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Am 21. November 2019 hat die Große Kammer des Europäischen Gerichtshofs für Menschenrechte in Straßburg (EGMR) seine Entscheidung über die ungarischen Transitzonen gefällt (Rs. Ilias and Ahmed vs. Hungary), die im Sommer 2015, inmitten der großen Fluchtbewegungen in Europa, eingerichtet wurden. Die zwei Beschwerdeführer Herr Ilias und Herr Ahmed, beide Staatsangehörige aus Bangladesch, verbrachten 23 Tage in der Transitzone, bevor sie nach der Ablehnung ihrer Asylanträge nach Serbien verbracht wurden. Sie legten Individualbeschwerden vor dem Straßburger Gerichtshof ein und machten geltend, dass ihre Abschiebung nach Serbien das Verbot der Folter oder der inhumanen bzw. erniedrigenden Behandlung nach Art. 3 EMKR verletzt habe, die Bedingungen in der Transitzone ebenfalls mit Art. 3 EMRK unvereinbar gewesen seien sowie ihr Aufenthalt in der Transitzone faktisch einer Inhaftierung entsprochen habe und dies eine Verletzung ihrer Freiheit begründete (Art. 5 Abs. 1 und 4 EMRK). Die Entscheidung dürfte in Bezug auf Transitzonen an europäischen Landgrenzen einen Präzedenzfall geschaffen haben – wobei das Urteil sehr problematische Implikationen enthält.
Faul sein. Den Sonntag gemütlich auf der Couch verbringen. Die To-Do-Liste zur Seite legen. Mal keinem getakteten Tagesablauf folgen. Die Zeit einfach vorbeiziehen lassen. Zur Ruhe kommen und nichts tun geht häufig mit einem negativen Gefühl einher. Von Vorwürfen der Unproduktivität bis hin zu rassistischen Ressentiments, die mit dem Nichtstun verknüpft werden: Faulheit gehört zu den Dingen, die in der kapitalistischen Gesellschaft keinerlei Wertschätzung erfahren. Neu ist die negative Konnotation des Begriffs allerdings nicht. Bereits im vierten Jahrhundert verpönt die christliche Theologie die "Trägheit" als eine der sieben Todsünden. Die abschätzige Bewertung überdauerte den christlichen Glauben, wurde sozusagen profanisiert und ist heute – in Zeiten von Überstunden, Zweit- oder auch gleich Drittjobs und ständiger Verfügbarkeit – ein No-Go. ...
Background: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin–kexin type 9 inhibition in such patients is undetermined.
Objectives: This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.
Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint.
Results: Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: −2.4% to 6.2%), and 13.0% (95% CI: −2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: −0.1% to 1.0%), 1.3% (95% CI: −1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%).
Conclusions: In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402)
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans.
Albumin, the most abundant plasma protein, not only controls osmotic blood pressure, but also serves as a carrier for various small molecules, including pharmaceuticals. Its impact on pharmacological properties of many drugs has been extensively studied over decades. Here, we focus on its interaction with the following mobilizing agents: Granulocyte-colony stimulating factor (G-CSF) and AMD3100, where such analyses are lacking. These compounds are widely used for hematopoietic stem cell mobilization of healthy donors or patients. Using albumin-deficient (Alb−/−) mice, we studied the contribution of albumin to mobilization outcomes. Mobilization with the bicyclam CXCR4 antagonist AMD3100 was attenuated in Alb−/− mice compared to wild-type littermates. By contrast, mobilization with recombinant human G-CSF (rhG-CSF), administered twice daily over a five-day course, was significantly increased in Alb−/− mice. In terms of a mechanism, we show that rhG-CSF bioavailability in the bone marrow is significantly improved in Alb−/− mice, compared to wild-type (WT) littermates, where rhG-CSF levels dramatically drop within a few hours of the injection. These observations likely explain the favorable mobilization outcomes with split-dose versus single-dose administration of rhG-CSF to healthy donors.
Members of conflicting groups experience threats to different identity dimensions, resulting in the need to restore the aspect of identity that was threatened. Do these needs translate into specific goals in social interactions? In the present research, we examined the hypotheses that (1) experiencing one’s ingroup as illegitimately disadvantaged or victimized arouses agentic goals (to act and appear assertive and confident) when interacting with the advantaged or victimizing group, while (2) experiencing one’s ingroup as illegitimately advantaged or perpetrating transgressions arouses communal goals (to act and appear warm and trustworthy) when interacting with the disadvantaged or victimized group. Study 1 (N = 391) generally supported both hypotheses across diverse intergroup contexts involving gender, national/ethnic, and consumer identities. Study 2 (N = 122) replicated this pattern in a context of occupational identities. Study 2 further showed that the effect of ingroup role on agentic and communal intergroup goals was not moderated by participants’ general dispositional preferences for agentic and communal goals in interpersonal interactions, thus demonstrating how ingroup role exerts a distinct and robust influence on goals for interactions with other groups. Theoretical and practical implications are discussed.
This article explores the relations between affects and music in George Sand's novel "Adriani" (1853). It examines how the figuration of music highlights the importance of emotions, as they shift from aesthetic (admiration) to moral (compassion), in her protagonists' moral transformations. However, Sand's transposition of an imaginary musical world in the novel is part and parcel of a much more ambitious project, that of social transformations, notably of relations between the sexes. It is through their dialogue in and via music that her heroes discover each other and themselves, while their intimate trajectories enable the reader to imagine interpersonal relations among equals founded on emotional, intellectual and social reciprocity.
Bioaerosols are considered to play a relevant role in atmospheric processes, but their sources, properties and spatiotemporal distribution in the atmosphere are not yet well characterized. In the Amazon Basin, primary biological aerosol particles (PBAP) account for a large fraction of coarse particulate matter, and fungal spores are among the most abundant PBAP there as well as in other vegetated continental regions. furthermore, PBAP could also be important ice nuclei in Amazonia. Measurement data on the release of fungal spores under natural conditions, however, are sparse. Here we present an experimental approach to analyze and quantify the spore release from fungi and other spore producing organisms under natural and laboratory conditions. For measurements under natural conditions, the samples were kept in their natural environment and a setup was developed to estimate the spore release numbers and sizes together with the microclimatic factors temperature and air humidity, as well as the mesoclimatic parameters net radiation, rain, and fog occurrence. For experiments in the laboratory, we developed a cuvette to assess the particle size and number of newly released fungal spores under controlled conditions, simultaneously measuring temperature and relative humidity inside the cuvette. Both approaches were combined with bioaerosol sampling techniques to characterize the released particles by microscopic methods. For fruiting bodies of the basidiomycetous species, Rigidoporus microporus, the model species for which these techniques were tested, the highest frequency of spore release occurred in the range of 62 and 96 % relative humidity. The results obtained for this model species reveal characteristic spore release patterns linked to environmental or experimental conditions, indicating that the moisture status of the sample may be a regulating factor, while temperature and light seem to play a minor role for this species. The presented approach enables systematic studies aimed at the quantification and validation of spore emission rates and inventories, which can be applied to a regional mapping of cryptogamic organisms under given environmental conditions.
Gene families evolve by the processes of speciation (creating orthologs), gene duplication (paralogs), and horizontal gene transfer (xenologs), in addition to sequence divergence and gene loss. Orthologs in particular play an essential role in comparative genomics and phylogenomic analyses. With the continued sequencing of organisms across the tree of life, the data are available to reconstruct the unique evolutionary histories of tens of thousands of gene families. Accurate reconstruction of these histories, however, is a challenging computational problem, and the focus of the Quest for Orthologs Consortium. We review the recent advances and outstanding challenges in this field, as revealed at a symposium and meeting held at the University of Southern California in 2017. Key advances have been made both at the level of orthology algorithm development and with respect to coordination across the community of algorithm developers and orthology end-users. Applications spanned a broad range, including gene function prediction, phylostratigraphy, genome evolution, and phylogenomics. The meetings highlighted the increasing use of meta-analyses integrating results from multiple different algorithms, and discussed ongoing challenges in orthology inference as well as the next steps toward improvement and integration of orthology resources.
The hepatitis C virus (HCV) RNA replication cycle is a dynamic intracellular process occurring in three-dimensional space (3D), which is difficult both to capture experimentally and to visualize conceptually. HCV-generated replication factories are housed within virus-induced intracellular structures termed membranous webs (MW), which are derived from the Endoplasmatic Reticulum (ER). Recently, we published 3D spatiotemporal resolved diffusion–reaction models of the HCV RNA replication cycle by means of surface partial differential equation (sPDE) descriptions. We distinguished between the basic components of the HCV RNA replication cycle, namely HCV RNA, non-structural viral proteins (NSPs), and a host factor. In particular, we evaluated the sPDE models upon realistic reconstructed intracellular compartments (ER/MW). In this paper, we propose a significant extension of the model based upon two additional parameters: different aggregate states of HCV RNA and NSPs, and population dynamics inspired diffusion and reaction coefficients instead of multilinear ones. The combination of both aspects enables realistic modeling of viral replication at all scales. Specifically, we describe a replication complex state consisting of HCV RNA together with a defined amount of NSPs. As a result of the combination of spatial resolution and different aggregate states, the new model mimics a cis requirement for HCV RNA replication. We used heuristic parameters for our simulations, which were run only on a subsection of the ER. Nevertheless, this was sufficient to allow the fitting of core aspects of virus reproduction, at least qualitatively. Our findings should help stimulate new model approaches and experimental directions for virology.
During the past 15 years there have been dramatic changes in the medical landscape, particularly in oncology and regenerative medicine. Cell therapies have played a substantial part in this progress. Cellular immunotherapies can use immune cells, such as T cells or natural killer cells that, after functional modification ex vivo, exert powerful anti-cancer effects when given to the patient. Innovative technologies, such as re-programming terminally differentiated cells into pluripotent stem cells or into other cell types and applying specific enzymes to more precisely edit the human genome, are paving the way towards more potent cell and gene therapies.
Mesenchymal stromal cells are promising cellular immunotherapeutics, which also have potential for use in tissue engineering strategies and other regenerative medicine applications. However, substantial gaps in our knowledge of their biology and therapeutic efficacy present major challenges to their sustainable implementation in the clinical routine.
In this article, progress in the field of cell therapeutics during the past 15 years will be briefly discussed, with a focus on mesenchymal stromal cells, highlighting the impact of this field on patient care.
Cerebral radiation necrosis is a common complication of the radiotherapy of brain tumours that can cause significant mortality. Corticosteroids are the standard of care, but their efficacy is limited and the consequences of long-term steroid therapy are problematic, including the risk of adrenal insufficiency (AI). Off-label treatment with the vascular endothelial growth factor A antibody bevacizumab is highly effective in steroid-resistant radiation necrosis. Both the preservation of neural tissue integrity and the cessation of steroid therapy are key goals of bevacizumab treatment. However, the withdrawal of steroids may be impossible in patients who develop AI. In order to elucidate the frequency of AI in patients with cerebral radiation necrosis after treatment with corticosteroids and bevacizumab, we performed a retrospective study at our institution’s brain tumour centre. We obtained data on the tumour histology, age, duration and maximum dose of dexamethasone, radiologic response to bevacizumab, serum cortisol, and the need for hydrocortisone substitution for AI. We identified 17 patients with cerebral radiation necrosis who had received treatment with bevacizumab and had at least one available cortisol analysis. Fifteen patients (88%) had a radiologic response to bevacizumab. Five of the 17 patients (29%) fulfilled criteria for AI and required hormone substitution. Age, duration of dexamethasone treatment, and time since radiation were not statistically associated with the development of AI. In summary, despite the highly effective treatment of cerebral radiation necrosis with bevacizumab, steroids could yet not be discontinued due to the development of AI in roughly one-third of patients. Vigilance to spot the clinical and laboratory signs of AI and appropriate testing and management are, therefore, mandated.
La sfida del nominalismo alla realtà degli universali (sia in filosofia che in teologia) è stata un motore del pensiero moderno. Tradotta in termini estetici, ha favorito la resistenza alle generiche convenzioni e ha contribuito a minare le nozioni essenzialiste della forma estetica. Theodor W. Adorno ebbe una risposta tipicamente dialettica al nominalismo, plaudendo alla sua sovversione delle reificazioni categoriche, ma allarmato dal suo livellamento indiscriminato della distinzione tra concetto e oggetto, che poteva anche cancellare la distinzione tra opere d'arte e oggetti di uso quotidiano. In termini musicali, ha apprezzato l'enfasi nominalista sui singoli lavori rispetto alle generiche categorie formali e ha elogiato la rivoluzione atonale di Arnold Schoenberg. Ma era anche consapevole del fatto che, portato all'estremo, il nominalismo poteva condurre al dominio soggettivo di una natura considerata priva di proprie caratteristiche essenziali. Nella sua tardiva riflessione sulla musique informelle, ammirò una musica che evitava sia le categorie reificate che il dominio soggettivo dell'apparente contingenza del mondo materiale, una musica che esprimeva un nominalismo che avrebbe potuto essere meglio chiamato "magico" piuttosto che "convenzionale".
Prognosis of refractory childhood cancers despite multimodal treatment strategies remains poor. Here, we report a single center experience encountered in 18 patients with refractory solid malignancies treated with adoptive cellular immunotherapy (ACI) from haploidentical or matched donors following hematopoietic stem cell transplantation. While seven patients were in partial and six in complete remission (CR), five patients suffered from relapsed diseases at the time of ACI. 1.5-year probabilities of overall survival (OS) and progression-free survival (PFS) were 19.5% and 16.1% for all patients. Patients in CR showed estimated 1.5-year OS and PFS of 50.1% and 42.7%, respectively. CR was induced or rather sustained in ten children, with two still being alive 9.6 and 9.3 years after ACI. Naïve, central and effector memory T-cells correlated with responses. However, the majority of patients relapsed. Cumulative incidence of relapse was 79.8% at 1.5 years. Acute graft versus host disease (aGVHD) occurred in nine of 18 patients (50%) with aGVHD grade I–II observed in six (33%) and aGVHD grade III seen in three (17%) patients, manageable in all cases.
Altogether, study results indicate that donor-derived ACI at its current state offers palliation but no clear curative benefit for refractory childhood cancers and warrants further improvement.
Adjuvanted influenza vaccines constitute a key element towards inducing neutralizing antibody responses in populations with reduced responsiveness, such as infants and elderly subjects, as well as in devising antigen-sparing strategies. In particular, squalene-containing adjuvants have been observed to induce enhanced antibody responses, as well as having an influence on cross-reactive immunity. To explore the effects of adjuvanted vaccine formulations on antibody response and their relation to protein-specific immunity, we propose different mathematical models of antibody production dynamics in response to influenza vaccination. Data from ferrets immunized with commercial H1N1pdm09 vaccine antigen alone or formulated with different adjuvants was instrumental to adjust model parameters. While the affinity maturation process complexity is abridged, the proposed model is able to recapitulate the essential features of the observed dynamics. Our numerical results suggest that there exists a qualitative shift in protein-specific antibody response, with enhanced production of antibodies targeting the NA protein in adjuvanted versus non-adjuvanted formulations, in conjunction with a protein-independent boost that is over one order of magnitude larger for squalene-containing adjuvants. Furthermore, simulations predict that vaccines formulated with squalene-containing adjuvants are able to induce sustained antibody titers in a robust way, with little impact of the time interval between immunizations.
Background & Aims: Adequate adherence to hepatitis C virus (HCV) treatment is believed to be a key component of treatment success because non‐adherence can potentially result in treatment failure and the emergence of resistant viral variants. This analysis assessed factors associated with non‐adherence to glecaprevir/pibrentasvir (G/P) therapy and the impact of non‐adherence on sustained virological response at post‐treatment week 12 (SVR12) rates in HCV genotype (GT) 1‐6‐infected patients.
Methods: Adherence was calculated by pill counts at study visits during treatment, and defined as having a lowest treatment adherence of ≥80% and ≤120% at each study visit. Exploratory logistic regression modelling assessed predictors of non‐adherence to G/P therapy. SVR12 rates by treatment adherence were assessed in the intent‐to‐treat (ITT) population and modified ITT (mITT) population, which excludes non‐virological failures.
Results: Overall, 97% (2024/2091) of patients were adherent to G/P therapy at all consecutive study visits. Alcohol use was the only baseline characteristic independently associated with non‐adherence to G/P therapy (OR: 2.38; 95% CI: 1.13‐5.01; P = .022). In the mITT population, overall SVR12 rates were high both in patients who were adherent to G/P therapy and those who were not (99% [1983/2008] and 95% [58/61] respectively; P = .047). Corresponding SVR12 rates in the ITT population were 98% (1983/2024) and 87% (58/67) respectively.
Conclusions: Most patients adhered to G/P therapy. SVR12 rates were high both in patients who were adherent to G/P treatment and those who were not. Patient education on treatment adherence should remain an important part of HCV treatment.
Clinical trials registration: NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, NCT02243293, NCT02446717.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.
Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients.
Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF).
Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes.
Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.
Records of Bahamas plume moths (Lepidoptera: Pterophoridae) collected since 2011 are summarized and four new species described: Michaelophorus salensis Matthews, new species, Oidaematophorus androsensis Matthews, new species, Hellinsia bahamensis Matthews, new species, and Hellinsia lucayana Matthews, new species. Species accounts including illustrations of adults and genitalia, diagnoses, larval hosts, habitats, and distributions are provided. Of the 23 species found, new larval host associations are reported for two species while the life histories remain unknown for seven species.
A review and update to the list of significant vascular plant taxa has been made for the c. 500 000 ha Wollemi National Park, approximately 100 km north-west of Sydney, New South Wales. A previous assessment in 2008 revealed the presence of 94 significant taxa, including 15 listed as Endangered and 22 listed as Vulnerable in NSW Threatened Species legislation. New field surveys, coupled with analysis of observation (NSW OEH Bionet Atlas) and specimen collection (Australasian Virtual Herbarium) databases, has added a further 16 significant taxa to the reserve total, elevating it to 110. A revised assessment of the total threatened flora, as listed on the NSW Biodiversity Conservation Act 2016, shows there to be 1 Critically Endangered, 19 Endangered, 26 Vulnerable taxa and 2 Endangered Populations. For Commonwealth listed taxa under the Environment Protection and Biodiversity Conservation Act 1999, there are 1 Critically Endangered, 9 Endangered and 23 Vulnerable taxa. Sixty-one taxa are currently unrepresented within either legislation and may be considered rare, 8 taxa remain scientifically undescribed (one addition in this revision, Pultenaea 'monticola' Mt Irvine), while updated names are provided for two taxa now formally described (Eucalyptus expressa and Prostanthera stenophylla). Following assessment of all newly added taxa against IUCN criteria, one currently unlisted species (Hibbertia coloensis) qualifies as Critically Endangered, while a second (Bertya linearifolia) qualifies as Endangered. Discussion is also provided on six taxa where database records show them to be present within Wollemi, but are here excluded following closer examination.
Objective: Randomized trials have shown that concomitant methotrexate (MTX) augments the effectiveness of tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA), but its benefit in psoriatic arthritis (PsA) has not been demonstrated. The goal of this study was to examine whether the impact of concomitant MTX on therapeutic outcomes in patients with PsA was similar to its effects in RA.
Methods: We used data from highly comparable and concurrent observational studies of patients with PsA (N = 1424) or RA (N = 3148) who initiated adalimumab therapy during routine clinical care. The 28-joint Disease Activity Score (DAS28) and patient-reported pain scores were evaluated in patients who received 24 months of continuous treatment with adalimumab monotherapy or adalimumab + MTX and in patients who initiated or stopped concomitant MTX during ongoing adalimumab therapy.
Results: Twenty-four months of continuous treatment with adalimumab + MTX was superior to adalimumab monotherapy in RA patients, while no significant difference was observed in patients with PsA. RA patients who added MTX during the study showed significant individual improvements in DAS28 and pain scores at 6 months after the change in therapy, while those who removed MTX had slight increases in disease activity. In contrast, in patients with PsA, neither initiation nor removal of MTX during continuous adalimumab therapy had a significant effect on therapeutic outcomes.
Conclusion: Addition of MTX to adalimumab confers further therapeutic benefit in patients with RA, but not in those with PsA, suggesting differences in MTX effects in these two patient populations.
Clinicaltrials.gov NCT01078090, NCT01077258, NCT01111240
A twentieth century-long coupled atmosphere-ocean regional climate simulation with COSMO-CLM (Consortium for Small-Scale Modeling, Climate Limited-area Model) and NEMO (Nucleus for European Modelling of the Ocean) is studied here to evaluate the added value of coupled marginal seas over continental regions. The interactive coupling of the marginal seas, namely the Mediterranean, the North and the Baltic Seas, to the atmosphere in the European region gives a comprehensive modelling system. It is expected to be able to describe the climatological features of this geographically complex area even more precisely than an atmosphere-only climate model. The investigated variables are precipitation and 2 m temperature. Sensitivity studies are used to assess the impact of SST (sea surface temperature) changes over land areas. The different SST values affect the continental precipitation more than the 2 m temperature. The simulated variables are compared to the CRU (Climatic Research Unit) observational data, and also to the HOAPS/GPCC (Hamburg Ocean Atmosphere Parameters and Fluxes from Satellite Data, Global Precipitation Climatology Centre) data. In the coupled simulation, added skill is found primarily during winter over the eastern part of Europe. Our analysis shows that, over this region, the coupled system is dryer than the uncoupled system, both in terms of precipitation and soil moisture, which means a decrease in the bias of the system. Thus, the coupling improves the simulation of precipitation over the eastern part of Europe, due to cooler SST values and in consequence, drier soil.
Diagnosing and treating acute severe and recurrent antivenom-related anaphylaxis (ARA) is challenging and reported experience is limited. Herein, we describe our experience of severe ARA in patients with neurotoxic snakebite envenoming in Nepal. Patients were enrolled in a randomised, double-blind trial of high vs. low dose antivenom, given by intravenous (IV) push, followed by infusion. Training in ARA management emphasised stopping antivenom and giving intramuscular (IM) adrenaline, IV hydrocortisone, and IV chlorphenamine at the first sign/s of ARA. Later, IV adrenaline infusion (IVAI) was introduced for patients with antecedent ARA requiring additional antivenom infusions. Preantivenom subcutaneous adrenaline (SCAd) was introduced in the second study year (2012). Of 155 envenomed patients who received ≥ 1 antivenom dose, 13 (8.4%), three children (aged 5−11 years) and 10 adults (18−52 years), developed clinical features consistent with severe ARA, including six with overlapping signs of severe envenoming. Four and nine patients received low and high dose antivenom, respectively, and six had received SCAd. Principal signs of severe ARA were dyspnoea alone (n=5 patients), dyspnoea with wheezing (n=3), hypotension (n=3), shock (n=3), restlessness (n=3), respiratory/cardiorespiratory arrest (n=7), and early (n=1) and late laryngeal oedema (n=1); rash was associated with severe ARA in 10 patients. Four patients were given IVAI. Of the 8 (5.1%) deaths, three occurred in transit to hospital. Severe ARA was common and recurrent and had overlapping signs with severe neurotoxic envenoming. Optimising the management of ARA at different healthy system levels needs more research. This trial is registered with NCT01284855.
Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.
Gram‐negative bacteria are intrinsically resistant against cytotoxic substances by means of their outer membrane and a network of multidrug efflux systems, acting in synergy. Efflux pumps from various superfamilies with broad substrate preferences sequester and pump drugs across the inner membrane to supply the highly polyspecific and powerful tripartite resistance–nodulation–cell division (RND) efflux pumps with compounds to be extruded across the outer membrane barrier. In Escherichia coli, the tripartite efflux system AcrAB–TolC is the archetype RND multiple drug efflux pump complex. The homotrimeric inner membrane component acriflavine resistance B (AcrB) is the drug specificity and energy transduction center for the drug/proton antiport process. Drugs are bound and expelled via a cycle of mainly three consecutive states in every protomer, constituting a flexible alternating access channel system. This review recapitulates the molecular basis of drug and inhibitor binding, including mechanistic insights into drug efflux by AcrB. It also summarizes 17 years of mutational analysis of the gene acrB, reporting the effect of every substitution on the ability of E. coli to confer resistance toward antibiotics (http://goethe.link/AcrBsubstitutions). We emphasize the functional robustness of AcrB toward single‐site substitutions and highlight regions that are more sensitive to perturbation.
Acetylcholine (ACh) is the major excitatory neurotransmitter in the insect central nervous system (CNS). However, besides the neuronal expression of ACh receptors (AChR), the existence of non-neuronal AChR in honeybees is plausible. The cholinergic system is a popular target of insecticides because the pharmacology of insect nicotinic acetylcholine receptors (nAChRs) differs substantially from their vertebrate counterparts. Neonicotinoids are agonists of the nAChR and are largely used in crop protection. In contrast to their relatively high safety for humans and livestock, neonicotinoids pose a threat to pollinating insects such as bees. In addition to its effects on behavior, it becomes increasingly evident that neonicotinoids affect developmental processes in bees that appear to be independent of neuronal AChRs. Brood food (royal jelly, worker jelly, or drone jelly) produced in the hypopharyngeal glands of nurse bees contains millimolar concentrations of ACh, which is required for proper larval development. Neonicotinoids reduce the secreted ACh-content in brood food, reduce hypopharyngeal gland size, and lead to developmental impairments within the colony. We assume that potential hazards of neonicotinoids on pollinating bees occur neuronally causing behavioral impairments on adult individuals, and non-neuronally causing developmental disturbances as well as destroying gland functioning.
Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.
Background: With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated.
Methods: This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment.
Results: Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0–81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2–133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2–11.1) and the median PFS was 10.8 months (95%CI: 9.6–11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001).
Conclusions: This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.
Abiotic formation of n-alkane hydrocarbons has been postulated to occur within Earth's crust. Apparent evidence was primarily based on uncommon carbon and hydrogen isotope distribution patterns that set methane and its higher chain homologues apart from biotic isotopic compositions associated with microbial production and closed system thermal degradation of organic matter. Here, we present the first global investigation of the carbon and hydrogen isotopic compositions of n-alkanes in volcanic-hydrothermal fluids hosted by basaltic, andesitic, trachytic and rhyolitic rocks. We show that the bulk isotopic compositions of these gases follow trends that are characteristic of high temperature, open system degradation of organic matter. In sediment-free systems, organic matter is supplied by surface waters (seawater, meteoric water) circulating through the reservoir rocks. Our data set strongly implies that thermal degradation of organic matter is able to satisfy isotopic criteria previously classified as being indicative of abiogenesis. Further considering the ubiquitous presence of surface waters in Earth’s crust, abiotic hydrocarbon occurrences might have been significantly overestimated.
Introduction: Previous studies have established graph theoretical analysis of functional network connectivity (FNC) as a potential tool to detect neurobiological underpinnings of psychiatric disorders. Despite the promising outcomes in studies that examined FNC aberrancies in bipolar disorder (BD) and major depressive disorder (MDD), there is still a lack of research comparing both mood disorders, especially in a nondepressed state. In this study, we used graph theoretical network analysis to compare brain network properties of euthymic BD, euthymic MDD and healthy controls (HC) to evaluate whether these groups showed distinct features in FNC.
Methods: We collected resting‐state functional magnetic resonance imaging (fMRI) data from 20 BD patients, 15 patients with recurrent MDD as well as 30 age‐ and gender‐matched HC. Graph theoretical analyses were then applied to investigate functional brain networks on a global and regional network level.
Results: Global network analysis revealed a significantly higher mean global clustering coefficient in BD compared to HC. We further detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality.
Conclusion: In conclusion, our findings indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.
Systematic reviews represent the core and backbone of evidence-based medicine (EBM) strategies in all fields of medicine. In order to depict a first global sketch of the international efforts in the Cochrane database systematic reviews (CDSR), we analyzed the systematic reviews of the Cochrane database. Our global maps of systematic reviewing offer intriguing structural insights into the world of EBM strategies. They demonstrate that for the CDSR, the UK and Commonwealth countries take the lead position. Since patients, care providers and health systems all over the world benefit from systematic reviewing, institutions in other countries should increase their commitment.
Background: Esophageal cancer (EC) is one of the deadliest cancers worldwide. The contemporary strong increase of the adenocarcinomas in Western countries and the high mortality rates require the intensification of prospective multinational studies.
Methods: Therefore, this global health issue has been chosen for the bibliometric review of the global publication output. As source for meta and citation data, the Web of Science has been used and Density Equalizing Maps were applied for visualization.
Results: 17,387 articles on EC could be identified. The years with publication and citation maxima correspond to the appearance of the most prolific articles. China is the most publishing country, followed by Japan and the USA. Germany and the UK ranked 4th and 5th. The analysis of the ratios articles and socio-economic parameters emphasizes the leading position of the Scandinavian countries and Japan. Here, the high-income countries come out on top. The high incidence regions are mainly represented by Chinese and Japanese research. The association of the publication output and the overall research funding could be shown.
Conclusions: A strengthened international network increasingly consisting of the scientifically best positioned countries as well as more of the high incidence countries worldwide is mandatory for future research. The findings deliver scientists, clinicians and decision makers backgrounds for future decisions all over the world.
A world dataset on the geographic distributions of Solenidae razor clams (Mollusca: Bivalvia)
(2019)
Background: Using this dataset, we examined the global geographical distributions of Solenidae species in relation to their endemicity, species richness and latitudinal ranges and then predicted their distributions under future climate change using species distribution modelling techniques (Saeedi et al. 2016a, Saeedi et al. 2016b). We found that the global latitudinal species richness in Solenidae is bi-modal, dipping at the equator most likely derived by high sea surface temperature (Saeedi et al. 2016b). We also found that most of the Solenidae species will shift their distribution ranges polewards due to global warming (Saeedi et al. 2016a). We also provided a comprehensive review of the taxon to test whether the latitudinal gradient in species richness was uni-modal with a peak in the tropics or northern hemisphere or asymmetric and bimodal as proposed previously (Chaudhary et al. 2016).
New information: This paper presents an integrated global geographic distribution dataset for 77 Solenidae taxa, including 3,034 geographic distribution records. This dataset was compiled after a careful data-collection and cleaning procedure over four years. Data were collected using field sampling, literature and from open-access databases. Then all the records went through quality control procedures such as validating the taxonomy of the species by examining and re-identifying the specimens in museum collections and using taxonomic and geographic data quality control tools in the World Register of Marine Species (WoRMS) and the r-OBIS package (Provoost and Bosch 2017). This dataset can thus be further used for taxonomical and biogeographical studies of Solenidae.
An album of 50 watercolour illustrations depicting Norfolk Island plants attributed to convict artist John Doody, in the early 1790s, and associated notes apparently written by William Paterson (1755-1810), one-time commander of the military detachment on Norfolk Island, Lieutenant Governor of New South Wales, and amateur botanist, are described and assessed. Illustrated are 48 plant species growing on Norfolk Island at the time, all but three of which are indigenous. The notes and the watercolours represent the only treatment of the island's flora in the 18th century and include descriptive and ecological material for the species at the time of first European occupation. Two of the species are now extinct. Paterson's notes also include an introductory description of the flora and fauna of the Island. The importance of this material to the modern study of the Norfolk Island flora is highlighted.
Demographic change is supposed to be the most important indirect driver for changing biodiversity. In this article, a systematic review of 148 studies was conducted to examine the scientific evidence for this relationship and to identify potential gaps in research. We explored the spatial distribution of studies, the categories addressed with respect to biodiversity and demographic change, and the ways in which their relationships were conceptualised (spatially and temporally) and valued. The majority of studies were carried out in Africa, Europe and North America. Our analysis confirms the trend that demographic phenomena were mostly found to negatively influence biodiversity. However, a considerable number of studies also point towards impacts that were context dependent, either positive or negative under certain circumstances. In addition to that we identified significant gaps in research. In particular, there is a lack of addressing (1) other demographic aspects such as population decline, age structure or gender differences, (2) spatial variability of, e.g. human population growth, (3) long-term effects of demographic processes, and (4) the context dependency (e.g. regulations/law enforcement, type of human activities, and choice of scale or proxy). We conclude there is evidence that the relationship between biodiversity and demographic change is much more complex than expected and so far represented in research. Thus, we call for a social–ecological biodiversity research that particularly focusses on the functional relation between biodiversity and human activities, namely the different types, context, and interdependent dynamics (spatial and temporal) of this complex relation.
The relativistic method of moments is one of the most successful approaches to extract second order viscous hydrodynamics from a kinetic underlying background. The equations can be systematically improved to higher order, and they have already shown a fast convergence to the kinetic results. In order to generalize the method we introduced long range effects in the form of effective (medium dependent) masses and gauge (coherent) fields. The most straightforward generalization of the hydrodynamic expansion is problematic at higher order. Instead of introducing an additional set of approximations, we propose to rewrite the series in terms of moments resumming the contributions of infinite non-hydrodynamics modes. The resulting equations are are consistent with hydrodynamics and well defined at all order. We tested the new approximation against the exact solutions of the Maxwell-Boltzmann-Vlasov equations in (0 + 1)-dimensions, finding a fast and stable convergence to the exact results.
Background: Posttraumatic stress disorder (PTSD) after childhood abuse (CA) is often related to severe co-occurring psychopathology, such as symptoms of borderline personality disorder (BPD). The ICD-11 has included Complex PTSD as a new diagnosis, which is defined by PTSD symptoms plus disturbances in emotion regulation, self-concept, and interpersonal relationships. Unfortunately, the empirical database on psychosocial treatments for survivors of CA is quite limited. Furthermore, the few existing studies often have either excluded subjects with self-harm behaviour and suicidal ideation — which is common behaviour in subjects suffering from Complex PTSD. Thus, researchers are still trying to identify efficacious treatment programmes for this group of patients.
We have designed DBT-PTSD to meet the specific needs of patients with Complex PTSD. The treatment programme is based on the rules and principles of dialectical behavioural therapy (DBT), and adds interventions derived from cognitive behavioural therapy, acceptance and commitment therapy and compassion-focused therapy. DBT-PTSD can be provided as a comprehensive residential programme or as an outpatient programme. The effects of the residential programme were evaluated in a randomised controlled trial. Data revealed significant reduction of posttraumatic symptoms, with large between-group effect sizes when compared to a treatment-as-usual wait list condition (Cohen’s d = 1.5).
The first aim of this project on hand is to evaluate the efficacy of the outpatient DBT-PTSD programme. The second aim is to identify the major therapeutic variables mediating treatment efficacy. The third aim is to study neural mechanisms and treatment sensitivity of two frequent sequelae of PTSD after CA: intrusions and dissociation.
Methods: To address these questions, we include female patients who experienced CA and who fulfil DSM-5 criteria for PTSD plus borderline features, including criteria for severe emotion dysregulation. The study is funded by the German Federal Ministry of Education and Research, and started in 2014. Participants are randomised to outpatient psychotherapy with either DBT-PTSD or Cognitive Processing Therapy. Formal power analysis revealed a minimum of 180 patients to be recruited. The primary outcome is the change on the Clinician-Administered PTSD Scale for DSM-5.
Discussion: The expected results will be a major step forward in establishing empirically supported psychological treatments for survivors of CA suffering from Complex PTSD.
Trial registration: German Clinical Trials Register: registration number DRKS00005578, date of registration 19 December 2013.
The frequency of extreme events has changed, having a direct impact on human lives. Regional climate models help us to predict these regional climate changes. This work presents an atmosphere–ocean coupled regional climate system model (RCSM; with the atmospheric component COSMO-CLM and the ocean component NEMO) over the European domain, including three marginal seas: the Mediterranean, North, and Baltic Sea. To test the model, we evaluate a simulation of more than 100 years (1900–2009) with a spatial grid resolution of about 25 km. The simulation was nested into a coupled global simulation with the model MPI-ESM in a low-resolution configuration, whose ocean temperature and salinity were nudged to the ocean–ice component of the MPI-ESM forced with the NOAA 20th Century Reanalysis (20CR). The evaluation shows the robustness of the RCSM and discusses the added value by the coupled marginal seas over an atmosphere-only simulation. The coupled system is stable for the complete 20th century and provides a better representation of extreme temperatures compared to the atmosphere-only model. The produced long-term dataset will help us to better understand the processes leading to meteorological and climate extremes.
O artigo trata da análise crítica de Jürgen Habermas da redefinição do papel político da Europa, mais voltada para a justiça social e a solidariedade, para um viés predominantemente econômico, de versão mais econômico-liberal, mais próxima da produtividade e da concorrência. A mudança política da integração europeia busca reforçar o pilar econômico da união monetária pela implementação de programas de ajustamento econômico do FMI. A consequência da opção da União Europeia por uma Europa-mercado de formato neoliberal é o desmonte do Estado social (mais voltado para justiça social) e a corrosão do elemento democrático das democracias nacionais (o esvaziamento da democracia). A consequência política dessa opção pelo neoliberalismo é a centralização supranacional de competências reguladoras para agências e organismos transnacionais europeus (Banco Central Europeu, Comissão Europeia, Tribunal Europeu, Parlamento Europeu), que lidam com acordos, contratos e tratados internacionais que deveriam funcionar como equivalentes de uma regulação política. O problema é a aprovação, a portas fechadas, de medidas que visam o controle da política econômica em detrimento da coordenação política. Isso implica a imposição de resoluções em áreas centrais de responsabilidade dos parlamentos dos Estados membros, potencializando nos Estados nacionais os problemas de legitimação necessária para implementar as políticas recomendadas de cima, explicitando a falha na construção da união monetária pela ausência dos instrumentos de uma política econômica comum.
BACKGROUND: Patients with hereditary angioedema with C1 inhibitor deficiency or dysfunction have burdensome recurrent angioedema attacks. The safety, efficacy, and health-related quality of life (HRQoL) outcomes of C1 inhibitor (C1-INH) prophylaxis (intravenously administered) in patients aged 6-11 years were investigated.
METHODS: Eligible patients were enrolled in a randomized, single-blind, crossover, phase 3 trial. After a 12-week baseline observation period (BOP), patients received 500 or 1000 U C1-INH, twice weekly, for 12 weeks before crossing over to the alternate dose for 12 weeks. The primary efficacy end-point was the monthly normalized number of angioedema attacks (NNA). HRQoL was assessed using the EuroQoL 5-dimensional descriptive system youth version and visual analog scale (EQ-VAS).
RESULTS: Twelve randomized patients had a median (range) age of 10.0 (7-11) years. Mean (SD) percentage reduction in monthly NNA from BOP was 71.1% (27.1%) with 500 U and 84.5% (20.0%) with 1000 U C1-INH. Mean (SD) within-patient difference (-0.4 [0.58]) for monthly NNA with both doses was significant (P = 0.035 [90% CI, -0.706 to -0.102]). Cumulative attack severity, cumulative daily severity, and number of acute attacks treated were reduced. No serious adverse events or discontinuations occurred. Mean EQ-VAS change from BOP to week 9 of treatment (500 U C1-INH, 10.4; 1000 U C1-INH, 21.6) was greater than the minimal important difference, indicating a meaningful HRQoL change.
CONCLUSIONS: C1-INH prophylaxis was effective, safe, and well tolerated in children aged 6-11 years experiencing recurrent angioedema attacks. A post hoc analysis indicated a meaningful improvement in HRQoL with C1-INH.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02052141.
Den deutschen Linksterrorismus der RAF und ihre gesellschaftlichen Folgen behandelt Gerald Bär anhand der Filme "Deutschland im Herbst" und "Der Baader Meinhof Komplex", berücksichtigt wird dabei auch die Aufnahme dieser Ereignisse in Portugal, so wie das Lied "Sedas a Vento", das Vitorino Salomé der toten Ulrike Meinhof widmete.
A propósito de tres diccionarios de DaF: sobre el estado de la lexicografía de aprendices del alemán
(2019)
Un diccionario de aprendices es un diccionario especialmente diseñado para ayudar a aprendices en el proceso de enseñanza-aprendizaje de una lengua extranjera. A pesar de una larga tradición en investigación lexicográfica, los diccionarios de aprendices del alemán constituyen un desarrollo tardío de la lexicografía de esa lengua. El objetivo del presente trabajo es evaluar el estado del arte de la lexicografía pedagógica del alemán por medio de tres diccionarios de esa clase de obras lexicográficas. Como marco metodológico se emplean principios metalexicográficos tales como la distinción entre definición macroestructural cuantitativa y cualitativa, el análisis del programa informaciones microestructurales y la distinción entre funciones de decodificación y codificación. Así se establece que estos diccionarios son obras de referencia confiables para el aprendiz del alemán como lengua extranjera.
Insects visiting flowering trees of Syzygium floribundum, Syzygium smithii and Tristaniopsis laurina (Myrtaceae) were recorded in lowland subtropical rainforest communities in the Manning Valley, mid-north coast of New South Wales. These species are visited by a taxonomically broad assemblage of insects, many of which are known to frequent other rainforest- and open forest-flowering plant species. Consequently there is likely to be a regional pool of potential pollinators found throughout the range of each plant.
Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers.
In the early 21st century, scientists once more declared God a delusion and announced the end of faith, boosting the current critique of religious belief known as 'New Atheism'. Yet the contemporary British and Irish novel engage with religion in various forms, and religion has indeed "returned", Andrew Tate argues, "to the study of literature". The Bible in particular proves a rich source for novelists as different as Colm Tóibín, Zadie Smith, and Philip Pullman among others. Where Colm Tóibín's 'The Testament of Mary' (2012) offers a fictional memoir by the mother of God, depicting the Virgin Mary as "a powerful, unsparing figure" ('Guardian'), Zadie Smith's 'NW' (2012) describes the lives of its two female protagonists against the backdrop of the stories of Mary and Elizabeth in the Gospel of Luke. And Philip Pullman's bestselling trilogy 'His Dark Materials' (1995- 2000) is a re-writing of Milton's 'Paradise Lost' (1667) that "only really makes sense" according to Tate "if the reader has a detailed knowledge of the biblical scriptures against which it writes". Despite being written from a very critical, ironic or atheist stance, all these novels rely on the Bible as an intertext in crucial ways. The Bible, in other words, is once more living up to its ancient reputation as "the Book of Books", "the Urtext of Western literature".
A novel osteotomy preparation technique to preserve implant site viability and enhance osteogenesis
(2019)
The preservation of bone viability at an osteotomy site is a critical variable for subsequent implant osseointegration. Recent biomechanical studies evaluating the consequences of site preparation led us to rethink the design of bone-cutting drills, especially those intended for implant site preparation. We present here a novel drill design that is designed to efficiently cut bone at a very low rotational velocity, obviating the need for irrigation as a coolant. The low-speed cutting produces little heat and, consequently, osteocyte viability is maintained. The lack of irrigation, coupled with the unique design of the cutting flutes, channels into the osteotomy autologous bone chips and osseous coagulum that have inherent osteogenic potential. Collectively, these features result in robust, new bone formation at rates significantly faster than those observed with conventional drilling protocols. These preclinical data have practical implications for the clinical preparation of osteotomies and alveolar bone reconstructive surgeries.
Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8+ T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses.
Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.
Methods: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL.
Results: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases.
Conclusion: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation.
Trial registration: ClinicalTrials.gov identifier: NCT01716234
The Bolivian Oreodera pergeri Wappes and Santos-Silva (Coleoptera: Cerambycidae: Lamiinae) is described as new. Oreodera howdeni Monné and Fragoso, 1988 is newly recorded for the state of Chiapas in Mexico and for Belize, and the main differences between the sexes are reported. Other new records reported are: Oreodera boucheri Néouze and Tavakilian, 2010 for Peru; O. vulgata Monné and Fragoso, 1988 for Paraguarí Department in Paraguay; and O. stictica Monné and Fragoso, 1988 for Bolivia (Santa Cruz). Oreodera sororcula Martins and Monné, 1993 is illustrated, and notes on color, morphological variations, and correction in the published sex of a paratype provided.
A new species of the genus Bomansius Lacroix (Coleoptera: Lucanidae), which had been illustrated in the literature but never formally named, is described from Aneityum Island, Vanuatu (former New Hebrides) under the name of Bomansius cheesmanae Kakinuma, new species. The generic redescription of Bomansius and the redescription of B. gabrieli Lacroix, 1978 are also given based on additional specimens. Bomansius is transferred to tribe Aegini Huang and Chen, 2013.
Phymatodes (Phymatodes) huetheri Wappes and Santos-Silva (Coleoptera: Cerambycidae: Cerambycinae: Callidiini) from upstate New York, USA and Canada is described and illustrated. Phymatodes (Phymatodes) rainieri Van Dyke, 1937 is placed in synonymy with Phymatodes (Phymatodes) fulgidus Hopping, 1928.
Purpose: Tongue edema is a potential cause of treatment target underdosage in high-dose-rate interstitial brachytherapy (HDR-ISBT) of mobile tongue cancer. To prevent such edema-associated alteration of dosimetry, we developed a special silicon device. In this report we communicate our initial experience with two mobile tongue cancer patients whom we treated using this new device.
Material and methods: The device consists of silicone tubes with a fixed width and scalable length depending on tongue size. These tubes are lined and fixed like a palisade, allowing the device to be used also as a template. The device is placed next to the lateral border of the tongue and on the floor of the mouth. In addition, a vinyl template can be placed on the dorsal tongue surface with both devices combined for implantation guidance. Between June and August 2012, two patients with locally confined tongue cancer were treated.
Results: Between June and August 2012, two mobile tongue cancer patients classified as cT2N0M0 were treated with HDR-ISBT using the silicone device. They underwent ISBT as monotherapy with fractional doses of 6.0 Gy up to a total physical dose of 54.0 Gy. The D90 (CTV) values of both patients were 6.3 Gy and 6.6 Gy and the D2cc (mandible) values were 3.4 Gy and 2.6 Gy, respectively. At present, both patients remain without local disease recurrence at 60 and 56 months after ISBT, respectively.
Conclusions: The described silicone device has the potential to prevent underdosage to the treatment target related to tongue edema. It has been shown to be safe and easy to implement.
A new genus and new species of Onciderini Thomson, 1860 (Coleoptera: Cerambycidae: Lamiinae) are described and illustrated: Velozideres buntyni, from Ecuador. The following two new synonymies in Onciderini are proposed: Oncideres paurosoma Noguera, 1993 = Microcanus minor (Bates, 1885); Oncioderes piauiensis Martins and Galileo, 2013 = Oncioderes rondoniae Martins and Galileo, 1990. The following seven new country records are reported: Clavidesmus chicae Giorgi, 1998 (Onciderini) (Argentina); Ecthoea quadricornis (Olivier, 1795) (Onciderini) (Venezuela); Oncideres ophthalmalis Dillon and Dillon, 1946 (Onciderini) (Costa Rica); Oncideres punctata Dillon and Dillon, 1946 (Onciderini) (El Salvador); Oncideres xavieri Galileo and Martins, 2010 (Onciderini) (Peru); Trestonia signifera Buquet, 1859 (Onciderini) (Brazil); and Oideterus crenatocerus (Galileo, 1987) (Cerambycidae: Prioninae: Anacolini) (Costa Rica).
Thomsonista Nearns and Nascimento, a new genus of Onciderini Thomson, 1860 (Coleoptera: Cerambycidae: Lamiinae), is described and illustrated. Seven new species of Onciderini are described and illustrated: Hesychotypa antonkozlovi from Ecuador; Hesychotypa danilevskyi from Panama; Lingafelteria pandolfii from Brazil; Oncideres antonkozlovi and Oncideres erwini from Peru; Oncideres johnmarvini from Costa Rica and Panama; and Thomsonista antonkozlovi from Colombia.
Relying on the theory of Saward (2010) and Disch (2015), we study political representation through the lens of representative claim-making. We identify a gap between the theoretical concept of claim-making and the empirical (quantitative) assessment of representative claims made in the real world’s representative contexts. Therefore, we develop a new approach to map and quantify representative claims in order to subsequently measure the reception and validation of the claims by the audience. To test our method, we analyse all the debates of the German parliament concerned with the introduction of the gender quota in German supervisory boards from 2013 to 2017 in a two-step process. At first, we assess which constituencies the MPs claim to represent and how they justify their stance. Drawing on multiple correspondence analysis, we identify different claim patterns. Second, making use of natural language processing techniques and logistic regression on social media data, we measure if and how the asserted claims in the parliamentary debates are received and validated by the respective audience. We come to the conclusion that the constituency as ultimate judge of legitimacy has not been comprehensively conceptualized yet.
With every glimpse of our eyes, we sample only a small and incomplete fragment of the visual world, which needs to be contextualized and integrated into a coherent scene representation. Here we show that the visual system achieves this contextualization by exploiting spatial schemata, that is our knowledge about the composition of natural scenes. We measured fMRI and EEG responses to incomplete scene fragments and used representational similarity analysis to reconstruct their cortical representations in space and time. We observed a sorting of representations according to the fragments' place within the scene schema, which occurred during perceptual analysis in the occipital place area and within the first 200 ms of vision. This schema-based coding operates flexibly across visual features (as measured by a deep neural network model) and different types of environments (indoor and outdoor scenes). This flexibility highlights the mechanism's ability to efficiently organize incoming information under dynamic real-world conditions.
In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.
Following a brief review of current efforts to identify the neuronal correlates of conscious processing (NCCP) an attempt is made to bridge the gap between the material neuronal processes and the immaterial dimensions of subjective experience. It is argued that this "hard problem" of consciousness research cannot be solved by only considering the neuronal underpinnings of cognition. The proposal is that the hard problem can be treated within a naturalistic framework if one considers not only the biological but also the socio-cultural dimensions of evolution. The argument is based on the following premises: perceptions are the result of a constructivist process that depends on priors. This applies both for perceptions of the outer world and the perception of oneself. Social interactions between agents endowed with the cognitive abilities of humans generated immaterial realities, addressed as social or cultural realities. This novel class of realities assumed the role of priors for the perception of oneself and the embedding world. A natural consequence of these extended perceptions is a dualist classification of observables into material and immaterial phenomena nurturing the concept of ontological substance dualism. It is argued that perceptions shaped by socio-cultural priors lead to the construction of a self-model that has both a material and an immaterial dimension. As priors are implicit and not amenable to conscious recollection the perceived immaterial dimension is experienced as veridical and not derivable from material processes—which is the hallmark of the hard problem. These considerations let the hard problem appear as the result of cognitive constructs that are amenable to naturalistic explanations in an evolutionary framework.
A1AO ATP synthases with a V-type c subunit have only been found in hyperthermophilic archaea which makes bioenergetic analyses impossible due to the instability of liposomes at high temperatures. A search for a potential archaeal A1AO ATP synthase with a V-type c subunit in a mesophilic organism revealed an A1AO ATP synthase cluster in the anaerobic, acetogenic bacterium Eubacterium limosum KIST612. The enzyme was purified to apparent homogeneity from cells grown on methanol to a specific activity of 1.2 U·mg−1 with a yield of 12%. The enzyme contained subunits A, B, C, D, E, F, H, a, and c. Subunit c is predicted to be a typical V-type c subunit with only one ion (Na+)-binding site. Indeed, ATP hydrolysis was strictly Na+-dependent. N,N′-dicyclohexylcarbodiimide (DCCD) inhibited ATP hydrolysis, but inhibition was relieved by addition of Na+. Na+ was shown directly to abolish binding of the fluorescence DCCD derivative, NCD-4, to subunit c, demonstrating a competition of Na+ and DCCD/NCD-4 for a common binding site. After incorporation of the A1AO ATP synthase into liposomes, ATP-dependent primary transport of 22Na+ as well as ΔµNa+-driven ATP synthesis could be demonstrated. The Na+ A1AO ATP synthase from E. limosum is the first ATP synthase with a V-type c subunit from a mesophilic organism. This will enable future bioenergetic analysis of these unique ATP synthases.
Background: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma.
Methods: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics.
Results: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on "double-hit" MYC and BCL2 transformed lymphomas.
Conclusions: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
A machine-learned analysis suggests non-redundant diagnostic information in olfactory subtests
(2019)
Background: The functional performance of the human sense of smell can be approached via assessment of the olfactory threshold, the ability to discriminate odors or the ability to identify odors. Contemporary clinical test batteries include all or a selection of these components, with some dissent about the required number and choice.
Methods: Olfactory thresholds, odor discrimination and odor identification scores were available from 10,714 subjects (3662 with anomia, 4299 with hyposmia, and 2752 with normal olfactory function). To assess, whether the olfactory subtests confer the same information or each subtest confers at least partly non-redundant information relevant to the olfactory diagnosis, we compared the diagnostic accuracy of supervised machine learning algorithms trained with the complete information from all three subtests with that obtained when performing the training with the information of only two or one subtests.
Results: The training of machine-learned algorithms with the full information about olfactory thresholds, odor discrimination and odor identification from 2/3 of the cases, resulted in a balanced olfactory diagnostic accuracy of 98% or better in the 1/3 remaining cases. The most pronounced decrease in the balanced accuracy, to approximately 85%, was observed when omitting olfactory thresholds from the training, whereas omitting odor discrimination or identification was associated with smaller decreases (balanced accuracies approximately 90%).
Conclusions: Results support partly non-redundant contributions of each olfactory subtest to the clinical olfactory diagnosis. Olfactory thresholds provided the largest amount of non-redundant information to the olfactory diagnosis.
The coordinate and momentum space configurations of the net baryon number in heavy ion collisions that undergo spinodal decomposition, due to a first-order phase transition, are investigated using state-of-the-art machine-learning methods. Coordinate space clumping, which appears in the spinodal decomposition, leaves strong characteristic imprints on the spatial net density distribution in nearly every event which can be detected by modern machine learning techniques. On the other hand, the corresponding features in the momentum distributions cannot clearly be detected, by the same machine learning methods, in individual events. Only a small subset of events can be systematically differ- entiated if only the momentum space information is available. This is due to the strong similarity of the two event classes, with and without spinodal decomposition. In such sce- narios, conventional event-averaged observables like the baryon number cumulants signal a spinodal non-equilibrium phase transition. Indeed the third-order cumulant, the skewness, does exhibit a peak at the beam energy (Elab = 3–4 A GeV), where the transient hot and dense system created in the heavy ion collision reaches the first-order phase transition.
Drei französische Romane der 70er Jahre von Robert Merle, Raymond Jean und Pascal Lainé stehen im Zentrum des Beitrags von Luís Gonçalves. Die Bemühungen um das theoretische Werk Marx' - so seine Analyse - bleiben dabei deutlich hinter dem Wunsch, sich selbst zu befreien, zurück. Die theoretischen Gewährsmänner dieser Bewegung waren nicht die Klassiker des Sozialismus, sonder eher Wilhelm Reich und Guy Debord.
By running a temperature series of molecular dynamics (MD) simulations starting from the known low-temperature phase, the experimentally observed phase transition in a `jumping crystal' was captured, thereby providing a prediction of the unknown crystal structure of the high-temperature phase and clarifying the phase-transition mechanism. The phase transition is accompanied by a discontinuity in two of the unit-cell parameters. The structure of the high-temperature phase is very similar to that of the low-temperature phase. The anisotropic displacement parameters calculated from the MD simulations readily identified libration as the driving force behind the phase transition. Both the predicted crystal structure and the phase-transition mechanism were verified experimentally using TLS (translation, libration, screw) refinement against X-ray powder diffraction data.
O trabalho retoma a análise freudiana de "Der Sandmann", presente num ensaio de 1919 que se provou paradigmático para as interpretações futuras da obra de E. T. A. Hoffmann. No dito ensaio, o pai da psicanálise faz diversos juízos sobre a construção argumentativa da novela romântica que, nos estudos literários, vêm sendo indevidamente atribuídos ao próprio Hoffmann. Seu programa estético supostamente seria aquele de um analista dos mecanismos psíquicos de suas personagens, revelando-o como um curioso conhecedor avant la lettre das teorias psicanalíticas. É como se a criação de um imaginário horripilante que caracteriza sua prosa servisse a um impulso interpretativo das áreas ocultas da psique a fim de detrair tendências irracionalistas e animistas de suas personagens. A crítica freudiana ao animismo é um dos aspectos mais contestados por estudiosos recentes como Bruno Latour e Isabelle Stengers e, por isso, retomaremos seus argumentos num segundo momento. Então, alguns de seus argumentos serão retomados em um segundo momento do artigo para que possamos voltar a Hoffmann e reinterpretar sua estética como uma defesa de certo tipo de animismo, para além dos paradigmas psicanalíticos que nunca cessaram de o ensombrar.
Objectives: To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs).
Methods: Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24.
Results: The primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients.
Conclusions: IXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.
The haloarchaeon Haloferax volcanii contains nearly 2800 small non-coding RNAs (sRNAs). One intergenic sRNA, sRNA132, was chosen for a detailed characterization. A deletion mutant had a growth defect and thus underscored the importance of sRNA132. A microarray analysis identified the transcript of an operon for a phosphate-specific ABC transporter as a putative target of sRNA132. Both the sRNA132 and the operon transcript accumulated under low phosphate concentrations, indicating a positive regulatory role of sRNA132. A kinetic analysis revealed that sRNA132 is essential shortly after the onset of phosphate starvation, while other regulatory processes take over after several hours. Comparison of the transcriptomes of wild-type and the sRNA132 gene deletion mutant 30 min after the onset of phosphate starvation revealed that sRNA132 controls a regulon of about 40 genes. Remarkably, the regulon included a second operon for a phosphate-specific ABC transporter, which also depended on sRNA132 for rapid induction in the absence of phosphate. Competitive growth experiments of the wild-type and ABC transporter operon deletion mutants underscored the importance of both transporters for growth at low phosphate concentrations. Northern blot analyses of four additional members of the sRNA132 regulon verified that all four transcripts depended on sRNA132 for rapid regulation after the onset of phosphate starvation. Importantly, this is the first example for the transient importance of a sRNA for any archaeal and bacterial species. In addition, this study unraveled the first sRNA regulon for haloarchaea.
Wetlands such as bogs, swamps, or freshwater marshes are hotspots of biodiversity. For 5.1 million km2 of inland wetlands, the dynamics of area and water storage, which strongly impact biodiversity and ecosystem services, were simulated using the global hydrological model WaterGAP. For the first time, the impacts of both human water use and man‐made reservoirs (WUR) and future climate change (CC) on wetlands around the globe were quantified. WUR impacts are concentrated in arid/semiarid regions, where WUR decreased mean wetland water storage by more than 5% on 8.2% of the mean wetland area during 1986–2005 (Am), with highest decreases in groundwater depletion area. Using output of three climate models, CC impacts on wetlands were quantified, distinguishing unavoidable impacts [i.e., at 2 °C global warming (GW)] from avoidable impacts (difference between 3 °C and 2 °C impacts). Even unavoidable CC impacts are projected to be much larger than WUR impacts, also in arid/semiarid regions. On most wetland area with reliable estimates, avoidable CC impacts are more than twice as large as unavoidable impacts. In case of 2 °C GW, half of Am is estimated to be unaffected by mean storage changes of more than 5%, but only one third in case of 3 °C GW. Temporal variability of water storage will increase for most wetlands. Wetlands in dry regions will be affected the most, particularly by water storage decreases in the dry season. Different from wealthier countries, low‐income countries will dominantly suffer from a decrease in wetland water storage due to CC.
Video and image data are regularly used in the field of benthic ecology to document biodiversity. However, their use is subject to a number of challenges, principally the identification of taxa within the images without associated physical specimens. The challenge of applying traditional taxonomic keys to the identification of fauna from images has led to the development of personal, group, or institution level reference image catalogues of operational taxonomic units (OTUs) or morphospecies. Lack of standardisation among these reference catalogues has led to problems with observer bias and the inability to combine datasets across studies. In addition, lack of a common reference standard is stifling efforts in the application of artificial intelligence to taxon identification. Using the North Atlantic deep sea as a case study, we propose a database structure to facilitate standardisation of morphospecies image catalogues between research groups and support future use in multiple front-end applications. We also propose a framework for coordination of international efforts to develop reference guides for the identification of marine species from images. The proposed structure maps to the Darwin Core standard to allow integration with existing databases. We suggest a management framework where high-level taxonomic groups are curated by a regional team, consisting of both end users and taxonomic experts. We identify a mechanism by which overall quality of data within a common reference guide could be raised over the next decade. Finally, we discuss the role of a common reference standard in advancing marine ecology and supporting sustainable use of this ecosystem.
A estrutura silábica do alemão como língua estrangeira na interlíngua de aprendizes brasileiros
(2019)
A presente pesquisa explora as estratégias de reformulação de constituintes silábicos complexos na Interlíngua de 18 brasileiros aprendizes do Alemão como Língua Estrangeira. Nossa hipótese prevê que estes aprendizes possuem dificuldades na produção de ataques iniciais e codas finais do ALE e, ao tentar acomodá-las ao molde silábico da LM, aplicam diferentes estratégias de reparação. A partir do conceito de Interlíngua (SELINKER 1972) como língua natural, sistemática e emergente de um processo complexo e dinâmico, desenvolvida autonomamente por falantes não-nativos de uma LE em seu processo de aquisição/aprendizagem com o objetivo de comunicar-se estrategicamente, e que sofre adaptações a partir da testagem de hipóteses acerca da LE e eventos de interação, realizamos análise transversal das ocorrências de ataque e coda complexas em correlação com o nível de proficiência do aprendiz, o estilo (LIN 2001, 2003) e a marcação do constituinte (GRENNBERG 1966b). Os dados revelaram que a frequência de modificação de clusters apresenta correlação com estes fatores: quanto mais formal a tarefa e avançado o aprendiz, menos modificações ocorrem. A influência da marcação silábica e dos universais linguísticos foi constatada para a coda, tipologicamente marcada, sendo mais frequentemente modificada que o ataque.
A encenação autoral de Christian Kracht: o caso d' "Os Mortos" de Kracht, de Joyce e de Huston
(2019)
Partimos do pressuposto que os escritores, ao longo da história, sempre se utilizaram de estratégias encenatórias tanto em relação às suas obras como às suas figuras públicas, e de que o fazem não só para se estabelecer no campo literário, mas para o fazê-lo de um modo específico (JÜRGENSEN; KAYSER, 2011; BOURDIEU, 2000). Tendo em vista o último romance de Christian Kracht, "Die Toten" (2016), cujo título pode ser livremente traduzido como "Os Mortos", e as relações intertextuais que podem ser estabelecidas com o conto homônimo de James Joyce (1914) e sua adaptação para o cinema dirigida por John Huston (1987), temos por objetivo investigar de que modo essas relações contribuem para a encenação de Christian Kracht e para seu posicionamento no campo literário.
Concebido para suprir as lacunas de uma existência que se tornara pública e notória com a publicação do "Werther", o relato autobiográfico de "Dichtung und Wahrheit" dedicará boa parte das quase 300 páginas de seus sete últimos livros à narração das circunstâncias que teriam possibilitado a Goethe encontrar um campo de atuação e influência compatíveis com a estrondosa repercussão do "Werther", mas ao mesmo tempo condizentes com uma vocação poética a que Goethe recusa qualquer interferência direta e 'didática' nos assuntos humanos, visto como passa a concebê-la 'inteiramente como natureza'. O artigo se propõe passar em revista esse momento decisivo de elaboração da 'Bildung' goethiana compreendido sobretudo nos livros 13 a 16, o qual coincide com a definição dos fundamentos da vocação poética que marcará a fisionomia espiritual da produção de Goethe vida afora. Para tanto, investigará a pertinência do conceito de teleologia como princípio explicativo oportuno à elucidação do referido momento, à luz da discussão proposta por Fotis Jannidis (1996); e analisará o papel das referências e influências que maior importância tiveram para Goethe nesse processo: Lavater, Basedow e Zimmermann, entre os convivas, Spinoza e Prometeu entre os luminares.
Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.
Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin–based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo‐controlled, randomized cross‐over study, seven different pain‐related readouts were acquired in 16 healthy individuals before and after oral administration of 300 mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain‐related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.
Rezension zu: Psychology of Retention:Theory, Research and Practice / Melinde Coetzee, Ingrid L. Potgieter and Nadia Ferreira (Eds.), ISBN:978-3-319-98919-8 Publisher:Springer Nature, 2018, R1600 (Preis SA)
The following five species of Dermestidae (Coleoptera) are recorded for the first time from Guatemala: Attagenus fasciatus (Thunberg), Dermestes (Dermestinus) caninus caninus Germar, Orphinus fulvipes (Guérin-Méneville), Trogoderma simplex Jayne and Thorictodes heydeni Reitter. The species are recorded from the Guatemalan departments of Petén, Izabal and Zacapa.
Background: The differentiation between Gaucher disease type 3 (GD3) and type 1 is challenging because pathognomonic neurologic symptoms may be subtle and develop at late stages. The ophthalmologist plays a crucial role in identifying the typical impairment of horizontal saccadic eye movements, followed by vertical ones. Little is known about further ocular involvement. The aim of this monocentric cohort study is to comprehensively describe the ophthalmological features of Gaucher disease type 3. We suggest recommendations for a set of useful ophthalmologic investigations for diagnosis and follow up and for saccadometry parameters enabling a correlation to disease severity.
Methods: Sixteen patients with biochemically and genetically diagnosed GD3 completed ophthalmologic examination including optical coherence tomography (OCT), clinical oculomotor assessment and saccadometry by infrared based video-oculography. Saccadic peak velocity, gain and latency were compared to 100 healthy controls, using parametric tests. Correlations between saccadic assessment and clinical parameters were calculated.
Results: Peripapillary subretinal drusen-like deposits with retinal atrophy (2/16), preretinal opacities of the vitreous (4/16) and increased retinal vessel tortuosity (3/16) were found. Oculomotor pathology with clinically slowed saccades was more frequent horizontally (15/16) than vertically (12/16). Saccadometry revealed slowed peak velocity compared to 100 controls (most evident horizontally and downwards). Saccades were delayed and hypometric. Best correlating with SARA (scale for the assessment and rating of ataxia), disease duration, mSST (modified Severity Scoring Tool) and reduced IQ was peak velocity (both up- and downwards). Motility restriction occurred in 8/16 patients affecting horizontal eye movements, while vertical motility restriction was seen less frequently. Impaired abduction presented with esophoria or esotropia, the latter in combination with reduced stereopsis.
Conclusions: Vitreoretinal lesions may occur in 25% of Gaucher type 3 patients, while we additionally observed subretinal lesions with retinal atrophy in advanced disease stages. Vertical saccadic peak velocity seems the most promising "biomarker" for neuropathic manifestation for future longitudinal studies, as it correlates best with other neurologic symptoms. Apart from the well documented abduction deficit in Gaucher type 3 we were able to demonstrate motility impairment in all directions of gaze.
Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.
Aim: Predicting future changes in species richness in response to climate change is one of the key challenges in biogeography and conservation ecology. Stacked species distribution models (S‐SDMs) are a commonly used tool to predict current and future species richness. Macroecological models (MEMs), regression models with species richness as response variable, are a less computationally intensive alternative to S‐SDMs. Here, we aim to compare the results of two model types (S‐SDMS and MEMs), for the first time for more than 14,000 species across multiple taxa globally, and to trace the uncertainty in future predictions back to the input data and modelling approach used.
Location: Global land, excluding Antarctica.
Taxon: Amphibians, birds and mammals.
Methods: We fitted S‐SDMs and MEMs using a consistent set of bioclimatic variables and model algorithms and conducted species richness predictions under current and future conditions. For the latter, we used four general circulation models (GCMs) under two representative concentration pathways (RCP2.6 and RCP6.0). Predicted species richness was compared between S‐SDMs and MEMs and for current conditions also to extent‐of‐occurrence (EOO) species richness patterns. For future predictions, we quantified the variance in predicted species richness patterns explained by the choice of model type, model algorithm and GCM using hierarchical cluster analysis and variance partitioning.
Results: Under current conditions, species richness predictions from MEMs and S‐SDMs were strongly correlated with EOO‐based species richness. However, both model types over‐predicted areas with low and under‐predicted areas with high species richness. Outputs from MEMs and S‐SDMs were also highly correlated among each other under current and future conditions. The variance between future predictions was mostly explained by model type.
Main conclusions: Both model types were able to reproduce EOO‐based patterns in global terrestrial vertebrate richness, but produce less collinear predictions of future species richness. Model type by far contributes to most of the variation in the different future species richness predictions, indicating that the two model types should not be used interchangeably. Nevertheless, both model types have their justification, as MEMs can also include species with a restricted range, whereas S‐SDMs are useful for looking at potential species‐specific responses.
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.
A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer
(2019)
Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions.
Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms.
Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.
O Brasil, como um país colônia cuja parte considerável da população é formada por imigrantes vindos de várias partes do mundo, possui diversas comunidades em que tais imigrantes se concentram. A fim de preservar parte de suas culturas, esses imigrantes continuam comunicando-se com a língua do seu país de origem. Devido a isso, seus filhos acabam por desenvolver a língua dos pais, juntamente do português, constituindo assim, um ambiente bilíngue. Tendo essas comunidades em mente, pretende-se entender de que forma o desenvolvimento linguístico e pessoal de uma criança pode ser afetado na aquisição quase simultânea de duas línguas, por ocorrer em momentos distintos, mas ainda na infância, e se há interferência de um idioma no outro. Nesse contexto, mesmo que as características das línguas sejam diferentes, há uma competência linguística comum entre as linguagens, o que possibilita que algumas habilidades sejam transferidas de uma língua para outra. Além disso, sabe-se que no léxico de crianças que falam duas línguas, é possível acessar palavras de qualquer uma delas ao mesmo tempo, verificando a conexão entre os idiomas (SCHUETZE, 2001). Para a realização desta pesquisa, a comunidade bilíngue abordada foi no oeste de Santa Catarina, onde concentra-se uma grande população descendente de imigrantes alemães. Foi realizada uma entrevista com dois jovens falantes de português e alemão, junto de seus pais, buscando definir o processo de aquisição das duas línguas na infância e a interferência das mesmas entre si. A análise das informações obtidas teve a influência do conhecimento prévio de uma das autoras da pesquisa, devido à aquisição de linguagem similar. Nos casos investigados, as crianças adquiriram o alemão em casa como primeira língua e o português como segunda em ambiente escolar. Os resultados apontam que ocorre influência de um idioma em outro e que há troca de letras ou palavras, como justifica o code-switching. Pesquisas como esta se fazem necessárias tendo em vista o crescente número de imigrantes vindos ao Brasil, cujos filhos estarão em um ambiente bilíngue, tendo que desenvolver o português enquanto os pais possuem apenas a língua do seu país de origem.
Anaerobic ammonium oxidation (anammox) is a major process in the biogeochemical nitrogen cycle in which nitrite and ammonium are converted to dinitrogen gas and water through the highly reactive intermediate hydrazine. So far, it is unknown how anammox organisms convert the toxic hydrazine into nitrogen and harvest the extremely low potential electrons (−750 mV) released in this process. We report the crystal structure and cryo electron microscopy structures of the responsible enzyme, hydrazine dehydrogenase, which is a 1.7 MDa multiprotein complex containing an extended electron transfer network of 192 heme groups spanning the entire complex. This unique molecular arrangement suggests a way in which the protein stores and releases the electrons obtained from hydrazine conversion, the final step in the globally important anammox process.
Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer’s disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.
The title compound, C4H9N5O2+·SO42−·H2O, is the monohydrate of the commercially available compound `C4H7N5O·H2SO4·xH2O'. It is obtained by reprecipitation of C4H7N5O·H2SO4·xH2O from dilute sodium hydroxide solution with dilute sulfuric acid. The crystal structure of anhydrous 2,4,5-triamino-1,6-dihydropyrimidin-6-one sulfate is known, although called by the authors 5-amminium-6-amino-isocytosinium sulfate [Bieri et al. (1993[Bieri, J. H., Prewo, R. & Linden, A. (1993). Private communication (refcode HACDEU). CCDC, Cambridge, England]). Private communication (refcode HACDEU). CCDC, Cambridge, England]. In the structure, the sulfate group is deprotonated, whereas one of the amino groups is protonated (R2C—NH3+) and one is rearranged to a protonated imine group (R2C=NH2+). This arrangement is very similar to the known crystal structure of the anhydrate. Several tautomeric forms of the investigated molecule are possible, which leads to questionable proton attributions. The measured data allowed the location of all hydrogen atoms from the residual electron density. In the crystal, ions and water molecules are linked into a three-dimensional network by N—H⋯O and O—H⋯O hydrogen bonds.
The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that peripheral antiinflammatory mechanisms contribute to antinociception. In this study, we investigated the impact of AICAR on the immune cell composition in inflamed paws, as well as the regulation of inflammatory and resolving markers in macrophages. By using fluorescence-activated cell sorting (FACS) analysis and immunofluorescence, we found a significantly increased fraction of proresolving M2 macrophages and anti-inflammatory interleukin (IL)-10 in inflamed tissue, while M1 macrophages and proinflammatory cytokines such as IL-1 were decreased by AICAR in wild type mice. In AMPKα2 knock-out mice, the M2 polarization of macrophages in the paw was missing. The results were supported by experiments in primary macrophage cultures which also showed a shift to a proresolving phenotype with decreased levels of proinflammatory mediators and increased levels of antiinflammatory mediators. However, in the cell cultures, we did not observe differences between the AMPKα2+/+ and −/− cells, thus indicating that the AICAR-induced effects are at least partially AMPK-independent. In summary, our results indicate that AICAR has potent antiinflammatory and proresolving properties in inflammation which are contributing to a reduction of inflammatory edema and antinociception.
48Si: An atypical nucleus?
(2019)
Using the relativistic Hartree–Fock Lagrangian PKA1, we investigate the properties of the exotic nucleus 48Si, which is predicted to be an atypical nucleus characterized by i) the onset of doubly magicity, ii) its location at the drip line, iii) the presence of dual semi-bubble structure (distinct central depletion in both of neutron and proton density profiles) in the ground state, and iv) the occurrence of pairing reentrance at finite temperature. While not being new for each, these phenomena are found to simultaneously occur in 48Si. For instance, the dual semi-bubble structure reduces the spin–orbit splitting of low-ℓ orbitals and upraises the s orbitals, leading therefore to distinct N=34 and Z=14 magic shells in 48Si. Consequently, the doubly magicities provide extra stability for such extreme neutron-rich system at the drip line. Associating with the neutron shell N=34 and continuum above, the pairing correlations are reengaged interestingly at finite temperature. Theoretical nuclear modelings are known to be poorly predictive in general, and we asset our confidence in the prediction of our modeling on the fact that the predictions of PKA1 in various regions of the nuclear chart have systematically been found correct and more specifically in the region of pf shell. Whether our predictions are confirmed or not, 48Si provides a concrete benchmark for the understanding of the nature of nuclear force.
Die Tagung bot eine breite Themenvielfalt in insgesamt neun parallel verlaufenden Sektionen. Zwei davon waren praxisorientierten Fragestellungen gewidmet, in drei anderen wurden wiederum Projekte der Aussteller präsentiert und vier weitere Sektionen beschäftigten sich mit folgenden fachlichen Blickwinkeln: "Europäische Literatur im Zusammenhang der Sprach- und Kulturvermittlung", "Unterrichtsinteraktion und Zweitspracherwerb Deutsch", "Niederschwellige Deutschangebote im A1-/A2-Bereich" und Zielgruppenspezifik" und "Evaluatives Feedback und Qualitätsentwicklung".
Patient therapy is based mainly on a combination of diagnosis, suitable monitoring or support devices and drug treatment and is usually employed for a pre-existing disease condition. Therapy remains predominantly symptom-based, although it is increasingly clear that individual treatment is possible and beneficial. However, reasonable precision medicine can only be realized with the coordinated use of diagnostics, devices and drugs in combination with extensive databases (4Ds), an approach that has not yet found sufficient implementation. The practical combination of 4Ds in health care is progressing, but several obstacles still hamper their extended use in precision medicine.
Aims: The examination of histological sections is still the gold standard in diagnostic pathology. Important histopathological diagnostic criteria are nuclear shapes and chromatin distribution as well as nucleus-cytoplasm relation and immunohistochemical properties of surface and intracellular proteins. The aim of this investigation was to evaluate the benefits and drawbacks of three-dimensional imaging of CD30+ cells in classical Hodgkin Lymphoma (cHL) in comparison to CD30+ lymphoid cells in reactive lymphoid tissues.
Materials and results: Using immunoflourescence confocal microscopy and computer-based analysis, we compared CD30+ neoplastic cells in Nodular Sclerosis cHL (NScCHL), Mixed Cellularity cHL (MCcHL), with reactive CD30+ cells in Adenoids (AD) and Lymphadenitis (LAD). We confirmed that the percentage of CD30+ cell volume can be calculated. The amount in lymphadenitis was approx. 1.5%, in adenoids around 2%, in MCcHL up to 4,5% whereas the values for NScHL rose to more than 8% of the total cell cytoplasm. In addition, CD30+ tumour cells (HRS-cells) in cHL had larger volumes, and more protrusions compared to CD30+ reactive cells. Furthermore, the formation of large cell networks turned out to be a typical characteristic of NScHL.
Conclusion: In contrast to 2D histology, 3D laser scanning offers a visualisation of complete cells, their network interaction and spatial distribution in the tissue. The possibility to differentiate cells in regards to volume, surface, shape, and cluster formation enables a new view on further diagnostic and biological questions. 3D includes an increased amount of information as a basis of bioinformatical calculations.
Holographic imaging techniques, which exploit the coherence properties of light, enable the reconstruction of the 3D scenery being viewed. While the standard approaches for the recording of holographic images require the superposition of scattered light with a reference field, heterodyne detection techniques enable direct measurement of the amplitude and relative phase of the electric light field. Here, we explore heterodyne Fourier imaging and its capabilities using active illumination with continuous-wave radiation at 300 GHz and a raster-scanned antenna-coupled field-effect transistor (TeraFET) for phase-sensitive detection. We demonstrate that the numerical reconstruction of the scenery provides access to depth resolution together with the capability to numerically refocus the image and the capability to detect an object obscured by another object in the beam path. In addition, the digital refocusing capability allows us to employ Fourier imaging also in the case of small lens-object distances (virtual imaging regime), thus allowing high spatial frequencies to pass through the lens, which results in enhanced lateral resolution.
Am 16. April 1994 fanden sich 18 Personen in einem Tagungsraum des Bielefelder Mövenpick-Hotels zusammen, um eine literarische Gesellschaft neuartigen Typs zu gründen: das Forum Vormärz Forschung. Neuartig insofern, als diese Vereinigung nicht zu dem Zweck gegründet wurde, einer Autorin/ einem Autor die Ehre zu erweisen, ihr/sein Andenken zu pflegen und ihrem/ seinem Werk neue LeserInnen zuzuführen, sondern um eine ganze Epoche zum Gegenstand ihrer vielfältigen Bemühungen zu machen und zwar möglichst interdisziplinär: den Vormärz. Für die LiteraturwissenschaftlerInnen, HistorikerInnen, TheologInnen, Kunst- und MusikwissenschaftlerInnen, die sich hier zusammenfanden, galt und gilt es als ausgemacht, dass Vormärz die einzig sachgerechte Bezeichnung für den Zeitraum zwischen 1815 (Wiener Kongress) und 1849 (Ende der Revolution von 1848/49) ist und eben nicht die konkurrierenden Epochenbezeichnungen Biedermeier oder Restaurationszeit. [...]
Introduction: Epoxyeicosatrienoic acids (EETs) are able to enhance angiogenesis and regulate inflammation that is especially important in wound healing under ischemic conditions. Thus, we evaluated the effect of local EET application on ischemic wounds in mice.
Methods: Ischemia was induced by cautherization of two of the three supplying vessels to the mouse ear. Wounding was performed on the ear three days later. Wounds were treated either with 11,12 or 14,15 EET and compared to untreated control and normal wounds. Epithelialization was measured every second day. VEGF, TNF-α, TGF-β, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP), Ki67, and SDF-1α were evaluated immunohistochemically in wounds on day 3, 6, and 9.
Results: Ischemia delayed wound closure (12.8 days ± 1.9 standard deviation (SD) for ischemia and 8.0 days ± 0.94 SD for control). 11,12 and14,15 EET application ameliorated deteriorated wound healing on ischemic ears (7.6 ± 1.3 SD for 11,12 EET and 9.2 ± 1.4 SD for 14,15 EET). Ischemia did not change VEGF, TNF-α, TGF-β, SDF-1α, TIMP, MMP7 or MMP9 level significantly compared to control. Local application of 11,12 as well as 14,15 EET induced a significant elevation of VEGF, TGF-β, and SDF-1α expression as well as proliferation during the whole phase of wound healing compared to control and ischemia alone.
Conclusion: In summary, EET improve impaired wound healing caused by ischemia as they enhance neovascularization and alter inflammatory response in wounds. Thus elevating lipid mediator level as 11,12 and 14,15 EET in wounds might be a successful strategy for amelioration of deranged wound healing under ischemia.