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Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.
HADES experiment at GSI is the only high precision experiment probing nuclear matter in the beam energy range of a few AGeV. Pion, proton and ion beams are used to study rare dielectron and strangeness probes to diagnose properties of strongly interacting matter in this energy regime. Selected results from p + A and A + A collisions are presented and discussed.
Schiller and Goethe have very different conceptions of tragedy. In his play Don Carlos, Schiller, especially in the character of Philip II, shows us the conflict between blood and positive law. In Goethe´s novel Elective Affinities, the individual will is ignorant of fate and helpless against it. So to speak, Schiller applies the "Antigone´s Model" and Goethe applies the "Oedipus Model". In his dramatic vision of the conflict, Schiller is inspired by Shakespeare´s plays. However, Goethe´s point of view is based on his reflections on Natural Philosophy.
Land surface and hydrologic models (LSMs/HMs) are used at diverse spatial resolutions ranging from catchment-scale (1–10 km) to global-scale (over 50 km) applications. Applying the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the chosen resolution, i.e., fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent hydrologic parameter fields. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB, and WaterGAP models demonstrate the pitfalls of deficient parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge's 1982 statement on the unsolved problem of parameterization in these models remains true. Based on a review of existing parameter regionalization techniques, we postulate that the multiscale parameter regionalization (MPR) technique offers a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. Herein, we develop a general model protocol to describe how MPR can be applied to a particular model and present an example application using the PCR-GLOBWB model. Finally, we discuss potential advantages and limitations of MPR in obtaining the seamless prediction of hydrological fluxes and states across spatial scales.
Land surface and hydrologic models (LSM/HM) are used at diverse spatial resolutions ranging from 1-10 km in catchment-scale applications to over 50 km in global-scale applications. Application of the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the model resolution and fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent and realistic parameter fields for land surface geophysical properties. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB and WaterGAP models are conducted to demonstrate the pitfalls of poor parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge’s 1982 statement on the unsolved problem of parameterization in these models remains true. We provide a short review of existing parameter regionalization techniques and discuss a method for obtaining seamless hydrological predictions of water fluxes and states across multiple spatial resolutions. The multiscale parameter regionalization (MPR) technique is a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. A general model protocol is presented to describe how MPR can be applied to a specific model, with an example of this application using the PCR-GLOBWB model. Applying MPR to PCR-GLOBWB substantially improves the flux-matching condition. Estimation of evapotranspiration without MPR at 5 arcmin and 30 arcmin spatial resolutions for the Rhine river basin results in a difference of approximately 29%. Applying MPR reduce this difference to 9%. For total soil water, the differences without and with MPR are 25% and 7%, respectively.
A booming middle class, new attractive study destinations and a resulting shift in student mobility trends have recently established a new dynamic in international higher education. To stay competitive, countries apply marketing strategies to promote and "sell" their higher education to international students-cum-customers. With the growing use of the Internet to research study destinations, the role of online channels in higher education promotion is becoming increasingly important. The current study investigates the case of Malaysian higher education branding in cyberspace. By applying content analysis to the two major higher education online platforms, this study identifies the core brand values of Malaysian higher education and evaluates their coherence. The research findings demonstrate that both platforms combine nation and higher education branding efforts to create a harmonised image of the national higher education system. Additionally, several suggestions are made concerning the optimisation of the architecture and information presentation of the websites to enhance their attractiveness for users. Finally, the necessity of further investigation into higher education branding for the successful implementation of internationalisation policies in Malaysia is emphasised.
Taxonomically dissimilar epiphyte species can have comparable morphological and physiological traits in similar environmental conditions. However, the degree of trait similarity has not been examined in a comparison of bryophytic and vascular epiphytes across elevational and tree gradients. We assess whether epiphyte species that occupy comparable realised niche spaces within host tree and landscape scale gradients have similarities in taxonomy, morphology or physiology. Vascular and moss epiphytes were surveyed within four height zones at five elevations (300-1100 m asl) in the sub-tropical rainforest of Australia. Epiphyte species distributions were agglomeratively classified using Ward’s method. Chi square tests were used to test for differences in the incidences of taxonomic groups, life forms, leaf thickness, photosynthetic pathways and other drought resistant morphologies between these distributional groups. These traits were also tested for correlation with light and humidity. Six groups were identified based on distribution. Vascular epiphytes with CAM, thickened leaves and other drought-mitigating morphologies were common in the groups that occupied the most xeric situations. All drought resistant traits were associated with high light and low humidity. Vascular species with few to no drought-mitigating characteristics were common in groups that occupied moister situations. Moss morphology was less congruent with environmental conditions than vascular plant morphology, suggesting that moss life forms are responding to a different scale of environmental variation.
O ensaio traz como base a crítica ao capitalismo, no que se refere aos efeitos negativos que ele impõe aos indivíduos, a partir dos estudos da primeira geração da Escola de Frankfurt. Analisar-se-á a história das ideias a partir de Walter Benjamin, Herbert Marcuse, Theodor Adorno e Max Horkheimer. Benjamin afirma que vive-se a perda da aura das obras de arte, já que a sua comercialização faz com que se perca a essência daquelas obras. Ademais, a imposição da novidade às obras e aos produtos consumidos representa uma ferramenta de manipulação do capitalismo, culminando na pobreza da experiência humana. Marcuse afirma que a sociedade vive o princípio do desempenho, que provoca modos de vida uniformizados, baseados numa concepção de trabalho e diversão homogêneos. Adorno propôs que o tempo livre provocava uma sensação de liberdade nos indivíduos, mas, na realidade, tratava-se do exercício de uma não liberdade, já que as formas de diversão seguiam à risca os padrões exigidos pelo capital. A partir do método adotado pela própria Teoria Crítica, afirma-se que a presente discussão teórica só se torna efetiva quando aplicada à prática, à sociedade atual.
The population size and distribution of Phaethon aethereus on Raso Islet was studied from August to December 2016. In total, 42 biometric measures were collected from 38 adults and four juveniles. No recapture was identified although some individuals were ringed in 2014. The means of biometrics variables obtained for the different body segments and eggs were within the ranges of P. aethereus mesonauta from tropical North Atlantic. The two largest agglomerations of P. aethereus identified on Raso were overlapping colonies of brown boobies Sula leucogaster which allowed the maximum direct count of only 90 individuals. The inaccessibility of some breeding areas conditioned the identification and monitoring of just 117 nests. Thus, we estimate the population by the number of nests in more than 100 pairs. However, without an annual census, it is difficult to estimate the population size of this species. So, annual studies are recommended to better understand the population dynamics of P. aethereus on Raso.
Objective: The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and ΔpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets.
Methods: Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures.
Results: NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification.
Conclusion: These results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.
HADES is a fixed target experiment using SIS18 heavy-ion beams. It investigates the microscopic properties of matter formed in heavy-ion, proton and pion - induced reactions in the 1-3.5 GeV/u energy regime. In 2014 HADES used a secondary pion beam produced by interaction between high-intensity nitrogen primary beam and a beryllium target. In these conditions beam losses, generated by slow extraction and beam transport to the experimental area, led to activation of the beam line elements and triggered radiation alarms. The primary beam intensity had to be reduced and the beam optics modified in order to keep radiation levels within the allowed limits. Similar beam conditions are requested by HADES experiment for upcoming run in 2018 and in the following years. Therefore, a number of measures have been proposed to improve beam transmission and quality. These measures are: additional shielding, additional beam instrumentation, modification of beam optics and increase of vacuum chambers' apertures in critical locations. The optics study and preliminary results of FLUKA simulations for optimization of location of loss detectors are presented.
Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein α-1 Antitrypsin (AAT) as a potent suppressor of staurosporine (STS)-induced apoptosis in human neutrophils through a mechanism implicating caspases-independent pathways. We show here that serum levels of AAT, potentially in part released by stimulated neutrophils, are markedly elevated in major trauma patients suffering from systemic inflammatory response syndrome (SIRS). Notably, AAT depletion from serum increased sensitivity of human neutrophils for STS-induced cell death. In fact, AAT was demonstrated to confer intrinsic apoptosis resistance by preventing PKC/Akt inactivation and subsequent proteasomal degradation of antiapoptotic Mcl-1 protein in response to STS treatment. Neither MAP kinase ERK1/2 nor caspases were found to be involved in AAT-triggered antiapoptotic pathways in neutrophils. In summary, these results establish a novel pivotal role of circulating AAT in mediating survival by antagonizing the proapoptotic action of the PKC inhibitor STS and should be considered for AAT augmentation therapies in future.
The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.
Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxide resulting from the activation of NADPH oxidase 4 (NOX4). As the role of this NOX in early alcoholic liver injury has not been addressed, we studied NOX4-mediated regulation of CCR2/CCL2 mRNA stability. NOX4 mRNA was significantly induced in patients with alcoholic liver injury, and was co-localized with αSMA-expressing activated HSC. We generated HSC-specific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNFα, and IL-6 was significantly reduced in NOX4HSCKO compared to fl/fl mice. NOX4 promoter was induced in HSC by acetaldehyde treatment, and NOX4 has significantly increased mRNA half-life of CCR2 and CCL2 in conjunction with Ser221 phosphorylation and cytoplasmic shuttling of HuR. In conclusion, NOX4 is induced in early alcoholic liver injury and regulates CCR2/CCL2 mRNA stability thereby promoting recruitment of inflammatory cells and production of proinflammatory cytokines.
Erwin Wittstock (1899-1962), the writer of German expression from Romania, has created a monumental body of works (short stories and novels), which stem from German history and culture from Transylvania. The characters he created are projections of his own life. His novel Januar ’45 oder Die höhere Pflicht, reviewed in the present article from an intercultural point of view, is dedicated to the problem of deportation, a topic which was taboo in the communist regime. His work on the topic is shaped into a novel in Balzacian style, the author writing from the perspective of an eye witness. The problematic invites the description of power, of terror and of repression in totalitarian states. As member of the German community in Romania he depicts the Transylvanian multiethnic and multicultural society in his fiction. The elements of interculturality in his novel can be summarized as: social interethnic relations, imagology, respectively the outlining of the image of otherness, also on a linguistic level.
We derive three exact sum rules for the spectral function of the electromagnetic current with zero spatial momentum at finite temperature. Possible applications of the three sum rules to lattice computations of the spectral function and transport coefficients are also discussed: We propose an ansatz for the spectral function that can be applied to all three sum rules and fit it to available lattice data of the Euclidean vector correlator above the critical temperature. As a result, we obtain estimates for both the electrical conductivity σ and the second order transport coefficient τJ.
Was Du heute kannst besorgen, das verschiebe nicht auf morgen: Dieser sprichwörtliche Rat kommt nicht von ungefähr. Viele von uns schieben oft wochenlang eine Aufgabe vor sich her – häufig mit schlechtem Gewissen. Doch woher kommt das ewige Aufschieben eigentlich? Wer ist davon betroffen? Und was kann man dagegen tun?
Der Mensch besteht aus vielen Körperteilen, und doch ist es fast ausschließlich das Gesicht, an dem wir ein Individuum erkennen. Aber erkennen wir es wirklich? In Zeiten des Selfie-Kults und der biometrischen Verfahren ist diese Frage aktueller denn je. Wir leben in einer »fazialen« Gesellschaft: Das Gesicht ist Medium für alle erdenklichen Arten, sich mitzuteilen.
Verschlafen? Ausgeschlafen!
(2017)
The bilingual phraseography with German contains significant shortcomings regarding both the conceptional orientation of the dictionary and the structure of the dictionary articles. The present paper reflects upon the relevance of certain criteria that are decisive for the quality of a dictionary and aims at showing to what extent the description of the selected phraseologisms is adequate with regard to potential users and the specifics of phraseological phenomena.