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Principles of cognitive maps
(2021)
This thesis analyses the concept of a cognitive map in the research fields of geography. Cognitive mapping research is essential as it investigates the relations between cognitive maps and external representations of space that people regularly use by acquiring spatial knowledge, such as maps in geographic information systems. Moreover, cognitive maps, when expanded on semantic maps, explain the relations between people and things in a non-physically environment, where the considered space is not spanned by distance but with other non-spatially variables. Nevertheless, cognitive maps are often distorted. Although a good formation of a cognitive map is vital in navigation processes, cognitive distortions are barely investigated in the field of geography. By analyzing the relevant work, especially Tobler’s first law of geography, a new lexical variant of Tobler’s first law could be stated that could presumably describe a specific distortion in the processing of landmarks in cognitive maps.
The myrmecophilous Paederinae rove beetle genus Megastilicus Casey, 1889 from North America is reviewed based on museum specimens. Prior to this study, the genus was monotypic with one species Megastilicus formicarius Casey, 1889 described. Here, we provide a redescription of the genus and the type species, designate a lectotype, and provide pictures of habitus and illustrations of the aedeagus and genital segments. Additionally, we describe a new species for the genus, Megastilicus iowaensis sp. nov., include an identification key to the two species and present the distribution map of both of them, including new state records. We discuss the assignment of the genus to the subtribe Stilicina based on morphological features.
Standard biorelevant media reflect the average gastrointestinal (GI) physiology in healthy volunteers. The use of biorelevant media in in vitro experiments has become an important strategy to predict drug behaviour in vivo and is often combined with in silico tools in order to simulate drug plasma profiles over time. In addition to the healthy population, the effects of disease state or co-administration of other drugs on plasma profiles must be considered to assure drug efficacy and safety. Thus, there is a need for a more accurate representation of the human GI physiology when it is altered by disease or co-administered drugs in in vitro dissolution experiments.
This thesis focused on the development of biorelevant media and dissolution tests reflecting GI physiology in circumstances where the gastric pH is elevated. Diseases linked to an elevated gastric pH are hypochlorhydria and achlorhydria, but these days treatment with acid-reducing agents (ARAs) is the single greatest cause of elevation in gastric pH. pH-dependent drug-drug interactions (DDIs) with ARAs are frequent, as the ARAs are used in a number of diseases using a variety of drugs. As the drugs currently on the market are often poorly soluble and ionisable, their dissolution is highly dependent on the pH of the GI tract, especially the gastric pH.
The thesis research consisted of several steps. In the first step, physiological changes in the human GI tract during the therapy with ARAs were identified. Parameters of the standard biorelevant gastric medium FaSSGF were adjusted to the identified changes to reflect the impact of ARA co-administration on the gastric physiology. The media aim to assess the potential extent of the ARA impact on gastric physiology by introducing biorelevant media pairs, ARA pH 4 and pH 6 media, of which one reflects a lesser, and the other a stronger impact of ARAs.
In the second step these ARA media were implemented in in vitro dissolution set-ups.
The dissolution of poorly soluble ionisable drugs was assessed using one-stage, two-stage and transfer model set-ups, as well as using a more evolved in vitro system TIM-1. Comparison of results from dissolution set-ups using the standard, low pH, gastric biorelevant medium FaSSGF (pH 1.6 or 2), and the same set-ups using ARA pH 4 and pH 6 media, shows a decrease in dissolution rate and extent for weakly basic compounds PSWB 001 and dipyridamole, and an increase in rate and extent of dissolution for the weakly acidic compound raltegravir potassium, when the gastric pH is elevated. Due to different physicochemical properties, the extent of the impact of physiological changes during ARA therapy (when either ARA pH 4 or pH 6 medium is selected) on dissolution varied among the model drugs. Thus, the bracketing approach, which considers a range of the possible ARA co-administration impact on drug dissolution, was confirmed to be best practice in assessing the impact of ARAs.
In the third step, dissolution data from in vitro experiments with ARA media was implemented into in silico models. The predictions using various in silico model approaches in Simcyp™ Simulator (minimal and full PBPK model, dissolution input using DRM and DLM) successfully bracketed in vivo data on drug administration during ARA therapy and correctly predicted an overall decrease in plasma concentration for the two model weakly basic compounds and an increase in plasma concertation for the model weakly acidic compound.
In all assessed scenarios, the ARA methods proved to be an essential part of evaluating and predicting the impact of ARAs on drug pharmacokinetics, and appropriately predicted the extent of a possible impact of ARAs on the drug plasma profiles. Thus, the ARA biorelevant media and dissolution tests were demonstrated to be valuable tools reflecting administration of drugs when the gastric pH is elevated and able to predict the impact of ARA therapy on drug administration.
The ability to evaluate the impact of human (patho) physioloy on drug behaviour in the gastrointestinal tract is of great importance, as the GI conditions play a significant role in drug release and absorption. Thus, there is great interest on the part of the pharmaceutical industry and regulatory agencies to develop best practices in this field, especially for pH-dependent DDIs. The media and dissolution tests developed in this thesis are biorelevant methods appropriate for evaluation of the impact of elevated gastric pH on drug efficacy and safety. Such methods, used as a risk assessment tool, in connection with evaluation of the efficacy window and potential toxicity, may help to increase confidence about decisions as to whether a pH-effect will occur and whether it is relevant or not, prior to conducting clinical studies. They may also enable changes in inclusion/exclusion criteria during recruiting for large-scale efficacy trials. In fact, the biopharmaceutic approach to drug development is becoming standard practice on a number of fronts, including metabolic DDIs, renal and hepatic insufficiency, powering decision-making process and possibly even waiving certain types of clinical studies.
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Selizitapia gen. nov. (Hemiptera: Fulgoromorpha: Flatidae) from tapia woodlands of Madagascar
(2021)
A new monotypic genus of flatid planthoppers (Hemiptera: Fulgoromorpha: Flatidae), Selizitapia gen. nov., is described for Selizitapia pennyi gen. et sp. nov. (type species) from the island of Madagascar. Habitus, male and female external and internal genital structures of the new species are illustrated and compared with similar taxa. Selizitapia pennyi gen. et sp. nov. is endemic to Madagascar where it is known to date only from one locality in the Central Plateau and is associated with tapia woodland formation.
Resistant microbes are a growing concern. It was estimated that about 33,000 of people die because of the infections caused by multidrug resistant bacteria each year in Europe (ECDC, 2018, https://www.ecdc.europa.eu/). Bacteria can acquire resistance against toxic compounds via different mechanisms and intrinsic active efflux is one of the first mechanisms deployed by bacterial cells. The membrane-localized efflux pumps catalysing this reaction, extract toxic compounds from the interior of the cell and transport these to the outside, thereby maintaining sub-lethal toxin levels in the cytoplasm, periplasm and membranes. Gram-negative three-component efflux pumps, analysed in this study, are composed of an inner membrane protein, a member of the Resistance-Nodulation cell Division (RND) superfamily, an Outer Membrane Factor (OMF) protein and a Membrane Fusion Protein (MFP) that connects the two afore mentioned components into an active efflux pump. The pumps described in this work, AcrAB-TolC and EmrAB-TolC, are drug efflux pumps belonging to the RND and MFS superfamilies, respectively, while CusCBA is an efflux pump that belongs to the RND heavy metal efflux family. Another efflux pump that was used as a model for the design of an in vitro assay for the silver ion transport studies, CopA, belongs to the P-type ATPase superfamily. All pumps analysed in this study are part of the resistance system of Escherichia coli, which is a highly clinically relevant pathogen.
In order to examine the AcrAB-TolC, CopA and CusA efflux pumps, the individual components were separately produced in E. coli, purified to monodispersity and reconstituted in large unilamellar vesicles, LUVs. Means for the optimized production and adequate conditions for efficient reconstitution were presented in this study. The activity of AcrB in LUVs was detected using fluorescence quenching of the dye 8-hydroxy-1,3,6 pyrenetrisulfonate (pyranine), which is incorporated inside the proteoliposomes and is sensitive to the pH changes in its surrounding. The inactive AcrB variant with a substitution in the proton relay network, D407N, showed no activity in proteoliposomes, which correlates with the measurements done in empty liposomes. When AcrA was co-reconstituted with AcrB D407N proteoliposomes it did not restore protein activity. To test the assembly of the AcrAB-TolC pump out of its single components, an in vitro assay was established where the complex assembly was tested with AcrAB- and TolC-containing liposomes. These experiments showed putative AcrAB-TolC formation in the presence or absence of a pump substrate, taurocholate, as well as in the presence of the pump inhibitor, MBX3132. The assembly appeared stable over time and results were invariant in the presence or absence of a pH gradient across the AcrAB-containing membrane.
After determination of the ATPase activity of the P-type ATPase, CopA, in detergent micelles, the protein was reconstituted in LUVs. Quenching of the Ag+-sensitive dye Phen Green SK (PGSK), present on the inside of the CopA-containing proteoliposomes, was observed in presence of ATP and Ag+. Under the same conditions, but in absence of Ag+-ions, quenching was reduced by 80 % after 300 seconds. No PGSK-quenching was observed in control liposomes in the presence of ATP and Ag+. The additional presence of sodium azide led to minimal reduction of the PGSK-quenching as expected since sodium azide is not an inhibitor of P-type ATPases, but the quenching rate was similar to that of the same experimental condition with control liposomes.
The RND superfamily member CusA, as part of the tripartite CusCBA efflux pump, has been proposed to sequester Ag+ or Cu+ from either the cytoplasmic or periplasmic side of the inner membrane. The periplasmic transport of silver ions was implied from an in vitro assay where the quenching of a pH sensitive dye, 9-amino-6-chloro-2-methoxyacridine (ACMA), indicates acidification of the lumen of the proteoliposomes containing CusA when an inwardly directed pH was imposed. The same experiment with the CusA D405N variant, which was previously reported to be an inactive variant, also led to ACMA quenching, although at a slightly lower rate. Under application of an inwardly directed pH and a (negative inside), CusA-containing proteoliposomes showed a strong quenching of the incorporated PGSK dye, suggesting strong Ag+ influx.
The Major Facilitator Superfamily-(MFS-) type EmrAB-TolC pump has an analogous structural setup as the RND-type AcrAB-TolC pump. To examine the efflux of one of its substrates, carbonyl - cyanide m-chlorophenylhydrazone (CCCP), a plate-based susceptibility assay was used. The presence of the EmrAB-TolC pump confers lower susceptibility levels towards CCCP in E. coli, compared to cells not expressing the pump or cells expressing only the MFS component, indicating that EmrAB-TolC extrudes CCCP.
The work done in this study opens up a path towards investigation of drug and metal resistance in vitro. The methodologies to obtain proteoliposomal samples of multicomponent efflux pumps and subsequent measurements of drug/metal ion and H+ fluxes, as well as the determination of pump assembly are crucial for the future research on pump catalysis and transport kinetics. The in vivo drug-plate assays done in this work provide initial insights for future investigations of the drug susceptibility of E. coli expressing the MFS-type tripartite efflux pumps.
Terahertz (THz) technology is an emerging field that considers the radiation between microwave and far-infrared regions where the electronic and photonic technologies merge. THz generation and THz sensing technologies should fill the gap between photonics and electronics which is defined as a region where THz generation power and THz sensing capabilities are at a low technology readiness level (TRL). As one of the options for THz detection technology, field-effect transistors with integrated antennae were suggested to be used as THz detectors in the 1990s by M. Dyakonov and M. Shur from where the development of field-effect transistor-based detector began. In this work, various FET technologies are presented, such as CMOS, AlGaN/GaN, and graphene-based material systems and their further sensitivity enhancement in order to reach the performance of well-developed Schottky diode-based THz sensing technology. Here presented FET-based detectors were explored in a wide frequency range from 0.1 THz up to 5 THz in narrowband and broadband configurations.
For proper implementation of THz detectors, the well-defined characterization is of high importance. Therefore, this work overviews the characterization methods, establishes various definitions of detector parameters, and summarizes the state-of-the-art THz detectors. The electrical, optical, and cryogenic characterization techniques are also presented here, as well as the best results obtained by the development of the characterization methods, namely graphene FET stabilization, low-power THz source characterization for detector calibration, and technology development for cryogenic detection.
Following the discussion about the detector characterization, a wide range of THz applications, which were tested during the last four years of Ph.D. and conducted under the ITN CELTA project from HORIZON2020 program, are presented in this work. The studies began with spectroscopy applications and imaging and later developed towards hyperspectral imaging and even passive imaging of human body THz radiation. As various options for THz applications, single-pixel detectors as well as multi-pixel arrays are also covered in this work.
The conducted research shows that FET-based detectors can be used for spectroscopy applications or be easily adapted for the relevant frequency range. State-of-the-art detectors considered in this work reach the resonant performance below 20 pW/√Hz at 0.3 THz and 0.5 THz, as well as 404 pW/√Hz cross-sectional NEP at 4.75 THz. The broadband detectors show NEP as low as 25 pW/√Hz at around 0.6 THz for the best AlGaN/GaN design and 25 pW/√Hz around 1 THz for the best CMOS design. As one of the most promising applications, metamaterial characterization was tested using the most sensitive devices. Furthermore, one of the single-pixel devices and a multi-pixel array were tested as an engineering solution for a radio astronomy system called GREAT in a stratosphere observatory named SOFIA. The exploration of the autocorrelation technique using FET-based devices shows the opportunity to employ such detectors for direct detection of THz pulses without an interferometric measurement setup.
This work also considers imaging applications, which include near-field and far-field visualization solutions. A considerable milestone for the theory of FET technology was achieved when scanning near-field microscopy led to the visualization of plasma (or carrier density) waves in a graphene FET channel. Whereas another important milestone for the THz technology was achieved when a 3D scan of a mobile phone was performed under the far-field imaging mode. Even though the imaging was done through the phone’s plastic cover, the image displayed high accuracy and good feature recognition of the smartphone, inching the FET-based detector technology ever so close to practical security applications. In parallel, the multi-pixel array testing was carried out on 6x7 pixel arrays that have been implemented in configurable-size aperture and imaging configurations. The configurable aperture size allowed the easier detector focusing procedure and a better fit for the beam size of the incident radiation. The imaging has been tested on various THz sources and compared to the TeraSense 16x16 pixel array. The experimental results show the big advantage of the developed multi-pixel array against the used commercial technology.
Furthermore, two ultra-low-power applications have been successfully tested. The application on hyper-frequency THz imaging tested in the specially developed dual frequency comb and our detector system for 300 GHz radiation with 9 spectral lines led to outstanding imaging results on various materials. The passive imaging of human body radiation was conducted using the most sensitive broadband CMOS detector with a log-spiral antenna working in the 0.1 – 1.5 THz range and reaching the optical NEP of 42 pW/√Hz. The NETD of this device reaches 2.1 K and overcomes the performance limit of passive room-temperature imaging of the human body radiation, which was less than 10 K above the room temperature. This experiment opened a completely new field that was explored before only by the multiplier chain-based or thermal detectors.
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Three subterranean leptodirine leiodid taxa, viz., Bozidaria Ćurčić & Pavićević gen. nov., Bozidaria serbooccidentalis Ćurčić & Pavićević gen. et sp. nov. and Proleonhardella (Proleonhardella) tarensis Ćurčić & Pavićević sp. nov., are described and diagnosed. Bozidaria Ćurčić & Pavićević gen. nov. belongs to the phyletic series of “Leonhardella”. The new beetle taxa differ from their closest relatives in numerous morphological characters. They most likely belong to phyletic lineages of Pliocene age. The new leiodid taxa are endemic to the Dinaric mountain chain of western Serbia. Keys to the leptodirine leiodid genera of the phyletic series of “Leonhardella” and to the taxa of the genus Proleonhardella Jeannel, 1910 are included.
Dieser Beitrag beschäftigt sich mit sprachbezogenen Witzen und ihrem konkreten Einsatz im Deutsch als Fremdsprachenunterricht. Der Fokus dieses Beitrags liegt auf der Empfehlung von Anwendungsbeispielen für die Nutzung von sprachbezogenen Witzen im DaF-Unterricht, die das vorrangige Ziel der Beschäftigung mit Stereotypen und der Entwicklung einer interkulturellen Kompetenz anstreben. Hierzu wird vorerst klargestellt was mit dem Begriff Witz gemeint wird, insbesondere, was als "sprachbezogener Witz" in der Studie angesehen wird. Im Nachhinein wird auf die Bedeutung des Einsatzes von Witzen im Fremdsprachenunterricht eingegangen, sodass der Bedarf und Grund für die Anwendung dargelegt werden kann. Zur Lieferung adäquater Antworten auf die Forschungsfragen soll der Forschungsstand beschrieben werden und im praktischen Teil sollen Witze aus verschiedenen online Quellen ausgesucht und bewertet werden, die das Thema "Sprache" vorweisen. Die Witze wurden zum Schluss als jeweils ein Didaktisierungsvorschlag erarbeitet. Mit den Didaktisierungsvorschlägen wurde aufgezeigt, dass sprachbezogene Witze sich für die Entwicklung einer interkulturellen Kompetenz, durch die Beschäftigung mit Stereotypen und Vorurteilen im DaF-Unterricht, sehr gut eignen können. Die Didaktisierungsvorschläge wurden nach dem Modell "Didaktische Analyse" erstellt.
Bu çalışmada Turizm Fakültesi öğrencilerinin seçmeli yabancı dil derslerine (Almanca, Fransızca ve İtalyanca) yönelik kaygı düzeylerinin çeşitli değişkenlere göre incelenmesi amaçlanmaktadır. Araştırmada nicel araştırma yöntemlerinden tarama modeli kullanılmıştır. Araştırmanın evrenini Türkiye'de Turizm Fakültelerinde eğitim alan öğrenciler oluşturmaktadır. Araştırmanın örneklemini ise bir devlet üniversitesinin Turizm Fakültesinde eğitim alan ikinci, üçüncü ve dördüncü sınıf öğrencileri oluşturmaktadır. Araştırmaya toplam 141 öğrenci katılmıştır. Katılımcıların %46,1'i kadın, %53,9'u ise erkektir. Çalışmada veri toplama araçları olarak araştırmacı tarafından oluşturulan kişisel bilgi formu ile Horwitz, Horwitz ve Cope (1986) tarafından geliştirilmiş "yabancı dil dersi kaygı ölçeği" kullanılmıştır. Ölçek 33 madde ve 3 alt boyuttan oluşmaktadır. Araştırmada yer alan verilerin analizinde SPSS 22 paket programı kullanılmıştır. Örnekleme ait istatistikler frekans analiz ile hesaplanmıştır. Bağımsız değişkenlerin hesaplanmasında t-testi ve tek yönlü varyans analizi (ANOVA) testleri kullanılmıştır. Tüm hesaplamalarda anlamlılık düzeyi p<,05 olarak kabul edilmiştir. Araştırmanın sonucunda, “dil dersinde konuşma kaygısı” boyutunda erkek öğrencilerin kadın öğrencilere göre daha kaygılı oldukları; eğitim alınan bölüm değişkenine bağlı olarak "dil dersine yönelik ilgi" ve "yabancılarla konuşma kaygısı" boyutlarında anlamlı bir şekilde farklılaştığı; eğitim alınan sınıf düzeyi değişkenine göre herhangi bir farka rastlanmadığı; seçilen yabancı dil değişkenine bağlı olarak yalnızca "yabancılarla konuşma kaygısı" boyutunda anlamlı şekilde farklılaştığı; başarı durumu değişkenine göre bir farka rastlanmadığı ve mezuniyet sonrası plan değişkenine bağlı olarak ise yalnızca "dil dersinde konuşma kaygısı" boyutunda anlamlı farklılık gösterdiği ortaya konmuştur.
"Öğrenci Törless'in bunalımları" : 20. yüzyıl başındaki eğitim sorunsalı ve Hitler'in ayak sesleri
(2021)
Robert Musil (1880-1942), modern roman türünün oluşumuna ve gelişimine önemli katkıları olan, 20. yüzyılda Avusturya Edebiyatı'nın en önde gelen yazarlarındandır. Eserlerinde 20. yüzyıl başındaki dönüşümü ve bu dönüşümün birey ve toplum üzerindeki etkilerini konu edinmektedir. 1906 yılında yayınlanan ilk romanı "Öğrenci Törless'in Bunalımları'nda" da içinde yaşanılan dönemin ve sınıf farkının eğitime yansıması, eğitim ve yatılı okul sisteminin insanlıkla bağdaşmayan yanları, buna bağlı olarak genç ve yaratıcı bireylerin sorunları ve otonom gelişimlerinin engellenmesi gibi konular ele alınmıştır. Ayrıca eserde yüzyıl başındaki dönüşüme paralel olarak toplumda yavaş yavaş hissedilmeye başlanan faşizmin ayak sesleri konu edinilmiştir. Bu çalışmada, 20. yüzyıl başındaki modernist dönüşümün eğitim ve okul sistemi üzerindeki izleri gün ışığına çıkarılmaya ve Hitler ekolünün alttan alta gelişi gösterilmeye çalışılmıştır. Bu vesileyle çalışmamızın özellikle o dönemdeki eğitim sorunsalı ve Hitler zihniyetinin doğuşu üzerine yapılacak çalışmalara bir rehber olması amaçlanmıştır. Araştırma sürecinde metne bağlı, yorum bilimine dayalı inceleme yöntemlerine ve yer yer de metinlerarasılık yöntemine başvurulmuştur.
Hitaplar gerek formal konuşmada gerekse informal dilde belirleyici bir özelliğe sahiptir. Hitaplar konuşmaya, yazmaya veya herhangi bir yazılı belgeye başlarken kullanılan ve göndericinin alıcıya yönelik bakış açısını belirten dilsel ifadelerdir. Hitap edilen kişi veya gruplar muhatap olarak adlandırılır. Selamlama ve hitap araştırmalarında, bir muhataba hitap ederken kullanılan dilsel araçlara hitap biçimleri denir. Dilsel hitap biçimleri, ad ve zamir kategorisine ayrılabilir. Ad kategorisindeki hitap türleri isimlerin, mesleki ve diğer unvanların kullanımını içerir. Hitapların zamir biçimleri kendilerini şahıs zamirlerinde gösterir. Zamirlerin bir alt sınıfı olarak, şahıs zamirleri gönderene veya kişilere atıfta bulunur. Dilsel iletişim hitaplar ile başlar. Herhangi bir konu hakkında birisiyle birdenbire konuşmaya başlamamak toplumsal uzlaşımın bir parçasıdır. Bu bağlamda hitaplar yaşamın her anında yer bulmaktadır. Bu makalede, Türk ve Alman dijital ortamlarda kadınların hitap ifadelerinin incelenmesi amaçlanmaktadır. İnternet günümüzde toplumun h er alanındaki insanların zorunlu bir alışkanlığı haline gelmiştir. Toplumdaki bireyler etkileşimlerini büyük oranda internet aracılığı ile gerçekleştirmekte, sosyal medyayı takip ederek merak ettikleri konular hakkında fikir sahibi olabilmektedirler. Toplumda, arasında kadınların da önemli bir yere sahip olduğu büyük bir kesim günün her anında sosyal medya üzerinden iletişim kurmakta, kurdukları her tür iletişimde farklı hitap türleri sergilemektedir. Bu çalışma, kullandıkları hitaplar açısından kadınların dilsel davranışlarını içermektedir. Bilindiği gibi kadınlar ve erkekler birçok açıdan ayrıdırlar. Kadın ve erkekler arasındaki bu farklılıklar kendine dijital ortamda da yer bulmaktadır. Makalenin birinci bölümünü oluşturan kuramsal kısımda, hitapların tanımından yola çıkılarak konunun ayrıntıları ortaya konacaktır. Çalışmanın uygulama bölümünde, Türkçe ve Almancadaki sosyal medya metinleri her iki dilde hitaplar açısından karşılaştırılarak incelenecektir. Elde edilen veriler kadınların iki dildeki hitap kullanımı bağlamında değerlendirilecektir. Bu değerlendirme sonucunda Türkçe ve Almancada kadın dilinin hitaplar açısından nasıl bir kullanım alanının olduğu görülecek, her iki dilde ne tür farklılıklar ve benzerliklerin gözlemlenebildiği sonucuna ulaşılacaktır. Çalışmada Türkçe ve Almanca hitaplar karşılaştırılacağından inceleme genel olarak kontrastif söylem analizi ve deskriptif-analitik yöntemler doğrultusunda karma bir yöntem ile yürütülecektir.
2000’li yılların başından itibaren gençler sorunlarını, sevinçlerini, fikirlerini, hayat görüşlerini, yaşam tarzlarını pek çok farklı dijital platformda farklı kültürlerdeki ve ülkelerdeki gençler ile paylaşabilmektedir. Bu şekilde kendine has yeni bir yaşam felsefesi oluşturan ve Z-Kuşağı olarak anılan bir kuşak ortaya çıkmıştır. Bu çalışma, özellikle 2000 yılından sonra yazılmış olan Alman gençlik edebiyatı eserlerinden bazılarının örneklem olarak ele alınmasıyla bir alanyazın taraması yapmayı hedeflemektedir. Bu sayede Alman gençlik edebiyatında ele alınan konuların neler olduğu, hangi sebeplerden dolayı bu konuların ele alınmış olabileceği ortaya konmaya çalışılmıştır. İkincil hedef ise çalışmanın sonuç kısmında Türkiye’deki gençlik edebiyatı alanına ilişkin önerilerde bulunmaktır. Çalışmadan elde edilen sonuca göre Alman gençlik edebiyatında sıklıkla arkadaş ilişkileri, toplum içerisinde kimlik arayışı, okulu terk etme, uyuşturucu kullanımı ve doğurduğu sonuçlar, adaletsizlik, aile içi iletişim sorunları, ebeveyni ayrı olan gençlerin hikâyeleri, Cyber-Mobbing, aşk, bilimkurgu, göç, kültürlerarasılık, suç gibi konularının aktarıldığı tespit edilmiştir.
The methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme in acetogenic CO2 fixation. The MetVF-type enzyme has been purified from four different species and the physiological electron donor was hypothesized to be reduced ferredoxin. We have purified the MTHFR from Clostridium ljungdahlii to apparent homogeneity. It is a dimer consisting of two of MetVF heterodimers, has 14.9 ± 0.2 mol iron per mol enzyme, 16.2 ± 1.0 mol acid-labile sulfur per mol enzyme, and contains 1.87 mol FMN per mol dimeric heterodimer. NADH and NADPH were not used as electron donor, but reduced ferredoxin was. Based on the published electron carrier specificities for Clostridium formicoaceticum, Thermoanaerobacter kivui, Eubacterium callanderi, and Clostridium aceticum, we provide evidence using metabolic models that reduced ferredoxin cannot be the physiological electron donor in vivo, since growth by acetogenesis from H2 + CO2 has a negative ATP yield. We discuss the possible basis for the discrepancy between in vitro and in vivo functions and present a model how the MetVF-type MTHFR can be incorporated into the metabolism, leading to a positive ATP yield. This model is also applicable to acetogenesis from other substrates and proves to be feasible also to the Ech-containing acetogen T. kivui as well as to methanol metabolism in E. callanderi.
The relations between Turkey and Germany have a long history that involves collaboration and partnership in many areas. After 1960s, this relationship gained a new dimension as hundreds of thousands of Turkish workers immigrated to Germany. This paper presents a brief history of the relations between the two countries, and the cultural and language-related problems experienced by Turkish people in Germany. More specifically, it focuses on the background and current state of the Turkish Language and Culture course taught to the Turkish youth in German schools. Problems regarding the implementation of this course are discussed with reference to official statistics. Finally, suggestions are offered to address the challenges faced to improve the Turkish Language and Culture course so that Turkish children can successfully learn their origin-language, and eventually achieve competence in both Turkish and German in their academic studies.
The Tanaidacea are ubiquitous and amongst the most abundant taxa in the deep sea. However, their diversity in submarine canyons remains largely unknown. Here, two new species and a new genus of Paratanaoidea are described. Paranarthrura cousteaui sp. nov. is distinguished by the combination of the following characters: post-cheliped sclerites not fused, presence of one seta in the maxilliped endite, one long midventral seta in cheliped, one penicillate seta in the basis of pereopods 4–6, uropod endopod bi-articulated and uropod exopod shorter than endopod article 1. This species was found at the upper reaches of three Portuguese canyons, Cascais, Setúbal and Nazaré Canyons, and the adjacent open slope, between 897 and 1001 m water depths. Tirana vallis gen. et sp. nov. presents a combination of the characters that define the other two genera of Paranarthrurellidae, Paranarthrurella and Armatognathia, but also unique characters within the family: the antenna, cheliped and uropod are more elongate than the rest of the species; the pereopods 4–6 carpus spines reach at least half of the length of the propodus and the propodus of pereopods 4–6 have ramified subdistal spines. This species was found at the middle reaches of Setúbal Canyon (3214–3219 m water depth).
Background: Through the rapid development in DNA sequencing methods and tools, microbiome studies on a various number of species were performed during the last decade. This advance makes it possible to analyze hundreds of samples from different species at the same time in order to obtain a general overview of the microbiota. However, there is still uncertainty on the variability of the microbiota of different animal orders and on whether certain bacteria within a species are subject to greater fluctuations than others. This is largely due to the fact that the analysis in most extensive comparative studies is based on only a few samples per species or per study site. In our study, we aim to close this knowledge gap by analyzing multiple individual samples per species including two carnivore suborders Canoidea and Feloidea as well as the orders of herbivore Perissodactyla and Artiodactyla held in different zoos. To assess microbial diversity, 621 fecal samples from 31 species were characterized by sequencing the V3–V4 region of the 16S rRNA gene using Illumina MiSeq.
Results: We found significant differences in the consistency of microbiota composition and in fecal microbial diversity between carnivore and herbivore species. Whereas the microbiota of Carnivora is highly variable and inconsistent within and between species, Perissodactyla and Ruminantia show fewer differences across species boundaries. Furthermore, low-abundance bacterial families show higher fluctuations in the fecal microbiota than high-abundance ones.
Conclusions: Our data suggest that microbial diversity is significantly higher in herbivores than in carnivores, whereas the microbiota in carnivores, unlike in herbivores, varies widely even within species. This high variability has methodological implications and underlines the need to analyze a minimum amount of about 10 samples per species. In our study, we found considerable differences in the occurrence of different bacterial families when looking at just three and six samples. However, from a sample number of 10 onwards, these within-species fluctuations balanced out in most cases and led to constant and more reliable results.
Hintergrund
In Anbetracht ihres bedeutenden Potenzials zur Verbesserung der medizinischen Versorgung wird Telemedizin weiterhin zu wenig genutzt. Trotz einiger erfolgreicher Pilotprojekte in den vergangenen Jahren ist insbesondere über die Hindernisse der Etablierung und Verstetigung von Telemedizin wenig bekannt. Diese Studie hatte das Ziel, die Einstellung niedergelassener Neurologen hinsichtlich der Nutzung von Telemedizin in der Epileptologie und resultierende Hinderungsgründe zu verstehen. Gleichzeitig werden mögliche Lösungsansätze präsentiert.
Methoden
Mithilfe eines individuell erstellten 14-Item-Fragebogens befragten wir prospektiv alle Neurologen, die zuvor die Teilnahme an einem transregionalen Telemedizinpilotprojekt im Bereich der Epileptologie abgelehnt oder keine Rückmeldung gegeben hatten, zu Gründen für und gegen den generellen Einsatz von bzw. die Teilnahme an Telemedizin.
Ergebnisse
Von 58 kontaktierten Neurologen antworteten 33 (57 %). Die häufigsten Gründe für die fehlende Nutzung der Telemedizin waren ein vermuteter Zeitmangel oder ein vermuteter zu großer organisatorischer Aufwand (49 %). Zudem wurden Bedenken bezüglich der technischen Ausstattung (30 %) und eine Präferenz für alternative Wege der intersektoralen Kommunikation (30 %) angegeben. Befürchtete Probleme in Bezug auf die Kostenerstattung für telemedizinische Leistungen waren für 27 % ein Hindernis. Neurologen in ländlichen Gebieten waren signifikant häufiger bereit, zunächst eine telemedizinische Konsultation anzufordern, bevor sie eine Überweisung ausstellen (p = 0,006).
Schlussfolgerungen
Die flächendeckende Etablierung von Telemedizinstrukturen ist immer noch durch Hindernisse erschwert, die meist im organisatorischen Bereich liegen. Die bestehenden Herausforderungen im Gesundheitswesen in ländlichen Gebieten sind eine besondere Chance für die Implementierung von Telemedizin. Die meisten Probleme der Telemedizin können gelöst werden, sollten aber bereits bei der Konzeptionierung von Projekten mitbedacht werden, um ihre Verstetigung zu erleichtern.
Background: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC.
Methods: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019).
Results: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533–7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780–1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503–3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs.
Conclusions: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting. Trial registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.
The COVID-19 lockdown has significantly disrupted the higher education environment within the Netherlands and led to changes in available study-related resources and study demands of students. These changes in study resources and study demands, the uncertainty and confusion about educational activities, the developing fear and anxiety about the disease, and the implementation of the COVID-19 lockdown measures may have a significant impact on the mental health of students. As such, this study aimed to investigate the trajectory patterns, rate of change, and longitudinal associations between study resources–demands and mental health of 141 university students from the Netherlands before and during the COVID-19 lockdown. The present study employed a longitudinal design and a piecewise latent growth modeling strategy to investigate the changes in study resources and mental health over a 3 month period. The results showed that moderate levels of student resources significantly decreased before, followed by a substantial rate of increase during, lockdown. In contrast, study demands and mental health were reported to be moderate and stable throughout the study. Finally, the growth trajectories of study resources–demands and mental health were only associated before the lockdown procedures were implemented. Despite growing concerns relating to the negative psychological impact of COVID-19 on students, our study shows that the mental health during the initial COVID-19 lockdown remained relatively unchanged.
The strengths use scale: psychometric properties, longitudinal invariance and criterion validity
(2021)
Strengths use is an essential personal resource to consider when designing higher-educational programs and interventions. Strengths use is associated with positive outcomes for both the student (e.g., study engagement) and the university (e.g., academic throughput/performance). The Strengths Use Scale (SUS) has become a popular psychometric instrument to measure strengths use in educational settings, yet its use has been subjected to limited psychometric scrutiny outside of the U.S. Further, its longitudinal stability has not yet been established. Given the wide use of this instrument, the goals of this study were to investigate (a) longitudinal factorial validity and the internal consistency of the scale, (b) its equivalence over time, and (c) criterion validity through its relationship with study engagement over time. Data were gathered at two-time points, 3 months apart, from a sample of students in the Netherlands (n = 360). Longitudinal confirmatory factor analyses showed support for a two-factor model for overall strengths use, comprised of Affinity for Strengths and Strengths Use Behaviors. The SUS demonstrated high levels of internal consistency at both the lower- and upper bound limits at both time points. Further, strict longitudinal measurement invariance was established, which confirmed the instrument's temporal stability. Finally, criterion validity was established through relating strengths use to study engagement at different time stamps. These findings support the use of the SUS in practice to measure strengths use and to track the effectiveness of strengths use interventions within the higher education sector.
The constitution and regulation of effector repertoires shape host–microbe interactions. Ustilago maydis and Sporisorium reilianum are two closely related smut fungi, which both infect maize but cause distinct disease symptoms. Understanding how effector orthologs are regulated in these two pathogens can therefore provide insights into the evolution of different infection strategies. We tracked the infection progress of U. maydis and S. reilianum in maize leaves and used two distinct infection stages for cross-species RNA-sequencing analyses. We identified 207 of 335 one-to-one effector orthologs as differentially regulated during host colonization, which might reflect the distinct disease development strategies. Using CRISPR-Cas9-mediated gene conversion, we identified two differentially expressed effector orthologs with conserved function between two pathogens. Thus, differential expression of functionally conserved genes might contribute to species-specific adaptation and symptom development. Interestingly, another differentially expressed orthogroup (UMAG_05318/Sr10075) showed divergent protein function, providing a possible case for neofunctionalization. Collectively, we demonstrated that the diversification of effector genes in related pathogens can be caused both by alteration on the transcriptional level and through functional diversification of the encoded effector proteins.
Aim: Comparison of the clinical efficacy (digitally volumetric, aesthetic, patient-centred outcomes) of tunnel technique (TUN) with subepithelial connective tissue graft (CTG) versus coronally advanced flap (CAF) with enamel matrix derivate (EMD) 5 years after gingival recession therapy. Materials and methods: In 18 patients contributing 36 RT1 recessions, study models were collected at baseline and follow-ups. Optical scans assessed recessions computer-assisted [recession depth, recession reduction (RECred), complete root coverage (CRC), percentage of root coverage (RC), pointwise (pTHK) and mean areal (aTHK) marginal soft tissue thickness]. Root coverage aesthetic Score (RES) was used for aesthetic evaluation and visual analogue scales for patient-centred data collection applied. Results: Sixty months after surgery, 50.0% (TUN+CTG) and 0.0% (CAF+EMD) of sites showed CRC (p = 0.0118), 82.2% (TUN+CTG) and 32.0% (CAF+EMD) achieved RC, respectively (p = 0.0023). CTG achieved significantly better RECred (TUN+CTG: 1.75±0.74 mm; CAF+EMD: 0.50 ± 0.39 mm; p = 0.0009) and aTHK (TUN+CTG: 0.95 ± 0.41 mm; CAF+EMD: 0.26 ± 0.28 mm; p = 0.0013). RES showed superior outcomes (p = 0.0533) for TUN+CTG (6.86 ± 2.31) compared to CAF+EMD (4.63 ± 1.99). The study failed to find significant differences related to patient-centred outcomes (TUN+CTG: 8.30 ± 2.21; CAF+EMD: 7.50 ± 1.51; p = 0.1136). Conclusions: Five years after treatment, CTG resulted in better clinical and aesthetic outcomes than CAF+EMD. Increased THK was associated with improved outcomes for RECred and RC.
The genus Trypheridium Brancucci, 1985 is endemic to the Hindu Kush Himalayan Region, and is currently known from a single species, T. nuristanicum (Wittmer, 1956). Here, the genus is reviewed, T. nuristanicum nom. emend. is re-described and T. kashmiricum sp. nov. is described from Kashmir Himalayan Region of India. Descriptions, diagnoses, high quality images, distribution maps and identification keys are presented. The morphology and distribution of Trypheridium are discussed and compared with those of the closely related genus Trypherus LeConte, 1851.
The article is about mediating an involvement in the development of the Rosswald Castle Theater between 1750 and 1760. Attention is paid to the theater repertoire and the representation of the artistic atmosphere in the Rosswald Castle. Last but not least, the article outlines the role of the Rosswald sentimental garden, in which the dramas, operas and ballet performances were also located. The article points to the incorporation of creative impulses of Enlightenment into the repertoire of the Rosswald cultural scene. The focus of the investigation is on the activity of Johann Heinrich Friedrich Müller, who implemented the dramatic rules of the Enlightenment in the Rosswald Castle Theater.
Correspondence study field experiments with political elites are a recent addition to legislative studies research, in which unsolicited emails are sent to elites to gauge their responsiveness. In this article, we discuss their ethical implications. We advance from the viewpoint that correspondence study field experiments involve trade-offs between costs and benefits that need to be carefully weighted. We elaborate this argument with two contributions in mind. First, we synthesize ethical considerations in published work to explore what the specific trade-offs are and how they can be mitigated by experimental design. We conclude that correspondence study field experiments with political elites are worth pursuing given their potential to further good governance. But they also involve distinct trade-offs that are particularly challenging. Second, we draw from our own considerations while designing a comparative correspondence study field experiment and stress challenges resulting from cross-national designs. In sum, we aim to facilitate further reasoned discussion on an important methodological issue.
Das kolorektale Karzinom stellt die zweithäufigste Krebstodesursache bei Männern und Frauen in der Bundesrepublik Deutschland dar
Das CRC hat aus diesem Grund eine große Bedeutung in chirurgischen und radiologischen Fachgebieten. Hierbei spielen zahlreiche Verfahren und Behandlungsmethoden eine zentrale Rolle, um das CRC und die hiervon ausgehenden kolorektalen Lebermetastasen zu behandeln und eine bestmögliche Therapie zu evaluieren. Über die letzten Jahrzehnte haben sich daher viele verschiedene Methoden für die Behandlung von CRLMs entwickelt, wie Mikrowellenablation (MWA), laserinduzierte interstitielle Thermotherapie (LITT), Radiofrequenzablation (RFA) und das chirurgische Vorgehen. Die vielversprechendste unter den Techniken und Verfahren stellt die chirurgische Resektion dar. Problematisch ist hierbei, dass viele erkrankte Patienten keine ausreichend gute körperliche Verfassung mehr aufweisen, um eine Resektion ohne große Risiken durchführen zu können.
Das Hauptziel dieser Studie war es nun, eine möglichst genaue und
aussagekräftige Untersuchung von Patientengruppen durchzuführen, bei denen eine kolorektale Lebermetastase diagnostiziert wurde. In der vorliegenden Studie wurden 132 Patienten mit kolorektalen Lebermetastasen (CRLM) untersucht, welche zwischen 2010 und 2018 mit einer CT-gesteuerten MWA-Therapie im Institut für Diagnostische und Interventionelle Radiologie des Universitätsklinikums in Frankfurt am Main behandelt wurden. Hierbei war von besonderer Bedeutung, welche prognostischen Parameter die Überlebenszeiten und Überlebensraten beeinflussen. Die Daten konnten anhand von vielfältigen Personendaten und den dazugehörigen Therapieverläufen erhoben werden. Außerdem wurden CT-Bilder, welche im Zuge der Behandlung entstanden waren, für die Erhebung zusätzlicher Parameter verwendet. Die erhobenen Daten und Messwerte wurden retrospektiv ermittelt und umfassten eine große Patientengruppe. Dies steigert die Aussagekraft der Ergebnisse und Kennzahlen wesentlich. Ein besonderes Augenmerk lag auf der Einteilung der Patienten in zwei Gruppen entsprechend ihrer Behandlungsindikation.
Zu den prognostischen Faktoren zählten das Ablationssystem, die Lokation der Metastasen, die Anzahl der Metastasen, der technische Erfolg, die Energie und Leistung, der Durchmesser und das Volumen der Metastasen, die Vor- und Nachbehandlung und die Lokalrezidive.
Die Patientengruppe mit palliativer Therapieindikation (1.08 Jahre) zeigte eine signifikant geringere mediane Überlebenszeit im Vergleich mit der kurativen Patientengruppe (3.48 Jahre). Die mediane Überlebenszeit aller Patienten betrug insgesamt 2.68 Jahre. Zusätzlich wurden die Überlebensraten der Patienten ermittelt. Die 1- und 3-Jahres-Überlebensraten aller behandelten Patienten im Untersuchungszeitraum lagen bei 82.7% und 41.6%. Die 1- und 3-JahresÜberlebensraten der 57 Patienten mit palliativer Behandlungsindikation waren 54.4% und 14.9%. Im Vergleich hierzu betrugen die 1- und 3-JahresÜberlebensraten der kurativ behandelten Patientengruppe 96.9% und 55.1%. Die mediane Beobachtungszeit nach der Behandlung betrug 2.39 Jahre. In dieser Zeit erreichten 96.2% aller Patienten eine lokale Tumorkontrolle (127/132). Die Überlebenszeit von Patienten mit einer, zwei oder drei, vier oder fünf und multiplen Lebermetastasen betrug 3.79, 2.13, 1.09 und 0.93 Jahre (alle p<0,017). Es gab eine einzige relevante Komplikation (Abszess) bei allen Behandlungen (1/257; 0,4%). Alle Unterschiede der Überlebenszeiten im primären Tumorursprung (p <0,038) und bei der Anzahl der Metastasen waren signifikant. Die anderen prognostischen Faktoren zeigten keine statistische Signifikanz. Prognostische Faktoren wie die Anzahl der Lebermetastasen, die Lokation des Primärtumors und das verwendete Ablationssystem haben einen bedeutenden Einfluss auf die Überlebenszeiten der CRLM-Patienten in dieser Studie gezeigt. Die Ergebnisse dieser Studie sind als vornehmlich anzusehen, weil eine strenge Zuteilung der Patienten in kurative und palliative Behandlungsindikationen für die Analyse der Überlebensdaten in dieser Form bis zu diesem Zeitpunkt nicht durchgeführt worden war.
Die Prognosefaktoren und deren Einfluss auf die Überlebenszeiten stellen für zukünftige radiologische Prognosen und Therapiemaßnahmen in Bezug auf CRLM Patienten gute Richtwerte dar. Sowohl für die Radiologen und Ärzte als auch für die Patienten und Angehörigen sind dies zukunftsweisende Anhaltspunkte.
Background and Objectives: We tested if a novel combination of predictors could improve the accuracy of outcome prediction after transfemoral transcatheter aortic valve implantation (TAVI). Materials and Methods: This prospective study recruited 169 participants (49% female; median age 81 years). The primary endpoint was midterm mortality; secondary endpoints were acute Valve Academic Research Consortium (VARC)-3 complication rate and post-TAVI in-hospital length of stay (LoS). EuroSCORE II (ESII), comorbidities (e.g., coronary artery disease), eGFR (estimated glomerular filtration rate; based on cystatin C), hemoglobin, creatinine, N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels and patient-reported outcome measures (PROMs, namely EuroQol-5-Dimension-5-Levels, EQ5D5L; Kansas City Cardiomyopathy Questionnaire, KCCQ; clinical frailty scale, CFS) at baseline were tested as predictors. Regression (uni- and multi-variate Cox; linear; binary logistic) and receiver operating characteristic (ROC)-curve analysis were applied. Results: Within a median follow-up of 439 (318–585) days, 12 participants died (7.1%). Independent predictors of mortality using multivariate Cox regression were baseline eGFR (p = 0.001) and KCCQ (p = 0.037). Based on these predictors, a Linear Prediction Score (LPS1) was calculated. The LPS1-area under the curve (AUC)-value (0.761) was significantly higher than the ESII-AUC value (0.597; p = 0.035). Independent predictors for LoS > 6 days (the median LoS) were eGFR (p = 0.028), NTproBNP (p = 0.034), and EQ5D5L values (p = 0.002); a respective calculated LPS2 provided an AUC value of 0.677 (p < 0.001). Eighty participants (47.3%) experienced complications. Male sex predicted complications only in the univariate analysis. Conclusions: The combination of KCCQ and eGFR can better predict midterm mortality than ES II alone. Combining eGFR, NTproBNP, and EQ5D5L can reliably predict LoS after TAVI. This novel method improves personalized TAVI risk stratification and hence may help reduce post-TAVI risk.
Akzidentielle Injektion eines unbekannten Notfallantidots zur Acetylcholinesteraseaktivierung
(2021)
Endothelial tip cells are essential for VEGF-induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial-specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down-regulated in EVL-deficient P5-retinal endothelial cells. Consistently, EVL deletion impairs VEGF-induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor-2 internalization and signaling.
Jan-Hendrik Müller und Stefanie Zingl verfolgen mit ihrem radikal empathischen Ansatz des Archivierens Strategien des In-Beziehung-Setzens filmischen und afilmischen Materials, wobei sie den Nachlass der österreichischen Schauspielerin und Filmemacherin, Elfriede Irrall, ins Zentrum ihrer Untersuchung stellen. Ziel dieser Auslegungen des archivarischen Kuratierens ist es, dominierender Filmgeschichtsschreibung von den Rändern her zu begegnen und sie mit anti-kanonischen Ordnungsprämissen zu konfrontieren, die dem teleologischen Positivismus der Filmgeschichte etwas entgegenstellen.
Plastic products leach chemicals that induce in vitro toxicity under realistic use conditions
(2021)
Plastic products contain complex mixtures of extractable chemicals that can be toxic. However, humans and wildlife will only be exposed to plastic chemicals that are released under realistic conditions. Thus, we investigated the toxicological and chemical profiles leaching into water from 24 everyday plastic products covering eight polymer types. We performed migration experiments over 10 days at 40 °C and analyzed the migrates using four in vitro bioassays and nontarget high-resolution mass spectrometry (UPLC-QTOF-MSE). All migrates induced baseline toxicity, 22 an oxidative stress response, 13 antiandrogenicity, and one estrogenicity. Overall, between 17 and 8681 relevant chemical features were present in the migrates. In other words, between 1 and 88% of the plastic chemicals associated with one product were migrating. Further, we tentatively identified ∼8% of all detected features implying that most plastic chemicals remain unknown. While low-density polyethylene, polyvinyl chloride, and polyurethane induced most toxicological endpoints, a generalization for other materials is not possible. Our results demonstrate that plastic products readily leach many more chemicals than previously known, some of which are toxic in vitro. This highlights that humans are exposed to many more plastic chemicals than currently considered in public health science and policies.
Plastics contain a complex mixture of chemicals including polymers, additives, starting substances and side-products of processing. These plastic chemicals are prone to leach into the packaged goods, in the case of food contact materials (FCMs), or into the natural environment, in the case of plastic debris. Thus, plastics represent an exposure source of chemicals for humans and wildlife alike. While it is widely known that individual plastic chemicals, such as bisphenol A and phthalates, are hazardous, little is known on the overall chemical composition and toxicity of plastics. When fragmented into smaller particles, referred to as microplastics (< 5 mm), the plastic itself can be ingested by many species. It is well established that microplastic ingestion can have negative consequences for a wide range of organisms including invertebrates, but the contribution of plastic chemicals to the toxicity of microplastics is unclear.
Given the above, the present thesis aimed at a comprehensive toxicological, ecotoxicological and chemical characterization of everyday plastics. For a comparative evaluation, 77 plastic products were selected covering 16 material types (e.g., polyethylene) made from petroleum or renewable feedstocks. These products included biodegradable products, FCMs and non-FCMs, as well as raw materials and final products, respectively. In the first two studies, the chemical mixtures contained in the 77 products were extracted with methanol and extracts were analyzed in a set of four in vitro bioassays and by non-target high-resolution gas or liquid chromatography mass spectrometry. Since an exposure only occurs if chemicals actually leach under realistic conditions, in a third study migration experiments with water were conducted for 24 out of the 77 products. The aqueous migrates were assessed in the same way as the methanolic extracts. In addition, the freshwater invertebrate Daphnia magna was exposed chronically to microplastics made of polyvinylchloride (PVC), polyurethane (PUR) and polylactic acid (PLA) to investigate the contribution of chemicals in microplastic toxicity, in a fourth study.
The experimental findings demonstrate that a wide variety of chemicals is present in plastics. A single plastic product can contain up to several thousand chemical features, most of which unique to that product and at the same time unknown. The results also indicate that the majority of these chemical mixtures are toxic in vitro. Accordingly, 65% of the plastic extracts induced baseline toxicity and 42% an oxidative stress response, while 25% had an antiandrogenic and 6% an estrogenic activity. This implies that chemicals causing unspecific toxicity are more prevalent in plastics than such with endocrine effects. These chemicals can also leach from plastics under realistic conditions. Between 17 and 8936 chemical features were detected in a single migrate sample and all 24 tested migrates induced in vitro toxicity. This means that humans and wildlife can actually be exposed to toxic plastic chemicals under realistic conditions. Generally, each product has its individual toxicological and chemical fingerprint. Thus, neither material type, feedstock, biodegradability nor the food contact suitability of a product can serve as a predictor for the toxicity, the chemical composition or complexity of a product. Likewise, this means that bio-based and biodegradable materials are not superior to their petroleum-based counterparts from a toxicological perspective despite being promoted as sustainable alternatives to conventional plastics.
Moreover, the present thesis demonstrates that plastic chemicals can be the main driver for microplastic toxicity. Irregular microplastics made of PVC, PUR and PLA adversely affected life-history traits of D. magna in a polymer type- and endpoint-dependent manner at concentrations between 100 and 500 mg L-1 and with a higher efficiency than natural kaolin particles. While the toxicity of PVC was triggered by the chemicals used in the material, the effects of PUR and PLA were induced by the physical properties of the particle.
In addition, in the fifth study, results and observations made during this thesis were integrated inter- and transdisciplinarily with the perspectives of a social scientist and a product manufacturer. This elucidated that knowledge on plastic ingredients is often concealed, is lacking or not applicable in practice. These intransparencies hinder the safety evaluation of plastic products as well as the choice and sale of the least toxic packaging material.
Overall, the present thesis highlights that the chemical safety of plastics and their bio-based and biodegradable alternatives is currently not ensured. Thus, chemicals require more consideration in the toxicity and risk assessment of plastics and microplastics. Product-specific and complex chemical compositions, including unknown compounds, pose a challenge here. Two essential steps towards non-toxic products are to increase transparency along the product life cycle and to reduce the chemical complexity of plastics by communication and regulation. The results of the present thesis indicate that products exist which do not contain toxic chemicals. These can serve to direct the design of safer plastics. Since toxicity and chemical complexity seem to increase with processing, the integration of toxicity testing during the production steps would further support the safe and sustainable production and use of plastic products.
To what extent does cultural distance interfere with or limit literary experience? What kind of intimacy is needed to make a text into a work? This essay seeks to answer these questions by focusing on the writings of Arvind Krishna Mehrotra. In doing so, it suggests that the challenges of cultural distance may be most acute when dealing with texts from homo-linguistic literary environments, and that we might overcome these challenges by undertaking a world literary criticism that attends to localized fields and materials without forgetting the charge of particular works.
Tiotropium as an add-on treatment option for severe uncontrolled asthma in preschool patients
(2021)
Background: Toddlers with asthma suffer disproportionally more than school-aged children from exacerbations with emergency visits and hospital admissions despite inhaled corticosteroid (ICS) treatment. A recent trial for children ≤ 5 years showed tolerability of tiotropium and potential to reduce asthma-related events.
Methods: We conducted a retrospective analysis of electronic outpatient records (2017‒2019) of children < 6 years treated with ICS plus long-acting β2-agonists (LABAs) plus tiotropium as an add-on for uncontrolled severe asthma. The primary endpoint was a comparison of systemic corticosteroid (SCS) prescriptions 6 months before and after ICS/LABA/tiotropium start. Secondary endpoints included physician visits, hospitalisations and antibiotic prescriptions. We compared outcomes with children without asthma matched for age, sex, season and screening date.
Results: Compared with a mean 2.42 (95% CI: 1.75, 3.36) SCS courses per patient within 6 months prior to ICS/LABA/tiotropium, 0.74 (95% CI: 0.25, 1.08) SCS courses per patient were prescribed within 6 months after starting ICS/LABA/tiotropium (P< 0.001). Physician visits dropped from 9.23 (95% CI: 7.15, 12.72) to 5.76 (95% CI: 3.10, 7.70) per patient (P< 0.01). Nineteen hospitalisations were recorded 6 months before ICS/LABA/tiotropium compared with one hospitalisation after (P< 0.01). A mean 1.79 antibiotic courses (95% CI: 1.22, 2.23) per patient were prescribed before ICS/LABA/tiotropium compared with 0.74 (95% CI: 0.22, 1.00) after ICS/LABA/tiotropium (P< 0.001). Hospitalisation rates for patients at observation end were not statistically different from healthy controls before/after matching.
Interpretation: Our retrospective study showed that adding tiotropium to ICS/LABA is a new treatment option for patients with severe preschool asthma; however, larger confirmatory studies are needed.
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)
Introduction: Cesarean section (CS) rates are increasing worldwide. One constant indication is the breech presentation at term. By offering external cephalic version (ECV) and vaginal breech delivery CS rates can be further reduced. Objective: This study aimed to analyze the ECV at 38 weeks of gestation with the associate uptake rate, predicting factors, success rate, and complications at a tertiary healthcare provider in Germany specializing in vaginal breech delivery. Methods: We conducted a prospective cohort study with retrospective data acquisition. All women with a singleton fetus in breech presentation presenting after 34 weeks of gestation for counseling between 2013 and 2017 were included. ECV impact factors were analyzed using logistic regression. Results: A total of 1,598 women presented for breech birth planning. ECV was performed on 353 patients. The overall success rate was 22.4%. A later week of gestation (odds ratio [OR] 1.69), an abundant amniotic fluid index (AFI score) (OR 5.74), fundal (OR 3.78) and anterior (OR 0.39) placental location, and an oblique lie (OR 9.08) were significantly associated with successful ECV in our population. No major complications were observed. The overall vaginal delivery rates could be increased to approximately 14% with ECV. Conclusion: The demand for alternative birth modes other than CS for breech birth is high in the area of Frankfurt, Germany. Our study offers evidence of the safety of ECV at 38 weeks. Centers with expertise in vaginal breech delivery and ECV can reduce CS-rates. To further establish vaginal breech delivery and ECV as alternate options, the required knowledge and skill should be implemented in the revised curricula.
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Microsurgical free flap reconstruction in acute burn care offers the option of reconstructing even challenging defects in a single stage procedure. Due to altered rheological and hemodynamic conditions in severely burned patients, it bears the risk of a higher complication rate compared to microsurgical reconstruction in other patients. To avoid failure, appropriate indications for free flap reconstruction should be reviewed thoroughly. Several aspects concerning timing of the procedure, individual flap choice, selection and preparation of the recipient vessels, and perioperative measures must be considered. Respecting these specific conditions, a low complication rate, comparable to those seen in microsurgical reconstruction of other traumatic limb defects, can be observed. Hence, the free flap procedure in acute burn care is a relatively safe and reliable tool in the armamentarium of acute burn surgery. In reconstructive burn care, microsurgical tissue transfer is routinely used to treat scar contractures. Due to the more robust perioperative condition of patients, even lower rates of complication are seen in microsurgical reconstruction.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
Co-design of a trustworthy AI system in healthcare: deep learning based skin lesion classifier
(2021)
This paper documents how an ethically aligned co-design methodology ensures trustworthiness in the early design phase of an artificial intelligence (AI) system component for healthcare. The system explains decisions made by deep learning networks analyzing images of skin lesions. The co-design of trustworthy AI developed here used a holistic approach rather than a static ethical checklist and required a multidisciplinary team of experts working with the AI designers and their managers. Ethical, legal, and technical issues potentially arising from the future use of the AI system were investigated. This paper is a first report on co-designing in the early design phase. Our results can also serve as guidance for other early-phase AI-similar tool developments.
Damselflies recorded before the administrative partition of the Indian Subcontinent and now housed at National Insect Museum (NIM), Islamabad were reviewed and catalogued. This collection is the divided part of National PUSA Collection (NPC) transferred to the Pakistan during 1947. Data for this collection had never been available or published. A record of 104 taxa is reported herein. Few of the species were found double named, misidentified and not updated as per valid classification. Some of the specimens were found unidentified. All such issues were resolved by following regional literature.
Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution. To better understand the interactions of dyes and nanoparticles and their biological environment, we explored PLGA nanoparticles labeled with four widely used dyes encapsulated (coumarin 6, rhodamine 123, DiI) or bound covalently to the polymer (Cy5.5.). The DiI label was stable in both aqueous and lipophilic environments, whereas the quick release of coumarin 6 was observed in model media containing albumin (42%) or liposomes (62%), which could be explained by the different affinity of these dyes to the polymer and lipophilic structures and which we also confirmed by computational modeling (log PDPPC/PLGA: DiI—2.3, Cou6—0.7). The importance of these factors was demonstrated by in vivo neuroimaging (ICON) of the rat retina using double-labeled Cy5.5/Cou6-nanoparticles: encapsulated Cou6 quickly leaked into the tissue, whereas the stably bound Cy.5.5 label remained associated with the vessels. This observation is a good example of the possible misinterpretation of imaging results because the coumarin 6 distribution creates the impression that nanoparticles effectively crossed the blood–retina barrier, whereas in fact no signal from the core material was found beyond the blood vessels.
In this paper, four new cave-dwelling species of the subgenus Tachycines (Gymnaeta) from Guangxi, Hunan and Jiangxi are described, i.e., Tachycines (Gymnaeta) quadratus sp. nov., Tachycines (Gymnaeta) shiziensis sp. nov., Tachycines (Gymnaeta) sparsispinus sp. nov. and Tachycines (Gymnaeta) papilious sp. nov. The female of Tachycines (Gymnaeta) liboensis Zhu, Chen & Shi, 2020 is recorded for the first time. Moreover, images illustrating the morphology of the four new and three previously described species are provided.
New fossil records of Xyelidae (Hymenoptera) from the Middle Jurassic of Inner Mongolia, China
(2021)
A new genus and two new species of Xyelidae Newman, 1834 (Hymenoptera Linnaeus, 1758), Platyxyela tenuis sp. nov. and Scleroxyela daohugouensis gen. et sp. nov. are described and illustrated from the Middle Jurassic Daohugou Beds of Ningcheng, Inner Mongolia, China. Platyxyela tenuis sp. nov. (Xyelinae Newman, 1834, Liadoxyelini Rasnitsyn, 1966) can be distinguished from its congeners by short forewing length and ovipositor sheath strongly narrowed toward acute apex. Scleroxyela daohugouensis gen. et sp. nov. is placed within Macroxyelinae Ashmead, 1898, Xyeleciini Benson, 1945 based on pterositigma completely sclerotised and costal space sclerotised before ptrostigma, 1-Rs half as long as 1-M, and 1m-cu short. It is the first recorded species of Xyeleciini in Daohugou Beds. Furthermore, an updated key of identification of subfamilies and tribes of Xyelidae is provided. Our findings of new morphological data provide insights into the early evolution of Hymenoptera, as well as effectively enrich our understanding of the diversity of Xyelidae in the Mesozoic.
The glidobactin-like natural products (GLNPs) glidobactin A and cepafungin I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881–1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli. Their chemical diversity results from a relaxed substrate specificity and flexible product release in the assembly line of GLNPs. Crystal structure analysis of the yeast proteasome in complex with new GLNPs suggests that the degree of unsaturation and the length of the aliphatic tail are critical for their bioactivity. The results in this study provide the basis to engineer the BGC for the generation of new GLNPs and to optimize these natural products resulting in potential drugs for cancer therapy.