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Institute
- Medizin (989)
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- Biowissenschaften (203)
- Frankfurt Institute for Advanced Studies (FIAS) (172)
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- Biochemie, Chemie und Pharmazie (154)
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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.
Recombinant DNA technology is an essential area of life engineering. The main aim of research in this field is to experimentally explore the possibilities of repairing damaged human DNA, healing or enhancing future human bodies. Based on ethnographic research in a Czech biochemical laboratory, the article explores biotechnological corporealities and their specific ontology through dealings with bio-objects, the bodywork of scientists. Using the complementary concepts of utopia and heterotopia, the text addresses the situation of bodies and bio-objects in a laboratory. Embodied utopias are analyzed as material semiotic phenomena that are embodied by scientists in their visions and emotions and that are related to potential bodies and to future, not-yet-actualized embodiments. As a counterpart to this, the text explores embodied heterotopias, which are always the other spaces, like biotechnological bio-objects that are simulated in computers or stored in special solutions.
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.
With the introduction of the virtual allocation crossmatch in the Eurotransplant (ET) region in 2023, the determination of unacceptable antigen mismatches (UAM) in kidney transplant recipients is of utmost importance for histocompatibility laboratories and transplant centers. Therefore, a joined working group of members from the German Society for Immunogenetics (Deutsche Gesellschaft für Immungenetik, DGI) and the German Transplantation Society (Deutsche Transplantationsgesellschaft, DTG) revised and updated the previous recommendations from 2015 in light of recently published evidence. Like in the previous version, a wide range of topics is covered from technical issues to clinical risk factors. This review summarizes the evidence about the prognostic value of contemporary methods for HLA antibody detection and identification, as well as the impact of UAM on waiting time, on which these recommendations are based. As no clear criteria could be determined to differentiate potentially harmful from harmless HLA antibodies, the general recommendation is to assign all HLA against which plausible antibodies are found as UAM. There is, however, a need for individualized solutions for highly immunized patients. These revised recommendations provide a list of aspects that need to be considered when assigning UAM to enable a fair and comprehensible procedure and to harmonize risk stratification prior to kidney transplantation between transplant centers.
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.
Background: Compound flaps offer the advantage of one stage defect reconstruction respecting all relevant tissues and early functional recovery by optimal vascularity of all components. Due to its specific vascular anatomy and the three-dimensional donor site, compound flaps with bone components may result in higher complication rates compared to soft tissue compound flaps. The meta-analysis summarizes the available evidence and evaluates whether bone components are a risk factor for periprocedural complications in upper extremity multidimensional defect reconstruction. Method: PubMed and Embase were searched for all publications addressing compound free flaps for upper extremity defect reconstruction with bone or soft tissue components published between January 1988 and May 2018. The methodological quality was assessed with the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies. Flap loss, thrombosis rate, early infection, hematoma, seroma, as well as donor site complications were extracted and analyzed. Results: Twelve out of 1157 potentially eligible studies (evidence-III) comprising 159 patients were finally included with publication bias for all summarized complication rates. Complication rates for flaps with/ without bone components were: total flap loss 5%, 95% CI = 3%–10% (6%/5%); partial flap loss 8%, 95% CI = 5%–15%, (9%/8%); arterial/venous thrombosis 7%, 95% CI = 4%–12%, (8%/5%)/14%, 95% CI = 9%–21% (16%/6%, P < .05) with higher risk for flaps with bone components; infection 6%, 95% CI = 3%–12% (6%/6%); hematoma 6%, 95% CI = 3%–11% (6%/5%); seroma 5%, 95% CI = 3%–10% (5%/5%); dehiscence 10%, 95% CI = 6%–17% (11%/9%). Conclusion: Compound flaps for upper extremity defect reconstruction including bone components have a higher venous thrombosis rate compared to compound soft-tissue flaps.
The genus Afronurus has several very common mayfly species in China and they are widely distributed in this country. Some of them are quite similar to each other in both imaginal and nymphal stages. However, these species have not been systematically compared and reviewed so far. In this study, six species are recognized. All nymphs of them share the following characters: gills V–VI with additional arrow-like accessory lobes, branched dentisetae, two rows of bristles and setae on hindtibiae and spotted abdominal terga. The males have divergent penes and clearly expressed titillators. The nymphs of the new species A. drepanophyllus sp. nov. have sickle-like gills I, spotted and striped body color, and males have unique genitalia. The nymphal stages of A. furcatus and A. hunanensis, which are associated and described for the first time, have similar body color to A. drepanophyllus sp. nov., but their pale dots on the head capsules and the shape of the hypopharynx are different. Keys to males and nymphs of the six species are provided.
Light axion fields, if they exist, can be sourced by neutron stars due to their coupling to nuclear matter, and play a role in binary neutron star mergers. We report on a search for such axions by analyzing the gravitational waves from the binary neutron star inspiral GW170817. We find no evidence of axions in the sampled parameter space. The null result allows us to impose constraints on axions with masses below 10−11 eV by excluding the ones with decay constants ranging from 1.6×1016 to 1018 GeV at a 3𝜎 confidence level. Our analysis provides the first constraints on axions from neutron star inspirals, and rules out a large region in parameter space that has not been probed by the existing experiments.
Hintergrund: Seit mehr als 50 Jahren werden in Deutschland Herzschrittmacher-Implantationen durchgeführt, mittlerweile mit mehr als 100.000 Implantationen pro Jahr. Obwohl es sich um einen gängigen Eingriff handelt, existieren wenig prospektiv randomisierte Studien zu technischen Aspekten der Implantation, insbesondere dem Wundverschluss am Ende der Operation. Ziel der vorliegenden Arbeit war es, an einem Kollektiv von Patienten unerwünschte Ereignisse und kosmetische Ergebnisse, in Abhängigkeit des beim Hautverschluss verwendeten Nahtmaterials (resorbierbarer bzw. nicht-resorbierbarer Faden), miteinander zu vergleichen.
Methoden: In einem Zeitraum von Juli 2018 bis April 2019 wurden Patienten mit geplanter de novo Herzschrittmacher-Implantation ohne Defibrillationstherapie prospektiv in die Studie eingeschlossen und anhand einer Randomisierungliste in zwei Probandengruppen eingeteilt: nicht-resorbierbares Nahtmaterial (Gruppe Prolene®) bzw. resorbierbares Nahtmaterial (Gruppe Monocryl®).
Ein Tag (Beobachtungszeitpunkt 1), sechs Wochen (Beobachtungszeitpunkt 2) und ein Jahr post-OP (Beobachtungszeitpunkt 3) erfolgte die Beurteilung der Narbe bezüglich des kosmetischen Ergebnisses und klinisch relevanter, unerwünschter Ereignisse. Zur kosmetischen Beurteilung diente die Wundbreite in mm, eine auftretende Kelloidbildung und die „Patient and Observer Scar Assessment Scale“ (POSA-Score). Dieser wurde zu Beobachtungszeitpunkt 1 seitens des Patienten auf zwei Fragen (Schmerzhaftigkeit, Juckreiz) reduziert. Die erhobenen klinisch relevanten Parameter waren Nachblutungen, Infektionen, Insuffizienz der Naht und Revisions-OP aufgrund eines Lokalbefundes.
Ergebnisse: Es konnten 114 Patienten in die Studie eingeschlossen werden. Zu Beobachtungszeitpunkt 2 und Beobachtungszeitpunkt 3 belief sich die Anzahl auf jeweils 92 Probanden. Zu allen drei Beobachtungszeitpunkten konnte zwischen beiden Gruppen weder ein signifikanter Unterschied im kosmetischen Ergebnis noch im Auftreten klinisch relevanter Ereignisse festgestellt werden.
Schlussfolgerung: Anhand der vorliegenden Studie scheint das verwendete Nahtmaterial keinen großen Einfluss auf das kosmetische Ergebnis der Narbe, sowie auf das Auftreten von unerwünschten Ereignissen zu haben. Eine multizentrische prospektiv randomisierte Studie mit größerer Patientenanzahl ist notwendig, um die hier erhobenen Daten zu verifizieren.
In the COVID-19 pandemic, human solidarity plays a crucial role in meeting this maybe greatest modern societal challenge. Public health communication targets enhancing collective compliance with protective health and safety regulations. Here, we asked whether authoritarian/controlling message framing as compared to a neutral message framing may be more effective than moralizing/prosocial message framing and whether recipients’ self-rated trait autonomy might lessen these effects. In a German sample (n = 708), we measured approval of seven regulations (e.g., reducing contact, wearing a mask) before and after presenting one of three Twitter messages (authoritarian, moralizing, neutral/control) presented by either a high-authority sender (state secretary) or a low-authority sender (social worker). We found that overall, the messages successfully increased participants’ endorsement of the regulations, but only weakly so because of ceiling effects. Highly autonomous participants showed more consistent responses across the two measurements, i.e., lower response shifting, in line with the concept of reactive autonomy. Specifically, when the sender was a social worker, response shifting correlated negatively with trait autonomy. We suggest that a trusted sender encourages more variable responses to imposed societal regulations in individuals low in autonomy, and we discuss several aspects that may improve health communication.
Simple Summary: Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection.
Abstract: There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.
Trotz der Verfügbarkeit von siRNA, dem aktuellen Goldstandard zur Generierung von RNAInterferenz-vermitteltem Gen-silencing, stellen unerwünschte Immunantworten des Organismus auf doppelsträngige RNA exogenen Ursprungs noch immer ein fundamentales Problem dar, besonders mit Hinblick auf die Entwicklung Oligonukleotid-basierter Wirkstoffe.
Durch das begrenzte Repertoire an Modifikationen, welches durch die Abhängigkeit von zelleigenen Faktoren unter anderem zur Steigerung der intrazellulären Stabilität und zur Reduktion unerwünschter Effekte zur Verfügung steht, konnte bis dato nur einer überschaubaren Anzahl entsprechender Oligonukleotide eine offizielle Zulassung für die therapeutische Anwendung in der Medizin erteilt werden.
Hier bergen künstliche Ribonukleasen, welche die Umesterungsreaktion unabhängig von der zellinternen Maschinerie ebenfalls effizient und sequenzspezifisch bewerkstelligen können, großes Potential als eine Alternative. Während Metall-basierte Systeme in der Regel auf unphysiologisch hohe Konzentrationen zweiwertiger Übergangsmetallionen, wie beispielsweise Lanthanoide oder auch Kupfer, angewiesen sind, könnten metallfreie Katalysatoren dahingehend eine wesentlich flexiblere Option darstellen. Die Optimierung Guanidin-basierter RNA-Spalter für den Einsatz in der Bioanalytik und Medizin stellt seit geraumer Zeit eines der obersten Ziele unseres Arbeitskreises dar. Unter diesen bewährte sich vor allem das Tris(2-aminobenzimidazol), welches in Form von Konjugaten mit Antisense-Oligonukleotiden kurze Modellsubstrate sequenzspezifisch spaltet.
Neben der äußerst mühseligen, vielstufigen Synthese eines konjugierbaren Tris(2-aminobenzimidazol)s waren die untersuchten Systeme mit Halbwertszeiten von teilweise über 20 Stunden jedoch viel zu langsam, um auch potentiell beobachtbare Veränderung des Phänotyps in vivo induzieren zu können. Ein weiterer begrenzender Faktor stellte die Konjugationstrategie des Spalters über Aktivester-Chemie und Aminolinker dar, welche eine Kupplungsausbeute von 0 % bis im besten Fall ca. 30 % lieferte. Um eine Methode zu erhalten, welche routinemäßig zur sequenzspezifischen Spaltung einer Vielzahl verschiedener RNA-Substrate genutzt werden kann, war folglich eine praktikablere Synthesestrategie zur Darstellung der Spalterkonjugate einerseits und zudem eine Erhöhung der Katalysatoraktivität andererseits notwendig, um auch kurzlebige Ziel-RNAs wirkungsvoll ausschalten zu können. In diesem Zusammenhang wurde eine neue Syntheseroute erarbeitet, welche den für die Konjugation funktionalisierten Spalter über wenige Stufen in Mengen von über 10 g lieferte. Daran anschließend konnte die Synthese eines Phosphoramidits realisiert werden, welches in einer manuellen Kupplungsprozedur die Darstellung von 5‘-Konjugaten des Tris(2-aminobenzimidazol)s in exzellenten Ausbeuten und, im Vergleich zur vorherigen Methode, wesentlich kürzeren Kupplungszeiten ermöglichte. Die vollständige Kompatibilität des Phosphoramidits mit der automatisierten Festphasensynthese konnte im Rahmen dieser Arbeit jedoch nicht erreicht werden. Während die manuelle Prozedur Konjugationsausbeuten von über 90 % lieferte, wurden an einem handelsüblichen Oligonukleotid-Synthesizer auch nach Modifikation der Kupplungsprotokolle und bei erhöhtem Amiditverbrauch lediglich 65 %erzielt. Durch Inkorporation von LNA-Nukleotiden in zwei gegen die PIM1-mRNA gerichtete 15mer DNA-Konjugate ließ sich eine Reduktion der Halbwertszeit von Cy5-markierten 22mer Modellsubstrate auf unter 4 h erreichen, wobei dieses Resultat auch anhand eines 412mer Modellsubstrats und in Gegenwart hoher Phosphatkonzentrationen reproduziert werden konnte. Darüber hinaus wurde die besondere Rolle des closing base pairs, sowohl bezüglich der Selektivität als auch der Kinetik der Spaltung, offensichtlich. Während stärker hybridisierende GC-Basenpaare generell eine hohe Präzision gewährleisteten, trat im Falle von AT-Basenpaaren fraying auf, d. h. es konnte auch innerhalb des vermeintlichen Duplex Spaltung beobachtet werden. Genauere Studien zur Positionierung von LNA-Nukleotiden ergaben bei unmittelbarer Lokalisation am 5‘-Terminus von AT-closing base pairs zwar einen selektivitätssteigernden Effekt, überraschenderweise konnte in diesem Fall jedoch auch eine Inhibierung der Spaltungskinetik festgestellt werden. Durch Verschiebung in die vorletzte Position konnte die Aktivität des Konjugats ohne Präzisionsverlust jedoch wiederhergestellt werden. Erste Experimente zur intrazellulären Stabilität der Spalterkonjugate ergaben quantitative, stufenweise Zersetzung, sowohl des DNA- als auch der Mixmer-Konjugate nach wenigen Stunden, was die Notwendigkeit weiterer stabilitätssteigernder Modifikationen zur Vorbereitung auf in vivo-Experimente impliziert. Auf der Suche nach neuen Spaltern stellte sich vor allem das 2-Aminoimidazol als einer der aussichtsreichsten Kandidaten für genauere Untersuchungen heraus. Das korrespondierende Tris(2-aminoimidazol) konnte über eine Marckwald-Synthese in wenigen Stufen dargestellt werden. Erste Spaltexperimente ergaben vor allem in niedrigen Konzentrationen (10 μM) eine im Vergleich zum Benzimidazol-Analogon vielfach höhere Aktivität. Obwohl die Synthese eines funktionalisierten Bisimidazol-benzimidazols gelang, steht dessen Konjugation mit Oligonukleotiden und deren Aktivitätsbestimmung noch aus.
Le "Printemps olympien" de Spitteler est considéré comme une oeuvre plutôt ennuyeuse dans laquelle la recherche a vu, en partie, une mythologie construite par l'auteur. Cette impression est contredite par le plaisir que procure encore aujourd'hui la lecture de ce texte. Cet article vise à cerner ce "plaisir du texte" en analysant les procédés poétiques de Spitteler. La contribution examine la structure du monde fictionnel et démontre qu'elle ne correspond nullement au modèle mythologique. Dans l'univers du "Printemps olympien", les dieux souffrent comme les humains et sont généralement dépourvus de pouvoirs surnaturels. De plus, Spitteler dissout l'identité des dieux en les dotant de nouveaux attributs par rapport au pré-texte (par exemple les Légendes de l'Antiquité classique de Schwab) ou en les faisant entrer dans de nouvelles constellations. Sa langue non plus ne correspond pas à la conception "classique", puisqu'il mélange le dialecte et la langue standard avec nombre de termes de sa propre création, et il a une prédilection particulière pour les mots composés longs. C'est dans le recours à ces moyens et dans le refus de se contenter d'une simple reproduction de la réalité quotidienne que se manifeste sa modernité.
Im EU-Projekt „Regulatory Control Networks of Synthetic Lethality“ (SYNLET) wurden durch Vergleich der Genexpressionsprofile auf Transkriptionsebene von parentalen sensitiven Neuroblastom-Zelllinien und ihren Vincristin-resistenten Sublinien bioinformatisch 40 Kandidatengene ermittelt, die für Vincristin-Resistenz und damit Zellüberleben essentiell sein könnten. Diese Kandidatengene wurden im Rahmen dieser Dissertation einzeln in Neuroblastomzellen der Vincristin-resistenten Sublinie UKF-NB-2rVCR20 herunterreguliert durch Transfektion (Elektroporation) von small interfering RNAs (siRNAs; knock down). Anschließend wurden die Zellen ohne und mit verschiedenen Vincristin-Konzentrationen auf Zellviabilitätsveränderungen getestet. Beim Kandidatengen mit den niedrigsten Zellviabilitäten (SMARCC1) wurde ein Western Blot gemacht, um die Herunterregulierung zu bestätigen. Zu Beginn wurde das effektivste Programm zur Elektroporation der UKF-NB-2rVCR20-Zellen durch eine Transfektionsoptimierung ermittelt. Alle Kandidatengene wurden 2x transfiziert, bei unklaren oder besonders interessanten Ergebnissen auch 3x. Als positive Kontrolle wurde der ABC-Transporter MDR1 herunterreguliert, da hier die Auswirkungen auf die Resistenz gegen Vincristin bekannt sind. Bei 10 von 40 Kandidatengenen waren die Zellviabilitäten ohne Vincristin und/oder bei mindestens einer Vincristin-Konzentration extrem verändert (FOXJ1, MAP2K1, NFYB, RICS, SMARCA1, SMARCB1, SMARCC1, STK35, TOCA1 und TPM2). Das entspricht einem Prozentsatz von 25 % Kandidatengenen, bei denen die bioinformatisch vorhergesagte Wirkung in vitro bestätigt werden konnte. Allerdings sind bei diesen 10 effektiven Kandidatengenen auch 2 Gene dabei, nach deren Herunterregulierung es zu einer erhöhten Zellviabilität kam (FOXJ1 und RICS). Bei der Frage, welche Gene das Absterben der Tumorzellen beschleunigen und als ein mögliches Therapieziel in Frage kommen könnten, bleiben also 8 Kandidatengene (20 % aller Kandidatengene). Das interessanteste Kandidatengen ist SMARCC1, da die Herunterregulierung alleine (ohne Zugabe von Vincristin) zu einer massiven Abnahme der Zellviabilität führte. Damit stellt SMARCC1 ein interessantes Ziel zur Therapie in Tumorzellen dar.
This dissertation analyses the degrees and trajectories of financialisation in the region of South-Eastern Europe. It modifies and applies an eclectic comparative framework for comparing the degrees of financialisation across time and space on different levels. The thesis finds that from the turn of the century until the Great Financial Crisis of 2008, most South-Eastern European countries have increased their degree of financialisation on the different levels, especially on the levels of household, international financialisation and partly the financial sector. Financialisation of non-financial companies is barely existing. After the financial crisis, financialisation is revealed to stagnate in the region. In a second step, the dissertation conducts three case studies on extreme cases: financial sector financialisation in Bulgaria, international financialisation in Serbia and non-financial company and household financialisation in Croatia. Their trajectories are exposed to be mainly driven by deregulation, changed practices by foreign banks, the privatisation of public goods and the liberation of capital controls. The dissertation serves to geographically enlarge the research of financialisation to a peripheral region of the Global North and to add to the discussion on comparative financialisation approaches.
Immune profile and radiological characteristics of progressive multifocal leukoencephalopathy
(2021)
Background and purpose: Progressive multifocal leukoencephalopathy (PML) constitutes a severe disease with increasing incidence, mostly in the context of immunosuppressive therapies. A detailed understanding of immune response in PML appears critical for the treatment strategy. The aim was a comprehensive immunoprofiling and radiological characterization of magnetic resonance imaging (MRI) defined PML variants.
Methods: All biopsy-confirmed PML patients (n = 15) treated in our department between January 2004 and July 2019 were retrospectively analysed. Data from MRI, histology as well as detailed clinical and outcome data were collected. The MRI-defined variants of classical (cPML) and inflammatory (iPML) PML were discriminated based on the intensity of gadolinium enhancement. In these PML variants, intensity and localization (perivascular vs. parenchymal) of inflammation in MRI and histology as well as the cellular composition by immunohistochemistry were assessed. The size of the demyelinating lesions was correlated with immune cell infiltration.
Results: Patients with MRI-defined iPML showed a stronger intensity of inflammation with an increased lymphocyte infiltration on histological level. Also, iPML was characterized by a predominantly perivascular inflammation. However, cPML patients also demonstrated certain inflammatory tissue alterations. Infiltration of CD163-positive microglia and macrophage (M/M) subtypes correlated with PML lesion size.
Conclusions: The non-invasive MRI-based discrimination of PML variants allows for an estimation of inflammatory tissue alterations, although exhibiting limitations in MRI-defined cPML. The association of a distinct phagocytic M/M subtype with the extent of demyelination might reflect disease progression.
The role and timing of radiotherapy (RT) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) remains controversial. While recent trials support the oncological safety of early salvage RT (SRT) compared to adjuvant RT (ART) in selected patients, previous randomized studies demonstrated that ART might improve recurrence-free survival in patients at high risk for local recurrence based on adverse pathology. Although ART might improve survival, this approach is characterized by a risk of overtreatment in up to 40% of cases. SRT is defined as the administration of RT to the prostatic bed and to the surrounding tissues in the patient with PSA recurrence after surgery but no evidence of distant metastatic disease. The delivery of salvage therapies exclusively in men who experience biochemical recurrence (BCR) has the potential advantage of reducing the risk of side effects without theoretically compromising outcomes. However, how to select patients at risk of progression who are more likely to benefit from a more aggressive treatment after RP, the exact timing of RT after RP, and the use of hormone therapy and its duration at the time of RT are still open issues. Moreover, what the role of novel imaging techniques and genomic classifiers are in identifying the most optimal post-operative management of PCa patients treated with RP is yet to be clarified. This narrative review summarizes most relevant published data to guide a multidisciplinary team in selecting appropriate candidates for post-prostatectomy radiation therapy.
The role of orthographic knowledge for reading performance in German elementary school children
(2021)
Reading is crucial for successful participation in the modern world. However, 3-8% (e.g., Moll et al., 2014) of children in elementary school age show reading difficulties, which can lead to limited education and enhance risks of social and financial disadvantages (Valtin, 2017). Therefore, it is important to identify reading relevant components (Tippelt & Schmidt-Hertha, 2018). In this context, especially phonological awareness (i.e., awareness of the sound structure of the language) and naming speed (i.e., fast and automatized retrieval of information) were identified as significant components for reading skills (e.g., Georgiou et al., 2012; Landerl & Thaler, 2006; Vellutino, Fletcher, Snowling, & Scanlon, 2004). One further component, which is of growing interest to the recent research, is orthographic knowledge. It comprises the knowledge about the spelling of specific words (word-specific orthographic knowledge) and about legal letter patterns (general orthographic knowledge; Apel, 2011).
Previous research focused predominantly on examining the role of orthographic knowledge on basic reading level, including word identification and word meaning (Conrad et al., 2013; Rothe et al., 2015). The relationship between orthographic knowledge and reading comprehension as the core objective of reading, including understanding of the relationship between words within a sentence as well as building a coherence between sentences (Perfetti et al., 2005), was on the contrary scarcely the object of research. The first goal of this dissertation is, therefore, to provide a remedy by investigating the role of orthographic knowledge on higher reading processes (sentence- and text-level). The scarce body of research investigating children with reading difficulties provide a mixed result pattern (e.g., Ise et al., 2014). Therefore, this dissertation aims at clarifying the influence of orthographic knowledge on word-, sentence-, and text-level in children without and with reading difficulties.
A thorough understanding of reading relevant components is also important for conception of interventions aiming at individual reading performance improvements in order to prevent school failure. One promising approach to help children to overcome their reading difficulties is a text-fading based reading training. During this procedure, reading material is faded out letter by letter in reading direction (i.e., in German from left to right; Breznitz & Nevat, 2006). The aim of this manipulation is to prompt the individual to read faster than usual, resulting in reading rate and comprehension improvements (e.g., Nagler et al., 2015). However, the underlying mechanisms leading to improvements of reading performance are still unclear. Considering previous findings showing orthographic skills to influence training outcomes (Berninger et al., 1999), and also word reading performance after a reading intervention (Stage et al., 2003), it seems plausible to include orthographic knowledge when investigating potential training effects. Therefore, this dissertation aims at investigating the predictive value of orthographic knowledge for comprehension performance during the text-fading based reading training.
In order to answer the first research question, two empirical papers are implemented (see Appendix A: Zarić et al., 2020 and Appendix B: Zarić & Nagler, 2021), which investigate the role of orthographic knowledge for reading at word-, sentence-, and text-level in German school children without and with reading difficulties. The study by Zarić et al. (2020) examines the incremental predictive value for explained reading variance of both word-specific and general orthographic knowledge in relation to variance amount explained by general intelligence and phonological awareness. For this purpose, data from 66 German third-graders without reading difficulties were analyzed. Correlation and multiple regression analyses have shown that word-specific and general orthographic knowledge contribute a unique significant amount to the variance of reading comprehension on word-, sentence-, and text-level, over and above the explained variance by general intelligence and phonological awareness. In order to answer the question whether word-specific and general orthographic knowledge also explain variance in children with poor reading proficiency, in addition to established predictors phonological awareness and naming speed, the data from 103 German third-graders with reading difficulties were analyzed in a second study (Zarić & Nagler, 2021). The analyses revealed that word-specific and general orthographic knowledge explain a unique significant amount of the variance of reading on word- and sentence-level. On text-level, these two components did not explain a significant amount of unique variance. Here, only phonological awareness was shown to be a significant predictor. The results indicate that the knowledge about the spelling of specific words (word-specific orthographic knowledge) and the knowledge about legal letter patterns (general orthographic knowledge) contribute to reading comprehension on word-level. Following the assumptions, for instance, of the Lexical Quality Hypothesis (Perfetti & Hart, 2002) high-quality orthographic representations are considered to be important for higher reading processes, such as comprehension.
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Objectives: To discuss optimal management of recurrent urinary tract infections (UTIs) in women. About every second woman experiences at least one UTI in her lifetime, of those 30% experience another UTI, and 3% further recurrences. Especially young healthy women without underlying anatomical deficiencies suffer from recurrent UTIs (rUTI), which are associated with significant morbidity and reduction in quality of life.
Methods: This is a narrative review, investigating publications dealing with recurrent UTI in women. Risk factors and options for management are discussed.
Results: The increased susceptibility of women to rUTI is based on the female anatomy in addition to behavioural, genetic, and urological factors. However, why some women are more likely than others to develop and maintain rUTI remains to be clarified. Invasive characteristics of certain uropathogenic Escherichia coli that are able to form extra- and intracellular biofilms and may therefore cause delayed release of bacteria into the bladder, may play a role in this setting. Treatment recommendations for an acute episode of rUTI do not differ from those for isolated episodes. Given the nature of rUTI, different prophylactic approaches also play an important role. Women with rUTI should first be counselled to use non-antibiotic strategies including behavioural changes, anti-adhesive treatments, antiseptics, and immunomodulation, before antibiotic prophylaxis is considered. In addition to the traditional treatment and prophylactic therapies, new experimental strategies are emerging and show promising effects, such as faecal microbiota transfer (FMT), a treatment option that transfers microorganisms and metabolites of a healthy donor’s faecal matter to patients using oral capsules, enemas, or endoscopy. Initial findings suggest that FMT might be a promising treatment approach to interrupt the cycle of rUTI. Furthermore, bacteriophages, infecting and replicating in bacteria, have been clinically trialled for UTIs.
Conclusion: Due to the limitation of available data, novel treatment options require further clinical research to objectify the potential in treating bacterial infections, particularly UTIs.
One of the most challenging problems in solid state systems is the microscopic analysis of electronic correlations. A paramount minimal model that encodes correlation effects is the Hubbard Hamiltonian, which—regardless of its simplicity—is exactly solvable only in a few limiting cases and approximate many-body methods are required for its solution. In this review, an overview on the non-perturbative two-particle self-consistent method (TPSC), which was originally introduced to describe the electronic properties of the single-band Hubbard model, is presented. A detailed derivation of the multi-orbital generalization of TPSC is introduced here and particular features of the method on exemplary interacting models in comparison to dynamical mean-field theory results are discussed.
The formation of amyloid-β oligomers plays a key role in the onset of Alzheimer’s disease. We investigated the aggregation of amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing those structural properties, which lead to the formation of mature fibrils. We can show that the arrangement of the first oligomers is crucial for the topology of the resulting species, leading to the formation of non-toxic aggregates or fibrils.
B-cell acute lymphoblastic leukaemia (B-ALL) is characterized by the overproduction of lymphoblasts in the bone marrow (BM), and it is the most common cancer in children while being comparatively uncommon in adults. On the other hand, in chronic myeloid leukaemia (CML), 70% of cases are found in patients older than 50 years, making it uncommon in children. All CML cases and up to 3% of paediatric B- ALL (and 25% of adult B-ALL) cases are due to fusion gene BCR-ABL1, which gives rise to the cytoplasmatic, constitutively active oncoprotein, tyrosine kinase BCR-ABL1 through a reciprocal translocation between chromosomes 9 and 22. The constitutively active BCR-ABL tyrosine kinase leads to deregulation of different signal transduction pathways such as cell growth, proliferation and cell survival. The role of the bone marrow microenvironment (BMM) can mediate disease initiation (only in mice), progression, therapy resistance, and relapse, as has been increasingly recognized over the last two decades. In general, the BMM is a very complex arrangement of various cell types such as osteoblasts, osteoclasts, endothelial cells, adipocytes, mesenchymal stromal cells, macrophages and several others. In addition, the BMM is composed of multiple chemical and mechanical factors and extra cellular matrix (ECM) proteins which contribute to the BMM’s features influencing leukaemia behaviour. Considering the incidence of B-ALL and CML in children and in adults respectively, we hypothesized that the young and/or an aged BMM might also play a previously unrecognized role in the aggressiveness of B-ALL and CML. We proposed that BM, transduced with BCR-ABL1-expressing retrovirus in the murine transduction/transplantation model of B-ALL, transplanted into young versus old recipient mice would lead to a more aggressive disease in young mice, and similarly CML would be more aggressive in old recipient mice. In close recapitulation with the human incidence, induction of CML led to a significantly shorted survival in old recipient mice. On the other hand, induction of B-ALL showed a shortened survival in young compared to old syngeneic mice, as well as in a xenotransplantation model. Among the highly heterogenous composition of the BMM, we implicate young BM macrophages as a supportive niche for B-ALL cells. The results were found to be mostly due to potential soluble factors differentially secreted from young and old macrophages. Therefore, we hypothesized that the chemokine CXCL13, which has been demonstrated to play a role in B cell migration and act as a diagnostic marker in the cerebrospinal fluid of patients with neuroborreliosis, might be responsible for the observed phenotype. CXCL13 was found to be more highly expressed in healthy and leukaemic young mice as well as in conditioned medium of young macrophages. Using a variety of in vitro experiments, CXCL13 showed to significantly increase the proliferation and the migration of leukaemia cells when exposed to young macrophages, and the phenotype was rescued while using a CXCL13 neutralizing antibody. The CXCL13 role was also confirmed in vivo, since macrophage ablation led to a prolongation of survival in young mice and a reduction of CXCL13 levels. The use of an additional mouse model, leukaemia cells with CXCR5 deficiency, led to a significant prolongation of survival of young mice, confirming the importance of the CXCL13-CXCR5 axis in B-ALL. In line with our murine results, we found that human macrophages and CXCL13 levels were higher in pediatric B-ALL patients than in adults. Consistent with our murine data, the expression level of CXCR5 may act as a prognostic marker in B-ALL, as well as a predictive marker for central nervous system relapse in human B-ALL. The overall findings show that a young BMM, and in particular macrophages, influences B-ALL progression. We specifically identified CXCL13, secreted by young macrophages, as a promoter of proliferation of B-ALL cells, influencing survival in B-ALL via CXCR5. The CXCR5-CXCL13 axis may be relevant in human B-ALL, and higher CXCR5 expression in human B-ALL may act as a predictive marker.
Nicola Zambon beschäftigt sich mit einer Phänomenologie der Berührung. Er verfolgt die Rolle von Taktilität in den Philosophien Edmund Husserls und Maurice Merleau-Pontys und fragt danach, inwieweit insbesondere Husserl einem Okularzentrismus verbunden bleibt. In Auseinandersetzung mit Husserls berühmter Beschreibung einer Selbstberührung der Hände und deren Modifikationen durch Merleau-Ponty macht der Beitrag einen Vorschlag für eine zukünftige Phänomenologie der Taktilität, die insbesondere die Fremdhautwahrnehmung zu berücksichtigen hätte.
One new genus, Zagrotes gen. nov., and 19 new species of ground spiders (Gnaphosidae) are described from Iran: Berinda bifurcata sp. nov. (♂, Bushehr, Khuzestan; southwestern and southern Iran), Berinda hoerwegi sp. nov. (♂♀, Fars, Ilam, Kermanshah, Kurdistan; western and southcentral Iran), Berlandina artaxerxes sp. nov. (♂ Yazd; central Iran), Cryptodrassus iranicus sp. nov. (♂, Kermanshah; western Iran), Drassodes persianus sp. nov. (♀, Kermanshah, Sistan & Baluchistan; western and southeastern Iran), Echemus caspicus sp. nov. (♀, Golestan; northern Iran), Gnaphosa qamsarica sp. nov. (♀, Isfahan; central Iran), Haplodrassus medes sp. nov. (♂, Fars; southcentral Iran), Haplodrassus qashqai sp. nov. (♂♀, Hormozgan, Khuzestan, Lorestan; southwestern to southern Iran), Marinarozelotes achaemenes sp. nov. (♀, Kohgiluyeh & Boyer-Ahmad; southwestern Iran), Marjanus isfahanicus sp. nov. (♀, Isfahan; central Iran), Nomisia ameretatae sp. nov. (♂, Tehran; northern Iran), Prodidomus inexpectatus sp. nov. (♂, Hormozgan; southern Iran), Scotophaeus anahita sp. nov. (♀, Isfahan; central Iran), Scotophaeus elburzensis sp. nov. (♀, Tehran, Zanjan; northwestern and northern Iran), Sosticus montanus sp. nov. (♀, Ilam; western Iran), Synaphosus martinezi sp. nov. (♂♀, Kohgiluyeh & Boyer-Ahmad; southwestern Iran), Zagrotes apophysalis sp. nov. (♂♀, Hormozgan, Kohgiluyeh & Boyer-Ahmad; southwestern to southern Iran) and Zelotes hyrcanus sp. nov. (♀, Mazandaran; northern Iran). These are the first records of the genera Berinda Roewer, 1928, Echemus Simon, 1878 and Marjanus Chatzaki, 2018 in Iran. Additionally, the previously unknown female of Callipelis deserticola Zamani & Marusik, 2017 is described and illustrated, and Berlandina mesopotamica Al-Khazali, 2020 is recorded in Iran for the first time. Furthermore, Berinda idae Lissner, 2016 syn. nov. (Greece, Cyprus) is synonymized with Berinda infumatus (O. Pickard-Cambridge, 1872) comb. nov. (ex. Heser Tuneva, 2004; Greece, Tanzania, Egypt, Israel, introduced to Japan).
Five species of the subgenus Clessiniella of Cochlostoma (Cochlostomatidae) are recognized, viz. Cochlostoma (Clessiniella) villae (Strobel, 1851), Cochlostoma (Clessiniella) tergestinum (Westerlund, 1878), Cochlostoma (Clessiniella) waldemari (A.J. Wagner, 1897), Cochlostoma (Clessiniella) anomphale Boeckel, 1939 and Cochlostoma (Clessiniella) stelucarum sp. nov. The shells and the genitalia are described and the distributional data are summarized for all the species.
Studium der Lebewesen : im Masterprogramm »Ökologie und Evolution« wird Diversität großgeschrieben
(2021)
In der vorliegenden Arbeit wurde das Zinkfinger-µ-Protein HVO_2753 des halophilen Archaeons Haloferax volcanii hinsichtlich seiner biologischen Funktion und seiner Struktur charakterisiert.
Zinkfinger-µ-Proteine wurden bisher nur sehr wenig untersucht, während ihnen jedoch in den letzten Jahren steigendes Interesse entgegengebracht wird. Im Genom von H. volcanii sind mehr als 40 solcher Zinkfinger-µ-Proteine codiert. Von diesen besitzt mit HVO_2753 lediglich eines nicht nur zwei, sondern vier der charakteristischen C(P)XCG-Muster, was für die Anwesenheit von zwei Zinkfinger-Motiven spricht. Während Homologe von HVO_2753 in vielen Euryachaeota vorkommen und manche davon als Zink-Ribbon RNA-Bindeproteine annotiert sind, ist über ihre Funktion jedoch nichts bekannt. Zur Charakterisierung des Proteins wurde zunächst eine in frame-Deletionsmutante seines Gens erstellt und diese einer phänotypischen Charakterisierung unterzogen. Die Mutante wies, verglichen mit dem Wildtyp, keine Unterschiede im Wachstum in Komplexmedium oder in synthetischem Medium mit Glukose als Kohlenstoffquelle auf. Ein schweres Defizit konnte jedoch sowohl bei der Adhäsion und Biofilmbildung als auch der Schwärmfähigkeit der Deletionsmutante festgestellt werden. Während die Schwärmfähigkeit des Wildtyps durch plasmidische Expression von HVO_2753 in der Deletionsmutante teilweise wiederhergestellt werden konnte, war eine solche Komplementation bei der Biofilmbildung nicht möglich. Die Analyse der Relevanz ausgewählter Aminosäuren, wie beispielsweise das jeweils erste Cystein in jedem C(P)XCG-Muster zeigte, dass die Substitution jeder einzelnen der getesteten Aminosäuren einen Funktionsverlust des Proteins nach sich zieht. Die Untersuchung des HVO_2753-Transkripts mittels Northern Blot-Analyse bestätigte erste Hinweise aus vorangegangenen dRNA- und RNA-Seq-Studien, die eine Co-Transkription von HVO_2753 mit dem Nachbargen HVO_2752, das für den Translations-Elongationsfaktor aEF-1 beta codiert, aufzeigten. Daraufhin erfolgte eine Untersuchung des Ribosomenprofils, bei der keine Unterschiede zwischen der Deletionsmutante und der Überexpressionsmutante von HVO_2753 festgestellt werden konnten.
Eine Variante von HVO_2753 mit N-terminalem Hexahistidin-Tag wurde homolog überproduziert und aufgereinigt. Die Überproduktion und Aufreinigung wurden im Zuge dieser Arbeit weiter, speziell für HVO_2753, optimiert. So konnten große Mengen von HVO_2753n überproduziert und bei nativen Salzbedingungen mittels Nickel-Affinitätschromatographie und anschließender Größenausschlusschromatographie aufgereinigt werden. Eine massenspektrometrische Analyse bestätigte sowohl das Molekulargewicht als auch die Abwesenheit posttranslationaler Modifikationen. Die Untersuchung der Menge an gebundenem Zink im Protein erfolgte beim Zink-Assay mit Hilfe des hochsensitiven und hochspezifischen Fluorophors ZnAF-2F. Dabei konnte gezeigt werden, dass überraschenderweise lediglich ein Zink-Ion in HVO_2753 gebunden vorliegt.
Zur weiteren Funktionsaufklärung erfolgte eine Interaktionspartnersuche. Hierfür wurde HVO_2753 überproduziert, ein in vivo-Crosslink und anschließend eine native Aufreinung durchgeführt. Die massenspektrometrische Analyse ausgewählter Fraktionen nach der Größenausschlusschromatographie ergaben eine Vielzahl an möglichen Bindepartnern. Besonders häufig wurde hier die GalE family Epimerase/Dehydratase gefunden. Eine weitere Methode zur Suche nach Interaktionspartnern richtete sich auf RNAs. Hier konnten mittels eines eigens entwickelten Protokolls neben RNAs des Translationsapparates auch mehrfach die tRNA(Glu) gefunden werden.
Zusätzlich sollte die Transkriptomanalyse mittels RNA-Sequenzierung Unterschiede zwischen Wildtyp, Deletionsmutante und Komplementationsmutante aufzeigen. Hier wurden weitreichende Auswirkungen der Deletion von HVO_2753 gefunden. Zahlreiche Gene in mehreren Operons zur Motilität und Chemotaxis lagen in der Deletionsmutante stark herunterreguliert vor, während die Gene einiger Metallionen-Transporter und der Eisen(III)-Siderophor-Biosynthese hochreguliert vorlagen. In der Komplementationsmutante konnten nur von den letzteren Genen Transkriptlevel vergleichbar mit denen des Wildtyps wiedergefunden werden.
In dieser Arbeit konnte gezeigt werden, dass das kleine Zinkfinger-Protein HVO_2753 eine essenzielle Rolle in der positiven Regulation der Motilität, Chemotaxis und der Adhäsion bzw. Biofilmbildung spielt. Gleichzeitig übt HVO_2753 eine negative Regulation auf den Metallionen-Transport und die Biosynthese des Eisen(III)-Siderophors aus.
Contemporary information systems make widespread use of artificial intelligence (AI). While AI offers various benefits, it can also be subject to systematic errors, whereby people from certain groups (defined by gender, age, or other sensitive attributes) experience disparate outcomes. In many AI applications, disparate outcomes confront businesses and organizations with legal and reputational risks. To address these, technologies for so-called “AI fairness” have been developed, by which AI is adapted such that mathematical constraints for fairness are fulfilled. However, the financial costs of AI fairness are unclear. Therefore, the authors develop AI fairness for a real-world use case from e-commerce, where coupons are allocated according to clickstream sessions. In their setting, the authors find that AI fairness successfully manages to adhere to fairness requirements, while reducing the overall prediction performance only slightly. However, they find that AI fairness also results in an increase in financial cost. Thus, in this way the paper’s findings contribute to designing information systems on the basis of AI fairness.
By focusing on the cost conditions at issuance, I find that not only the Covid-19 pandemic effects were different across bonds and firms at different stages, but also that the market composition was significantly affected, collapsing on investment- grade bonds, a segment in which the share of bonds eligible to the ECB corporate programmes strikingly increased from 15% to 40%. At the same time the high-yield segment shrunk to almost disappear at 4%. In addition to a market segmentation along the bond grade and the eligibility to the ECB programmes, another source of risk detected in the pricing mechanism is the weak resilience to pandemic: the premium requested is around 30 basis points and started to be priced only after the early containment actions taken by the national authorities. On the contrary, I do not find evidence supporting an increased risk for corporations headquartered in countries with a reduced fiscal space, nor the existence of a premium in favour of green bonds, which should be the backbone of a possible “green recovery”.
Having a gatekeeper position in a collaborative network offers firms great potential to gain competitive advantages. However, it is not well understood what kind of collaborations are associated with such a position. Conceptually grounded in social network theory, this study draws on the resource-based view and the relational factors view to investigate which types of collaboration characterize firms that are in a gatekeeper position, which ultimately could improve firm performance in subsequent periods. The empirical analysis utilizes a unique longitudinal data set to examine dynamic network formation. We used a data crawling approach to reconstruct collaboration networks among the 500 largest companies in Germany over nine years and matched these networks with performance data. The results indicate that firms in gatekeeper positions often engage in medium-intensity collaborations and less likely weak-intensity collaborations. Strong-intensity collaborations are not related to the likelihood of being a gatekeeper. Our study further reveals that a firm's knowledge base is an important moderator and that this knowledge base can increase the benefits of having a gatekeeper position in terms of firm performance.
Ziel der Studie: Eine psychische Komorbidität spielt im Kontext mit weiteren persönlichen, sozialen und beruflichen Faktoren bei der Ermittlung des spezifischen Rehabilitationsbedarfs der Patienten in Deutschland eine immer bedeutendere Rolle. Um die Zuweisung von Patienten zu einer Rehabilitationsform besser ausdifferenzieren zu können, soll im Rahmen dieser retrospektiven Analyse ermittelt werden, von welchem der beiden untersuchten Rehabilitationskonzepte (OR/VMO) Patienten mit psychischer Komorbidität unter Berücksichtigung von Geschlecht, Erwerbsstatus und orthopädischer Hauptdiagnose stärker profitieren.
Methodik: Mittels der Screening-Fragebögen HADS-A, HADS-D, SIMBO und BPI sowie eines Klinikfragebogens zu Beginn der Rehabilitation wurden Angaben von 913 Probanden (529 m/384 w) ausgewertet. Hiervon wurden 43 % der OR und 57 % der VMO zugewiesen. So wurde die Häufigkeitsverteilung der Faktoren psychische Komorbidität, Geschlecht, Erwerbsstatus und orthopädische Hauptdiagnose festgestellt. Mittels HADS wurde am Ende der Therapie der Benefit durch Vergleich der Scorewert-Mediane ermittelt.
Ergebnisse: Häufigkeitsverteilungen und die Entwicklung der HADS-Scores zeigen, dass die im Vorfeld erfolgte Einteilung gemäß psychischer Komorbidität korrekt war. Frauen waren häufiger von einer psychischen Komorbidität betroffen und erzielten in der VMO größere Erfolge. Bezüglich der orthopädischen Hauptdiagnose ergab sich eine hohe Prävalenz von HWS- und LWS-Beschwerden. Beim Erwerbsstatus (Arbeits(un)fähigkeit, Arbeitslosigkeit, berufliche Problemlage) zeigte sich ein diffuseres Bild, das keine generalisierende Aussage bezüglich der arbeitsweltbezogenen Faktoren zulässt.
Schlussfolgerungen: Das Vorliegen einer psychischen Komorbidität stellt einen zielführenden Indikator dar, der als eines der Hauptzuweisungskriterien zur VMO beizubehalten ist. Auch das weibliche Geschlecht in Verbindung mit dem Vorliegen einer psychischen Komorbidität ist als adäquates Kriterium anzusehen. Bezüglich der orthopädischen Hauptdiagnose können insbesondere HWS-Beschwerden als Zuweisungskriterium geeignet sein. Aufgrund der sehr heterogenen Ergebnisse hinsichtlich der Aspekte des Erwerbsstatus lässt sich festhalten, dass diesbezüglich eine Zuweisung zu einem arbeitsweltbezogenen Therapiekonzept (z. B. MBOR) zielführender erscheint.
An automated NMR chemical shift assignment algorithm was developed using multi-objective optimization techniques. The problem is modeled as a combinatorial optimization problem and its objective parameters are defined separately in different score functions. Some of the heuristic approaches of evolutionary optimization are employed in this problem model. Both, a conventional genetic algorithm and multi-objective methods, i.e., the non-dominated sorting genetic algorithms II and III (NSGA2 and NSGA3), are applied to the problem. The multi-objective approaches consider each objective parameter separately, whereas the genetic algorithm followed a conventional way, where all objectives are combined in one score function. Several improvement steps and repetitions on these algorithms are performed and their combinations are also created as a hyper-heuristic approach to the problem. Additionally, a hill-climbing algorithm is also applied after the evolutionary algorithm steps. The algorithms are tested on several different datasets with a set of 11 commonly used spectra. The test results showed that our algorithm could assign both sidechain and backbone atoms fully automatically without any manual interactions. Our approaches could provide around a 65% success rate and could assign some of the atoms that could not be assigned by other methods.
The function of the cerebral cortex essentially depends on the ability to form functional assemblies across different cortical areas serving different functions. Here we investigated how developmental hearing experience affects functional and effective interareal connectivity in the auditory cortex in an animal model with years-long and complete auditory deprivation (deafness) from birth, the congenitally deaf cat (CDC). Using intracortical multielectrode arrays, neuronal activity of adult hearing controls and CDCs was registered in the primary auditory cortex and the secondary posterior auditory field (PAF). Ongoing activity as well as responses to acoustic stimulation (in adult hearing controls) and electric stimulation applied via cochlear implants (in adult hearing controls and CDCs) were analyzed. As functional connectivity measures pairwise phase consistency and Granger causality were used. While the number of coupled sites was nearly identical between controls and CDCs, a reduced coupling strength between the primary and the higher order field was found in CDCs under auditory stimulation. Such stimulus-related decoupling was particularly pronounced in the alpha band and in top–down direction. Ongoing connectivity did not show such a decoupling. These findings suggest that developmental experience is essential for functional interareal interactions during sensory processing. The outcomes demonstrate that corticocortical couplings, particularly top-down connectivity, are compromised following congenital sensory deprivation.
In dengue-endemic countries such as Indonesia, Zika may be misdiagnosed as dengue, leading to underestimates of Zika disease and less foreknowledge of pregnancy-related complications such as microcephaly. Objective: To assess the attitudes of frontline physicians in a dengue-endemic country toward testing for Zika infection among patients with dengue-like illnesses. Methods: A cross-sectional online survey was conducted among general practitioners (GPs) in Indonesia. The survey assessed their attitude and also collected sociodemographic data, characteristics of their medical education, professional background, and workplace, and exposure to Zika cases. A two-step logistic regression analysis was used to assess possible variables associated with these attitudes. Results: A total of 370 GPs were included in the final analysis of which 70.8% had good attitude. Unadjusted analyses suggested that GPs who were 30 years old or older and those who had medical experience five years or longer had lower odds of having a positive attitude compared to those who aged younger than 30 years and those who had medical experience less than five years, OR: 0.58; 95%CI: 0.37, 0.91 and OR: 0.55; 95%CI: 0.35, 0.86, respectively. No explanatory variable was associated with attitude in the fully adjusted model. Conclusion: Our findings point to younger GPs with a shorter medical experience being more likely to consider testing for Zika infection among their patients presenting with dengue-like illnesses. Strategic initiatives may be needed to enhance older or longer-experienced physicians' capacity in diagnosing Zika infection.
The adult heart has a limited capacity to replace or regenerate damaged cardiac tissue following severe myocardial injury. Thus, therapies facilitating the induction of cardiac regeneration holds great promise for the treatment of end-stage heart failure, and for pathologies invoking severe cardiac dysfunction as a result of cardiomyocyte death. Recently, a number of studies have demonstrated that cardiac regeneration can be achieved through modulation and/or reprogramming of cardiomyocyte proliferation, differentiation, and survival signaling. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are reported to play critical roles in regulating key aspects of cardiomyocyte physiologic and pathologic signaling, including the regulation of cardiac regeneration both in vitro and in vivo. In this review, we will explore and detail the current understanding of ncRNA function in cardiac regeneration, and highlight established and novel strategies for the treatment of heart failure through modulation of ncRNAs-driven cardiac regeneration.
Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.
The genus Chassalia (Gentianales: Rubiaceae-Palicoureeae) in Borneo is revised based on a morphological survey of herbarium specimens using classical taxonomic methods. The tribal placement and probable paraphyly of Chassalia as currently delimited is reviewed. Previously, four described species of Chassalia were known from Borneo, with only one endemic species, Chassalia psychotriformis I.M.Turner nom. nov. (≡ Cephaelis psychotrioides Valeton). A key is given to the 18 species of the genus recognised from Borneo in this study. In total, 14 new species are described, all of them endemic to Borneo. These are: Chassalia atropurpurea T.Y.Yu sp. nov., Chassalia beamanii T.Y.Yu sp. nov., Chassalia calamus T.Y.Yu sp. nov., Chassalia chewii T.Y.Yu sp. nov., Chassalia involucrata T.Y.Yu sp. nov., Chassalia kinabaluensis T.Y.Yu sp. nov., Chassalia lancifolia T.Y.Yu sp. nov., Chassalia lancifolioides T.Y.Yu sp. nov., Chassalia longipes T.Y.Yu sp. nov., Chassalia macrocarpa T.Y.Yu sp. nov., Chassalia muluensis T.Y.Yu sp. nov., Chassalia muscicola T.Y.Yu sp. nov., Chassalia northiana T.Y.Yu sp. nov. and Chassalia ramosa T.Y.Yu sp. nov. Circumscriptions and discussions are given for all Bornean species recognised. A morphological glossary for Asian species of Chassalia is provided. Three separate species groups are recognised, the Chassalia curviflora and C. javanica groups, represented by a single species each in Borneo, and a new informal group, the ‘Involucrate group’, which is proposed and circumscribed to encompass the majority (16) of the Bornean species. Proposals for further work on Asian Chassalia are given.
Release of neuropeptides from dense core vesicles (DCVs) is essential for neuromodulation. Compared to the release of small neurotransmitters, much less is known about the mechanisms and proteins contributing to neuropeptide release. By optogenetics, behavioral analysis, electrophysiology, electron microscopy, and live imaging, we show that synapsin SNN-1 is required for cAMP-dependent neuropeptide release in Caenorhabditis elegans hermaphrodite cholinergic motor neurons. In synapsin mutants, behaviors induced by the photoactivated adenylyl cyclase bPAC, which we previously showed to depend on acetylcholine and neuropeptides (Steuer Costa et al., 2017), are altered like in animals with reduced cAMP. Synapsin mutants have slight alterations in synaptic vesicle (SV) distribution, however, a defect in SV mobilization was apparent after channelrhodopsin-based photostimulation. DCVs were largely affected in snn-1 mutants: DCVs were ∼30% reduced in synaptic terminals, and not released following bPAC stimulation. Imaging axonal DCV trafficking, also in genome-engineered mutants in the serine-9 protein kinase A phosphorylation site, showed that synapsin captures DCVs at synapses, making them available for release. SNN-1 co-localized with immobile, captured DCVs. In synapsin deletion mutants, DCVs were more mobile and less likely to be caught at release sites, and in non-phosphorylatable SNN-1B(S9A) mutants, DCVs traffic less and accumulate, likely by enhanced SNN-1 dependent tethering. Our work establishes synapsin as a key mediator of neuropeptide release.
Aim: Knowledge concerning species distribution is important for biodiversity conservation and environmental management. Fungi form a large and diverse group of species and play a key role in nutrient cycling and carbon storage. However, our understanding of fungal diversity and distribution remains limited, particularly at large spatial scales. Here, we predicted the diversity and distribution of ectomycorrhizal and saprotrophic macrofungi at relatively fine spatial resolution at a continental scale and examined the importance of variables that affect the distribution of these two functional groups. Location: Europe. Time period: 1990–2018. Major taxa studied: Macrofungi. Methods: From observations of 1,845 macrofungal species, we predicted the diversity and distribution of two functional groups of macrofungi at a resolution of 5 km across eight European countries based on 25 environmental variables using the MAXENT model. We determined the importance of variables that affect the distribution of these two functional groups of macrofungi using the built-in jackknife test in the model. Results: Analysis of the modelling results showed that eastern Denmark and southern Sweden are biodiversity hotspots for both functional groups of macrofungal species. Tree species and human disturbance (i.e., the human footprint index) were found to be the two most important predictor variables explaining the distribution of ectomycorrhizal and saprotrophic macrofungi. Main conclusions: Overall, our study demonstrates that tree species and human disturbance have played a more important role than climatic factors in determining the diversity and distribution of macrofungi at the continental scale. Our study suggests that fungal diversity and distribution might change considerably if the strongest predictors (i.e., tree species) were to be affected by climate change and/or human activity. Changes in fungal diversity might, in turn, influence other processes, because fungi are important in driving ecosystem processes, such as nutrient and carbon cycling.
Objective: Nationwide data on the epidemiology, treatment characteristics, and long-term outcome of severe traumatic brain injury (TBI) in Germany is not yet existing. Neurosurgeons from the German Neurosurgery Society (DGNC) and traumatologists from the German Trauma Society (DGU), therefore, joined forces in 2016 to conceptualize a TBI module for the well-established Trauma Register of the DGU (TR-DGU). Here, we report how this “German National TBI registry (GNTR)” has been developed, implemented, and tested in a recently completed pilot period.
Methods: The conception and implementation process of the GNTR from August 2016 to February 2019 is described, and results of its 23-months long pilot period from February 2019 to December 2020 are presented. For the pilot period, TBI patients were prospectively enrolled at nine neurosurgical and traumatological hospitals across Germany. Inclusion criteria were treatment on the ICU ≥ 24h, or an ISS score ≥ 16. A variety of clinical, imaging, and laboratory parameters were collected, and the GOSE score was used to assess the outcome at discharge and 6- and 12 months follow-up.
Results: Details on the structure and dataset of the GNTR as well as milestones and pitfalls during its conception and implementation, are outlined. During the pilot period, a total of 264 TBI patients were enrolled. Their demographic characteristics, clinical, imaging, and radiological findings, and their early mortality and functional outcome are described. Furthermore, factors associated with an unfavorable outcome (GOSE 1-4) are assessed using uni- and multivariate regression analyses. Finally, problems and future directions of the GNTR are discussed.
Conclusion: The pilot period of the GNTR offers a first glance at the current epidemiology and treatment characteristics of TBI patients in Germany. More importantly, they show how a national TBI registry yielding high-quality prospective data can be developed, implemented, and tested within four years
The stress-dependent dynamics of Saccharomyces cerevisiae tRNA and rRNA modification profiles
(2021)
RNAs are key players in the cell, and to fulfil their functions, they are enzymatically modified. These modifications have been found to be dynamic and dependent on internal and external factors, such as stress. In this study we used nucleic acid isotope labeling coupled mass spectrometry (NAIL-MS) to address the question of which mechanisms allow the dynamic adaptation of RNA modifications during stress in the model organism S. cerevisiae. We found that both tRNA and rRNA transcription is stalled in yeast exposed to stressors such as H2O2, NaAsO2 or methyl methanesulfonate (MMS). From the absence of new transcripts, we concluded that most RNA modification profile changes observed to date are linked to changes happening on the pre-existing RNAs. We confirmed these changes, and we followed the fate of the pre-existing tRNAs and rRNAs during stress recovery. For MMS, we found previously described damage products in tRNA, and in addition, we found evidence for direct base methylation damage of 2′O-ribose methylated nucleosides in rRNA. While we found no evidence for increased RNA degradation after MMS exposure, we observed rapid loss of all methylation damages in all studied RNAs. With NAIL-MS we further established the modification speed in new tRNA and 18S and 25S rRNA from unstressed S. cerevisiae. During stress exposure, the placement of modifications was delayed overall. Only the tRNA modifications 1-methyladenosine and pseudouridine were incorporated as fast in stressed cells as in control cells. Similarly, 2′-O-methyladenosine in both 18S and 25S rRNA was unaffected by the stressor, but all other rRNA modifications were incorporated after a delay. In summary, we present mechanistic insights into stress-dependent RNA modification profiling in S. cerevisiae tRNA and rRNA.
We provide extensions of the dual variational method for the nonlinear Helmholtz equation from Evéquoz and Weth. In particular we prove the existence of dual ground state solutions in the Sobolev critical case, extend the dual method beyond the standard Stein Tomas and Kenig Ruiz Sogge range and generalize the method for sign changing nonlinearities.
The fauna of the bryocorine plant bug tribe Eccritotarsini from India and Sri Lanka is reviewed and updated. Ten genera and 20 species are reported from the region including two genera and six species described as new: Harpedona vittlaensis sp. nov., Lopidolon dandeliensis sp. nov., Mertila rubrocephala sp. nov., Namyatovia gen. nov. for N. castlerockensis gen. et sp. nov. (as the type species) and N. sirsiensis gen. et sp. nov., and Stonedahlia gen. nov. for S. mishmiensis gen. et sp. nov. The genus Bromeliaemiris Schumacher, 1919 is synonymized with Lopidolon Poppius, 1911. Dioclerus lutheri (Poppius, 1912) and Ernestinus ramkeshariae Yasunaga & Ishikawa, 2016 are reported from India for the first time. Differential diagnoses, keys, habitus photographs, illustrations of male genitalic structures, host and distributional information are provided for all genera and species.
The species of Stenothemus Bourgeois, 1907 from Southwest China are reviewed. Three species are transferred to this genus, S. davidi (Pic, 1926) comb. nov. (from Malthacus Kirby, 1837), S. minutissimus (Pic, 1933) comb. nov. (from Micropodabrus Pic, 1920) and S. singularicollis (Pic, 1933) comb. nov. (from Lycocerus Gorham, 1895). Two new synonyms are suggested, S. dinshuiensis Švihla, 2011 syn. nov. is synonymized with S. davidi and S. melleus Švihla, 2005 syn. nov. with S. singularicollis. Stenothemus shaanxiensis Švihla, 2004 stat. nov. is raised to species level from a subspecies of S. benesi Švihla, 2004. Five new species are described, S. gracilis Y. Yang & X. Yang sp. nov., S. chongqingensis Y. Yang & H. Liu sp. nov., S. flavicollis Y. Yang & S. Ge sp. nov., S. jindraimimus Y. Yang & X. Yang sp. nov. and S. laticornis Y. Yang & H. Liu sp. nov., which are illustrated with photographs of habitus, aedeagi, abdominal sternites VIII and internal genitalia of the female. Characters of the female reproductive system are described for the first time for the following species: S. diffusus Wittmer, 1974, S. dundai Švihla, 2004, S. grahami Wittmer, 1974, S. jindrai Švihla, 2004, S. tryznai Švihla, 2004 and S. singularicollis. Some additional distribution information is added for previously known species. A key for the identification of all studied species is provided.
The species of Stenothemus Bourgeois, 1907 from Southeast China are reviewed. Stenothemus fukienensis Wittmer, 1974 and S. kuatunensis Wittmer, 1979 are supplementarily described. Two new species are described, S. longicornis Y. Yang & H. Liu sp. nov. (China: Guangdong) and S. flavus Y. Yang & X. Yang sp. nov. (China: Zhejiang). Five new combinations are established: S. biimpressiceps (Pic, 1930) comb. nov. (from Cantharis L.), S. chinensis (Wittmer, 1982) comb. nov., S. limbatipennis (Pic, 1926) stat. rev. et comb. nov., S. nigriceps (Wittmer, 1955) comb. nov. and S. pallicolor (Wittmer, 1951) comb. nov. (from Lycocerus Gorham). Leiothorax atrosanguineus Švihla, 2005 syn. nov. is synonymized with S. chinensis, Lycocerus limatus Kazantsev, 2007 syn. nov. with S. limbatipennis. The above species are illustrated with habitus photos, aedeagi, abdominal sternites VIII and internal genitalia of female. A key for the identification of the above species is provided.