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Gen- und Stammzelltherapie stehen für das, wovon die Medizin schon immer geträumt hat: geschädigtes Gewebe durch gesundes ersetzen und die Wirkung defekter Gene durch intakte Kopien korrigieren. Wie ist der Stand der weltweiten Forschung? Welche Hindernisse sind zu überwinden, damit mehr Patienten von der regenerativen Medizin profi tieren werden?
During early G1 phase, Rb is exclusively mono-phosphorylated by cyclin D:Cdk4/6, generating 14 different isoforms with specific binding patterns to E2Fs and other cellular protein targets. While mono-phosphorylated Rb is dispensable for early G1 phase progression, interfering with cyclin D:Cdk4/6 kinase activity prevents G1 phase progression, questioning the role of cyclin D:Cdk4/6 in Rb inactivation. To dissect the molecular functions of cyclin D:Cdk4/6 during cell cycle entry, we generated a single cell reporter for Cdk2 activation, RB inactivation and cell cycle entry by CRISPR/Cas9 tagging endogenous p27 with mCherry. Through single cell tracing of Cdk4i cells, we identified a time-sensitive early G1 phase specific Cdk4/6-dependent phosphorylation gradient that regulates cell cycle entry timing and resides between serum-sensing and cyclin E:Cdk2 activation. To reveal the substrate identity of the Cdk4/6 phosphorylation gradient, we performed whole proteomic and phospho-proteomic mass spectrometry, and identified 147 proteins and 82 phospho-peptides that significantly changed due to Cdk4 inhibition in early G1 phase. In summary, we identified novel (non-Rb) cyclin D:Cdk4/6 substrates that connects early G1 phase functions with cyclin E:Cdk2 activation and Rb inactivation by hyper-phosphorylation.
Background: Computed tomography (CT) low-dose (LD) imaging is used to lower radiation exposure, especially in vascular imaging; in current literature, this is mostly on latest generation high-end CT systems.
Purpose: To evaluate the effects of reduced tube current on objective and subjective image quality of a 15-year-old 16-slice CT system for pulmonary angiography (CTPA).
Material and Methods: CTPA scans from 60 prospectively randomized patients (28 men, 32 women) were examined in this study on a 15-year-old 16-slice CT scanner system. Standard CT (SD) settings were 100 kV and 150 mAs, LD settings were 100 kV and 50 mAs. Attenuation of the pulmonary trunk, various anatomic landmarks, and image noise were quantitatively measured; contrast-to-noise ratios (CNR) and signal-to-noise ratios (SNR) were calculated. Three independent blinded radiologists subjectively rated each image series using a 5-point grading scale.
Results: CT dose index (CTDI) in the LD series was 66.46% lower compared to the SD settings (2.49 ± 0.55 mGy versus 7.42 ± 1.17 mGy). Attenuation of the pulmonary trunk showed similar results for both series (SD 409.55 ± 91.04 HU; LD 380.43 HU ± 93.11 HU; P = 0.768). Subjective image analysis showed no significant differences between SD and LD settings regarding the suitability for detection of central and peripheral PE (central SD/LD, 4.88; intra-class correlation coefficients [ICC], 0.894/4.83; ICC, 0.745; peripheral SD/LD, 4.70; ICC, 0.943/4.57; ICC, 0.919; all P > 0.4).
Conclusion: The LD protocol, on a 15-year-old CT scanner system without current high-end hardware or post-processing tools, led to a dose reduction of approximately 67% with similar subjective image quality and delineation of central and peripheral pulmonary arteries.
The re-emergence of tuberculosis in its present-day manifestations - single, multiple and extensive drug-resistant forms and as HIV-TB coinfections - has resulted in renewed research on fundamental questions such as the nature of the organism itself, Mycobacterium tuberculosis, the molecular basis of its pathogenesis, definition of the immunological response in animal models and humans, and development of new intervention strategies such as vaccines and drugs. Foremost among these developments has been the precise chemical definition of the complex and distinctive cell wall of M. tuberculosis, elucidation of the relevant pathways and underlying genetics responsible for the synthesis of the hallmark moieties of the tubercle bacillus such as the mycolic acid-arabinogalactan-peptidoglycan complex, the phthiocerol- and trehalose-containing effector lipids, the phosphatidylinositol-containing mannosides, lipomannosides and lipoarabinomannosides, major immunomodulators, and others. In this review, the laboratory personnel who have been the focal point of some to these developments review recent progress towards a comprehensive understanding of the basic physiology and functions of the cell wall of M. tuberculosis.
G-protein-coupled receptor (GPCR) expression is extensively studied in bulk cDNA, but heterogeneity and functional patterning of GPCR expression in individual vascular cells is poorly understood. Here, we perform a microfluidic-based single-cell GPCR expression analysis in primary smooth muscle cells (SMC) and endothelial cells (EC). GPCR expression is highly heterogeneous in all cell types, which is confirmed in reporter mice, on the protein level and in human cells. Inflammatory activation in murine models of sepsis or atherosclerosis results in characteristic changes in the GPCR repertoire, and we identify functionally relevant subgroups of cells that are characterized by specific GPCR patterns. We further show that dedifferentiating SMC upregulate GPCRs such as Gpr39, Gprc5b, Gprc5c or Gpr124, and that selective targeting of Gprc5b modulates their differentiation state. Taken together, single-cell profiling identifies receptors expressed on pathologically relevant subpopulations and provides a basis for the development of new therapeutic strategies in vascular diseases.
ATP-binding cassette (ABC) transporters, a superfamily of integral membrane proteins, catalyse the translocation of substrates across the cellular membrane by ATP hydrolysis. Here we demonstrate by nucleotide turnover and binding studies based on 31P solid-state NMR spectroscopy that the ABC exporter and lipid A flippase MsbA can couple ATP hydrolysis to an adenylate kinase activity, where ADP is converted into AMP and ATP. Single-point mutations reveal that both ATPase and adenylate kinase mechanisms are associated with the same conserved motifs of the nucleotide-binding domain. Based on these results, we propose a model for the coupled ATPase-adenylate kinase mechanism, involving the canonical and an additional nucleotide-binding site. We extend these findings to other prokaryotic ABC exporters, namely LmrA and TmrAB, suggesting that the coupled activities are a general feature of ABC exporters.
The title compound, C22H18N2O2, was derived from 1-(2-hydroxyphenyl)-3-(4-methoxyphenyl)propane-1,3-dione. The central pyrazole ring forms dihedral angles of 16.83 (5), 48.97 (4) and 51.68 (4)°, respectively, with the methoxyphenyl, phenyl and hydroxyphenyl rings. The crystal packing is stabilized by O-H...N hydrogen bonding. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.037; wR factor = 0.096; data-to-parameter ratio = 17.0.
Der Drömling ist mit einer Fläche von ca. 320 km2 das größte Feucht- und Niedermoorgebiet im deutschen Altpleistozän, das noch große geschlossene Niedermoorkomplexe aufweist. Das Gebiet ist Lebensraum zahlreicher seltener und vom Aussterben bedrohter Tier- und Pflanzenarten. Mit dem im Zuge der Kultivierung entstandenen umfangreichen Graben- und Stauanlagensystem und den historisch bedeutsamen Rimpau’schen Moordammkulturen ist die Drömlingsniederung zugleich eine einmalige Kulturlandschaft.
We investigate complexes of two paramagnetic metal ions Gd3+ and Mn2+ to serve as polarizing agents for solid-state dynamic nuclear polarization (DNP) of 1H, 13C, and 15N at magnetic fields of 5, 9.4, and 14.1 T. Both ions are half-integer high-spin systems with a zero-field splitting and therefore exhibit a broadening of the mS = −1/2 ↔ +1/2 central transition which scales inversely with the external field strength. We investigate experimentally the influence of the chelator molecule, strong hyperfine coupling to the metal nucleus, and deuteration of the bulk matrix on DNP properties. At small Gd-DOTA concentrations the narrow central transition allows us to polarize nuclei with small gyromagnetic ratio such as 13C and even 15N via the solid effect. We demonstrate that enhancements observed are limited by the available microwave power and that large enhancement factors of >100 (for 1H) and on the order of 1000 (for 13C) can be achieved in the saturation limit even at 80 K. At larger Gd(III) concentrations (≥10 mM) where dipolar couplings between two neighboring Gd3+ complexes become substantial a transition towards cross effect as dominating DNP mechanism is observed. Furthermore, the slow spin-diffusion between 13C and 15N, respectively, allows for temporally resolved observation of enhanced polarization spreading from nuclei close to the paramagnetic ion towards nuclei further removed. Subsequently, we present preliminary DNP experiments on ubiquitin by site-directed spin-labeling with Gd3+ chelator tags. The results hold promise towards applications of such paramagnetically labeled proteins for DNP applications in biophysical chemistry and/or structural biology.
It’s intuitively plausible to suppose that there are many things that we can be rationally certain of, at least in many contexts. The present paper argues that, given this principle of Abundancy, there is a Preface Paradox for (rational) credence. Section 1 gives a statement of the paradox, discusses its relation to its familiar counterpart for (rational) belief, and points out the congeniality between Abundancy and broadly contextualist trends in epistemology. This leads to the question whether considerations of context-sensitivity might lend themselves to solving the Preface for credence. Sections 2 and 3 scrutinize two approaches in this spirit—one mimicking Hawthorne’s (2002) Semantic Contextualist approach to an epistemic version of the Preface, the other one analogous to Clarke’s (2015) Sensitivist approach to the doxastic version—arguing that neither approach succeeds as it stands.
Protective ant-plant mutualisms that are exploited by non-defending parasitic ants represent prominent model systems for ecology and evolutionary biology. The mutualist Pseudomyrmex ferrugineus is an obligate plant-ant and fully depends on acacias for nesting space and food. The parasite Pseudomyrmex gracilis facultatively nests on acacias and uses host-derived food rewards but also external food sources. Integrative analyses of genetic microsatellite data, cuticular hydrocarbons and behavioral assays showed that an individual acacia might be inhabited by the workers of several P. gracilis queens, whereas one P. ferrugineus colony monopolizes one or more host trees. Despite these differences in social organization, neither of the species exhibited aggressive behavior among conspecific workers sharing a tree regardless of their relatedness. This lack of aggression corresponds to the high similarity of cuticular hydrocarbon profiles among ants living on the same tree. Host sharing by unrelated colonies, or the presence of several queens in a single colony are discussed as strategies by which parasite colonies could achieve the observed social organization. We argue that in ecological terms, the non-aggressive behavior of non-sibling P. gracilis workers — regardless of the route to achieve this social structure — enables this species to efficiently occupy and exploit a host plant. By contrast, single large and long-lived colonies of the mutualist P. ferrugineus monopolize individual host plants and defend them aggressively against invaders from other trees. Our findings highlight the necessity for using several methods in combination to fully understand how differing life history strategies affect social organization in ants.
Previous investigation of seismic anisotropy indicates the presence of a simple mantle flow regime beneath the Turkish-Anatolian Plateau and Arabian Plate. Numerical modeling suggests that this simple flow is a component of a large-scale global mantle flow associated with the African superplume, which plays a key role in the geodynamic framework of the Arabia-Eurasia continental collision zone. However, the extent and impact of the flow pattern farther east beneath the Iranian Plateau and Zagros remains unclear. While the relatively smoothly varying lithospheric thickness beneath the Anatolian Plateau and Arabian Plate allows progress of the simple mantle flow, the variable lithospheric thickness across the Iranian Plateau is expected to impose additional boundary conditions on the mantle flow field. In this study, for the first time, we use an unprecedented data set of seismic waveforms from a network of 245 seismic stations to examine the mantle flow pattern and lithospheric deformation over the entire region of the Iranian Plateau and Zagros by investigation of seismic anisotropy. We also examine the correlation between the pattern of seismic anisotropy, plate motion using GPS velocities and surface strain fields. Our study reveals a complex pattern of seismic anisotropy that implies a similarly complex mantle flow field. The pattern of seismic anisotropy suggests that the regional simple mantle flow beneath the Arabian Platform and eastern Turkey deflects as a circular flow around the thick Zagros lithosphere. This circular flow merges into a toroidal component beneath the NW Zagros that is likely an indicator of a lateral discontinuity in the lithosphere. Our examination also suggests that the main lithospheric deformation in the Zagros occurs as an axial shortening across the belt, whereas in the eastern Alborz and Kopeh-Dagh a belt-parallel horizontal lithospheric deformation plays a major role.
In order to elucidate what species among so many kind of marine organisms are likely to be consmed Iargely by the balaenopterid whales, the existing evidence on the food habits of baleen whales is reviewed. To meet with this primary purpose the report was mainly focussed on to describe qualitative aspects of food species having been known to date from the notable whaling grounds over the world rather than documenting quantitative subjects. One of interesting facts noticed throughout the contribution was that there exists fairly intense diversity in the assembly of food species composition by regions such as; northern hemisphere vs. southern hemisphere, Pacific region vs. Atlantic region, inshore waters vs. offshore waters, embayed waters vs. open waters, where the former usually shows more diversed complexity than the latter. The fact however suggests that although the composition of food species locally varies over the various whaling grounds, the food organisms as taxonomical groups are very similar one another even in locally isolated whaIing grounds when the food organisms and their assemblies are considered by the family or genus basis. In this connection many evidences given in the text may suggest that the balaenopterid whales as a whole may substantially live on quite simply compositioned forage assembly in comparison with tremendous variety of organisms existing in the marine ecosystems. One of important aspects of the baleen whales food must be found in their characteristics of forming dense swarms, schools, and/or aggregations in the shallower enough layers to be fed by the whales. The present and past status of larger baleen whales as the mighty monarch through their evolutional pathways may entirely depend upon the spatial distribution pattern of possible food organisms, i.e. the animal aggregations.
Objective: We sought to evaluate the efficacy and tolerability of intranasal midazolam (in‐MDZ) as first‐line inhospital therapy in patients with status epilepticus (SE) during continuous EEG recording.
Methods: Data on medical history, etiology and semiology of SE, anticonvulsive medication usage, efficacy and safety of in‐MDZ were retrospectively reviewed between 2015 and 2018. Time to end of SE regarding the administration of in‐MDZ and ß‐band effects were analyzed on EEG and with frequency analysis.
Results: In total, 42 patients (mean age: 52.7 ± 22.7 years; 23 females) were treated with a median dose of 5 mg of in‐MDZ (range: 2.5–15 mg, mean: 6.4 mg, SD: 2.6) for SE. The majority of the patients suffered from nonconvulsive SE (n = 24; 55.8%). In total, 24 (57.1%) patients were responders, as SE stopped following the administration of in‐MDZ without any other drugs being given. On average, SE ceased on EEG at 05:05 (minutes:seconds) after the application of in‐MDZ (median: 04:56; range: 00:29–14:53; SD:03:13). Frequency analysis showed an increased ß‐band on EEG after the application of in‐MDZ at 04:07 on average (median: 03:50; range: 02:20–05:40; SD: 01:09). Adverse events were recorded in six patients (14.3%), with nasal irritations present in five (11.9%) and prolonged sedation occurring in one (2.6%) patient.
Conclusions: This pharmaco‐EEG–based study showed that in‐MDZ is effective and well‐tolerated for the acute treatment of SE. EEG and clinical effects of in‐MDZ administration occurred within 04:07 and 5:05 on average. Intranasal midazolam appears to be an easily applicable and rapidly effective alternative to buccal or intramuscular application as first‐line treatment if an intravenous route is not available.
Her yeni edebî metnin kendinden öncekilerden ya ilham aldığı ya da yeniden üretilerek ortaya çıktığı gerçeği bugün edebiyat çevreleri tarafından kabul edilen bir görüştür. Sinema sanatı edebiyat ile her zaman yakın ilişki içerisinde olmuştur. Senaryolar ise edebî metinlerden beslenerek onlardan ilham almıştır ya da özgün senaryo ile edebî metin benzeşmiştir. Edebiyattan beslenen sinema böylece kendi türünü de oluşturmaya başlamıştır. Özellikle melodram türü sinema filmleri 1960 - 1975 yılları arasında Yeşilçam sinemasına hâkim olmuştur. Hamdi Değirmencioğlu'nun 1973 yılında 10. Antalya Altın Portakal Film Festivalinde kendisine ödül kazandıran "Hayat mı Bu?" adlı melodram türündeki senaryosu Grimm Kardeşlerin Halk efsanesi olan "Die zwei gleichen Söhne" ile benzerlikler taşımaktadır. Grimm Kardeşlerin 1816–1818 yılları arasında yayınlanmış olan "Deutsche Sagen" (Alman Efsaneleri) eserinde toplam 585 halk efsanesi yer almaktadır. Halk efsanesine konu olan Genç Kral Pepin / III. Pepin (714-768) tarihsel gerçek bir kişidir ve hikâyesi Alman efsaneleri arasında 441. sırada yer almaktadır. Onun hayatından yola çıkarak anne kompleksinin negatif özellikli arketipi olan üvey anne figürüne farklı bir yorum katan bu Alman halk efsanesi, Değirmencioğlu'nun senaryosunu yazdığı 1972 yapımlı Yeşilçam Sinema filmindeki üvey anne figürü ile benzeşmektedir. Bu çalışmada, Grimm Kardeşlerin "Die zwei gleichen Söhne" adlı efsanesi ile Hamdi Değirmencioğlu'nun "Hayat mı Bu?" adlı film senaryosu metinlerarasılık kuramı ile incelenmeye çalışılmıştır.
Günter Grass'ın 'Yengeç Yürüyüşü" Romanında 'Konrad' Karakterini Dijital Kuşak Olarak Çözümleme
(2021)
"Yengeç Yürüyüşü" romanında, 1945 yılında Nasyonal Sosyalist dönemde torpillenen "Wilhelm Gustloff" gemisinin batırılış öyküsüyle birlikte Pokriefke ailesinin üç kuşak üyelerinin de aile öyküsüne yer verilmiştir."Y kuşağı" teknolojiye olan yatkınlığı ile bilinirken, günümüzde "Z kuşağı", iletişim araçları olarak internet ve akıllı telefonları daha etkin bir şekilde kullanmaktadır. Bu durumda her iki dijital kuşak da iletişim teknolojilerini iyi derecede kullanan teknoloji gurusu olarak kabul edilmektedir. Dijital temelli teknolojik gelişmelerin yaşamı değiştirmeye başladığı iki binli yıllar bu bağlamda dönüm noktası olarak ele alınabilir. Romanın olay örgüsünde 1995'lere gelindiğinde genç Konrad'ın dijital iletişim aracı olarak bilgisayar kullanması sonucunda internetten beslenen antisemitizmle yollarının kesişmesinin de öyküsü anlatılır. Romanda, ben-anlatıcı Paul'un başarısız gazetecilik kariyeri, ironik bir şekilde, yetenekli bir bilgisayar kullanıcısı olan oğlu Konrad'ın Neo-Nazilerin www.blutzeuge.de sayfasını düzenli olarak ziyaret etmesi gerçeği ile bir paradox oluşturur. Baba Paul'un başarısızlığının aksine Konrad, büyükanne Tulla'nın yardımıyla bir bilgisayar edinerek ihtiyacı olan bilgiyi elde etmekte başarılı olacaktır. Ancak, istediği bilgiye kavuşan Konrad, internet aracılığıyla bir yandan başarılı araştırmalara imza atarken öte yandan da internet üzerinden tanıştığı bir genci öldürme eylemine karışır. Bu olayla Nasyonal Sosyalist döneminin ideolojik propaganda çalışmalarının Neonazizm aracılığıyla yürütülmeye devam edildiğine bir göndermede bulunulduğu söylenebilir. Bu çalışmada üçüncü kuşak aile üyesi olan Konrad'ın dijital ortamı kullanarak kendisinden önceki kuşakların hatalarını yinelediği kesitler, metin odaklı bir yaklaşımla irdelenerek örnek ve alıntılarla çözümlenmeye çalışılacaktır.