately after the climber has finished the route by pointing out the detected errors and by giving suggestions for improvement. Quantitative tests with three experienced climbers that were able to climb reference routes without any errors and intentionally with errors resulted in precision–recall curves evaluating the error detection performance. The results demonstrate that while the number of false positives is still in an acceptable range, the number of detected errors is sufficient to provide climbing novices with adequate suggestions for improvement. Moreover, our study reveals limitations that mainly originate from incorrect joint localizations caused by the LiDAR sensor range. With human pose estimation becoming increasingly reliable and with the advance of sensor capabilities, these limitations will have a decreasing impact on our system performance.

Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

Editorial in English and German on the technical infrastructures relevant for translation history. The editors share an invitation to make use of the Digital Library and Bibliography of Literature in Translation (DLBT) and discuss the needs of translation historians and the trends in translation history in regards to principles of open science and communism as described by Robert Merton.

Background: Several recent randomized therapeutic exploratory trials demonstrated improvement of progression-free survival and in some even overall survival using stereotactic body radiotherapy in patients with oligometastatic disease. However, only very few patients enrolled in these trials had breast cancer, and results from confirmatory trials are lacking. Methods/design: The OLIGOMA-trial is a randomized controlled multi-national multi-center therapeutic confirmatory trial studying the role of local ablative radiotherapy as an additive treatment in patients with oligometastatic breast cancer receiving standard systemic therapy. Patients will be randomized 1:1 to standard systemic therapy according to national guidelines with or without radiotherapy to all metastatic sites. Randomization will be stratified according to type and line of systemic therapy, which has to be determined by a multidisciplinary tumor board before enrollment. Patients with up to five metastatic lesions are eligible, including patients with up to three brain metastases (only in case of extracranial disease) and with locoregional recurrence (only in case of additional metastatic lesions). In the standard arm, palliative radiotherapy to symptomatic metastases is permitted if at least one lesion remains untreated. The co-primary endpoints are progression-free survival and quality of life. The primary hypothesis is that progression-free survival in the experimental arm will be superior to the standard arm while simultaneously demonstrating non-inferiority of quality of life at 12 weeks after randomization. Secondary endpoints are feasibility, overall survival, toxicity, quality of life and patient satisfaction. A translational sub-study with collection of ctDNA will be conducted. Discussion: The OLIGOMA-trial will provide high level evidence on the use of and benefit from local ablative radiotherapy for patients with oligometastatic breast cancer. Trial registration: The OLIGOMA-trial is registered at clinicialtrials.gov under the identification NCT04495309. The related information was first posted on July 31st 2020.

MAPK signaling suppresses autoimmunity mediated by the SUMM2 receptor in Arabidopsis. Here Huang et al. show that a trimeric complex consisting of the GPI anchored protein LLG1, and the two receptor-like proteins LET1 and LET2, promotes activation of SUMM2 according to MAPK signaling status.

The sole distinguishing feature of follicular lymphoma grade 3B and diffuse large B-cell lymphoma is the growth pattern assessed by histopathology. Diffuse growth defines diffuse large B-cell lymphoma but the clinical relevance of this finding when occurring in follicular lymphoma grade 3B is uncertain. To address this issue, individual and coexisting follicular lymphoma grade 3B and diffuse large B-cell lymphoma were separated and analyzed for immunophenotype and molecular genetic features by fluorescence in situ hybridization, targeted sequencing and gene expression profiling. Clinical features of follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma were studied in homogeneously treated patients from a prospective randomized trial. Follicular lymphoma grade 3B and diffuse large B-cell lymphoma frequently show an intermediate growth pattern and/or occur simultaneously in the same tissue at the time of initial diagnosis. When occurring simultaneously follicular lymphoma grade 3B and diffuse large B-cell lymphoma do not differ significantly for genetic aberrations or phenotype but have distinct gene expression features reflecting a divergent microenvironment. Follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma do not differ for major clinical parameters such as International Prognostic Index, response to immuno-chemotherapy, progression or overall survival. Follicular lymphoma grade 3B and simultaneous diffuse large B-cell lymphoma are molecularly homogenous. Histological detection of diffuse large B-cell lymphoma is not associated with features of a more aggressive disease and does not reflect transformation or progression of follicular lymphoma grade 3B.

Recent orthopaedic implant alloy design has focused on β-type Ti alloys, as the body centred cubic (BCC) crystal structure has the tendency to be characterised by a low elastic modulus. Nevertheless, the currently most used metal is Ti-6Al-4V, which mainly retains a hexagonal closed packed (HCP) crystal structure when produced by additive manufacturing. The benefits and disadvantages of the mechanical response of each crystal structure for implant applications is yet to be explored. Utilising the TiTa alloy system, low modulus Ti25Ta and Ti65Ta lattices were additively manufactured with opposing crystal structures of α′ martensite (HCP) and β grains (BCC). The lattices showed similar tensile, compressive and high cycle fatigue behaviour, indicating that the α' alloy was mechanically equal to the β alloy for implant applications. The mechanical properties of both the TiTa lattices were also superior to identically manufactured lattices in Ti-6Al-4V in both as-built and heat treated conditions.

Objective: to identify the prevalent neurological damage in patients admitted to an Intensive Care Unit and their relationship with social and clinical characteristics, care, and clinical outcome. Method: cross-sectional study with analysis of 83 medical records of patients with neurological damage and hospitalized in the period from 2016 to 2018. Results: predominance of Hemorrhagic Stroke (55.4%). Traumatic Brain Injury affected only men (16.9%). Systemic Arterial Hypertension was the main comorbidity evidenced (51.8%). Altered muscle strength was the main sign of severe neurological damage (36.2%). Analgesia prevailed among intensive care dedicated to patients with severe neurological damage (95.1%). Death as clinical outcome predominated (85.6%). Conclusion: Hemorrhagic stroke predominates, especially in women. Analgesia is the main care evidenced, and the mortality rate was higher than the rates found in the literature.

Burkitt lymphoma (BL) is the most common pediatric B-cell lymphoma. Here, within the International Cancer Genome Consortium, the authors performed whole genome and transcriptome sequencing of 39 sporadic BL, describing the landscape of mutations, structural variants, and mutational processes that underpin this disease how alterations on different cellular levels cooperate in deregulating key pathways and complexes.

Metallic material concepts associated with the sustainable and efficient use of resources are currently the subject of intensive research. Al addition to steel offers advantages in view of lightweight, durability, and efficient use of high-Fe scrap from the Al industry. In the present work, Al was added to Fe-12Cr-(9,12)Ni-3Mn-0.3C-xAl (x = 0.1–6) (wt.%) stainless steels to assess its influence on microstructure and mechanical properties. According to density measurements based on Archimedes’ principle, densities were between 7.70 and 7.08 g/cm3. High-energy X-ray diffraction estimations of the lattice parameter indicated that nearly 31% of density reduction was caused by the lattice expansion associated with Al addition. Depending on Al concentration, austenitic and duplex matrix microstructures were obtained at room temperature. In the presence of up to 3 wt.% Al, the microstructure remained austenitic. At the same time, strength and hardness were slightly enhanced. Al addition in higher quantities resulted in the formation of duplex matrix microstructures with enhanced yield strength but reduced ductility compared to the austenitic alloys. Due to the ready formation of B2-(Ni,Fe)Al intermetallics in the ferrite phase of the present alloy system, the increase in strength due to the presence of ferrite was more pronounced compared to standard duplex stainless steels. The occurrence of B2 intermetallics was implied by dilatometry measurements and confirmed by electron microscopy examinations and high-energy X-ray diffraction measurements.

Self-esteem has been shown to be both predictive of and predicted by characteristics of romantic relationships. While there is an increasing number of studies yielding support for reciprocal influences between self-esteem and perceived conflict in romantic relationships, longitudinal transactions between these constructs from both partners' perspectives have not been studied systematically to date. Our aim was to close this gap. To that end, we examined the transactional and longitudinal interplay between self-esteem and perceived relationship conflict in continuing romantic couples from a dyadic perspective. Our sample consisted of N = 1,093 young adult female-male relationships from the German Family Panel. Individuals' self-esteem, perceived conflict frequency, and their perceptions of their partners' dysfunctional conflict styles (i.e., unconstructive behavior, withdrawal) were examined annually throughout a time span of five years. Based on dyadic bivariate latent change models, we tested our assumption that self-esteem and aspects of perceived relationship conflict are negatively interrelated within individuals and between partners both within and across time. We found one actor effect of self-esteem on changes in unconstructive behavior above and beyond initial unconstructive behavior levels, supporting self-broadcasting perspectives. Moreover, we found strong support for sociometer perspectives. Actor effects highlighted the importance of perceived conflict frequency for subsequent self-esteem changes. In addition, perceived conflict styles affected both partners' self-esteem. The results imply that perceiving conflict is a between-person process, and might be more important for the development of self-esteem than vice versa.

Eine Rezension der folgenden Publikation: Chalvin, Antoine; Muller, Jean-Léon; Talviste, Katre & Vrinat-Nikolov, Marie (eds.) (2019): Histoire de la Traduction Littéraire en Europe Médiane. Des Origines à 1989. Rennes: Presses Universitaires de Rennes.

Das Editorial thematisiert Translationsgeschichte in Zeiten der Pandemie und stellt das Heft und den Fokus "Translation im II. Weltkrieg" vor. Die Herausgeber/innen präsentieren eine ausführliche Bibliographie zum Forschungsstand zu "Translation im II. Weltkrieg" und laden die Leser/innen dazu ein, ihnen bekannte Projekte und Publikationen dieses Themenbereichs zuzusenden. Eine erweiterte Bibliographie zum Thema soll in Zukunft über die Website von Chronotopos zugänglich gemacht werden.

The editorial addresses working on translation history in times of a pandemic and introduces the issue, and the focus "Translation in World War II". The editors present an extensive bibliography on the state of research on "Translation in World War II" and invite readers to send in projects and publications on this topic. An extended bibliography on the topic will be made available in the future via the Chronotopos website.

Introduction With increasing age, the risk of complications after surgery rises in elderly patients. Furthermore, the prevalence of multimorbidity and polypharmacy rises with age, making this elderly population especially vulnerable for drug-related problems and posing an additional risk for postoperative complications. Still, only few studies have concentrated on investigating how medication safety can be improved in these patients. The aim of this pilot study is to examine the impact of a comprehensive intervention (interprofessional systematic medication therapy management) on medication appropriateness in elderly polymedicated, multimorbid patients during hospital stay for elective surgery.Methods and analysis This pilot study will include a total number of 140 patients. Surgical high-risk patients ≥65 years taking more than five chronic systemic drugs will be recruited consecutively for 9 months in the control group capturing usual care regarding medication history and in-hospital medication therapy management without any study intervention. Recruitment of the intervention group will be conducted for another 9 months. The intervention consists of the following components: an additional medication history by a hospital pharmacist before admission, a subsequent medication review, optimisation of the long-term medication and recommendations to the patient’s general practitioner. A follow-up will be performed 3 months after surgery. As the primary study outcome, medication appropriateness will be measured using the Medication Appropriateness Index.Secondary outcomes are postoperative complications, incidence and frequency of adverse drug reactions and potentially inappropriate medication in the elderly, satisfaction with inpatient and outpatient care, medication reconciliation and health-related quality of life. Multivariable analyses will be used to analyse all quantitative research questions.Ethics and dissemination Ethics approval was obtained by the medical ethics committee of the Medical Chamber of Hamburg (study ID: PV5754). Data will be published in peer-reviewed journals and presented at conferences.Trial registration number The study is registered at www.drks.de: DRKS00014621.

Summary: Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.

Editorial on the future of translation history.

Vorwort der Herausgeberinnen und Herausgeber zur Zukunft der Translationsgeschichte.

SARS-CoV-2 causes substantial morbidity and mortality in elderly and immunocompromised individuals, particularly in retirement homes, where transmission from asymptomatic staff and visitors may introduce the infection. Here we present a cheap and fast screening method based on direct RT-qPCR to detect SARS-CoV-2 in single or pooled gargle lavages ("mouthwashes"). This method detects individuals with large viral loads (Ct≤29) and we use it to test all staff at a nursing home daily over a period of three weeks in order to reduce the risk that the infection penetrates the facility. This or similar approaches can be implemented to protect hospitals, nursing homes and other institutions in this and future viral epidemics.

Abstract: Gene expression profiling (GEP) by microarrays of diffuse large B-cell lymphoma (DLBCL) has enabled the categorization of DLBCL into activated B-cell–like and germinal center B-cell–like subclasses. However, as this does not fully embrace the great diversity of B-cell subtypes, we recently developed a gene expression assay for B-cell–associated gene signature (BAGS) classification. To facilitate quick and easy-to-use BAGS profiling, we developed in this study the NanoString-based BAGS2Clinic assay. Microarray data from 4 different cohorts (n = 970) were used to select genes and train the assay. The locked assay was validated in an independent cohort of 88 sample biopsies. The assay showed good correspondence with the original BAGS classifier, with an overall accuracy of 84% (95% confidence interval, 72% to 93%) and a subtype-specific accuracy ranging between 80% and 99%. BAGS classification has the potential to provide valuable insight into tumor biology as well as differences in resistance to immuno- and chemotherapy that can lead to novel treatment strategies for DLBCL patients. BAGS2Clinic can facilitate this and the implementation of BAGS classification as a routine clinical tool to improve prognosis and treatment guidance for DLBCL patients.

Abstract Background Colorectal cancer (CRC) is the fourth leading cause of cancer related deaths worldwide and prognosis in advanced tumor stage still remains poor. Since CK1 isoforms have been reported to be deregulated in several tumor entities CK1 has emerged as a novel drug target in cancer therapy. In this study we set out to investigate whether CK1α might have the potential to serve as prognostic marker. Methods CK1α RNA and protein expression levels in healthy and tumor tissue of CRC patients were analyzed using quantitative real-time PCR and Western Blot analysis, respectively. Prognostic relevance was investigated by correlating obtained CK1α expression levels with patients’ survival rate generating Kaplan-Meier survival plots. Results It could be shown that CK1α is overexpressed in colorectal tumor tissue compared to normal tissue and CK1α overexpression in tumor tissue correlates with poor survival in CRC patients. Results become more significant when only considering patients with high-grade tumors, as well as patients assigned to UICC II and UICC III stage. Furthermore, Cox regression analysis revealed that CK1α is an independent prognostic factor. In addition, tumors expressing decreased levels of the kinase reveal positive effects on overall survival when localized in the right colon compared to those in the left side. Conclusion In summary, this study provides evidence for the first time that CK1α RNA levels might serve as prognostic marker for CRC.

Due to their process-induced porous surfaces, additively manufactured structures are not optimized for applications in which friction is a key factor. To improve the frictional properties of additively manufactured titanium inserts of various thicknesses, two tribologically optimized POM materials, which differ in terms of filler composition and contents, were used to overmould the inserts. The titanium inserts were manufactured in two different building directions, resulting in a variation in surface roughness. The main challenge with respect to overmoulding is to maintain an even, thin plastic layer on the titanium insert. In order to evaluate the adhesion between plastic and metal, the interface is examined by optical microscopy and assessment of the peeling resistance. The peeling test shows that the overmoulded titanium inserts with a higher surface roughness are characterized by a higher peeling resistance. It is further revealed that the POM material with a special filler concept shows superior peeling resistance.

Abstract Background Bacterial symbionts transmitted from mothers to offspring are found in the majority of arthropods. Numerous studies have illustrated their wide impact on host biology, such as reproduction, behavior, and physiology One of the most common inherited symbionts is Rickettsia spp. (Alphaproteobacteria, Rickettsiales), which are found in about one-quarter of terrestrial arthropods, as well as in other invertebrates. In insect populations, Rickettsia spp. have been reported to cause reproductive modifications and fecundity-enhancing effects. Here, we investigated the incidence and genetic diversity of Rickettsia symbionts in green lacewings (Neuroptera, Chrysopidae), which are best known for their use as biological control agents against crop pests. Results We screened 18 species of green lacewings and allies for Rickettsia and found the symbiont in 10 species, infecting 20–100% of sampled individuals. Strain characterization based on multiple bacterial loci revealed an unprecedented diversity of Rickettsia associated with lacewings, suggesting multiple independent acquisitions. Further, the detected Rickettsia lineages are restricted to a specific lineage (i.e., species or genus) of investigated lacewings, and these associations are stable across multiple sampled locations and points in time. Conclusions We conclude that Rickettsia-lacewing symbioses are common and evolutionarily stable. The role of these symbionts remains to be identified, but is potentially important to optimizing their use in biological pest control.

GCN2 (general control nonrepressed 2) is a serine/threonine-protein kinase that regulates translation in response to stressors such as amino acid and purin deprivation, cold shock, wounding, cadmium, and UV-C exposure. Activated GCN2 phosphorylates the α-subunit of the eukaryotic initiation factor 2 (eIF2) leading to a drastic inhibition of protein synthesis and shifting translation to specific mRNAs. To investigate the role of GCN2 in responses to UV-B radiation its activity was analyzed through eIF2α phosphorylation assays in mutants of the specific UV-B and stress signaling pathways of Arabidopsis thaliana. EIF2α phosphorylation was detectable 30 min after UV-B exposure, independent of the UV-B photoreceptor UV RESISTANCE LOCUS8 and its downstream signaling components. GCN2 dependent phosphorylation of eIF2α was also detectable in mutants of the stress related MAP kinases, MPK3 and MPK6 and their negative regulator map kinase phosphatase1 (MKP1). Transcription of downstream components of the UV-B signaling pathway, the Chalcone synthase (CHS) was constitutively higher in gcn2-1 compared to wildtype and further increased upon UV-B while GLUTATHIONE PEROXIDASE7 (GPX7) behaved similarly to wildtype. The UVR8 independent FAD-LINKED OXIDOREDUCTASE (FADox) had a lower basal expression in gcn2-1 which was increased upon UV-B. Since high fluence rates of UV-B induce DNA damage the expression of the RAS ASSOCIATED WITH DIABETES PROTEIN51 (RAD51) was quantified before and after UV-B. While the basal expression was similar to wildtype it was significantly less induced upon UV-B in the gcn2-1 mutant. This expression pattern correlates with the finding that gcn2 mutants develop less cyclobutane pyrimidine dimers after UV-B exposure. Quantification of translation with the puromycination assay revealed that gcn2 mutants have an increased rate of translation which was also higher upon UV-B. Growth of gcn2 mutants to chronic UV-B exposure supports GCN2’s role as a negative regulator of UV-B responses. The elevated resistance of gcn2 mutants towards repeated UV-B exposure points to a critical role of GCN2 in the regulation of translation upon UV-B.

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In recent years, there is a growing interest in indoor positioning due to the increasing amount of applications that employ position data. Current approaches determining the location of objects in indoor environments are facing problems with the accuracy of the sensor data used for positioning. A solution to compensate inaccurate and unreliable sensor data is to include further information about the objects to be positioned and about the environment into the positioning algorithm. For this purpose, occupancy grid maps (OGMs) can be used to correct such noisy data by modelling the occupancy probability of objects being at a certain location in a specific environment. In that way, improbable sensor measurements can be corrected. Previous approaches, however, have focussed only on OGM generation for outdoor environments or require manual steps. There remains need for research examining the automatic generation of OGMs from detailed indoor map data. Therefore, our study proposes an algorithm for automated OGM generation using crowd-sourced OpenStreetMap indoor data. Subsequently, we propose an algorithm to improve positioning results by means of the generated OGM data. In our study, we used positioning data from an Ultra-wideband (UWB) system. Our experiments with nine different building map datasets showed that the proposed method provides reliable OGM outputs. Furthermore, taking one of these generated OGMs as an example, we demonstrated that integrating OGMs in the positioning algorithm increases the positioning accuracy. Consequently, the proposed algorithms now enable the integration of environmental information into positioning algorithms to finally increase the accuracy of indoor positioning applications.

Genome instability is an essential hallmark in tumor development, including colorectal cancer. We have recently identified the oxysterol binding protein-related protein 3 (ORP3), also known as oxysterol binding protein-like 3 (OSBPL3), as a novel ploidy-control gene, whose knock-out leads to aneuploidy induction and promotes tumor formation, indicating that ORP3 is a bona fide tumor suppressor protein. Here we analyzed expression of ORP3 in a cohort (n = 206) of colon cancer patients in relation to patient survival. We show that low ORP3 mRNA levels correlate with reduced survival of patients with advanced nodal metastasis (N2). While patient survival does not associate with grading when the whole cohort is evaluated, importantly, low ORP3 mRNA levels associate with worse survival of female patients with grade 3 colon cancer. Similarly, low ORP3 mRNA levels associate with worse survival of grade 3 colon cancer patients 70 years of age and younger while low ORP3 mRNA levels seem to be beneficial for colon cancer patients with a T2 tumor size. Together, the data show that ORP3 expression is downregulated during colon cancer progression, which correlates with reduced patient survival. Thus, ORP3 mRNA levels may be a prognostic marker for better stratification of colon cancer patients.

Cell walls are not only a protective barrier surrounding protoplasts but serve as signaling platform between the extracellular environment and the intracellular physiology. Ions of heavy metals and trace elements, summarized to metal ions, bind to cell wall components, trigger their modification and provoke growth responses. To examine if metal ions trigger cell wall sensing receptor like kinases (RLKs) of the Catharanthus roseus RLK1-like (CrRLK1L) family we employed a molecular genetic approach. Quantitative transcription analyses show that HERCULES1 (HERK1), THESEUS1 (THE1), and FERONIA (FER) were differently regulated by cadmium (Cd), nickel (Ni), and lead (Pb). Growth responses were quantified for roots and etiolated hypocotyls of related mutants and overexpressors on Cd, copper (Cu), Ni, Pb, and zinc (Zn) and revealed a complex pattern of gene specific, overlapping and antagonistic responses. Root growth was often inversely affected to hypocotyl elongation. For example, both HERK genes seem to negatively regulate hypocotyl elongation upon Cd, Ni, Zn, and Pb while they support root growth on Cd, Cu, and Ni. The different THE1 alleles exhibited a similar effect between roots and hypocotyls on Ni, where the loss-of-function mutant was more tolerant while the gain of function mutants were hypersensitive indicating that THE1 is mediating Ni specific inhibition of hypocotyl elongation in the dark. In contrast hypocotyl elongation of the knock-out mutant, fer-4, was hypersensitive to Ni but exhibited a higher tolerance to Cd, Cu, Pb, and Zn. These data indicate an antagonistic action between THE1 and FER in relation to hypocotyl elongation upon excess of Ni. FERs function as receptor for rapid alkalinization factors (RALFs) was tested with the indicator bromocresol purple. While fer-4 roots strongly acidified control and metal ion containing media, the etiolated hypocotyls alkalized the media which is consistent with the already shorter hypocotyl of fer-4. No other CrRLK1L mutant exhibited this phenotype except of the THE1:GFP overexpressor on Ni suggesting that THE1 might be involved in Ni induced and hypocotyl specific RALF signaling and growth regulating pathway. Overall, our findings establish a molecular link between metal ion stress, growth and the cell wall integrity sensors of the CrRLK1L family.

Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.

MicroRNA are well-established players in post-transcriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNA/target messenger RNA interaction is mostly lacking. Within the International Cancer Genome Consortium Project “Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing”, we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas. Twenty-two miRNA separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC. Moreover, we found expression of three hitherto unreported microRNA. Additionally, we detected recurrent mutations of hsa-miR-142 in diffuse large B-cell lymphomas and follicular lymphomas, and editing of the hsa-miR-376 cluster, providing evidence for microRNA editing in lymphomagenesis. To interrogate the direct physical interactions of microRNA with messenger RNA, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments. MicroRNA directly targeted 208 messsenger RNA in the Burkitt lymphomas and 328 messenger RNA in the non-Burkitt lymphoma models. This integrative analysis discovered several regulatory pathways of relevance in lymphomagenesis including Ras, PI3K-Akt and MAPK signaling pathways, also recurrently deregulated in lymphomas by mutations. Our dataset reveals that messenger RNA deregulation through microRNA is a highly relevant mechanism in lymphomagenesis.

Tobias Kalisch1, Julia Richter3, Melanie Lenz1, Jan-Christoph Kattenstroth2, Izabela Kolankowska2, Martin Tegenthoff1, Hubert R Dinse21Department of Neurology, BG-Kliniken Bergmannsheil, 2Neural Plasticity Lab, Institute for Neuroinformatics, Department of Theoretical Biology, 3Faculty of Psychology, Department of Methods, Diagnostics and Evaluation, Ruhr-University Bochum, GermanyBackground: Gerontological research aims at understanding factors that are crucial for mediating “successful aging”. This term denotes the absence of significant disease and disabilities, maintenance of high levels of physical and cognitive function, and preservation of social and productive activities. Preservation of an active lifestyle is considered an effective means through which everyday competence can be attained. In this context, it is crucial to obtain ratings of modern day older adults’ everyday competence by means of appropriate assessments. Here, we introduce the Everyday Competence Questionnaire (ECQ), designed to assess healthy older adults' everyday competence.Methods: The ECQ includes 17 items, covering housekeeping, leisure activities, sports, daily routines, manual skills, subjective well-being, and general linguistic usage. The ECQ was administered to a population of 158 healthy subjects aged 60–91 years, who were divided into groups on the basis of their physical activity. These groups were community-dwelling subjects, those living independently and having a sedentary lifestyle, those living independently but characterized by a general lifestyle without any noteworthy physical activity, and those living independently and exercising regularly. Age, gender, and education levels were balanced between the groups.Results: Using the ECQ, we could identify and distinguish different everyday competence levels between the groups tested: Subjects characterized by an active lifestyle outperformed all other groups. Subjects characterized by a general lifestyle showed higher everyday competence than those with a sedentary lifestyle or subjects who needed care. Furthermore, the ECQ data showed a significant positive correlation between individual physical activity and everyday competence.Conclusion: The ECQ is a novel tool for the questionnaire-based evaluation of everyday competence among healthy subjects. By including leisure activities, it considers the changed living conditions of modern-day older adults.Keywords: successful aging, everyday competence, questionnaire-based evaluation

Gaseous and liquid fluids in agates (banded chalcedony—SiO2) of different localities were investigated systematically by thermogravimetry-mass-spectrometry within a temperature range from 25 to 1450 °C, for the first time. Chalcedony and macrocrystalline quartz from twelve agate samples were investigated, from Germany (Schlottwitz, St. Egidien, Chemnitz and Zwickau), Brazil (Rio Grande do Sul), Scotland (Ayrshire) and the USA (Montana). They originate from mafic and felsic volcanic rocks as well as hydrothermal and sedimentary environments. The results were evaluated regarding compounds of hydrogen with fluorine, chlorine, nitrogen, carbon and sulphur. Additionally, oxygen compounds were recognized with hydrogen, fluorine, nitrogen, sulphur and carbon. The nature of the compounds was identified based on their mass-charge-ratio and the intensity ratios of the associated fragments. Due to interferences of different compounds with the same mass-charge-ratio, only H2O, HF, NO, S, SO, CO3—as well as several hydrocarbon compounds (for example CO32− or CO)—could be properly identified. The main degassing temperatures were detected at around 500 and 1000 °C. Generally, a difference between quartz and chalcedony regarding the composition of their fluids could not be found. The results indicate a silica source for the agate formation from aqueous solutions but also a possible role of fluorine compounds. Additionally, CO2 and other fluids were involved in the alteration of volcanic rocks and the mobilization and transport of SiO2.

Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC+ lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC+-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ double-hit lymphomas. BCL2+/MYC+ double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC+ lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC+ lymphomas sharing various molecular characteristics.

NLRP7 is a maternal effect gene as maternal mutations in this gene cause recurrent hydatidiform moles, spontaneous abortions and stillbirths, whereas live births are very rare. We have studied a patient with multiple anomalies born to a mother with a heterozygous NLRP7 mutation. By array-based CpG methylation analysis of blood DNA from the patient, his parents and 18 normal controls on Illumina Infinium HumanMethylation27 BeadChips we found that the patient had methylation changes (delta ß ≥ 0.3) at many imprinted loci as well as at 87 CpGs associated with 85 genes of unknown imprinting status. Using a pseudoproband (permutation) approach, we found methylation changes at only 7-24 CpGs (mean 15; standard deviation 4.84) in the controls. Thus, the number of abberantly methylated CpGs in the patient is more than 14 standard deviations higher. In order to identify novel imprinted genes among the 85 conspicuous genes in the patient, we selected 19 (mainly hypomethylated) genes for deep bisulfite amplicon sequencing on the ROCHE/454 Genome Sequencer in the patient and at least two additional controls. These controls had not been included in the array analysis and were heterozygous for a single nucleotide polymorphism at the test locus, so that allele-specific DNA methylation patterns could be determined. Apart from FAM50B, which we proved to be imprinted in blood, we did not observe allele-specific DNA methylation at the other 18 loci. We conclude that the patient does not only have methylation defects at imprinted loci but (at least in blood) also an excess of methylation changes at apparently non-imprinted loci.

The title compound, [Pt(C42H48N4)], was obtained through metallation of the corresponding free base with PtCl2, followed by crystallization from methylene chloride/methanol. The molecule exhibits an almost planar macrocycle with an average deviation of the 24 macrocyclic atoms from their least-squares plane (Δ24) of 0.04 Å and an average Pt—N bond length of 2.022 Å. Despite the unsymmetrical substitution pattern, there is no significant difference between distortion of the geometry at the phenyl substituted meso position and those of unsubstituted meso positions.

Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.

Cytosine methylation provides an epigenetic level of cellular plasticity that is important for development, differentiation and cancerogenesis. We adopted microdroplet PCR to bisulfite treated target DNA in combination with second generation sequencing to simultaneously assess DNA sequence and methylation. We show measurement of methylation status in a wide range of target sequences (total 34 kb) with an average coverage of 95% (median 100%) and good correlation to the opposite strand (rho = 0.96) and to pyrosequencing (rho = 0.87). Data from lymphoma and colorectal cancer samples for SNRPN (imprinted gene), FGF6 (demethylated in the cancer samples) and HS3ST2 (methylated in the cancer samples) serve as a proof of principle showing the integration of SNP data and phased DNA-methylation information into "hepitypes" and thus the analysis of DNA methylation phylogeny in the somatic evolution of cancer.

Genomic imprinting is an epigenetic process leading to parent-of-origin-specific DNA methylation and gene expression. To date, approximately 60 imprinted human genes are known. Based on genome-wide methylation analysis of a patient with multiple imprinting defects, we have identified a differentially methylated CpG island in intron 2 of the retinoblastoma (RB1) gene on chromosome 13. The CpG island is part of a 5'-truncated, processed pseudogene derived from the KIAA0649 gene on chromosome 9 and corresponds to two small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In four other KIAA0649 pseudogene copies, which are located on chromosome 22, the two CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analysing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2'-deoxycytidine-treated lymphoblastoid cells, we have found that differential methylation of the CpG island skews RB1 gene expression in favor of the maternal allele. Thus, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation.