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Background: Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. Methods: We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1–2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1–10) in adults and 7 (2–11) in children. Results: The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36–55%) in adults and 64% (45–80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38–56%), 35% (27–44%) and 30% (22–39%) for adults, and 59% (40–74%), 42% (24–58%) and 35% (19–53%) for children, respectively (whole cohort: median OS 5.8 months). Conclusion: A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to establish the rate at which routine postoperative renal ultrasonography is able to detect urinary tract injury following gynecological surgery.Methods: A retrospective analysis was carried out for the study period 2015-2019 of all patients who had undergone subtotal or total hysterectomy, or radical hysterectomy or salpingectomy, salpingo-oophorectomy, or oophorectomy, and subsequently had a urinary tract injury.Results: In a total of 2068 patients, 25 urinary tract injuries occurred (1.21%), including 21 urinary bladder lesions (1.02%) and four ureteral injuries (0.19%). The incidence of urinary tract injuries was 3% in oncologic procedures and 0.86% in procedures for benign disease. Nineteen injuries (76%) were diagnosed intraoperatively, and six injuries (24%) were clinically diagnosed after surgery. All of the patients had uneventful postoperative renal ultrasound examinations.Conclusion: Routine postoperative renal ultrasonography was not capable of diagnosing urinary tract injuries after gynecologic surgery. Routine postoperative renal ultrasound examinations should, therefore, not be performed after gynecologic operations. [ABSTRACT FROM AUTHOR]

We explored the effects of resilience in the healthcare setting during the COVID-19 pandemic in Germany. Our study sheds light on the cross-level effects of resilience in hospitals and thus responds to calls to research this empirically. In a cross-sectional study design, the perceptions of resilience of employees in hospitals and of transformations at the individual, team, and organizational level were analyzed. An online survey was conducted in summer 2020 in Germany in which 1,710 healthcare workers completed a self-report questionnaire. Results indicate that resilience is both a highly interrelated construct on the individual and organizational level and also positively linked to perceptions of transformation as an indicator for demonstration of resilience. We also found a partial mediation effect of organizational resilience and team efficacy, respectively, on the relationship between individual resilience and perceived transformation on the individual and organizational level as well as a full mediation on the team level. The study highlights the interdependence of individual and organizational resilience (which is mediated by team efficacy) and its impact on perceived transformation in German hospitals during the COVID-19 pandemic. Whereas team efficacy is crucial for performance in regular work operations, during a pandemic the organizational level becomes more relevant. Theoretical and practical implications are discussed. [ABSTRACT FROM AUTHOR]

Internal states, e.g., emotions, cognitive states, or desires, are often verbalized by figurative means, in particular by embodied metaphors involving human senses, such as touch, taste, and smell. The present paper presents a database for German metaphorical expressions conveying internal states with human senses as their source domains. 168 metaphorical expressions from the source domains of vision, hearing, smell, taste, touch, and temperature combined with literal equivalents were collected and rated by 643 adults. The agreement between the metaphor and an equivalent literal expression, as well as emotional valence, arousal, and familiarity values were assessed using a 7-point Likert scale. Between the metaphorical expressions and their equivalents, familiarity, but not valence or arousal differed significantly while agreement ratings indicated high similarity in meaning. The novel database offers carefully controlled stimuli that can be used in both empirical metaphor research and research on internal state language. Using part of the stimuli in a sentence completion experiment revealed a significant preference for literal over metaphorical expressions that cannot be attributed to higher familiarity levels. [ABSTRACT FROM AUTHOR]

The processing of metaphors and idioms has been the subject of neuroscientific research for several decades. However, results are often contradictory, which can be traced back to inconsistent terminology and stimulus control. In this systematic review of research methods, we analyse linguistic aspects of 116 research papers which used EEG, fMRI, PET, MEG, or NIRS to investigate the neural processing of the two figurative subtypes metaphor and idiom. We critically examine the theoretical foundations as well as stimulus control by performing a systematic literature synthesis according to the PRISMA guidelines. We explicitly do not analyse the findings of the studies but instead focus on four primary aspects: definitions of figurative language and its subtypes, linguistic theory behind the studies, control for factors influencing figurative language processing, and the relationship between theoretical and operational definitions. We found both a lack and a broad variety in existing definitions and operationalisation, especially in regard to familiarity and conventionality. We identify severe obstacles in the comparability and validation potential of the results of the papers in our review corpus. We propose the development of a consensus in fundamental terminology and more transparency in the reporting of stimulus design in the research on figurative language processing. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult. [ABSTRACT FROM AUTHOR]

Human aggression can be differentiated into reactive aggression (RA), displayed in face of a real or perceived threat and associated with high levels of anxiety, and proactive aggression (PA), displayed to achieve a certain goal and linked to lower anxiety levels. To study the origins of these aggression subtypes and their relation to anxiety, we tested if both subtypes can be distinguished in a nonhuman primate species, characterized their occurrence within the study group, and examined the link between aggression subtype and anxiety. Data were collected on 29 individuals of a semi-free ranging group of Barbary macaques (Macaca sylvanus) at Affenberg Salem, Germany, via focal animal (303 hr) and event sampling (1,222 agonistic events). Using a priori definitions, each aggressive event was classified as either reactive or proactive. We found both aggression types in our study population as well as individual differences in the proportion at which they occurred. The predominant use of one subtype of aggression was linked to the individual's dominance rank, age and sex, but not related to standard behavioral and physiological measures of anxiety. Our results suggest that reactive and proactive subtypes of aggression also exist in Barbary macaques, indicating a deeper evolutionary history of these aggression types observed in humans. [ABSTRACT FROM AUTHOR]

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For the investigation of molecular processes underlying diseases of the bovine mammary gland, primary bovine mammary epithelial cells (pbMEC) are used. They are known to contribute to the innate immune system of the bovine mammary gland. The functionality of pbMEC depends on the maintenance of in vivo characteristics. So far, the optimization of pbMEC culture conditions was intended in a variety of experiments. For this purpose, most of the studies used stable cell lines or primary cells obtained from udder biopsies of slaughtered animals. By contrast, within our study, pbMEC of healthy and first lactating Brown Swiss cows were non-invasively isolated from fresh milk. The non-invasively isolated pbMEC were cultivated on the extracellular matrix-like scaffold Matrigel® Further, they were challenged with different compositions of proliferation media, containing lactogenic hormones and/or the essential amino acid l-lysine. Changes in expression levels of genes coding for milk proteins and for components of the janus kinase/signal transducers and activators of transcription (JAK-STAT) and mTOR pathways were analyzed by RT-qPCR. The secreted proteins were analyzed by LC-MS/MS measurements. We showed for the first time the establishment of a physiologically functional 3D cell culture model of pbMEC isolated from fresh milk. This represents a primary cell culture model system, based on non-invasive cell collection, that can be used to unravel physiological processes in an unbiased manner. [ABSTRACT FROM AUTHOR]

As the demographic change progresses, dementia is going to become a prevalent condition in many countries. In order to keep the Quality of Life (QoL) of People with Dementia (PwD) on a steady level, Assistive Technologies (AT) implemented on table-sized Surface Computers (SC) that promote playful and/or reminiscence-triggering activities turn out to be valuable tools for dementia care. This article gives an overview over two similar multimedia-based AT systems implemented on Microsoft PixelSense SCs and field-tested in dementia care institutions. The observations indicate that both systems can trigger positive emotions and activities as well as memories. [ABSTRACT FROM AUTHOR]

Patients with monoclonal gammopathy of undetermined significance ( MGUS) have a higher risk for the development of concomitant primary cancers such as multiple myeloma ( MM) and myelodysplastic syndrome ( MDS). We report the case of patient initially suffering from MGUS of the IgG lambda subtype for more than 10 yr, which evolved to MM and MDS with deletion (5q) with severe pancytopenia. Due to pancytopenia, he received dose-reduced treatment with lenalidomide and dexamethasone. He achieved an ongoing transfusion independency after about 1 month of treatment. Bone marrow taken 14 months after start of treatment showed a complete cytogenetic response of the del(5q) clone and a plasma cell infiltration below 5%. In contrast to the development of MM in MGUS patients, the subsequent occurrence of MDS after diagnosis of MGUS is infrequent. Moreover, the biological association of MDS with MGUS is not sufficiently understood, but the non-treatment-related occurrence supports the pathogenetic role of pre-existing alterations of stem cells. Here, we summarize data on concomitant MDS and MGUS/ MM with particular emphasis on molecular aspects. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex ( MHC) plays an important role in the immune response and may thus crucially affect an individual's fitness, relevant also for studies on evolutionary ecology and wildlife conservation. Detailed knowledge on the genomic organization, polymorphism and diversity of the MHC has a narrow taxonomic focus though and among macaques is only available for rhesus and long-tailed macaques-the species most commonly kept for biomedical research. The lack of data on wild populations is largely due to the difficulty of obtaining blood or tissue samples necessary for genotyping approaches. Here, we aimed at analyzing MHC-DRB from non-invasively collected fecal samples in wild Assamese macaques ( Macaca assamensis), utilizing the MHC-DRB-STR ( D6S2878) microsatellite marker. Due to the fecal DNA source incomplete genotypes occurred, which may be improved in the future by method refinement. We detected 28 distinct DRB-STR lengths in 43 individuals with individual genotypes containing 1-9 MHC-DRB-STRs and defined four haplotypes segregating between families in Mendelian fashion. Our results indicate that variability and diversity of MHC-DRB in Assamese macaques is comparable to that of other macaque species and importantly, that fecal samples can be used for non-invasive analysis of MHC genes after refinement of the applied methods, opening a number of opportunities for MHC research on natural populations. Am. J. Primatol. 9999:1-9, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article presents an essay of German social scientist Dr. Nadine Müller on the crisis of labour unions in the process of neo-liberal computerization. Müller analyzes the causes of the decline in members, and the increasing disregard for collective agreements. She addresses the impact of computerization on workflow, competence specialties, and the individualization of workers.

For overcoming the crisis of trade unions it seems necessary to revise its policies and internal organization. This crisis is not only reflected in a steady decline in membership, but also in the increasing loss of importance of traditional trade union instruments. It was triggered by a fundamental shift in labor relations that has led to an altered balance of power between capital and labor. This change cannot be limited to the impact of neoliberalism and its diffusion, but is also transformed by labor organization in the process of computerization. Therefore, in this article will be justified that the crisis of trade unions is also a result of computerization and its neo-liberal management. Based on these results it is possible to formulate requirements for a progressive and emancipatory approach to the unions. [ABSTRACT FROM AUTHOR]

Background: The soluble transferrin receptor (sTfR) is established as a test for iron deficiency (ID). In chronic lymphocytic leukemia (CLL), sTfR is not reliable for screening for ID as the latter is strongly dependent on tumor burden. Methods: We investigated whether the influence of the tumor load can be excluded or minimized using the sTfR/log ferritin ratio (TfR-F-Index) and the C-reactive protein (CRP)-adjusted TfR-F-Index in 87 patients with CLL. sTfR was measured nephelometrically (normal: 0.81–1.75 mg/L). A cut-off value of 1.5 for the TfR-F-Index and 0.8 for the CRP-adjusted TfR-F-Index, in patients with a CRP >5 mg/L, was used. Results: All Binet A patients had normal sTfR values (1.34±0.2 mg/L), TfR-F-Index (0.67±0.2) and a CRP-adjusted TfR-F-Index. In Binet B and C, sTfR and the TfR-F-Index were significantly increased compared to Binet A patients (p<0.0001). The differences between Binet B and C were not significant. sTfR was increased in 85%, TfR-F-Index in 46% and the CRP-adjusted TfR-F-Index in 54% of the Binet B patients, in Binet C patients, 80%, 50% and 60% showed increases, respectively. sTfR and the TfR-F-Index decreased or even normalized following successful treatment. Conclusions: Similar to sTfR, the TfR-F-Index is strongly associated with tumor burden in patients with CLL. Thus, these parameters do not allow for a reliable diagnosis of ID in this patient group. Clin Chem Lab Med 2009;47:1291–5. [ABSTRACT FROM AUTHOR]

Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely explored. We analyzed the expression of reporter constructs containing either 2′-deoxy-(5-fC/5-caC) or their BER-resistant 2′-fluorinated analogs, asymmetrically incorporated into CG-dinucleotide of the GC box cis-element (5′-TGGGCGGAGC) upstream from the RNA polymerase II core promoter. In the absence of BER, 5-caC caused a strong inhibition of the promoter activity, whereas 5-fC had almost no effect, similar to 5-methylcytosine or 5-hydroxymethylcytosine. BER of 5-caC caused a transient but significant promoter reactivation, succeeded by silencing during the following hours. Both responses strictly required thymine DNA glycosylase (TDG); however, the silencing phase additionally demanded a 5′-endonuclease (likely APE1) activity and was also induced by 5-fC or an apurinic/apyrimidinic site. We propose that 5-caC may act as a repressory mark to prevent premature activation of promoters undergoing the final stages of DNA demethylation, when the symmetric CpG methylation has already been lost. Remarkably, the downstream promoter activation or repression responses are regulated by two separate BER steps, where TDG and APE1 act as potential switches. [ABSTRACT FROM AUTHOR]

Vitamin B1 (thiamin) is an essential compound in all organisms acting as a cofactor in key metabolic reactions and has furthermore been implicated in responses to DNA damage and pathogen attack in plants. Despite the fact that it was discovered almost a century ago and deficiency is a widespread health problem, much remains to be deciphered about its biosynthesis. The vitamin is composed of a thiazole and pyrimidine heterocycle, which can be synthesized by prokaryotes, fungi, and plants. Plants are the major source of the vitamin in the human diet, yet little is known about the biosynthesis of the compound therein. In particular, it has never been verified whether the pyrimidine heterocycle is derived from purine biosynthesis through the action of the THIC protein as in bacteria, rather than vitamin B6 and histidine as demonstrated for fungi. Here, we identify a homolog of THIC in Arabidopsis and demonstrate its essentiality not only for vitamin B1 biosynthesis, but also plant viability. This step takes place in the chloroplast and appears to be regulated at several levels, including through the presence of a riboswitch in the 3′-untranslated region of THIC. Strong evidence is provided for the involvement of an iron-sulfur cluster in the remarkable chemical rearrangement reaction catalyzed by the THIC protein for which there is no chemical precedent. The results suggest that vitamin B1 biosynthesis in plants is in fact more similar to prokaryotic counterparts and that the THIC protein is likely to be the key regulatory protein in the pathway. [ABSTRACT FROM AUTHOR]

The objective of the present paper is to develop a validated numerical model of a water vortex power plant that serves as a digital twin for further studies such as assessments of the ethohydraulic characteristics or the performance of such devices. The reference for the validation process is a large-scale hydraulic installation equipped with a full-scale water vortex power plant prototype installed in Dresden (Germany), where flow field measurements were carried out using three-dimensional Acoustic Doppler Velocimetry. The numerical model was implemented within the software package Star-CCM+. The unsteady, two-phase flow was solved with the Reynolds-Averaged Navier–Stokes equations in a Eulerian Multiphase approach, deploying a Volume of Fluid method to describe the free-surface flow. Water level and flow velocities were systematically compared in key areas of the device, demonstrating that the simulation is in good agreement with experimental observations. Relative differences are limited to at most 4% regarding water height in the system, and even the much more challenging velocity fields are reproduced with typical relative errors of roughly 10%. This validates the ability of the model to model the challenging flow conditions found in a water vortex power plant, enabling subsequent studies of the characteristics of this power plant concerning fish migration. [ABSTRACT FROM AUTHOR]

Background: New treatment options are needed to prevent relapses following failed antibiotic therapies of Clostridium difficile infections (CDI) in humans. The concomitant therapy with an anti-C. difficile IgA containing whey protein concentrate can support the sustainable recovery of CDI patients. For 31 weeks, nine dairy cows were continuously vaccinated with several anti-C. difficile vaccines by certain routes of administration to produce anti-C. difficile IgA enriched milk. The study aimed at finding decisive differences between low responder (LR) and high responder (HR) cows (> 8.0 µg ml−1 total milk C. difficile specific IgA) concerning their immune response to vaccination on cellular and molecular biological levels. Results: The results of total and differential cell counting (DCC) in blood and milk and the outcomes of the gene expression analysis of selected immune factors were assessed relating to the usage of two vaccine batches for injection (MucoCD-I batch A and B), marking two immunization (IM) periods, and compared to a control group (Ctr). The MucoCD-I batch A caused short-term leukopenia followed by leukocytosis in the blood of LR and HR. The total somatic cell counts in milk were not altered by the treatment. The DCC revealed that the leukocytes of the treated groups were partly impaired by the treatment. The gene expression analysis exposed cumulative and sustainable differences (p < 0.05) between LR and HR for the genes encoding for lactoferrin, CXCL8, IL1β, IL2, IL6, IL12β, IFNγ, CD4 and CD163. The regulation of the epithelial IgA cell receptor PIGR was not impaired by the IM. In contrast to the vaccination with MucoCD-I batch A, the second IM period with MucoCD-I batch B resulted in mitigation and synchronization of the treated groups' immune responses. Conclusions: The inversely regulated cytokines in the blood and milk cells of the treated groups led to a variously directed, local T cell response resulting in their different production intensities of C. difficile specific IgA in milk. [ABSTRACT FROM AUTHOR]

Studying host parasite interactions and their implications for evolution and ecology recently received increasing attention, particularly with regard to host physiology and immunity. Here we assess variation of urinary neopterin (uNEO), a marker of cellular immune activation and iummunosenescence, in response to age and anthelmintic treatment in semi-free ranging Barbary macaques (Macaca sylvanus). Urinary NEO levels were measured via enzyme-immunoassay from 179 urine samples of 43 individuals between 5-29 years of age. Efficiency of treatment was assessed by Mc Master flotation on repeated faecal samples, including 18 untreated individuals as control group. We used linear mixed models with age and parasite status as main effects, controlling for sex and physical condition, assessed through urinary C-Peptide-levels, with social group and ID as random factors. Urinary NEO levels significantly increased with age, suggesting that changes in aging Barbary macaque immune responses are consistent with immunosenescence described in human and nonhuman primates and can be detected via uNEO measurements. Anthelmintic treatment, however, had no influence on uNEO levels, potentially due to quick reinfections or attenuated immune responses in repeated infections. We conclude that uNEO is a potential non-invasive marker for immune function and particularly immunosenescence in wildlife. [ABSTRACT FROM AUTHOR]