UTLS temperature validation of MPI-ESM decadal hindcast experiments with GPS radio occultations

Global Positioning System (GPS) radio occultation (RO) temperature data are used to validate MPI-ESM (Max Planck Institute – Earth System Model) decadal hindcast experiments in the upper troposphere and lower stratosphere (UTLS) region between 300 hPa and 10 hPa (8 km and 32 km) for the time period between 2002 and 2011. The GPSRO dataset is unique since it is very precise, calibration independent and covers the globe better than the usual radiosonde dataset. In addition it is vertically finer resolved than any of the existing satellite temperature measurements available for the UTLS and provides now a unique one decade long temperature validation dataset. The initialization of the MPI-ESM decadal hindcast runs mostly increases the skill of the atmospheric temperatures when compared to uninitialized climate projections with very high skill scores for lead-year one, and gradually decreases for the later lead-years. A comparison between two different initialization sets (b0, b1) of the low-resolution (LR) MPI-ESM shows increased skills in b1-LR in most parts of the UTLS in particular in the tropics. The medium resolution (MR) MPI-ESM initializations are characterized by reduced temperature biases in the uninitialized runs as compared to observations and a better capturing of the high latitude northern hemisphere interannual polar vortex variability as compared to the LR model version. Negative skills are found for the b1-MR hindcasts however in the regions around the mid-latitude tropospheric jets on both hemispheres and in the vicinity of the tropical tropopause in comparison to the b1-LR variant. It is interesting to highlight that none of the model experiments can reproduce the observed positive temperature trend in the tropical tropopause region since 2001 as seen by GPSRO data

Nordic partnership choices in a fierier security environment: Towards more alignment

Nordic states’ partnership choices in security and defence are more aligned than they were a decade ago. When Danish, Finnish, Norwegian and Swedish government officials now identify key security challenges and partners, and reflect on the potential for Nordic cooperation, they have the same reference points and use similar wording. Since 2014, the toolbox for Nordic defence cooperation has also solidified and different formal affiliations with NATO and the EU seem to matter less than before. Furthermore, an array of multi- and minilateral cooperation structures have emerged across and beyond the EU and NATO, expanding the possibilities for Nordic cooperation under a larger Euro-Atlantic umbrella. However, two limitations remain: First, Nordic security and defence cooperation still remains subordinate to and a supplement rather than an alternative to NATO. Second, putting Nordic response mechanisms into practice remains dependent not only on the context and issue at stake, but also on the political appetite of the individual Nordic governments to choose a Nordic solution.publishedVersio

Impact of tumor localization and molecular subtypes on the prognostic and predictive significance of p53 expression in gastric cancer

We investigated the prognostic and predictive impact of p53 expression for gastric cancer (GC) patients treated without or with preoperative chemotherapy (CTx) and its relationship with specific molecular GC subtypes. Specimens from 694 GC patients (562 surgical resection specimens without or after CTx, 132 biopsies before CTx) were analyzed by p53 immunohistochemistry. High (H) and low (L) microsatellite instability (MSI) and Epstein–Barr virus positivity were determined previously. Our results show that aberrant p53 expression was a negative prognostic factor in uni- and multivariable analysis in the resection specimens cohort (each p < 0.01). Subgroup analysis showed the strongest prognostic effect for patients with distally located tumors or no CTx treatment. In the biopsy cohort before CTx, p53 did not predict response or survival. p53 expression was significantly different among the molecular subtypes in surgical resection and bioptic specimens with strong association of altered p53 with MSI-L. Patients with MSI-H and aberrant p53 showed the worst survival in the biopsy cohort. In conclusion, the prognostic impact of p53 in GC differs according to tumor localization and CTx. Altered p53 is characteristic for MSI-L, and the p53 status in biopsies before CTx delineates MSI-H subtypes with inverse prognostic impact

Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+T cells in chronic infection

Virus-specific CD8+ T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8+ T cells in all chronically HCV genotype 1a-infected, HLA-A*02:01-positive patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two-thirds of these enriched HCV-specific CD8+ T-cell populations displayed an effector memory phenotype, whereas, surprisingly, one-third displayed a naive-like phenotype despite ongoing viral replication. CD8+ T cells with an effector memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naive-like CD8+ T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naive-like CD8+ T cells from patients with the consensus sequence in the corresponding T-cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8+ T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV-specific CD8+ T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence. IMPORTANCE In this study, we analyzed CD8+ T-cell responses specific for HLA-A*02:01-restricted epitopes in chronically HCV-infected patients, using MHC class I tetramer enrichment. Importantly, we could detect HCV-specific CD8+ T-cell populations in all patients. To further characterize these HCV-specific CD8+ T-cell populations that are not detectable using conventional techniques, we performed phenotypic, functional, and viral sequence analyses. These data revealed different mechanisms for CD8+ T-cell failure in HCV infection, including T-cell exhaustion, viral escape, and functional impairment of naive-like HCV-specific CD8+ T cells

The relevance of complement in pemphigoid diseases: A critical appraisal

Pemphigoid diseases are autoimmune chronic inflammatory skin diseases, which are characterized by blistering of the skin and/or mucous membranes, and circulating and tissue-bound autoantibodies. The well-established pathomechanisms comprise autoantibodies targeting various structural proteins located at the dermal-epidermal junction, leading to complement factor binding and activation. Several effector cells are thus attracted and activated, which in turn inflict characteristic tissue damage and subepidermal blistering. Moreover, the detection of linear complement deposits in the skin is a diagnostic hallmark of all pemphigoid diseases. However, recent studies showed that blistering might also occur independently of complement. This review reassesses the importance of complement in pemphigoid diseases based on current research by contrasting and contextualizing data from in vitro, murine and human studies

Key landscape features in the provision of ecosystem services : insights for management

Whereas ecosystem service research is increasingly being promoted in science and policy, the utilisation of ecosystem services knowledge remains largely underexplored for regional ecosystem management. To overcome the mere generation of knowledge and contribute to decision-making, scientists are facing the challenge of articulating specific implications of the ecosystem service approach for practical land use management. In this contribution, we compare the results of participatory mapping of ecosystem services with the existing management plan for the Pentland Hills Regional Park (Scotland, UK) to inform its future management plan. By conducting participatory mapping in a workshop with key stakeholders (n = 20), we identify hotspots of ecosystem services and the landscape features underpinning such hotspots. We then analyse to what extent these landscape features are the focus of the current management plan. We found a clear mismatch between the key landscape features underpinning the provision of ecosystem services and the management strategy suggested. Our findings allow for a better understanding of the required focus of future land use management to account for ecosystem services

Elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in gastric cancer: a distinct microsatellite instability type with potential clinical impact?

We investigated the clinical impact of elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in the context of neoadjuvant chemotherapy (CTx) in gastric/gastro-oesophageal adenocarcinomas. We analysed 583 resected tumours (272 without and 311 after CTx) and 142 tumour biopsies before CTx. If at least two or three of the five tetranucleotide repeat markers tested showed instability, the tumours were defined as EMAST (2+) or EMAST (3+), respectively. Expression of mismatch repair proteins including MSH3 was analysed using immunohistochemistry. Microsatellite instability (MSI) and Epstein-Barr virus (EBV) positivity were determined using standard assays. EMAST (2+) and (3+) were detected in 17.8 and 11.5% of the tumours, respectively. The frequency of EMAST (2+) or (3+) in MSI-high (MSI-H) tumours was 96.2 or 92.5%, respectively, demonstrating a high overlap with this molecular subtype, and the association of EMAST and MSI status was significant (each overall p < 0.001). EMAST (2+ or 3+) alone in MSI-H and EBV-negative tumours demonstrated only a statistically significant association of EMAST (2+) positivity and negative lymph node status (42.3% in EMAST (2+) and 28.8% in EMAST negative, p = 0.045). EMAST alone by neither definition was significantly associated with overall survival (OS) of the patients. The median OS for EMAST (2+) patients was 40.0 months (95% confidence interval [CI] 16.4-63.6) compared with 38.7 months (95% CI 26.3-51.1) for the EMAST-negative group (p = 0.880). The median OS for EMAST (3+) patients was 46.7 months (95% CI 18.2-75.2) and 38.7 months (95% CI 26.2-51.2) for the negative group (p = 0.879). No statistically significant association with response to neoadjuvant CTx was observed (p = 0.992 and p = 0.433 for EMAST (2+) and (3+), respectively). In conclusion, our results demonstrate a nearly complete intersection between MSI-H and EMAST and they indicate that EMAST alone is not a distinct instability type associated with noticeable clinico-pathological characteristics of gastric carcinoma patients

dolls/puppets like mensch – dolls/puppets as artificial beings. Part 1.2

Die dritte Ausgabe der Zeitschrift denkste: puppe / just a bit of: doll (de:do), ein multi-disziplinäres Online-Journal für Mensch-Puppen-Diskurse, erscheint als Doppelheft, dessen gemeinsamer Themenschwerpunkt lautet: puppen/dolls like mensch – puppen als künstliche meschen. Mit diesem Fokus wird ein Thema aufgegriffen, das Menschen seit der Antike berührt und bis heute ihren Verstand und ihre Imagination, ihre Bedürfnisse und ihre Gefühle in Unruhe versetzt. In Mythologien, literarischen Fiktionen und Narrativen für Erwachsene und Kinder, in Werken der bildenden Künste, im Film, in mechanisch-technischen Anwendungen und Utopien, in den performativen Künsten, in der (Spiel-)Pädagogik und in den verschiedenen Bereichen der Popkultur wirft das Motiv der Puppe mit seinen unterschiedlichsten Ausdrucksformen immer auch existenzielle Fragen auf: Wer und was ist der Mensch? Die Puppe als künstlicher Mensch ist in gewisser Weise wie mensch, ohne Mensch zu sein. Als von Menschen geschaffene Abbilder, Vorbilder, Nachahmungen und Entwürfe des Menschen spiegeln und bestätigen Puppen vorhandene Lebenswelten und loten gleichzeitig Potenziale und Abgründe des Mensch-Seins zwischen Utopie und Dystopie, zwischen Neugier und Hingabe, zwischen Horror und Glückseligkeit, zwischen Macht und Ohnmacht aus. Puppen/dolls like mensch – der doppelte Wortsinn betont die gegebene Ambiguität der Puppen und die spannenden, ihnen innewohnenden Ambivalenzen. Im ersten Teilband (1.1) wird den Spuren und Erscheinungsformen des Puppenmotivs und der Puppe(n) – als literarisches Narrativ, als künstlerisches Motiv, als materialisiertes Objekt – vor allem im Kontext von bildender Kunst, Literatur, Fotografie, Theater und Androidentechnologien nachgegangen. Im zweiten Teilband (1.2) werden zum einen kinderliterarische und (spiel-)didaktische Texte akzentuiert, zum anderen sind hier verschiedene mediale und popkulturelle Formate aus den Bereichen Computerspiel, Comic-Film-Adaptation, Film (unterschiedlicher Genres) und dem Figurentheater versammelt sowie Thematisierungen der Verknüpfung von materiellen Artefakten und literarischen Narrativen. Rezensionen in Form von Essays über literarische Puppen-Narrative, eine Foto-Ausstellung und ein Ballett runden beide Ausgaben ab. Die zeitliche Spanne reicht vom Mittelalter bis in die Gegenwart und Zukunft und zeigt einmal mehr, wie über das Narrativ der Puppe uralte Menschheitsfragen in Traditionslinien eingebunden werden und sie auf faszinierende Weisen fortschreiben.The third edition of the journal denkste: puppe / just a bit of: doll (de: do), a multidisciplinary online journal for human-doll discourses, is a double issue whose shared thematic focus is: puppen/dolls like mensch – dolls/puppets as artificial beings. With this focus, we take up a topic that has concerned mankind since ancient times and has always upset their 'minds' and 'hearts’, their needs and feelings. In mythologies, literary fictions and narratives for adults as well as for children, in works of the visual arts, in film, in mechanical-technical applications and utopias, in the performative arts, in (play-)pedagogy and in the various fields of pop culture, the motif of the doll with its various forms of expression always raises existential questions: Who is man, what is human? The doll as an artificial human being is in a certain way like mensch without being human. As man-made images, as models, imitations and designs of humans, dolls/puppets reflect and confirm existing worlds and at the same time sound out the potentials and abysses of being human between utopia and dystopia, between curiosity and devotion, between horror and bliss, between power and powerlessness. Dolls/puppets like mensch – the double meaning of these words emphasizes the given ambiguity of the dolls/puppets and the intriguing ambivalences inherent in them. In the first part of volume (1.1) the traces and manifestations of the doll motif and of doll(s) – as literary narrative, as artistic motif, as materialized object – will be explored primarily in the context of the fine arts, of literature, photography, theater and android technologies. In the second part of the volume (1.2), on the one hand, children's literature and (play)didactic texts are accentuated; on the other hand, various media and pop-cultural formats from the fields of computer games, comic-film adaptations, films (of different genres) and puppet theater performances are gathered here, as well as issues that link material artifacts and literary narratives. Reviews in the form of essays on literary doll narratives, a photo exhibition and a ballet round off both editions. The time span extends from the Middle Ages to the present and future and shows once again how age-old questions regarding mankind and humanity are integrated into traditional lines and are carried on continuously in fascinating ways

A Heat‐Activated Drug‐Delivery Platform Based on Phosphatidyl‐(oligo)‐glycerol Nanocarrier for Effective Cancer Treatment

The potential of cancer drugs is not fully exploited due to low tumor uptake and occurrence of systemic side effects, limiting maximum tolerated dose. Actively targeted nanocarriers improve efficacy while minimizing off‐target toxicity. Herein, it is the first time a drug‐delivery platform for heat‐triggered intravascular drug release is described, based on synthetic phosphatidyl‐(oligo)‐glycerols from organic synthesis to preclinical investigation in feline patients. For the nanocarrier formulated doxorubicin (DOX), superior tumor drug delivery and antitumor activity compared with free DOX, conventional liposomal DOX (Caelyx), and temperature‐sensitive lysolipid‐containing DOX‐liposomes in rat sarcoma are demonstrated. In a comparative oncological study with neoadjuvant treatment of feline sarcoma, a metabolic response determined with 18 F‐FDG‐positron emission tomography/magnetic resonance imaging (PET/MRI) and histopathological response after tumor resection are significantly better compared with free DOX, potentially by overcoming drug resistance based on improved intratumoral drug distribution. This novel drug‐delivery platform has great potential for the treatment of locally advanced tumors in humans

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events