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Combined diabetes-obesity syndromes severely impair regeneration of acute skin wounds in mouse models. This study assessed the contribution of subcutaneous adipose tissue to exacerbated wound inflammatory conditions. Genetically obese (ob/ob) mice showed an increased expression of positive transcriptional effectors of adipocyte differentiation such as Krüppel-like factor (KLF)-5 and peroxisome proliferator-activated receptor (PPAR)-γ and an associated expression of leptin and fatty acid-binding protein (FABP)-4, but also CXCL2 in isolated subcutaneous fat. This observation in obese mice is in keeping with differentially elevated levels of KLF-5, PPAR-γ, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1β/TNF-α) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-γ, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-γ agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-γ activation on CXCL2 release appeared to be a general anti-inflammatory effect in mature adipocytes, as cytokine-induced cyclooxygenase (Cox)-2 was simultaneously repressed by rosiglitazone. In accordance with these findings, oral administration of rosiglitazone to wounded obese mice significantly changed subcutaneous adipocyte morphology, reduced wound CXCL2 and Cox-2 expression and improved tissue regeneration. Thus, our data suggest that PPAR-γ might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions.
Within the SEASTAR project at RIKEN-RIBF, 66Cr and 70,72Fe have been produced via protonknockout reactions, and their first excited 2+ and 4+ states have been discovered. The combination of the liquid-hydrogen target and TPC system MINOS has been used in combination with the DALI2 detector array for the first time. A 345 MeV/u 238U beam with a mean intensity of about 12 pnA impinged on a Be target. Fission fragments were separated and identified using the BigRIPS spectrograph, and reaction products were analyzed using the ZeroDegree spectrograph. A plateau of excitation energies, with a small change in the systematic trends past N = 44, reveals an extension of the N = 40 region of collectivity toward N = 50. Hence, the isotopes of interest are located within the N = 40 island of inversion. An interpretation of the observed trends is offered through large scale shell model calculations.
Purpose: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization.
Methods: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16).
Results: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface.
Conclusion: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.
Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
Nuclear factor of activated T-cells (NFAT) and NF-kB pathway associated processes are involved in the pathogenesis of various inflammatory disorders, for example, periodontal disease. The activation of these pathways is controlled by the regulator of calcineurin 1 (RCAN1). The aim of this study was to elucidate the role of RCAN1 in periodontal disease. Healthy and inflamed periodontal tissues were analyzed by immunohistochemistry and immunofluorescence using specific rabbit polyclonal anti-RCAN1 antibodies. For expression analysis human umbilical vein endothelial cells (HUVEC) were used. HUVEC were incubated for 2 h with Vascular Endothelial Growth Factor (VEGF) or with wild type and laboratory strains of Porphyromonas gingivalis (P. gingivalis). Expression analysis of rcan1 and cox2 was done by real time PCR using specific primers for rcan1.4 and cox2. The expression of rcan1 was found to be significantly suppressed in endothelial cells of chronically inflamed periodontal tissues compared to healthy controls. Rcan1 and cox2 were significantly induced by VEGF and wild type and laboratory P. gingivalis strains. Interestingly, the magnitude of the rcan1 and cox2 induction was strain dependent. The results of this study indicate that RCAN1 is suppressed in endothelial cells of chronically inflamed periodontal tissues. During an acute infection, however, rcan1 seems to be upregulated in endothelial cells, indicating a modulating role in immune homeostasis of periodontal tissues.
Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
Purpose: To investigate the prognostic value of survivin expression in pretreatment specimens from patients with anal cancer treated with concurrent 5-FU and mitomycin C-based chemoradiation (CRT).
Material and methods: Immunohistochemical staining for survivin was performed in pretreatment biopsies of 62 patients with anal carcinoma. Survivin expression was correlated with clinical and histopathological characteristics as well as local failure free- (LFFS), distant metastases free- (DMFS), cancer specific- (CSS), and overall survival (OS).
Results: Survivin staining intensity was weak in 10%, intermediate in 48% and intense in 42% of the patients. No association between survivin expression and clinicopathologic factors (tumor stage, age and HIV status) could be shown. In univariate analysis, the level of survivin staining was significantly correlated with DMFS (low survivin vs. high survivin: 94% vs. 74%, p=0.04). T-stage, N-stage and the tumor grading were significantly associated with OS and CSS and with DMFS and LFFS, respectively. In multivariate analysis, survivin was confirmed as independent prognostic parameter for DMFS (RR, 0.04; p=0.02) and for OS (RR, 0.27; p=0.04).
Conclusion: Our results demonstrated that the level of pretreatment survivin is correlated with the clinical outcome in patients with anal carcinoma treated with concurrent CRT. Further studies are warranted to elucidate the complex role of survivin for the oncologic treatment and to exploit the protein as a therapeutic target in combined modality treatment of anal cancer.
Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-Å resolution X-ray crystal structure of a TSEN15–34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.
Background: Emergency ultrasound is gaining importance in medical education. Widespread teaching methods are frontal presentations and hands-on training. The primary goal of our study was to evaluate the impact of frontal presentations (PS) by analysis of retained knowledge rate (RKR) and learning load (LL).
Methods: Our study was conducted during four introductory courses in emergency ultrasound covering Extended Focused Assessment with Sonography for Trauma (E-FAST) and Focused Echocardiography Evaluation in Life Support (FEEL). Standardized PS (length of 10 to 50 min) were presented by experienced trainers, who were asked to provide keywords, key messages, and images and assign a score to each. Group 1 consisted of 11 medical students with no prior ultrasound experience, and group 2 consisted of 80 physicians. Each group was audience to seven to eight standard PS and requested to answer a free text questionnaire after 0 h, 2.5 h, 24 h, and 14 days.
Results: In group 1, 168/176 questionnaires were analyzed, and 161/202 were analyzed in group 2. RKR in group 1 was 32.5%, 15%, 16%, and 12% at 0 h, 2.5 h, 24 h, and 2 weeks. The physicians' RKR were 23%, 20.5%, and 22.4% after 0, 2.5, and 24 h of a respective PS. The LL was 1.6/min for students and 1.2/min for physicians. There was no difference in RKR when comparing PS with higher and lower LL for both groups; shorter or case-based PS were associated with a higher RKR (p < 0.01).
Conclusions: Our study provides evidence that only a limited amount of information can be processed at a time. Only 12% of knowledge is retained after 2 weeks. Presentations of short duration can increase the retained knowledge rate. Therefore, frontal presentations and classroom-based ultrasound training and teaching should be adapted.
CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis
(2019)
Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.
Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-Å resolution X-ray crystal structure of a TSEN15–34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.
Eines der zentralen Konzepte, auf das sich die Sowjetunion in ihrem Selbstverständnis als neue Zivilisation berief, war das Konzept der "Völkerfreundschaft" (družba narodov). Über den naheliegenden Zusammenhang mit der sowjetischen Nationalitätenpolitik (insbesondere stalinscher Prägung) hinaus verweist es auf die propagierte sowjetische Ethik – die Gleichheit aller Sowjetbürger nach der Abschaffung der Klassengesellschaft. Nach dem Zerfall der Sowjetunion wird dieses Modell des gemeinschaftlichen Zusammenlebens bezogen auf den Raum der Sowjetkultur vor allem als machtpolitische Strategie bzw. in seiner mythenhaften Dimension betrachtet. Anliegen des Workshops ist es, ausgehend vom sowjetischen Freundschaftsbegriff unterschiedliche Facetten und Implikationen der Freundschaft im interkulturellen Vergleich zu diskutieren. So haben Länder und Regionen im Süden und Osten Europas (wie Georgien) beispielsweise die Gastfreundschaft als kulturelle Praktik zu ihrem "Markenzeichen" erklärt. Die Art und Weise, wie die Gastfreundschaft in Literatur und Kunst verhandelt bzw. repräsentiert wird, ist ein Indiz für die nachhaltige Bedeutung des Paradigmas, das bis in aktuelle Konflikte und juristische Diskurse (wie etwa die Frage nach dem Gastrecht oder das ethnisch begründete Restitutionsgesetz im heutigen Abchasien) hineinreicht. Gefragt wird u.a. nach den politischen Implikationen des Freundschaftsbegriffs, nach der Übertragung des interpersonellen Konzepts Freundschaft auf Völker im (sowjetischen) Konzept der Völkerfreundschaft, nach Politisierungsstrategien, nach unterschiedlichen Praktiken der (Gast-)Freundschaft (u.a. im Kontext der Derridaschen Ethik oder der Positionen von C. Schmitt, P. Klossowski oder M. Mauss) oder etwa nach der Bildung formeller und informeller Netzwerke in unterschiedlichen kulturellen und historischen Kontexten. Schwerpunktmäßig im 20. und 21. Jahrhundert angesiedelt, wird im Rahmen des Workshops auch die Genese der (sowjetischen) Konzepte und Praktiken der Freundschaft aus der Antike bzw. der Vormoderne thematisiert.
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity.
Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59–0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43–0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators.
Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.
Background & Aims: In ACLF patients, an adequate risk stratification is essential, especially for liver transplant allocation, since ACLF is associated with high short-term mortality. The CLIF-C ACLF score is the best prognostic model to predict outcome in ACLF patients. While lung failure is generally regarded as signum malum in ICU care, this study aims to evaluate and quantify the role of pulmonary impairment on outcome in ACLF patients.
Methods: In this retrospective study, 498 patients with liver cirrhosis and admission to IMC/ICU were included. ACLF was defined according to EASL-CLIF criteria. Pulmonary impairment was classified into three groups: unimpaired ventilation, need for mechanical ventilation and defined pulmonary failure. These factors were analysed in different cohorts, including a propensity score-matched ACLF cohort.
Results: Mechanical ventilation and pulmonary failure were identified as independent risk factors for increased short-term mortality. In matched ACLF patients, the presence of pulmonary failure showed the highest 28-day mortality (83.7%), whereas mortality rates in ACLF with mechanical ventilation (67.3%) and ACLF without pulmonary impairment (38.8%) were considerably lower (p < .001). Especially in patients with pulmonary impairment, the CLIF-C ACLF score showed poor predictive accuracy. Adjusting the CLIF-C ACLF score for the grade of pulmonary impairment improved the prediction significantly.
Conclusions: This study highlights that not only pulmonary failure but also mechanical ventilation is associated with worse prognosis in ACLF patients. The grade of pulmonary impairment should be considered in the risk assessment in ACLF patients. The new score may be useful in the selection of patients for liver transplantation.
The study of neutron-induced reactions is of high relevance in a wide variety of fields, ranging from stellar nucleosynthesis and fundamental nuclear physics to applications of nuclear technology. In nuclear energy, high accuracy neutron data are needed for the development of Generation IV fast reactors and accelerator driven systems, these last aimed specifically at nuclear waste incineration, as well as for research on innovative fuel cycles. In this context, a high luminosity Neutron Time Of Flight facility, n_TOF, is operating at CERN since more than a decade, with the aim of providing new, high accuracy and high resolution neutron cross-sections. Thanks to the features of the neutron beam, a rich experimental program relevant to nuclear technology has been carried out so far. The program will be further expanded in the near future, thanks in particular to a new high-flux experimental area, now under construction.
High precision measurement of the radiative capture cross section of 238U at the n_TOF CERN facility
(2017)
The importance of improving the accuracy on the capture cross-section of 238U has been addressed by the Nuclear Energy Agency, since its uncertainty significantly affects the uncertainties of key design parameters for both fast and thermal nuclear reactors. Within the 7th framework programme ANDES of the European Commission three different measurements have been carried out with the aim of providing the 238U(n,γ) cross-section with an accuracy which varies from 1 to 5%, depending on the energy range. Hereby the final results of the measurement performed at the n_TOF CERN facility in a wide energy range from 1 eV to 700 keV will be presented.
Neutron-induced fission cross sections of 238U and 235U are used as standards in the fast neutron region up to 200 MeV. A high accuracy of the standards is relevant to experimentally determine other neutron reaction cross sections. Therefore, the detection effciency should be corrected by using the angular distribution of the fission fragments (FFAD), which are barely known above 20 MeV. In addition, the angular distribution of the fragments produced in the fission of highly excited and deformed nuclei is an important observable to investigate the nuclear fission process.
In order to measure the FFAD of neutron-induced reactions, a fission detection setup based on parallel-plate avalanche counters (PPACs) has been developed and successfully used at the CERN-n_TOF facility. In this work, we present the preliminary results on the analysis of new 235U(n,f) and 238U(n,f) data in the extended energy range up to 200 MeV compared to the existing experimental data.