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Purpose: To review the role of radiotherapy (RT) in the treatment of renal cell cancer (RCC) in the curative and palliative setting.
Content: Details related to the clinical outcomes of primary, preoperative, postoperative and palliative RT are discussed, along with a presentation of the established role of surgery and systemic therapy. An overview of data derived from mono- and multi-institutional trials is provided.
Conclusion: Radiotherapy has been shown to provide good symptom palliation and local control in RCC depending on the dose that can be delivered. There is emerging data suggesting that with the use of high-precision RT methods the indication spectrum of RT can be exploited covering different clinical situations particularly for unresectable local recurrences and oligometastatic disease.
The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1–deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte–associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
Das Phänomen Straßenmusik: Teil einer städtischen Identität? : eine Analyse am Fallbeispiel Dublin
(2019)
The objective of this work is to understand the significance of street music for the city of Dublin and to what extent street music is part of the collective identity of its inhabitants. The idea behind this topic is this: A modern city stands for concentrated diversity. Despite this enormous diversity of people, ideas and beliefs, there are certain factors that every identity in a city shares: in this case, it is the street music. The work first introduces the research „Das Dublin Projekt. Die Rolle der Straßenmusik in der Hauptstadtkultur" (The Dublin Project. The role of street music in the capital city culture) of 2018 and uses selected points of analysis to illustrate the observed high value of street music as well as the process of the research and an overview of the applied scientific methods. In the second part of this work, the actual research-thesis will be explained and various theories on „identity" will be illustrated. For this purpose, selected theories are used to interpret the own findings with regard to the research-thesis. The focus here is on urban and collective identity theories. Finally, the answers to the questions posed will be given as well as an outlook on possible, supplementary and further research. Medial support of this work comes from attached photos of the described scenes as well as from map sections showing the distances covered and the hotspots of the research.
SAFE Newsletter : 2019, Q1
(2019)
In the current study we compared the molecular signature of expanded mesenchymal stromal cells (MSCs) derived from selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs derived from non-selected bone marrow mononuclear cells by plastic adherence (PA-MSCs). Transcriptome analysis demonstrated for the first time the upregulation of 115 and downregulation of 131 genes in CD271-MSCs. Functional enrichment analysis showed that the upregulated genes in CD271-MSCs are significantly enriched for extracellular matrix (tenascin XB, elastin, ABI family, member 3 (NESH) binding protein, carboxypeptidase Z, laminin alpha 2 and nephroblastoma overexpressed) and cell adhesion (CXCR7, GPNMB, MYBPH, SVEP1, ARHGAP6, TSPEAR, PIK3CG, ABL2 and NCAM1). CD271-MSCs expressed higher gene transcript levels that are involved in early osteogenesis/chondrogenesis/adipogenesis (ZNF145, FKBP5). In addition, increased transcript levels for early and late osteogenesis (DPT, OMD, ID4, CRYAB, SORT1), adipogenesis (CTNNB1, ZEB, LPL, FABP4, PDK4, ACDC), and chondrogenesis (CCN3/NOV, CCN4/WISP1, CCN5/WISP2 and ADAMTS-5) were detected. Interestingly, CD271-MSCs expressed increased levels of hematopoiesis associated genes (CXCL12, FLT3L, IL-3, TPO, KITL). Down-regulated genes in CD271-MSCs were associated with WNT and TGF-beta signaling, and cytokine/chemokine signaling pathways. In addition to their capacity to support hematopoiesis, these results suggest that CD271-MSCs may contain more osteo/chondro progenitors and/or feature a greater differentiation potential.
Application of blood flow restriction to optimize exercise countermeasures for human space flight
(2019)
In recent years there has been a strong increase in publications on blood flow restriction (BFR) training. In particular, the fact that this type of training requires only low resistance to induce muscle strength and mass gains, makes BFR training interesting for athletes and scientists alike. For the same reason this type of training is particularly interesting for astronauts working out in space. Lower resistance during training would have the advantage of reducing the risk of strain-induced injuries. Furthermore, strength training with lower resistances would have implications for the equipment required for training under microgravity conditions, as significantly lower resistances have to be provided by the training machines. Even though we are only about to understand the effects of blood flow restriction on exercise types other than low-intensity strength training, the available data indicate that BFR of leg muscles is also able to improve the training effects of walking or running at slow speeds. The underlying mechanisms of BFR-induced functional and structural adaptations are still unclear. An essential aspect seems to be the premature fatigue of Type-I muscle fibers, which requires premature recruitment of Type-II muscle fibers to maintain a given force output. Other theories assume that cell swelling, anabolic hormones, myokines and reactive oxygen species are involved in the mediation of BFR training-related effects. This review article is intended to summarize the main advantages and disadvantages, but also the potential risks of such training for astronauts.
We present a study of the elliptic flow and RAA of D and D¯ mesons in Au+Au collisions at FAIR energies. We propagate the charm quarks and the D mesons following a previously applied Langevin dynamics. The evolution of the background medium is modeled in two different ways: (I) we use the UrQMD hydrodynamics + Boltzmann transport hybrid approach including a phase transition to QGP and (II) with the coarse-graining approach employing also an equation of state with QGP. The latter approach has previously been used to describe di-lepton data at various energies very successfully. This comparison allows us to explore the effects of partial thermalization and viscous effects on the charm propagation. We explore the centrality dependencies of the collisions, the variation of the decoupling temperature and various hadronization parameters. We find that the initial partonic phase is responsible for the creation of most of the D/D¯ mesons elliptic flow and that the subsequent hadronic interactions seem to play only a minor role. This indicates that D/D¯ mesons elliptic flow is a smoking gun for a partonic phase at FAIR energies. However, the results suggest that the magnitude and the details of the elliptic flow strongly depend on the dynamics of the medium and on the hadronization procedure, which is related to the medium properties as well. Therefore, even at FAIR energies the charm quark might constitute a very useful tool to probe the quark–gluon plasma and investigate its physics.
Background: Electrochemical signals play an important role in cell communication and behavior. Electrically charged ions transported across cell membranes maintain an electrochemical imbalance that gives rise to bioelectric signaling, called membrane potential or Vmem. Vmem plays a key role in numerous inter- and intracellular functions that regulate cell behaviors like proliferation, differentiation and migration, all playing a critical role in embryonic development, healing, and regeneration.
Methods: With the goal of analyzing the changes in Vmem during cell proliferation and differentiation, here we used direct current electrical stimulation (EStim) to promote cell proliferation and differentiation and simultaneously tracked the corresponding changes in Vmem in adipose derived mesenchymal stem cells (AT-MSC).
Results: We found that EStim caused increased AT-MSC proliferation that corresponded to Vmem depolarization and increased osteogenic differentiation that corresponded to Vmem hyperpolarization. Taken together, this shows that Vmem changes associated with EStim induced cell proliferation and differentiation can be accurately tracked during these important cell functions. Using this tool to monitor Vmem changes associated with these important cell behaviors we hope to learn more about how these electrochemical cues regulate cell function with the ultimate goal of developing new EStim based treatments capable of controlling healing and regeneration.
Do competition and incentives offered to designated market makers (DMMs) improve market liquidity? Using data from NYSE Euronext Paris, we show that an exogenous increase in competition among DMMs leads to a significant decrease in quoted and effective spreads, mainly through a reduction in adverse selection costs. In contrast, changes in incentives, through small changes in rebates and requirements for DMMs, do not have any tangible effect on market liquidity. Our results are of relevance for designing optimal contracts between exchanges and DMMs and for regulatory market oversight.
Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during acute (16 h) and chronic (72 h) hypoxia, compared to normoxia, to analyze the electron flows associated with glycolysis, glutamine, and fatty acid oxidation. Oxygen consumption under acute hypoxia predominantly demanded pyruvate, while under chronic hypoxia, fatty acid- and glutamine-oxidation dominated. Chronic hypoxia also elevated electron-transferring flavoproteins (ETF), and the knockdown of ETF–ubiquinone oxidoreductase lowered mitochondrial respiration under chronic hypoxia. Metabolomics revealed an increase in citrate under chronic hypoxia, which implied glutamine processing to α-ketoglutarate and citrate. Expression regulation of enzymes involved in this metabolic shunting corroborated this assumption. Moreover, the expression of acetyl-CoA carboxylase 1 increased, thus pointing to fatty acid synthesis under chronic hypoxia. Cells lacking complex I, which experienced a markedly impaired respiration under normoxia, also shifted their metabolism to fatty acid-dependent synthesis and usage. Taken together, we provide evidence that chronic hypoxia fuels the ETC via ETFs, increasing fatty acid production and consumption via the glutamine-citrate-fatty acid axis.
Application of the Luttinger theorem to the Kondo lattice YbRh2Si2 suggests that its large 4f-derived Fermi surface (FS) in the paramagnetic (PM) regime should be similar in shape and volume to that of the divalent local-moment antiferromagnet (AFM) EuRh2Si2 in its PM regime. Here we show by angle-resolved photoemission spectroscopy that paramagnetic EuRh2Si2 has a large FS essentially similar to the one seen in YbRh2Si2 down to 1 K. In EuRh2Si2 the onset of AFM order below 24.5 K induces an extensive fragmentation of the FS due to Brillouin zone folding, intersection and resulting hybridization of the Fermi-surface sheets. Our results on EuRh2Si2 indicate that the formation of the AFM state in YbRh2Si2 is very likely also connected with similar changes in the FS, which have to be taken into account in the controversial analysis and discussion of anomalies observed at the quantum critical point in this system.
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Purpose: To analyze leg pain severity data from a randomized controlled trial (RCT) of lumbar disc surgery using integrated approaches that adjust pain scores collected at scheduled follow-up visits for confounding clinical events occurring between visits. Methods. Data were derived from an RCT of a bone-anchored annular closure device (ACD) following lumbar discectomy versus lumbar discectomy alone (Control) in patients with large postsurgical annular defects. Leg pain was recorded on a 0 to 100 scale at 6 weeks, 3 months, 6 months, 1 year, and 2 years of follow-up. Patients with pain reduction ≥20 points relative to baseline were considered responders. Unadjusted analyses utilized pain scores reported at follow-up visits. Since symptomatic reherniation signifies clinical failure of lumbar discectomy, integrated analyses adjusted pain scores following a symptomatic reherniation by baseline observation carried forward for continuous data or classification as nonresponders for categorical data.
Results: Among 550 patients (272 ACD, 278 Control), symptomatic reherniation occurred in 10.3% of ACD patients and in 21.9% of controls (p < 0.001) through 2 years. There was no difference in leg pain scores at the 2-year visit between ACD and controls (12 versus 14; p = 0.33) in unadjusted analyses, but statistically significant differences favoring ACD (19 versus 29; p < 0.001) in integrated analyses. Unadjusted nonresponder rates were 6.0% with ACD and 6.7% with controls (p = 0.89), but 15.7% and 27.8% (p = 0.001) in integrated analyses. The probability of nonresponse was 16.4% with ACD and 18.3% with controls (p = 0.51) in unadjusted analysis, and 23.7% and 31.2% (p = 0.04) in integrated analyses.
Conclusion: In an RCT of lumbar disc surgery, an integrated analysis of pain severity that adjusted for the confounding effects of clinical failures occurring between follow-up visits resulted in different conclusions compared to an unadjusted analysis of pain scores reported at follow-up visits only.
Music is an effective means of stress-reduction. However, to date there has been no systematic comparison between musical and language-based means of stress reduction in an ambulatory setting. Furthermore, although the aim for listening to music appears to play a role in its effect, this has not yet been investigated thoroughly. We compared musical means, language-based means like guided relaxation or self-enhancement exercises, and a combination of both with respect to their potential to reduce perceived stress. Furthermore, we investigated whether the aim one wants to achieve by listening to these means had an impact on their effect. We tested 64 participants (age: M = 40.09 years; 18 female) for 3–10 days during their everyday life using an app containing three means: musical means, language-based means, and a combination of both. For the music and the combination conditions participants were asked to select an aim: relaxation or activation. We measured perceived stress, relaxation, activation, and electrical skin resistance (ESR) as a marker of sympathetic nervous system (SNS) activity before and after using the app. Participants were instructed to use the app as often as desired. Overall, perceived stress was reduced after using the app, while perceived relaxation and activation were increased. There were no differences between the three means regarding their effect on perceived stress and relaxation, but music led to a greater increase in ESR and perceived activation compared to the other means. There was a decrease in ESR only for music. Moreover, perceived stress was reduced and perceived relaxation was increased to greater extent if the aim “relaxation” had been selected. Perceived activation, however, showed a larger increase if the aim had been “activation,” which was even more marked in the case of music listening. Our results indicate that all three means reduced perceived stress and promoted feelings of relaxation and activation. For enhancing feelings of activation music seems to be more effective than the other means, which was reflected in increased SNS activity as well. Furthermore, the choice of an aim plays an important role for the reduction of stress, and promotion of relaxation and activation.
Background: Transcatheter aortic valve replacement (TAVR) is a therapeutic option for patients with aortic valve stenosis at increased surgical risk. Telomeres are an established marker for cellular senescence and have served to evaluate cardiovascular diseases including severe aortic valve stenosis. In our study, we hypothesized that telomere length may be a predictor for outcome and associated with comorbidities in patients with TAVR.
Methods and results: We analyzed leucocyte telomere length from 155 patients who underwent TAVR and correlated the results with 1-year mortality and severe comorbidities. The cohort was subdivided into 3 groups according to telomere length. Although a trend for a positive correlation of telomere length with a lower EuroSCORE could be found, telomere length was not associated with survival, aortic valve opening area or cardiovascular comorbidities (peripheral, coronary or cerebrovascular disease). Interestingly, long telomeres were significantly correlated to a reduced left ventricular ejection fraction (LVEF).
Conclusion: In elderly patients with severe aortic valve stenosis, leucocyte telomere length did not predict post-procedural survival. The correlation between long telomere length and reduced LVEF in these patients deserves further attention.
kurz und kn@pp news : Nr. 45
(2019)
Der Beitrag liest Hebbels Judith (1840) vor dem Hintergrund der politischen Ereignisse im postrevolutionären und postrestaurativen Europa, wobei das Interesse der imaginären Dimension der Politik gilt. Ausgehend von einer gespenstischen Hand im Theatertext und der jungfräulichen Titelfigur als Guillotine wiederholt das Drama die brutale Enthauptung, die Europa im ausgehenden 18. Jahrhundert erschütterte und eine kopflose Gemeinschaft hinterließ. Eine unheimliche Hand, die sich "aus der schwarzen Erde" ausstreckt, lässt den Theatertext zunächst nicht nur zwischen einer restaurativen und revolutionären Politik, sondern auch zwischen einer idealistisch-romantischen und realistischen Kunst oszillieren. Die dramatische Aufführungspraxis rechnet dabei zum einen mit der Romantik ab. Zum anderen lässt sich anhand von Modi des realistischen Darstellens auf der Theaterbühne beobachten, wie die restaurative Politik mit den Anfängen des realistischen Erzählens zusammenfällt.
Der Artikel schlägt vor, die Frage nach dem Berühren indirekt, d.h. ausgehend von einer Unhaltbarkeit der Unbetroffenheit aufzugreifen. In 'Schiffbruch mit Zuschauer' diskutiert Hans Blumenberg den Verlust der Zuschauerposition als einen rezeptionsgeschichtlichen Umschlagpunkt. Entscheidend hierfür sind die von Jacob Burckhardt beschriebenen Aporien der Geschichtsschreibung im "Revolutionszeitalter". Ein Blick auf Burckhardts Metaphernkonstellationen kann zeigen, dass die beschriebene "Krisis" die Logik der großen historischen Instanzen gerade unberührt lässt. Demgegenüber lässt sich mit Blumenbergs bereits 1979 angekündigter 'Theorie der Unbegrifflichkeit' eine Variante möglichen Distanzverlusts erschließen, die sich keinem hintergründigen Spiel historisch wirksamer Kräfte, sondern der immanenten – und darin keineswegs ahistorischen – Destruktion der Leistung des Begriffs verdankt. Unter dem Titel der Berührbarkeit wird die Wiederkehr des Sinnlichen zunächst als eine Krise methodischer Sicherungen reformulierbar.
Der Artikel arbeitet an Platons Gastmahl ein semantisches Netz rund um das Konzept des 'Berührens' heraus. Dabei bildet das Verb ἅπτομαι ein zentrales Relais, das zwischen dem vieldiskutierten 'philosophischen Gehalt' des Textes und der in ihrem performativen Beitrag meist unterschätzten Rahmenhandlung vermittelt. Im Nachvollzug der Konstellationen des Berührens zeigt sich, dass dem Berühren, als Berühren, nicht begrifflich beizukommen ist – es entzieht sich dem aneignenden Zugriff. Berühren ist eben nicht Begriff. Deshalb muss sich das Gastmahl der Berührung auf andere Weise nähern, nämlich berührend – wofür die narratologische Konstruktion des Textes von entscheidender Wichtigkeit ist. Er praktiziert Philo-Logie, d.h. nutzt die Macht der Worte, die genau daraus entsteht, dass sie in einer sehr präzisen Weise zwischen den Beteiligten aus einer konstitutiven Distanz heraus wirken.
Philologie der Hand
(2019)
Mit größter Selbstverständlichkeit spricht die Wissensgeschichte der Philologie von einer "Philologie des Ohrs" und einer "Philologie des Auges". Während sich die Ohrenphilologie in der Tradition des Phono(logo)zentrismus eingerichtet hat, beruft sich die Augenphilologie darauf, dass Literatur als Schrifttum zunächst optisch wahrgenommen werden müsse, bevor aus gesehenen Texten auch gelesene würden. Wie verkürzt beide Schulen argumentieren, zeigt sich nicht nur an Schriftsystemen, die den Tastsinn adressieren, oder an Sprachformen, die sich wesentlich auf die Handgeste stützen. Ein näherer Blick auf die Geschichte der Literatur enthüllt, dass die vermeintlich klare Aufteilung des philologischen Territoriums zwischen Akustik und Optik deutlich komplexer ist, denn die Dyade Auge-Ohr unterliegt permanenten Triangulierungen durch die Hand. Der Beitrag zeichnet diese Dreiecksbeziehungen mit ‚Blick‘ auf drei vernachlässigte Paradigmen der Moderne nach: Die Poetik der Geste, die Poetik des Werkzeugs und die Poetik der Berührung. Im Zentrum stehen dabei Konzepte des russischen Formalismus, der konstruktivistischen Produktionsliteratur, der symbolistischen Lautlehre und der futuristischen Haptologie.
Körper und ihre Sinneswahrnehmung gehören zu den Voraussetzungen von Literatur und, Philosophie; die Bestimmung ihrer Funktion zählt zugleich zu einer der schwierigsten und umstrittensten Aufgaben dieser Künste und Disziplinen. Der Komplex um das Berühren, zu dem Haptik, Taktilität und Gefühl, Motorik, Sensorik und Affektivität gleichermaßen gehören, ist in der Körper- und Sinnesgeschichte notorisch von Vernachlässigung bedroht, hat in den Kultur- und Medienwissenschaften aber zuletzt neue Aufmerksamkeit erfahren. Philologische Ansätze befinden sich derzeit noch am Rand dieser Debatten, obwohl ihre Begriffe und Verfahren sogar als besonders 'berührungsaffin' gelten können. Genaue philologische Lektüren bieten die Möglichkeit, das je singuläre Verhältnis von Affektion und Sinnlichkeit und die Bedeutung des Tastsinns im Zusammenspiel mit anderen Sinnen zu erfassen. Philologische Verfahren können das metaphorische Potenzial des Berührens ebenso ausloten wie sein Verhältnis zum 'Realen'. Die Beiträge dieses Bandes zur europäischen Literatur, aber auch zur Philosophie von der Antike bis ins späte 20. Jahrhundert untersuchen das Berühren als relationale Figur, in der poetische Gestaltung und Materialität, Bildlichkeit und Buchstäblichkeit, Begreifen und Ergreifen, Anschauung und Affizierung in Beziehung treten. Im Zentrum stehen Fragen nach dem Verhältnis von Gemeinschaft und Individualität, von Literatur und Philosophie sowie nach der Funktion von Ansteckungs- und Distanzierungsverfahren in diesen Zusammenhängen. Dabei geraten gerade auch Wahrnehmungsräume in den Blick, die zumeist unter dem Primat des Visuellen verhandelt wurden. In Re- und Gegenlektüren schlagen die Beiträge eine Ausweitung der Sinnesbezüge vor.
Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.
Global response of diacylglycerol kinase towards substrate binding observed by 2D and 3D MAS NMR
(2019)
Escherichia coli diacylglycerol kinase (DGK) is an integral membrane protein, which catalyses the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatic acid (PA). It is a unique trimeric enzyme, which does not share sequence homology with typical kinases. It exhibits a notable complexity in structure and function despite of its small size. Here, chemical shift assignment of wild-type DGK within lipid bilayers was carried out based on 3D MAS NMR, utilizing manual and automatic analysis protocols. Upon nucleotide binding, extensive chemical shift perturbations could be observed. These data provide evidence for a symmetric DGK trimer with all of its three active sites concurrently occupied. Additionally, we could detect that the nucleotide substrate induces a substantial conformational change, most likely directing DGK into its catalytic active form. Furthermore, functionally relevant interprotomer interactions are identified by DNP-enhanced MAS NMR in combination with site-directed mutagenesis and functional assays.
Background: The clinical presentation of gastroesophageal reflux disease (GERD) shows a large symptom variation also in different intensities among patients. As several studies have shown, there is a large overlap in the symptomatic spectrum between proven GERD and other disorders such as dyspepsia, functional heartburn and/or somatoform disorders.
Aim: To prospectively evaluate the GERD patients with and without somatoform disorders before and after laparoscopic antireflux surgery.
Methods: In a tertiary referral center for foregut surgery over a period of 3 years patients with GERD, qualifying for the indication of laparoscopic antireflux surgery, were investigated prospectively regarding their symptomatic spectrum in order to identify GERD and associated somatoform disorders. Assessment of symptoms was performed by an instrument for the evaluation of somatoform disorders [Somatoform Symptom Index (SSI) > 17]. Quality of life was evaluated by Gastrointestinal Quality of Life Index (GIQLI).
Results: In 123 patients an indication for laparoscopic antireflux surgery was established and in 43 patients further medical therapy was suggested. The portion of somatoform tendencies in the total patient population was 20.48% (34 patients). Patients with a positive SSI had a preoperative GIQLI of 77 (32-111). Patients with a normal SSI had a GIQLI of 105 (29-140) (P < 0.0001). In patients with GERD the quality of life could be normalized from preoperative reduced values of GIQLI 102 (47-140) to postoperative values of 117 (44-144). In patients with GERD and somatoform disorders, the GIQLI was improved from preoperative GIQLI 75 (47-111) to postoperative 95 (44-122) (P < 0.0043).
Conclusion: Patients with GERD and associated somatoform disorders have significantly worse levels of quality of life. The latter patients can also benefit from laparoscopic fundoplication, however they will not reach a normal level.
Global impact models represent process-level understanding of how natural and human systems may be affected by climate change. Their projections are used in integrated assessments of climate change. Here we test, for the first time, systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions. Using the 2003 European heat wave and drought as a historical analogue for comparable events in the future, we find that a majority of models underestimate the extremeness of impacts in important sectors such as agriculture, terrestrial ecosystems, and heat-related human mortality, while impacts on water resources and hydropower are overestimated in some river basins; and the spread across models is often large. This has important implications for economic assessments of climate change impacts that rely on these models. It also means that societal risks from future extreme events may be greater than previously thought.
The TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to decrease glycolysis, to activate the pentose phosphate pathway, and to provide protection against oxidative damage. Hypoxic regions are considered characteristic of glioblastoma and linked with resistance to current treatment strategies. Here, we established that LNT-229 glioma cell lines stably expressed shRNA constructs targeting TIGAR, and exposed them to hypoxia, irradiation and temozolomide. The disruption of TIGAR enhanced levels of reactive oxygen species and cell death under hypoxic conditions, as well as the effectiveness of irradiation and temozolomide. In addition, TIGAR was upregulated by HIF-1α. As a component of a complex network, TIGAR contributes to the metabolic adjustments that arise from either spontaneous or therapy-induced changes in tumor microenvironment.
Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
Introduction: Colorectal cancers (CRCs) deficient in the DNA mismatch repair protein MutL homolog 1 (MLH1) display distinct clinicopathological features and require a different therapeutic approach compared to CRCs with MLH1 proficiency. However, the molecular basis of this fundamental difference remains elusive. Here, we report that MLH1-deficient CRCs exhibit reduced levels of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1), and that tumor progression and metastasis of CRCs correlate with SPTAN1 levels.
Methods and results: To investigate the link between MLH1 and SPTAN1 in cancer progression, a cohort of 189 patients with CRC was analyzed by immunohistochemistry. Compared with the surrounding normal mucosa, SPTAN1 expression was reduced in MLH1-deficient CRCs, whereas MLH1-proficient CRCs showed a significant upregulation of SPTAN1. Overall, we identified a strong correlation between MLH1 status and SPTAN1 expression. When comparing TNM classification and SPTAN1 levels, we found higher SPTAN1 levels in stage I CRCs, while stages II to IV showed a gradual reduction of SPTAN1 expression. In addition, SPTAN1 expression was lower in metastatic compared with non-metastatic CRCs. Knockdown of SPTAN1 in CRC cell lines demonstrated decreased cell viability, impaired cellular mobility and reduced cell-cell contact formation, indicating that SPTAN1 plays an important role in cell growth and cell attachment. The observed weakened cell-cell contact of SPTAN1 knockdown cells might indicate that tumor cells expressing low levels of SPTAN1 detach from their primary tumor and metastasize more easily.
Conclusion: Taken together, we demonstrate that MLH1 deficiency, low SPTAN1 expression, and tumor progression and metastasis are in close relation. We conclude that SPTAN1 is a candidate molecule explaining the tumor progression and metastasis of MLH1-deficient CRCs. The detailed analysis of SPTAN1 is now mandatory to substantiate its relevance and its potential value as a candidate protein for targeted therapy, and as a predictive marker of cancer aggressiveness.
We show that banks that are facing relatively high locally non-diversifiable risks in their home region expand more across states than banks that do not face such risks following branching deregulation in the 1990s and 2000s. These banks with high locally non-diversifiable risks also benefit relatively more from deregulation in terms of higher bank stability. Further, these banks expand more into counties where risks are relatively high and positively correlated with risks in their home region, suggesting that they do not only diversify but also build on their expertise in local risks when they expand into new regions.
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.
Background: Polyploidy and apomixis are important factors influencing plant distributions often resulting in range shifts, expansions and geographical parthenogenesis. We used the Ranunculus auricomus complex as a model to asses if the past and present distribution and climatic preferences were determined by these phenomena.
Results: Ecological differentiation among diploids and polyploids was tested by comparing the sets of climatic variables and distribution modelling using 191 novel ploidy estimations and 561 literature data. Significant differences in relative genome size on the diploid level were recorded between the “auricomus” and “cassubicus” groups and several new diploid occurrences were found in Slovenia and Hungary. The current distribution of diploids overlapped with the modelled paleodistribution (22 kyr BP), except Austria and the Carpathians, which are proposed to be colonized later on from refugia in the Balkans. Current and historical presence of diploids from the R. auricomus complex is suggested also for the foothills of the Caucasus. Based on comparisons of the climatic preferences polyploids from the R. auricomus complex occupy slightly drier and colder habitats than the diploids.
Conclusions: The change of reproductive mode and selection due to competition with the diploid ancestors may have facilitated the establishment of polyploids within the R. auricomus complex in environments slightly cooler and drier, than those tolerated by diploid ancestors. Much broader distribution of polyploid apomicts may have been achieved due to faster colonization mediated by uniparental reproductive system.
The arrangement of the contents of real-world scenes follows certain spatial rules that allow for extremely efficient visual exploration. What remains underexplored is the role different types of objects hold in a scene. In the current work, we seek to unveil an important building block of scenes—anchor objects. Anchors hold specific spatial predictions regarding the likely position of other objects in an environment. In a series of three eye tracking experiments we tested what role anchor objects occupy during visual search. In all of the experiments, participants searched through scenes for an object that was cued in the beginning of each trial. Critically, in half of the scenes a target relevant anchor was swapped for an irrelevant, albeit semantically consistent, object. We found that relevant anchor objects can guide visual search leading to faster reaction times, less scene coverage, and less time between fixating the anchor and the target. The choice of anchor objects was confirmed through an independent large image database, which allowed us to identify key attributes of anchors. Anchor objects seem to play a unique role in the spatial layout of scenes and need to be considered for understanding the efficiency of visual search in realistic stimuli.
Objectives: Combined electric-acoustic stimulation (EAS) is a well-accepted therapeutic treatment for cochlear implant (CI) users with residual hearing in the low frequencies but severe to profound hearing loss in the high frequencies. The recently introduced SONNETeas audio processor offers different microphone directionality (MD) settings and wind noise reduction (WNR) as front-end processing. The aim of this study was to compare speech perception in quiet and noise between two EAS audio processors DUET 2 and SONNETeas, to assess the impact of MD and WNR on speech perception in EAS users in the absence of wind. Furthermore, subjective rating of hearing performance was registered.
Method: Speech perception and subjective rating with SONNETeas or DUET 2 audio processor were assessed in 10 experienced EAS users. Speech perception was measured in quiet and in a diffuse noise setup (MSNF). The SONNETeas processor was tested with three MD settings omnidirectional/natural/adaptive and with different intensities of WNR. Subjective rating of auditory benefit and sound quality was rated using two questionnaires.
Results: There was no significant difference between DUET 2 and SONNETeas processor using the omnidirectional microphone in quiet and in noise. There was a significant improvement in SRT with MD settings natural (2.2 dB) and adaptive (3.6 dB). No detrimental effect of the WNR algorithm on speech perception was found in the absence of wind. Sound quality was rated as “moderate” for both audio processors.
Conclusions: The different MD settings of the SONNETeas can provide EAS users with better speech perception compared to an omnidirectional microphone. Concerning speech perception in quiet and quality of life, the performance of the DUET 2 and SONNETeas audio processors was comparable.
Acinetobacter baumannii is a Gram-negative pathogen that causes a multitude of nosocomial infections. The Acinetobacter trimeric autotransporter adhesin (Ata) belongs to the superfamily of trimeric autotransporter adhesins which are important virulence factors in many Gram-negative species. Phylogenetic profiling revealed that ata is present in 78% of all sequenced A. baumannii isolates but only in 2% of the closely related species A. calcoaceticus and A. pittii. Employing a markerless ata deletion mutant of A. baumannii ATCC 19606 we show that adhesion to and invasion into human endothelial and epithelial cells depend on Ata. Infection of primary human umbilical cord vein endothelial cells (HUVECs) with A. baumannii led to the secretion of interleukin (IL)-6 and IL-8 in a time- and Ata-dependent manner. Furthermore, infection of HUVECs by WT A. baumannii was associated with higher rates of apoptosis via activation of caspases-3 and caspase-7, but not necrosis, in comparison to ∆ata. Ata deletion mutants were furthermore attenuated in their ability to kill larvae of Galleria mellonella and to survive in larvae when injected at sublethal doses. This indicates that Ata is an important multifunctional virulence factor in A. baumannii that mediates adhesion and invasion, induces apoptosis and contributes to pathogenicity in vivo.