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The script of Caryl Churchill’s short play Hot Fudge (like several other plays by this author) contains detailed directions for overlapping conversation. At certain points in the play these may be contributing to a number of effects similar to those described for the naturally occurring ‘collaborative floor’, such as enthusiasm and mutual support. The importance of an interactive approach to constructed conversation is pointed out in the article, particularly that of analysing the overlapped speaker’s response to appreciate the discursive significance of the overlapping turn. For instance, acknowledging and/or reusing the other speaker’s overlapping formulations in a non-oppositional format can show an understanding of these contributions as collaboratively oriented. Therefore, such an interpretation of overlapping dialogue in a dramatic text will affect the reader’s understanding of the interpersonal context (e.g. dominance-seeking/mutual support/collaboration between pairs of speakers). In particular, this approach is taken to show how certain kinds of overlapping similar to those described for the naturally occurring conversation can be used dramatically to supportive rather than conflictive ends. Overall, it is shown how the dramatic characters’ interpersonal orientations become inferable from their use of certain dialogic options.
Spleen injuries are among the most frequent trauma-related injuries. At present, they are classified according to the anatomy of the injury. The optimal treatment strategy, however, should keep into consideration the hemodynamic status, the anatomic derangement, and the associated injuries. The management of splenic trauma patients aims to restore the homeostasis and the normal physiopathology especially considering the modern tools for bleeding management. Thus, the management of splenic trauma should be ultimately multidisciplinary and based on the physiology of the patient, the anatomy of the injury, and the associated lesions. Lastly, as the management of adults and children must be different, children should always be treated in dedicated pediatric trauma centers. In fact, the vast majority of pediatric patients with blunt splenic trauma can be managed non-operatively. This paper presents the World Society of Emergency Surgery (WSES) classification of splenic trauma and the management guidelines.
Purpose: The aim of this study was to analyze systematically the influence of the relative centrifugation force (RCF) on leukocytes, platelets and growth factor release within fluid platelet-rich fibrin matrices (PRF).
Materials and methods: Systematically using peripheral blood from six healthy volunteers, the RCF was reduced four times for each of the three experimental protocols (I–III) within the spectrum (710–44 g), while maintaining a constant centrifugation time. Flow cytometry was applied to determine the platelets and leukocyte number. The growth factor concentration was quantified 1 and 24 h after clotting using ELISA.
Results: Reducing RCF in accordance with protocol-II (177 g) led to a significantly higher platelets and leukocytes numbers compared to protocol-I (710 g). Protocol-III (44 g) showed a highly significant increase of leukocytes and platelets number in comparison to -I and -II. The growth factors’ concentration of VEGF and TGF-β1 was significantly higher in protocol-II compared to -I, whereas protocol-III exhibited significantly higher growth factor concentration compared to protocols-I and -II. These findings were observed among 1 and 24 h after clotting, as well as the accumulated growth factor concentration over 24 h.
Discussion: Based on the results, it has been demonstrated that it is possible to enrich PRF-based fluid matrices with leukocytes, platelets and growth factors by means of a single alteration of the centrifugation settings within the clinical routine.
Conclusions: We postulate that the so-called low speed centrifugation concept (LSCC) selectively enriches leukocytes, platelets and growth factors within fluid PRF-based matrices. Further studies are needed to evaluate the effect of cell and growth factor enrichment on wound healing and tissue regeneration while comparing blood concentrates gained by high and low RCF.
The etiology and pathogenesis of rheumatoid arthritis (RA) are marked by a complex interplay of various cell populations and is mediated by different signaling pathways. Traditionally, therapies have primarily focused on pain relief, reducing inflammation and the recovery of joint function. More recently, however, researchers have discussed the therapeutic efficacy of autologous platelet-rich plasma (PRP). The main objective of this work is to examine the influences of platelet-released growth factor (PRGF) on human synoviocytes under inflammatory conditions. Additionally, it is checked to which extend treatment with platelet concentrate influences the release of cytokines form synoviocytes. For this purpose, an in vitro RA model was created by stimulating the cells with the TNF-α. The release of cytokines was measured by ELISA. The cytokine gene expression was analyzed by real-time PCR. It has been observed that the stimulation concentration of 10 ng/ml TNF-α resulted in a significantly increased endogenous secretion and gene expression of IL-6 and TNF-α. The anti-inflammatory effect of PRGF could be confirmed through significant reduction of TNF-α and IL-1β. An induced inflammatory condition seems to cause PRGF to inhibit the release of proinflammatory cytokines. Further study is required to understand the exact effect mechanism of PRGF on synoviocytes.
Correction to: Nature Communications https://doi.org/10.1038/s41467-017-01045-x, published online 31 October 2017
It has come to our attention that we did not specify whether the stimulation magnitudes we report in this Article are peak amplitudes or peak-to-peak. All references to intensity given in mA in the manuscript refer to peak-to-peak amplitudes, except in Fig. 2, where the model is calibrated to 1 mA peak amplitude, as stated. In the original version of the paper we incorrectly calibrated the computational models to 1 mA peak-to-peak, rather than 1 mA peak amplitude. This means that we divided by a value twice as large as we should have. The correct estimated fields are therefore twice as large as shown in the original Fig. 2 and Supplementary Fig. 11. The corrected figures are now properly calibrated to 1mA peak amplitude. Furthermore, the sentence in the first paragraph of the Results section ‘Intensity ranged from 0.5 to 2.5 mA (current density 0.125–0.625 mA mA/cm2), which is stronger than in previous reports’, should have read ‘Intensity ranged from 0.5 to 2.5 mA peak to peak (peak current density 0.0625–0.3125 mA/cm2), which is stronger than in previous reports.’ These errors do not affect any of the Article’s conclusions. Correct versions of Fig. 2 and Supplementary Fig. 11 are presented below as Figs. 1, 2.
Transcranial electrical stimulation has widespread clinical and research applications, yet its effect on ongoing neural activity in humans is not well established. Previous reports argue that transcranial alternating current stimulation (tACS) can entrain and enhance neural rhythms related to memory, but the evidence from non-invasive recordings has remained inconclusive. Here, we measure endogenous spindle and theta activity intracranially in humans during low-frequency tACS and find no stable entrainment of spindle power during non-REM sleep, nor of theta power during resting wakefulness. As positive controls, we find robust entrainment of spindle activity to endogenous slow-wave activity in 66% of electrodes as well as entrainment to rhythmic noise-burst acoustic stimulation in 14% of electrodes. We conclude that low-frequency tACS at common stimulation intensities neither acutely modulates spindle activity during sleep nor theta activity during waking rest, likely because of the attenuated electrical fields reaching the cortical surface.
Ribosome recycling orchestrated by the ATP binding cassette (ABC) protein ABCE1 can be considered as the final—or the first—step within the cyclic process of protein synthesis, connecting translation termination and mRNA surveillance with re-initiation. An ATP-dependent tweezer-like motion of the nucleotide-binding domains in ABCE1 transfers mechanical energy to the ribosome and tears the ribosome subunits apart. The post-recycling complex (PRC) then re-initiates mRNA translation. Here, we probed the so far unknown architecture of the 1-MDa PRC (40S/30S·ABCE1) by chemical cross-linking and mass spectrometry (XL-MS). Our study reveals ABCE1 bound to the translational factor-binding (GTPase) site with multiple cross-link contacts of the helix–loop–helix motif to the S24e ribosomal protein. Cross-linking of the FeS cluster domain to the ribosomal protein S12 substantiates an extreme lever-arm movement of the FeS cluster domain during ribosome recycling. We were thus able to reconstitute and structurally analyse a key complex in the translational cycle, resembling the link between translation initiation and ribosome recycling.
The endoplasmic reticulum–mitochondria encounter structure (ERMES) connects the mitochondrial outer membrane with the ER. Multiple functions have been linked to ERMES, including maintenance of mitochondrial morphology, protein assembly and phospholipid homeostasis. Since the mitochondrial distribution and morphology protein Mdm10 is present in both ERMES and the mitochondrial sorting and assembly machinery (SAM), it is unknown how the ERMES functions are connected on a molecular level. Here we report that conserved surface areas on opposite sides of the Mdm10 β-barrel interact with SAM and ERMES, respectively. We generated point mutants to separate protein assembly (SAM) from morphology and phospholipid homeostasis (ERMES). Our study reveals that the β-barrel channel of Mdm10 serves different functions. Mdm10 promotes the biogenesis of α-helical and β-barrel proteins at SAM and functions as integral membrane anchor of ERMES, demonstrating that SAM-mediated protein assembly is distinct from ER-mitochondria contact sites.
In this paper, we study the limit of compactness which is a graph index originally introduced for measuring structural characteristics of hypermedia. Applying compactness to large scale small-world graphs (Mehler, 2008) observed its limit behaviour to be equal 1. The striking question concerning this finding was whether this limit behaviour resulted from the specifics of small-world graphs or was simply an artefact. In this paper, we determine the necessary and sufficient conditions for any sequence of connected graphs resulting in a limit value of CB = 1 which can be generalized with some consideration for the case of disconnected graph classes (Theorem 3). This result can be applied to many well-known classes of connected graphs. Here, we illustrate it by considering four examples. In fact, our proof-theoretical approach allows for quickly obtaining the limit value of compactness for many graph classes sparing computational costs.
Background: To evaluate survival data and local tumor control after transarterial chemoembolization in two groups with different embolization protocols for the treatment of HCC patients.
Methods: Ninty-nine patients (mean age: 63.6 years), 78 male (78.8%) with HCC were repeatedly treated with chemoembolization in 4-week-intervals. Eighty-eight patients had BCLC-Stage-B and in 11 patients, chemoembolization was performed for bridging (BCLC-Stage-A). In total, 667 chemoembolization treatments were performed (mean 6.7 treatments/patient). The administered chemotherapeutic agent included mitomycin. For embolization, lipiodol only (n = 51;51.5%; mean age 63.8 years; 38 male), or lipiodol plus degradable starch microspheres (DSM) (n = 48; 48.5%; mean age 63.4 years; 40 male) were used. The local tumor response was assessed by MRI using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Patient survival times were evaluated using Kaplan-Meier curves and log-rank tests.
Results: The local tumor control in the lipiodol-group was: PR (partial response) in 11 (21.6%), SD (stable disease) in 32 (62.7%) and PD (progressive disease) in 8 cases (15.7%). In the lipiodol-DSM-group, PR was seen in 14 (29.2%), SD in 22 (45.8%), and PD in 12 (25.0%) individuals (p = 0.211). The median survival of patients after chemoembolization with lipiodol was 25 months and in the lipiodol-DSM-group 28 months (p = 0.845).
Conclusion: Our data suggest a slight benefit of the use of lipiodol and DSM in comparison of using lipiodol only for chemoembolization of HCC in terms of local tumor control and survival data, this trend did not reach the level of significance.
Age-related diseases, such as osteoarthritis, Alzheimer’s disease, diabetes, and cardiovascular disease, are often associated with chronic unresolved inflammation. Neutrophils play central roles in this process by releasing tissue-degenerative proteases, such as cathepsin G, as well as pro-inflammatory leukotrienes produced by the 5-lipoxygenase (5-LO) pathway. Boswellic acids (BAs) are pentacyclic triterpene acids contained in the gum resin of the anti-inflammatory remedy frankincense that target cathepsin G and 5-LO in neutrophils, and might thus represent suitable leads for intervention with age-associated diseases that have a chronic inflammatory component. Here, we investigated whether, in addition to BAs, other triterpene acids from frankincense interfere with 5-LO and cathepsin G. We provide a comprehensive analysis of 17 natural tetra- or pentacyclic triterpene acids for suppression of 5-LO product synthesis in human neutrophils. These triterpene acids were also investigated for their direct interference with 5-LO and cathepsin G in cell-free assays. Furthermore, our studies were expanded to 10 semi-synthetic BA derivatives. Our data reveal that besides BAs, several tetra- and pentacyclic triterpene acids are effective or even superior inhibitors of 5-LO product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as anti-inflammatory natural products and pharmacological leads for intervention with diseases related to aging.
Practical considerations when prescribing a long-acting muscarinic antagonist for patients with COPD
(2018)
COPD is characterized by persistent airflow limitation, progressive breathlessness, cough, and sputum production. Long-acting muscarinic antagonists (LAMAs) are one of the recommended first-choice therapeutic options for patients with COPD, and several new agents have been developed in recent years. A literature search identified 14 published randomized, placebo-controlled studies of the efficacy and safety of LAMAs in patients with COPD, with improvements seen in lung function, exacerbations, breathlessness, and health status. A greater weight of evidence currently exists for glycopyrronium (GLY) and tiotropium than for umeclidinium and aclidinium, especially in terms of exacerbation reductions. To date, there have been few head-to-head clinical studies of the different LAMAs. Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function, dyspnea, exacerbations, and health status. Overall, evidence demonstrates that currently available LAMAs provide effective and generally well-tolerated therapy for patients with COPD. Delivery devices for the different LAMAs vary, which may affect individual patient’s adherence to and preference for treatment. Subtle differences between individual therapeutic options may be important to individual patients and the final treatment choice should involve physician’s and patient’s experiences and preferences.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
Fabrication of three-dimensional (3D) nanoarchitectures by focused electron beam induced deposition (FEBID) has matured to a level that highly complex and functional deposits are becoming available for nanomagnetics and plasmonics. However, the generation of suitable pattern files that control the electron beam’s movement, and thereby reliably map the desired target 3D structure from a purely geometrical description to a shape-conforming 3D deposit, is nontrivial. To address this issue we developed several writing strategies and associated algorithms implemented in C++. Our pattern file generator handles different proximity effects and corrects for height-dependent precursor coverage. Several examples of successful 3D nanoarchitectures using different precursors are presented that validate the effectiveness of the implementation.
Background: Acute critical bleeding is one of the most feared complications during treatment with oral anticoagulating agents. As more patients undergo treatment with anticoagulating agents, critically bleeding episodes in patients with vitamin K antagonists, thrombin inhibitor, or factor Xa inhibitor-inducted coagulopathy will be encountered frequently by physicians. Hence, an effective treatment capable of reversing the iatrogenic coagulopathy in the acute setting is needed. In randomised clinical trials and observational studies, prothrombin complex concentrate has been reported to be superior to other acute interventions, and many guidelines recommend prothrombin complex concentrate in treatment of critically bleeding patients. The aim of this systematic review is to synthesise the evidence of the effects of prothrombin complex concentrate compared with placebo, no intervention, or other treatment options in critically bleeding patients treated with oral anticoagulants.
Methods/design: A comprehensive search for relevant published literature will be undertaken in Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, Science Citation Index, regulatory databases, and trial registers. We will include randomised clinical trials comparing prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients with oral anticoagulant-induced coagulopathy. Data extraction and risk of bias assessment will be handled by two independent review authors. Meta-analysis will be performed as recommended by Cochrane Handbook for Systematic Reviews of Interventions, bias will be assessed with domains, and trial sequential analysis will be conducted to control random errors. Certainty will be assessed by GRADE.
Discussion: As critical bleeding in patients treated with oral anticoagulants is an increasing problem, an up-to-date systematic review evaluating the benefits and harms of prothrombin complex concentrate is urgently needed. It is the hope that this review will be able to guide best practice in treatment and clinical research of these critically bleeding patients.
Systematic review registration: PROSPERO CRD42018084371
There are 63 known species of Thecaphora (Glomosporiaceae, Ustilaginomycotina), a third of which occur on Asteraceae. These smut fungi produce yellowish-brown to reddish-brown masses of spore balls in specific, mostly regenerative, plant organs. A species of Thecaphora was collected in the flower heads of Anthemis chia (Anthemideae, Asteraceae) on Rhodes Island, Greece, in 2015 and 2017, which represents the first smut record of a smut fungus on a host plant species in this tribe. Based on its distinctive morphology, host species and genetic divergence, this species is described as Thecaphora anthemidis sp. nov. Molecular barcodes of the ITS region are provided for this and several other species of Thecaphora. A phylogenetic and morphological comparison to closely related species showed that Th. anthemidis differed from other species of Thecaphora. Thecaphora anthemidis produced loose spore balls in the flower heads and peduncles of Anthemis chia unlike other flower-infecting species.
After initial formation, the heart tube grows by addition of second heart field progenitor cells to its poles. The transcription factor Isl1 is expressed in the entire second heart field in mouse, and Isl1-deficient mouse embryos show defects in arterial and venous pole development. The expression of Isl1 is conserved in zebrafish cardiac progenitors; however, Isl1 is required for cardiomyocyte differentiation only at the venous pole. Here we show that Isl1 homologues are expressed in specific patterns in the developing zebrafish heart and play distinct roles during cardiac morphogenesis. In zebrafish, isl2a mutants show defects in cardiac looping, whereas isl2b is required for arterial pole development. Moreover, Isl2b controls the expression of key cardiac transcription factors including mef2ca, mef2cb, hand2 and tbx20. The specific roles of individual Islet family members in the development of distinct regions of the zebrafish heart renders this system particularly well-suited for dissecting Islet-dependent gene regulatory networks controlling the behavior and function of second heart field progenitors in distinct steps of cardiac development.
Panmixia and dispersal from the Mediterranean Basin to Macaronesian Islands of a macrolichen species
(2017)
The Mediterranean region, comprising the Mediterranean Basin and the Macaronesian Islands, represents a center of diversification for many organisms. The genetic structure and connectivity of mainland and island microbial populations has been poorly explored, in particular in the case of symbiotic fungi. Here we investigated genetic diversity and spatial structure of the obligate outcrossing lichen-forming fungus Parmelina carporrhizans in the Mediterranean region. Using eight microsatellite and mating-type markers we showed that fungal populations are highly diverse but lack spatial structure. This is likely due to high connectivity and long distance dispersal of fungal spores. Consistent with low levels of linkage disequilibrium and lack of clonality, we detected both mating-type idiomorphs in all populations. Furthermore we showed that the Macaronesian Islands are the result of colonization from the Mediterranean Basin. The unidirectional gene flow, though, seemed not to be sufficient to counterbalance the effects of drift, resulting in comparatively allelic poor peripheral populations. Our study is the first to shed light on the high connectivity and lack of population structure in natural populations of a strictly sexual lichen fungus. Our data further support the view of the Macaronesian Islands as the end of the colonization road for this symbiotic ascomycete.
Nutrition support is a necessary therapy for critically ill cardiac surgery patients. However, conclusive evidence for this population, consisting of well-conducted clinical trials is lacking. To clarify optimal strategies to improve outcomes, an international multidisciplinary group of 25 experts from different clinical specialties from Germany, Canada, Greece, USA and Russia discussed potential approaches to identify patients who may benefit from nutrition support, when best to initiate nutrition support, and the potential use of pharmaco-nutrition to modulate the inflammatory response to cardiopulmonary bypass. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy is presented to benefit patients undergoing cardiac surgery.