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This paper provides descriptions of Calcigorgia gorgonians collected from the Sea of Okhotsk and shores of the Kurile Islands between 3 Aug. 1984 and 20 Aug. 1987. New species described are the deep-water gorgonians Calcigorgia matua sp. nov. and C. simushiri sp. nov., belonging to the temperate fauna of the North Pacific hemisphere. Specimens belonging to all species of the genus were examined and the distinctive characters for each one are provided and summarized in a table. A modified diagnosis of the genus is proposed. The finding of a previously undescribed species emphasizes the need of further surveys, particularly in shelf and deeper waters, in order to improve our knowledge of this neglected fauna in Far East seas.
Synchroidae Lacordaire, 1859 is a taxonomically and biologically poorly known group. In the present paper, diagnostic characters used to separate genera are analysed and the phylogenetic relationships within this family are preliminarily investigated. Results suggest that the characteristic Synchroa pangu Hsiao, Li, Liu & Pang, 2016 can be removed to establish a new genus, Thescelosynchroa gen. nov. The new combination, T. pangu (Hsiao, Li, Liu & Pang) gen. et comb. nov., is proposed. The definitions of Synchroa Newman, 1838 and Synchroina Fairmaire, 1898 are revised. Moreover, morphological analysis and character comparison also suggest that the familial placement of Mallodrya subaenea Horn, 1888 is questionable. Six species are re-examined and rediagnosed: Synchroa chinensis Nikitsky, 1999, S. elongatula Nikitsky, 1999, S. formosana Hsiao, 2015, S. melanotoides Lewis, 1895, S. punctata Newman, 1838 and Synchroina tenuipennis Fairmaire, 1898. The male of S. chinensis and the female of S. formosana are described for the first time. Synchroa elongatula and Synchroina tenuipennis are newly recorded from Laos and Indonesia, respectively. We also hypothesize that the Eastern Asian-North American disjunction of Synchroa could be connected to a Mid-Late Tertiary migration of plants via the Bering Land Bridge.
New species of Neanura MacGillivray, 1893 and Deutonura Cassagnau, 1979 are described from northern Iran. Both taxa are characterized by unusual features that place them in isolated positions within the genera. Neanura deharvengi sp. nov. differs from congeners by the extreme reduction of head chaetotaxy and fused lateral tubercles on the head. These characteristics of the new species broaden the existing diagnosis of the genus Neanura. An updated diagnosis is provided herein. Deutonura persica sp. nov. is most similar to D. plena (Stach, 1951), known from the Carpathians. The new species can be distinguished by the strong reduction of its head, labial, and labral chaetotaxy as well as the relative length of chaetae De2 and De3 on abdominal segments I–III. The Iranian records of D. decolorata (Gama & Gisin, 1964) are questioned. Brief remarks on the importance of the newly described species for the knowledge of both genera are also provided.
Two new species of the family Selachinematidae Cobb, 1915 from an intertidal sandy flat in the East China Sea are described. Both species are distinct rapacious nematodes, preying on other nematodes. Gammanema magnum sp. nov. is characterized by its leaf-like labial setae, large loop-shaped amphideal fovea in the male and small spiral ones in the female, an anterior buccal cavity reinforced by 12 rhabdia, each rhabdion with about six denticles, and two unequally long spicules. Gammanema magnum sp. nov. is a striking species, exhibiting extreme sexual dimorphism in the amphideal fovea, but lacking a gubernaculum or precloacal supplements, all features by which it can be differentiated from congeneric species. Synonchium caudatubatum sp. nov. is characterized by a posterior buccal cavity, with three mandibles each with a large tooth flanked by three smaller teeth on both sides, a transverse oval-shaped multispiral amphideal fovea, and a bluntly rounded tail with a protuberant caudal duct. Synonchium caudatubatum sp. nov. is unique in the genus in having a protuberant caudal duct in the tail end. Furthermore, it differs from its congeners by its mandibles, which have seven teeth each. Synonchium caudatubatum sp. nov. lacks a gubernaculum and a precloacal supplement, both features present in congeners except S. depressum Gerlach, 1954.
The vividly coloured Neotropical genus Callipia Guenée (1858) (Lepidoptera Linnaeus, 1758, Geometridae (Leach, 1815), Larentiinae (Leach, 1815), Stamnodini Forbes, 1948) is revised and separated into four species groups, according to a provisional phylogeny based on Cytochrome Oxidase I (COI) gene data and morphology. Fourteen new species are described using COI data and morphology: a) in the balteata group: C. fiedleri sp. nov., C. jakobi sp. nov., C. lamasi sp. nov.; b) in the vicinaria group: C. hausmanni sp. nov., C. walterfriedlii sp. nov.; c) in the parrhasiata group: C. augustae sp. nov., C. jonai sp. nov., C. karsholti sp. nov., C. levequei sp. nov., C. milleri sp. nov., C. sihvoneni sp. nov., C. wojtusiaki sp. nov. and d) in the constantinaria group: C. hiltae sp. nov., C. rougeriei sp. nov. One new subspecies is described: C. wojtusiaki septentrionalis subsp. nov. Two species are revived from synonymy: C. intermedia Dognin, 1914 stat. rev. and C. occulta Warren, 1904 stat. rev. The taxon hamaria Sperry, 1951 is transferred from being a junior synonym of C. constantinaria Oberthür, 1881 to being a junior synonym of C. occulta stat. rev. The taxon admirabilis Warren, 1904 is confirmed as being a junior synonym of C. paradisea Thierry-Mieg, 1904. The taxon languescens Warren, 1904 is confirmed as being a junior synonym of C. rosetta, Thierry-Mieg, 1904 and the taxon confluens Warren, 1905 is confirmed as being a junior synonym of C. balteata Warren, 1905. The status of the remaining species is not changed: C. aurata Warren, 1904, C. brenemanae Sperry, 1951, C. parrhasiata Guenée, 1858, C. flagrans Warren, 1904, C. fulvida Warren, 1907 and C. vicinaria Dognin. All here recognised 26 species are illustrated and the available molecular genetic information of 25 species, including Barcode Index Numbers (BINs) for most of the taxa is provided. The almost threefold increase from 10 to 26 valid species shows that species richness of tropical moths is strongly underestimated even in relatively conspicuous taxa. Callipia occurs from medium to high elevations in wet parts of the tropical and subtropical Andes from Colombia to northern Argentina. The early stages and host plants are still unknown.
A new species complex, the eparmata complex, is established within the subgenus Phortica s. str., based on eight known and five new species, all of which are endemic to the Oriental Region: P. bipartita (Toda & Peng, 1992), P. eparmata (Okada, 1977), P. lanuginosa Chen & Toda, 2007, P. latipenis Chen & Gao, 2005, P. pangi Chen & Wen, 2005, P. setitabula Chen & Gao, 2005, P. unipetala Chen & Wen, 2005 and P. zeta Chen & Toda, 2007; P. jadete sp. nov., P. kava sp. nov., P. mengda sp. nov., P. wongding sp. nov. and P. yena sp. nov. A key to all species of this complex is provided. Barcoding sequences (mitochondrial COI gene) were obtained for 22 specimens of five known and the five abovementioned new species. The intra- and inter-specific pairwise K-2P (Kimura’s two-parameter) distances of COI were determined. Phylogenetic analysis was performed using Bayesian inference based on COI sequences, confirming the monophyletic status of the eparmata complex, which is distinct from the species complexes of magna, omega, variegata and another two ungrouped species.
The Astyanax orthodus species-group includes nine species: Astyanax boliviensis sp. nov., A. bopiensis nom. nov., A. embera sp. nov., A. gandhiae sp. nov., A. moorii comb. nov., A. orthodus, A. superbus, A. villwocki and A. yariguies comb. nov. The group is diagnosed by the presence of a series of pinnate-shaped marks (chevrons) located along the lateral midline, which extends from the humeral region to the caudal peduncle. Astyanax bopiensis nom. nov. is proposed as a substitute name for Astyanacinus multidens, which, along with Astyanax yariguies comb. nov., we reassign to Astyanax. We also propose the synonymy of Astyanacinus with Astyanax. The members of the A. orthodus speciesgroup are distributed in northwestern South America, occurring in the Patia River drainage (A. embera sp. nov.) of the Pacific coast of Colombia, the Atrato River Basin (A. orthodus), the Magdalena River Basin (A. yariguies comb. nov.) of Caribbean Colombia, streams of the southern flank of the Andes of the Orinoco Basin in Venezuela (A. superbus), in the upper Amazon River Basin of Colombia, Ecuador and Peru (A. villwocki, A. gandhiae sp. nov.), from the upper Paraguay River (A. moorii comb. nov.), the Madidi and Mamore Rivers, Bolivia (A. boliviensis sp. nov. and A. bopiensis nom. nov.). All species currently included in Astyanacinus are reassigned to the Astyanax orthodus species-group.
The Quedius mutilatus group, a very poorly known presumably monophyletic complex of wingless, possibly hypogean species confined to the Tien-Shan Mountains, is characterized as such for the first time. Newly available material clarified the identity of Q. mutilatus Eppelsheim, 1888 and Q. kalabi Smetana, 1995, each hitherto known from a handful of non-conspecific and vaguely georeferenced specimens only. Additional material is reported for Q. equus Smetana, 2014 and bionomics for all these four species of the group are summarized.
Bees of the genus Lasioglossum (Hymenoptera: Halictidae) from Greater Puerto Rico, West Indies
(2018)
The species of Lasioglossum from Greater Puerto Rico are reviewed. Nine species are recognized, including five new species described herein: asioglossum (Dialictus) genaroi sp. nov., L. (D.) dispersum sp. nov., L. (D.) enatum sp. nov., L. (D.) monense sp. nov. and L. (D.) amona sp. nov. The latter two are known only from Mona Island. Keys and images are provided to assist in identification. Details of nesting biology, floral hosts and distribution are provided where available. Three species, L. (D.) parvum (Cresson, 1865), L. (D.) busckiellum (Cockerell, 1915), and L. (D.) mestrei (Baker, 1906) are removed from the list of species for Puerto Rico. Details on their revised distribution are provided. Three new records for Haiti, L. (D.) gundlachii (Baker, 1906), L. (D.) ferrerii (Baker, 1906) and L. (D.) busckiellum are documented. Notes on other species in the Greater Antilles are provided, including the synonymy of Lasioglossum bruesi (Cockerell, 1912) and L. jamaicae (Ellis, 1914) under L. gemmatum (Smith, 1853).
The genus Raveniola Zonstein, 1987 is found to be represented in Western Asia by 16 species: ♂♀ R. adjarica sp. nov. (Georgia), ♂ R. anadolu sp. nov. (Turkey), ♂ R. arthuri Kunt & Yağmur, 2010 (Turkey), ♂ R. birecikensis sp. nov. (Turkey), ♂♀ R. dunini sp. nov. (Armenia, Azerbaijan, Iran), ♂♀ R. hyrcanica Dunin, 1988 (Azerbaijan), ♂ R. marusiki sp. nov. (Iran), ♂ R. mazandaranica Marusik, Zamani & Mirshamsi, 2014 (Iran), ♂♀ R. micropa (Ausserer, 1871) (Turkey), ♀ R. nana sp. nov. (Turkey), ♂♀ R. niedermeyeri (Brignoli, 1972) (Iran), ♂♀ R. pontica (Spassky, 1937) (Russia, Georgia), ♀ R. sinani sp. nov. (Turkey), ♂♀ R. turcica sp. nov. (Turkey), ♂♀ R. vonwicki Zonstein, 2000 (Iran) and ♂♀ R. zaitzevi (Charitonov, 1948) (Azerbaijan, Georgia) = ♀ Brachythele recki Mcheidze, 1983, syn. nov. Eight species are described as new; others are redescribed from types and/or conspecific material. Males of R. micropa and R. zaitzevi, hitherto unknown, are described for the first time. Data on the variability, relationships, distribution and ecology of all considered species are also provided.
Two new species of marine Platyhelminthes, Microstomum laurae sp. nov. and Microstomum edmondi sp. nov. (Macrostomida: Microstomidae) are described from the west coast of Sweden. Microstomum laurae sp. nov. is distinguished by the following combination of characters: rounded anterior and posterior ends; presence of approximately 20 adhesive papillae on the posterior rim; paired lateral red eyespots located level with the brain; preoral gut extending anterior to brain and and very small sensory pits. Microstomum edmondi sp. nov. is a protandrous hermaphrodite with a single ovary, single testis and male copulatory organ with stylet. It is characterized by a conical pointed anterior end, a blunt posterior end with numerous adhesive papillae along the rim, and large ciliary pits. The stylet is shaped as a narrow funnel with a short, arched tip. In addition, the first records of fully mature specimens of Microstomum rubromaculatum von Graff, 1882 from Fiskebäckskil and a phylogenetic analysis of Microstomum Schmidt, 1848 based on the mitochondrial cytochrome oxidase I (COI) gene are presented.
The frog Pristimantis marmoratus was originally described als Hylodes marmoratus by George A. Boulenger in 1900 based on a single specimen reported to have been collected at the foot of Mount Roraima in Guyana in 1898. We herein discuss the exact location of the type locality of P. marmoratus and provide a redescription of the species based on new material from Kaieteur National Park and from the slopes of Maringma-tepui in Guyana. We also describe the previously unknown vocalization and breeding ecology of the species, and conducted an exploratory molecular analysis of the phylogenetic relationships within the genus Pristimantis represented by the members of the "unistrigatus species group" in the Guiana Shield. Pristimantis marmoratus is a small-sized species mainly distinguished from its known Guiana Shield congeners by the combination of F I < II, SVL ≤ 20.4 in males, presence of vocal slits in males, granular/pustulate dorsal skin with well-developed scapular ridges, basal webbing between fingers, fringes in fingers and toes, crossed iris, diffuse yellow or pale green wash on groin, and absence of flashy colour on axillary/pre-axillary region. The advertisement call consists of a single note repeated at a rate of ca 11 calls/min with a dominant frequency ranging from 2756 to 3101 Hz. Pristimantis marmoratus is primarily arboreal, exclusively active at dusk, and propably restricted to the pristine rainforests of the Pantepui uplands and highlands, east of the Gran Sabana between ca 600 and 1800 m above sea level. Preliminary molecular analyses recovered Pristimantis marmoratus as sister to an unnamed species from the Eastern Guiana Shield. On grounds of the newly established distributional extent we suggest maintaining the IUCN conservation status as Least Concern.
Following a taxonomic revision of Begonia L. (Begoniaceae, Cucurbitales) from Northeast India based on 332 herbarium specimens, 38 species are confirmed to occur in the region, of which ten are endemic. One new species is described, Begonia koelzii R.Camfield sp. nov., in B. sect. Platycentrum (Klotzsch) A.DC. One species is reduced into synonymy; B. barbata Wall. is now a synonym of B. thomsonii A.DC. Three species, B. difformis (Irmsch.) W.C.Leong, C.I Peng & K.F.Chung, B. labordei H.Lév. and B. handelii Irmsch., are reported new for India, and B. lushaiensis C.E.C.Fisch. is reinstated as an accepted species, having previously been synonymised under B. modestiflora Kurz. A key to the species in the region and preliminary conservation assessments are presented.
Chigger mites of the African continent are reviewed using data acquired from the literature and examination of the collections deposited at the Royal Museum for Central Africa (Tervuren, Belgium) and the Natural History Museum (London, UK). All findings for 443 valid chigger species belonging to 61 genera are reported, along with details on their collection locality and host species. Three new synonyms are proposed: Straelensia Vercammen-Grandjean & Kolebinova, 1968 (= Anasuscuta Brown, 2009 syn. nov.); Herpetacarus (Herpetacarus) Vercammen-Grandjean, 1960 (= Herpetacarus (Lukoschuskaaia) Kolebinova & Vercammen-Grandjean, 1980 syn. nov.); Gahrliepia brennani (Jadin & Vercammen-Grandjean, 1952) (= Gahrliepia traubi Audy, Lawrence & Vercammen-Grandjean, 1961 syn. nov.). A new replacement name is proposed: Microtrombicula squirreli Stekolnikov, 2017 nom. nov. pro Eltonella myonacis heliosciuri Vercammen-Grandjean, 1965 (praeocc. Vercammen-Grandjean, 1965). Ninety new combinations are proposed. Keys to subfamilies, genera and subgenera of African trombiculid larvae and diagnoses of these taxa are given.
Damacornu gen. nov. (type species: D. transversum gen. et sp. nov.), Geotypodon papei sp. nov. and Spinotarsus fortehamatus sp. nov. are described, and Helicochetus dimidiatus (Peters, 1855), H. mutaba Kraus, 1960 and Hoffmanides dissutus (Hoffman, 1963) are recorded from the Udzungwa Mts, Tanzania. A complete overview of the 39 odontopygid species now known from the Udzungwa Mts is given, including notes on endemism, biogeographical relationships and altitudinal distribution patterns.
A group of Amazonian harvestmen is recognized and described as Amazochroma gen. nov. This taxon includes Discocyrtus carvalhoi Mello-Leitão, 1941 (type species), the only species of Discocyrtus previously thought to occur in Amazonia, and Amazochroma pedroi gen. et sp. nov., described here from the Brazilian states of Acre and Rondônia. New records are added for Amazochroma carvalhoi gen. et comb. nov, expanding its distribution from the Brazilian state of Mato Grosso northwards also to Pará and Amazonas in Brazil and additionally French Guiana and Suriname. Diagnostic features of Amazochroma gen. nov. include: trichromatic pattern of legs, dry marks on the dorsal scutum and base of legs and diastema in the row of macrosetae C of the penis ventral plate. A morphological maximum parsimony analysis (1022 scorings; 16 taxa; 64 characters) is performed to test whether Amazochroma gen. nov. is a member of Discocyrtus and if the traditional allocation of Discocyrtus in Pachylinae is defendable. A clade is retrieved containing three groups: Amazochroma carvalhoi gen. et comb. nov, here described as a new subfamily of Gonyleptidae - Roeweriinae subfam. nov. Discocyrtanus Roewer, 1929 and Roeweria Mello-Leitão, 1923 are accordingly here transferred from Pachylinae to Roeweriinae subfam. nov.
The species of the subgenus Conocetus Desbrochers des Loges, 1875 are reviewed and Polydrusus (Conocetus) transjordanus sp. nov. is described. Upon examination of the holotype of Polydrusus bardus Gyllenhal, 1834, it was observed that the species hitherto determined sensu auctorum as P. bardus was a misidentification. The specimen in question was therefore unnamed and is thus newly described as Polydrusus (Conocetus) crinipes sp. nov. Polydrusus femoratus (Stierlin, 1888) is a junior synonym of P. angustus (Lucas, 1854). Polydrusus gracilicornis Kiesenwetter, 1864, P. cylindrithorax (Desbrochers des Loges, 1900) and P. quadraticollis (Desbrochers des Loges, 1902) are proposed as junior synonyms of P. bardus. Polydrusus zurcheri (Schilsky, 1912) is proposed as a junior synonym of P. grandiceps (Desbrochers des Loges, 1875). Polydrusus kahri Kirsch, 1865 is transferred from subgenus Conocetus to Denticonocetus subgen. nov., with P. siculus Desbrochers des Loges, 1872 and P. vodozi Desbrochers des Loges, 1903 both recognized as new junior synonyms of P. kahri. The lectotypes of P. gracilicornis, P. zurcheri, P. marcidus Kiesenwetter, 1864, P. gracilis (Stierlin, 1888), P. rhodiacus (Schilsky, 1912) and P. grandiceps are designated. A key, figures, label data and distribution maps are provided for all species, except for P. longus (Stierlin, 1884), for which no specimens were available for examination, and whose placement in the subgenus Conocetus remains uncertain (thus categorized as incertae sedis). Polydrusus angustus is recorded for the first time for Italy, P. rhodiacus for mainland Turkey and P. festae (Solari, 1925) for Greece.
Regulation of the antiapoptotic protein cFLIP by the glucocorticoid Dexamethasone in ALL cells
(2018)
We recently reported that the Smac mimetic BV6 and glucocorticoids, e.g. Dexamethasone (Dexa), synergize to induce cell death in acute lymphoblastic leukemia (ALL) in vitro and in vivo. Here, we discover that this synergism involves Dexa-stimulated downregulation of cellular FLICE-like inhibitory protein (cFLIP) in ALL cells. Dexa rapidly decreases cFLIPL protein levels, which is further enhanced by addition of BV6. While attenuating the activation of non-canonical nuclear factor-kappaB (NF-κB) signaling by BV6, Dexa suppresses cFLIPL protein but not mRNA levels pointing to a transcription-independent downregulation of cFLIPL by Dexa. Analysis of protein degradation pathways indicates that Dexa causes cFLIPL depletion independently of proteasomal, lysosomal or caspase pathways, as inhibitors of the proteasome, lysosomal enzymes or caspases all failed to protect from Dexa-mediated loss of cFLIPL protein. Also, Dexa alone or in combination with BV6 does not affect overall activity of the proteasome. Importantly, overexpression of cFLIPL to an extent that is no longer subject to Dexa-imposed downregulation rescues Dexa/BV6-mediated cell death. Vice versa, knockdown of cFLIP increases BV6-mediated cell death, thus mimicking the effect of Dexa. Altogether, these data demonstrate that Dexa-mediated downregulation of cFLIPL protein promotes Dexa/BV6-mediated cell death, thereby providing novel insights into the synergistic antitumor activity of this combination treatment.
Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of “classical” vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine.
The mechanisms involved in malignant transformation of mature B and T lymphocytes are still poorly understood. In a previous study, we compared gene expression profiles of the tumor cells of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) to their normal cellular counterparts and found the basic leucine zipper protein ATF-like 3 (BATF3) to be significantly upregulated in the tumor cells of both entities. To assess the oncogenic potential of BATF3 in lymphomagenesis and to dissect the molecular interactions of BATF3 in lymphoma cells, we retrovirally transduced murine mature T and B cells with a BATF3-encoding viral vector and transplanted each population into Rag1-deficient recipients. Intriguingly, BATF3-expressing B lymphocytes readily induced B-cell lymphomas after characteristic latencies, whereas T-cell transplanted animals remained healthy throughout the observation time. Further analyses revealed a germinal center B-cell-like phenotype of most BATF3-initiated lymphomas. In a multiple myeloma cell line, BATF3 inhibited BLIMP1 expression, potentially illuminating an oncogenic action of BATF3 in B-cell lymphomagenesis. In conclusion, BATF3 overexpression induces malignant transformation of mature B cells and might serve as a potential target in B-cell lymphoma treatment.
Titanium is a biocompatible material that is frequently used for making implantable medical devices. Nanoengineering of the surface is the common method for increasing material biocompatibility, and while the nanostructured materials are well-known to represent attractive substrata for eukaryotic cells, very little information has been documented about the interaction between mammalian cells and bactericidal nanostructured surfaces. In this study, we investigated the effect of bactericidal titanium nanostructures on PC12 cell attachment and differentiation—a cell line which has become a widely used in vitro model to study neuronal differentiation. The effects of the nanostructures on the cells were then compared to effects observed when the cells were placed in contact with non-structured titanium. It was found that bactericidal nanostructured surfaces enhanced the attachment of neuron-like cells. In addition, the PC12 cells were able to differentiate on nanostructured surfaces, while the cells on non-structured surfaces were not able to do so. These promising results demonstrate the potential application of bactericidal nanostructured surfaces in biomedical applications such as cochlear and neuronal implants.
A large body of evidence suggests that the 11+ warm-up programme is effective in preventing football-related musculoskeletal injuries. However, despite considerable efforts to promote and disseminate the programme, it is unclear as to whether team head coaches are familiar with the 11+ and how they rate its feasibility. The present study aimed to gather information on awareness and usage among German amateur level football coaches. A questionnaire was administered to 7893 individuals who were in charge of youth and adult non-professional teams. Descriptive and inferential statistics were used to analyse the obtained data. A total of 1223 coaches (16%) returned the questionnaire. There was no risk of a non-response bias (p>.05). At the time of the survey, nearly half of the participants (42.6%) knew the 11+. Among the coaches who were familiar with the programme, three of four reported applying it regularly (at least once per week). Holding a license (φ = .28, p < .0001), high competitive level (Cramer-V = .13, p = .007), and coaching a youth team (φ = .1, p = .001) were associated with usage of 11+. Feasibility and suitability of the 11+ were rated similarly by aware and unaware coaches. Although a substantial share of German amateur level coaches is familiar with the 11+, more than half of the surveyed participants did not know the programme. As the non-usage does not appear to stem from a lack of rated feasibility and suitability, existing communication strategies might need to be revised.
The structural diversity of terpenoids is limited by the isoprene rule which states that all primary terpene synthase products derive from methyl-branched building blocks with five carbon atoms. With this study we discover a broad spectrum of novel terpenoids with eleven carbon atoms as byproducts of bacterial 2-methylisoborneol or 2-methylenebornane synthases. Both enzymes use 2-methyl-GPP as substrate, which is synthesized from GPP by the action of a methyltransferase. We used E. coli strains that heterologously produce different C11-terpene synthases together with the GPP methyltransferase and the mevalonate pathway enzymes. With this de novo approach, 35 different C11-terpenes could be produced. In addition to eleven known compounds, it was possible to detect 24 novel C11-terpenes which have not yet been described as terpene synthase products. Four of them, 3,4-dimethylcumene, 2-methylborneol and the two diastereomers of 2-methylcitronellol could be identified. Furthermore, we showed that an E. coli strain expressing the GPP-methyltransferase can produce the C16-terpene 6-methylfarnesol which indicates the condensation of 2-methyl-GPP and IPP to 6-methyl-FPP by the E. coli FPP-synthase. Our study demonstrates the broad range of unusual terpenes accessible by expression of GPP-methyltransferases and C11-terpene synthases in E. coli and provides an extended mechanism for C11-terpene synthases.
Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies.
In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95–1.02) in group A, 0.98 (0.93–1.04) in group B, and 0.95 (0.89–1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07–1.23) in group A, 1.13 (1.05–1.22) in group B, and 1.12 (1.05–1.20) in group C.
Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Empiric antibiotics are often used in combination with mechanical debridement to treat patients suffering from periodontitis and to eliminate disease-associated pathogens. Until now, only a few next generation sequencing 16S rDNA amplicon based publications with rather small sample sizes studied the effect of those interventions on the subgingival microbiome. Therefore, we studied subgingival samples of 89 patients with chronic periodontitis (solely non-smokers) before and two months after therapy. Forty-seven patients received mechanical periodontal therapy only, whereas 42 patients additionally received oral administered amoxicillin plus metronidazole (500 and 400 mg, respectively; 3x/day for 7 days). Samples were sequenced with Illumina MiSeq 300 base pairs paired end technology (V3 and V4 hypervariable regions of the 16S rDNA). Inter-group differences before and after therapy of clinical variables (percentage of sites with pocket depth ≥ 5mm, percentage of sites with bleeding on probing) and microbiome variables (diversity, richness, evenness, and dissimilarity) were calculated, a principal coordinate analysis (PCoA) was conducted, and differential abundance of agglomerated ribosomal sequence variants (aRSVs) classified on genus level was calculated using a negative binomial regression model. We found statistically noticeable decreased richness, and increased dissimilarity in the antibiotic, but not in the placebo group after therapy. The PCoA revealed a clear compositional separation of microbiomes after therapy in the antibiotic group, which could not be seen in the group receiving mechanical therapy only. This difference was even more pronounced on aRSV level. Here, adjunctive antibiotics were able to induce a microbiome shift by statistically noticeably reducing aRSVs belonging to genera containing disease-associated species, e.g., Porphyromonas, Tannerella, Treponema, and Aggregatibacter, and by noticeably increasing genera containing health-associated species. Mechanical therapy alone did not statistically noticeably affect any disease-associated taxa. Despite the difference in microbiome modulation both therapies improved the tested clinical parameters after two months. These results cast doubt on the relevance of the elimination and/or reduction of disease-associated taxa as a main goal of periodontal therapy.
After entorhinal deafferentiation of the hippocampal dentate gyrus a reinnervation of the denervated neurons by axon collaterals can be observed. This process takes place in a matter of weeks. However, the overall functional effect on the hippocampal network is still unclear.
In an effort to investigate this effect of axonal sprouting on the neuronal network of the dentate gyrus we compared the electrophysiological response of the dentate gyrus after electric stimulation in wild-type mice (WT mice) with a normal post-lesion sprouting, with genetically modified mice with an overexpression of the growth-protein CAP23 (cytoskeleton-associated protein 23). CAP23 overexpressing mice (CAP23tg mice) are known to have an enhanced axonal growth and sprouting after lesion.
The mice (both the WT as well as the CAP23tg mice) were deeply anesthetized and a lesion of the perforant path was induced stereotactically with a wire knife. After that the mice were permitted to survive for 4-6 weeks for partial reinnervation of the dentate gyrus before they were again operated and evoked potentials were measured (extracellular recordings of evoked potentials in the dentate gyrus). Non-lesioned litter-mate mice were taken as reference. The sprouting and the correct position of the electrodes was confirmed histologically.
For electrophysiological investigation we assessed laminar profiles and calculated a current-source density (CSD). In lesioned CAP23tg mice compared to lesioned WT mice this CSD-analysis revealed a significant enhancement of the current sink in the area of deafferentiation (outer molecular layer) and a significant excitation in the granule-cell layer.
Our results show that axonal sprouting seems to enhance the excitability of granule-cells. Thus, even if an enhanced axonal sprouting might accelerate the reinnervation of denervated dendrites after lesion, but it also leads to posttraumatic hyperexcitability of the neuronal network. In a therapeutic approach of fascilitating axonal sprouting this hyperexcitability has to be taken into consideration.
Objective: The present study aims to elucidate the state of gender equality in high-quality dermatological research by analysing the representation of female authorships from January 2008 to May 2017.
Design: Retrospective, descriptive study.
Setting: 113 189 male and female authorships from 23 373 research articles published in 23 dermatological Q1 journals were analysed with the aid of the Gendermetrics Platform.
Results: 43.0% of all authorships and 50.2% of the firstauthorships, 43.7% of the coauthorships and 33.1% of the last authorships are held by women. The corresponding female-to-male ORs are 1.41 (95% CI 1.37 to 1.45) for first authorships, 1.07 (95% CI 1.04 to 1.10) for coauthorships and 0.60 (95% CI 0.58 to 0.62) for last authorships. The annual growth rates are 1.74% overall and 1.45% for first authorships, 1.53% for coauthorships and 2.97% for last authorships. Women are slightly under-represented at prestigious authorships compared with men (Prestige Index=−0.11). The under-representation remains stable in highly competitive articles attracting the highest citation rates, namely, articles with many authors and articles that were published in highest-impact journals. Multiauthor articles with male key authors are only slightly more frequently cited than those with female key authors. Women publish slightly fewer papers compared with men (47.2% women hold 43.0% of the authorships). At the level of individual journals, there is a high degree of uniformity in gender-specific authorship odds. By contrast, distinct differences at country level were revealed. The prognosis for the next decades forecasts a consecutive harmonisation of authorship odds between the two genders.
Conclusions: In high-quality dermatological research, the integration of female scholars is advanced as compared with other medical disciplines. A gender gap consists mainly in the form of a career dichotomy, with many female early career researchers and few women in academic leadership positions. However, this gender gap has been narrowed in the last decade and will likely be further reduced in the future.
In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group.
Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed.
No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P < .001, P = .022 and P = .0042, respectively). Recipient preoperative and perioperative characteristics were comparable. Postoperatively in group 1 there was a higher incidence of extracorporeal life support (27.3 vs 9.1%, P = .019). There were no significant differences in chronic lung allograft dysfunction-free survival between group 1 and 2: 92.3 vs 94% at 1 year and 65.9 vs 75.5% at 3 years (P = .99). The estimated cumulative survival rate was also similar between groups: 68.2 vs 83.2% at 1 year and 68.2% versus 72% at 3 years (P = .3758).
Hanging as a donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation.
Das menschliche Leben erscheint heute als in vielfältiger Weise mit seiner Umwelt verbunden. Bio- und neurowissenschaftliche Forschungen über die Interaktionsweisen mit der Umwelt verändern dabei das Bild des Körpers von einem hierarchisch aufgebauten Organismus zu einem organisch-kognitiv-verteilten Netzwerk. Nicht zuletzt Forschungen zur künstlichen Intelligenz haben gezeigt, dass das menschliche Gehirn nicht isoliert betrachtet werden kann, sondern verkörpert, vernetzt und damit in einer wechselwirkenden Abhängigkeit zu Körpern steht (embedded und extended mind). Epigenetische Forschungen haben ebenfalls auf die Umweltabhängigkeit auch genetischer Prozesse verwiesen (Postgenomik) und damit auf komplexe Wechselwirkungen zwischen Biotischem und Abiotischem aufmerksam gemacht. Diese komplexen Wechselwirkungen und Umweltabhängigkeiten zwischen Lebendigem und Nicht-Lebendigem werden inzwischen zusehends zum Gegenstand menschlicher Selbstorganisation. Sie tauchen in veränderter Form in den Plänen zu den sogenannten Industrien 4.0 auf, wenn es darum geht, intelligente Umgebungen mit dem Menschen interaktiv zu vernetzen. Die hierfür notwendigen digitalen Datenmengen stehen aber nur zur Verfügung, wenn Menschen sich aktiv vernetzen. Die Entstehung digitaler Daten- körper wird dadurch zu einem essentiellen Bestandteil sozialer Teilhabe, wodurch Soziales zum entwicklungsoffenen und unbestimmten Prozess wird. Wie sich Menschen wann und wo vernetzen, ist nicht vorherbestimmt. Digitalisierung ist dabei, so die These der Arbeit, sich zur grundlegenden Praxis menschlicher Vernetzung zu entwickeln.
Die Arbeit geht Digitalisierung aus einer Perspektive koevolutionärer Entstehungs- und Entwicklungszusammenhänge nach und zeigt, dass digitale Praxen zu einer neuen Form menschlicher Selbstorganisation weltweit geworden sind. Angesprochen wird damit, dass Digitalisierung nicht als etwas dem Menschen Äußerliches betrachtet werden kann, sondern in einen größeren kulturellen Entstehungszusammenhang eingebettet werden muss, der bis zu den Anfängen der Menschheit zurückreicht. Um dies zu veranschaulichen, werden in der Arbeit drei verschiedene Wissensformationen benannt, die sich jeweils in unterschiedlicher Art und Weise mit den aktuellen Veränderungen digitalisierter Lebenswelten auseinandersetzen.
Die erste Wissensformation (Kapitel 2) benennt den Humanismus, der im Aufkommen neuer Medientechnologien eine Bedrohung für den Menschen sieht. Eine zweite Wissensformation (Kapitel 3) widmet sich dem „Ende des Humanismus“, indem Ansätze der Science and Technology Studies (STS), der Akteur-Network-Theory (ANT) und des Agentiellen Realismus von Karan Barad diskutiert werden. Mit einer „neuen Ökonomie für eine neue Menschheit“ wird eine dritte Wissensformation (Kapitel 4) benannt, die, von postoperaistischen Ansätzen ausgehend, die These eines „dritten“ oder „kognitiven Kapitalismus“ diskutiert. Hier geht es um die These des Zusammenfallens von Ökonomischem und Sozialem, aus dem neue offene Sozialformationen entstehen. Schließlich wird eine vierte Wissensformation (Kapitel 5) formuliert, die, ausgehend vom Ansatz einer Anthropologie des Medialen (AdM) und dem Modell der Erweiterung kultureller Kapazitäten (EECC) versucht, die als digitalen Wandel bezeichneten Veränderungen in einen größeren Zusammenhang zu stellen.
Mit beiden Ansätzen kann schließlich gezeigt werden, dass sich Veränderungen menschlicher Selbstorganisation immer in der biologischen, individuellen, kulturellen und historisch-sozialen Entwicklungsdimension zugleich vollziehen. Dies lässt sich auch für die Prozesse der Digitalisierung zeigen. Nämlich, dass sich der Mensch als Teil der Natur in einem fortwährenden koevolutionären Prozess befindet. Weder Kultur, noch Soziales, noch Technologien sind unnatürlich. Sie können als „indirekte Biologie“, als „Künstliches“ oder als „Kultur der Biologie“ bezeichnet werden, die der Natur aber nie entkommen. Die Erweiterung kultureller Kapazitäten ist deshalb nicht als eine Ausdehnung des Menschen in die Natur hinaus zu verstehen, sondern bezeichnet die im Laufe der Menschheitsgeschichte komplexer werdenden Reichweiten und Zeittiefen menschlicher Selbstorganisation, die immer auf den drei Ebenen von Phylogenese, Ontogenese, Technogenese und der damit verbundenen Soziogenese basieren.
This study aimed to appraise two quantitative magnetic resonance imaging techniques, T2* imaging and diffusion-weighted imaging (DWI), for the diagnosis of the intervertebral disc degeneration of the cervico-thoracic junction. Influence of specific factors and diagnostic accuracy of both techniques were particularly explored. Sixty-one volunteers with neck and upper back pain were recruited and evaluated with both T2* imaging and DWI. The Pfirrmann grade, T2* relaxation time and apparent diffusion coefficient (ADC) value of each disc between C7 and T3 were recorded. Stratified analyses were performed for different anatomic levels, genders, age ranges and Pfirrmann grades. The diagnostic accuracy of both techniques was investigated using the receiver operating characteristic (ROC) curves. No statistically significant difference of either T2* relaxation time or ADC value was detected between males and females. Both parameters decreased with the increasing age and Pfirrmann grade. The ROC curves showed the higher sensitivity and specificity for T2* imaging than DWI to quantitatively identify the disc degeneration. Particularly, T2* imaging allowed for a quantitative distinguishing the normal, mild and moderate disc degeneration from the severe degeneration, which was unable to accomplish with DWI. In conclusion, we demonstrated that T2* imaging possess a better accuracy than DWI to quantitatively diagnose the intervertebral disc degeneration at the cervico-thoracic junction.
Perception, particularly in the visual domain, is drastically influenced by rhythmic changes in ambient lighting conditions. Anticipation of daylight changes by the circadian system is critical for survival. However, the neural bases of time-of-day-dependent modulation in human perception are not yet understood. We used fMRI to study brain dynamics during resting-state and close-to-threshold visual perception repeatedly at six times of the day. Here we report that resting-state signal variance drops endogenously at times coinciding with dawn and dusk, notably in sensory cortices only. In parallel, perception-related signal variance in visual cortices decreases and correlates negatively with detection performance, identifying an anticipatory mechanism that compensates for the deteriorated visual signal quality at dawn and dusk. Generally, our findings imply that decreases in spontaneous neural activity improve close-to-threshold perception.
Ideally located in the writer's position of the voice "contractus (& quasi contractus)" of the Dictionary, the author of this paper tries to discover the difficulties that his drafting could imply. The difficulties encountered come mainly from the chronology and the diversity of profiles between the members of the Salamanca School that deal with contracts, from the unusual historical and material extension of the elements they work with and from the need to understand their methods, their initial assumptions and the aims they pursue. At the end, some practical considerations are offered to the voice's drafting.
Reconstructing the evolution of baleen whales (Mysticeti) has been problematic because morphological and genetic analyses have produced different scenarios. This might be caused by genomic admixture that may have taken place among some rorquals. We present the genomes of six whales, including the blue whale (Balaenoptera musculus), to reconstruct a species tree of baleen whales and to identify phylogenetic conflicts. Evolutionary multilocus analyses of 34,192 genome fragments reveal a fast radiation of rorquals at 10.5 to 7.5 million years ago coinciding with oceanic circulation shifts. The evolutionarily enigmatic gray whale (Eschrichtius robustus) is placed among rorquals, and the blue whale genome shows a high degree of heterozygosity. The nearly equal frequency of conflicting gene trees suggests that speciation of rorqual evolution occurred under gene flow, which is best depicted by evolutionary networks. Especially in marine environments, sympatric speciation might be common; our results raise questions about how genetic divergence can be established.
Diagnostic approaches for invasive aspergillosis—specific considerations in the pediatric population
(2018)
Invasive aspergillosis (IA) is a major cause of morbidity and mortality in children with hematological malignancies and those undergoing hematopoietic stem cell transplantation. Similar to immunocompromised adults, clinical signs, and symptoms of IA are unspecific in the pediatric patient population. As early diagnosis and prompt treatment of IA is associated with better outcome, imaging and non-invasive antigen-based such as galactomannan or ß-D-glucan and molecular biomarkers in peripheral blood may facilitate institution and choice of antifungal compounds and guide duration of therapy. In patients in whom imaging studies suggest IA or another mold infection, invasive diagnostics such as bronchoalveolar lavage and/or bioptic procedures should be considered. Here we review the current data of diagnostic approaches for IA in the pediatric setting and highlight the major differences of performance and clinical utility of the tests between children and adults.
Background: Anger and aggression belong to the core symptoms of borderline personality disorder. Although an early and specific treatment of BPD is highly relevant to prevent chronification, still little is known about anger and aggression and their neural underpinnings in adolescents with BPD.
Method: Twenty female adolescents with BPD (age 15–17 years) and 20 female healthy adolescents (age 15–17 years) took part in this functional magnetic resonance imaging (fMRI) study. A script-driven imagery paradigm was used to induce rejection-based feelings of anger, which was followed by descriptions of self-directed and other-directed aggressive reactions. To investigate the specificity of the neural activation patterns for adolescent patients, results were compared with data from 34 female adults with BPD (age 18–50 years) and 32 female healthy adults (age 18–50 years).
Results: Adolescents with BPD showed increased activations in the left posterior insula and left dorsal striatum as well as in the left inferior frontal cortex and parts of the mentalizing network during the rejection-based anger induction and the imagination of aggressive reactions compared to healthy adolescents. For the other-directed aggression phase, a significant diagnosis by age interaction confirmed that these results were specific for adolescents.
Discussion: The results of this very first fMRI study on anger and aggression in adolescents with BPD suggest an enhanced emotional reactivity to and higher effort in controlling anger and aggression evoked by social rejection at an early developmental stage of the disorder. Since emotion dysregulation is a known mediator for aggression in BPD, the results point to the need of appropriate early interventions for adolescents with BPD.
Die vorliegende Arbeit befasst sich damit, wie die spezifische Durchführung eines besonderen psychologischen Laborexperiments in eine allgemeine, kausale Form übersetzt wird. Anstatt dazu formale Kriterien der Validität heranzuziehen, wird ein experimenteller Forschungsprozess ethnographisch begleitet.
Forschungsgegenstand ist ein Verhaltensexperiment aus der allgemeinen Psychologie zur Trainierbarkeit des Arbeitsgedächtnisses. Im Rahmen der Ethnographie werden teilnehmende Beobachtungen, Interviews und Dokumentensammlung kombiniert eingesetzt. Die Auswertung der Materialien erfolgt mithilfe der Situationsanalyse nach Clarke (2012), einer qualitativen Auswertungsmethode im Anschluss an die Grounded Theory.
In dieser Arbeit wird das Verhalten der Versuchsperson ins Zentrum gerückt, das die Messung in Gang setzt und hält und die Entstehung von zahlenförmigen Daten ermöglicht. Dazu wird in Orientierung an neueren Science & Technology Studies eine begriffliche Systematisierung der Experimentalpraxis aus dem empirischen Material herausgearbeitet, mit dem die Konstruktion und Transformation des Verhaltens der Versuchsperson im Verlauf des Datenerhebungs- Auswertungs- und Interpretationsprozesses beschrieben werden kann.
Die Ergebnisse der Ethnographie legen nahe, dass dieses Verhalten der Versuchsperson - korrespondierend zum kausal verfassten Endprodukt des Experiments - von der komplexen Erhebungssituation abhängig und paradoxerweise gleichzeitig unabhängig ist. Damit wird in Anlehnung an Latour (2002) zwischen konstruktivistischen und objektivistischen Positionen vermittelt. Zudem weisen die erforschten Praktiken die epistemische Stellung der Versuchsperson aus. Diese wird im Anschluss an die Terminologie von Rheinberger (2001/ 2006) als Mischform von epistemischem Ding (Neues) und technischem Ding (Bekanntes) bestimmt.
G-protein coupled receptors (GPCRs) are a predominant class of cell-surface receptors in eukaryotic life. They are responsible for the perception of a broad range of ligands and involved in a multitude of physiological functions. GPCRs are therefore of crucial interest for biological and pharmaceutical research. Molecular analysis and functional characterisation of GPCRs is frequently hampered by challenges in efficient large-scale production, non-destructive purification and long-term stability. Cell-free protein synthesis (CFPS) provides new production platforms for GPCRs by extracting the protein synthesis machinery of the cell in an open system that allows target-oriented modulations of the synthesis process and direct access to the nascent polypeptide chain. CFPS is fast, reliable and highly adaptable. Unfortunately, highly productive cell-free synthesis of GPCRs is often opposed by low product quality. This thesis was aimed to adapt and improve some of the new possibilities for the cell-free production of GPCRs in high yield and quality for structural and pharmaceutical analysis. An E. coli based CFPS system was applied to synthesise various turkey and human Beta-adrenergic receptor (Beta1AR) derivatives as well as human Endothelin receptors type A and B (ETA and ETB) constructs. Both receptor families are important drug targets and pharmacologically addressed in the treatment of several cardiovascular diseases. CF-synthesis was mainly performed in presence of nanodiscs (ND), which are reconstituted high density lipoprotein particles forming discoidal bilayer patches with a diameter varyring from 6 to approx. 15 nm. The supplementation of ND in the CF-synthesis reaction caused the co-translational solubilisation of the freshly synthesised GPCRs. The fraction of the solubilised GPCR that was correctly folded was analysed by the competence to bind its ligand alprenolol or Endothelin-1, respectively. Both the solubilisation efficiency and the ability to fold in a ligand binding competent state was strongly affected by the lipid composition of the supplied ND. Best results were generally achieved with lipids having phosphoglycerol headgroups and unsaturated fatty acid chains with 18 carbon atoms. Furthermore, thermostabilisation by introduction of point mutations had a large positive impact on the folding efficiency of both Beta1AR and ETB receptor. Formation of a conserved disulphide bridge in the extracellular region was additionally found to be crucial for the function of the ETB receptor. Disulphide bridge formation could be enhanced by applying a glutathione-based redox system in the CFPS. Further improvements in the quality of ETB receptor could be made by the enrichment of heat-shock chaperones in the CF-reaction. Depending on the receptor type and DNA-template, roughly 10 – 30 nmol (350 – 1500 µg) of protein could be synthesised in 1 ml of CF-reaction mixture. After the applied optimisation steps, the fractions of correctly folded receptor could be improved by several orders of magnitude and were finally in between 35% for the thermostabilised turkey Beta1AR, 9% for the thermostabilised ETB receptor, 6.5% for the non-stabilised ETB receptor, 1 - 5% for non-stabilised turkey Beta1AR and for human Beta1AR isoforms and 0.1% for ETA receptor. Therefore, between 2 and 120 µg of GPCR could be synthesised in a ligand binding competent form, depending on the receptor and its modifications. Correctly folded turkey Beta1AR and ETB receptors were thermostable at 30°C and could be stored at 4°C for several weeks after purification. Yields of the thermostabilised turkey Beta1AR were sufficient to purify the receptor in a two-step process by ligand-binding chromatography to obtain pure and correctly folded receptor in the lipid bilayer of a ND. Furthermore, a lipid dependent ligand screen could be demonstrated with the turkey Beta1AR and significant alterations in binding affinities to currently in-use pharmaceuticals were found. The established protocols are therefore suitable and highly competetive for a variety of applications such as screening of GPCR ligands, analysis of lipid effects on GPCR function or for the systematical biochemical characterisation of GPCRs. Most promising for future approaches appears to address the suspected bottlenecks of intial insertion of the GPCR-polypeptide chain in the ND bilayer and the thermal stability of the receptors. Nevertheless, the estabilised protocols for the analysed targets in this thesis are already highly competitive to previously published production protocols either in cell-based or cell-free systems with regard to yield of functional protein, speediness and costs. Moreover, the direct accessibility and other general characteristics of cell-free synthesis open a large variety of possible applications and this work can therefore contribute to the molecular characterisation of this important receptor type and to the development of new pharmaceuticals.
An die Soziologie werden zunehmend Fragen des ökonomischen Nutzens und der gesellschaftlichen Relevanz herangetragen. Ein Wissen um den gesellschaftlichen Impact soziologischen Wissens und die Artikulation eines Nutzens für die Praxis sind wertvolle Werkzeuge im Kampf um die Alimentation soziologischer Forschung. Aber wie wird soziologisches Wissen überhaupt angewendet? Um diese Frage zu beantworten, wird soziologisches Wissen definiert und dessen Anwendung expliziert. Unter Zuhilfenahme von Wissenschaftstheorie und Wissenssoziologie wird zunächst eine Definition erarbeitet. Anschließend werden Forschungsgebiete, die sich mit der Anwendung von (soziologischen) Wissen beschäftigen, vorgestellt – allen voran die soziologische Verwendungsforschung. Darauf aufbauend wird eine Explikation der Anwendung soziologischen Wissens erarbeitet, vor dessen Hintergrund aktuelle Bemühungen, soziologisches Wissen stärker anzuwenden, betrachtet werden. Die abschließende Diskussion beschäftigt sich mit den Möglichkeiten und Restriktionen der Anwendung soziologischen Wissens und betont die Rolle der Soziologie als kritische gesellschaftliche Aufklärungsinstanz.
Trotz aller Unsicherheit und kritischer Infragestellung sind Kunstlandschaftsbezeichnungen – und damit auch der „Mittelrhein“ – als Hilfsbegriffe für die Lokalisierung der Kunstwerke noch immer gebräuchlich. Aber es ist ganz besonders problematisch, vom Mittelrhein um 1500 als „Kunstlandschaft“ zu sprechen. Schon die Umgrenzung der Region fällt unterschiedlich aus, und noch mehr sind die Kriterien schwankend, die im Vergleich zu anderen Regionen den Mittelrhein definieren sollen. Vorherrschend sind bei solchen Vergleichen nach wie vor Stilbegriffe, welche Vorbehalte gegenüber dem Begriff des Stils auch geäußert werden. So ist die Frage, ob die für den Mittelrhein vorgeschlagene Kennzeichnung „Stilheterogenität“ als Kriterium der Abgrenzung tauglich ist oder mehr eine methodische Verlegenheitslösung darstellt.
Die Untersuchung konzentriert sich auf das Schnitzretabel, das als Leitmedium der spätgotischen Kunst im deutschsprachigen Raum zu betrachten ist. Die analysierten Schnitzretabel sind als Fallstudien anzusehen, wobei hier vor allem jene analysiert worden sind, die einen guten Erhaltungszustand aufweisen. Zwar haben die wenigsten ihr ursprüngliches Aussehen bewahrt, aber entweder sind die Veränderungen nur minimal oder der originale Zustand ist gut rekonstruierbar, sodass die Werkgruppe trotz der Eingriffe als repräsentativ gelten kann. Neben den traditionellen Untersuchungsmethoden konnte die Infrarotreflektographie mit beweglicher Kamera (Osiris) eingesetzt werden. Es soll mit der Vorstellung einer Gattung ein Ausschnitt der in der Region präsenten Kunst ohne „mittelrheinische Vorentscheidungen“ gezeigt werden.
Die meisten analysierten Retabel entstammen der Rhein-Main-Region mit Frankfurt und Mainz als Oberzentren des Mittelrheins; Oberwesel, Speyer und Gelnhausen markieren die Grenze für die Auswahl. Die 27 Einzeluntersuchungen finden sich im Katalogteil der Arbeit, während deren zusammenfassende Darstellung – im Hinblick auf Methode, Standort, Auftraggeber, Künstler, Retabeltyp, Bildprogramm sowie Einflüsse – sowie Ergebnisse im Hauptteil besprochen werden.
The article is designed to introduce and analyze authoritarian constitutionalism as an important phenomenon in its own right, not merely a deficient or deviant version of liberal constitutionalism. Therefore it is not adequate to dismiss it as sham or window-dressing. Instead, its crucial features – participation as complicity, power as property and the cult of immediacy – are related to the basic assumption that authoritarian constitutions are texts with a purpose that warrant careful analysis of the domestic and transnational audience.
This dissertation discusses the mutual influence between leaders and followers on perception, emotion and behavior, using an attachment theory perspective. Some individuals are more likely to be seen as leaders than others. On the one hand this is determined by the characteristics or attributes as well as skills of the person in question. However, on the other hand, followers’ perception and expectations play a big role as well, in particular which expectations of an ideal leader can be fulfilled by followers’ current leader. Although attachment theory and – styles have only recently entered the organizational psychology literature, this dissertation advances that literature by looking at the role of attachment orientations between leaders and followers. In doing so, this dissertation answers several recent research calls on this topic. The three main subsequent chapters discuss the predictive role of attachment orientations with regard to leader preferences, the transference of behavioural expectations from one leader to another, and the perception of leader prototypicality in groups. The first chapter discusses the connection between implicit leader preferences and attachment orientations as predictors. Results show that avoidant attached individuals prefer a more autonomous and independent leadership style, whereas anxious attached individuals prefer a supportive and team-oriented leadership style. In the second chapter I study the transference of behavioural expectations from one leader to another. Results show that avoidant attached individuals are more likely to engage in this transference process. In addition, I discuss and empirically test the influence of culture with regard to leader transference. In the final chapter, I examine the behavioural influence of attachment orientations on how likely someone is perceived to be a leader in groups. Based on 57 project groups, I find that team members actually perceive avoidant attached individuals to be the most leader-like. Put differently, given certain environmental conditions, insecure attachment orientations can be perceived as leaders. These results show that it is even more important that leaders somewhat adapt to their followers’ preferences and not commit to merely one particular leadership style.
Cells within a tissue form highly complex, cellular interactions. This architecture is lost in two-dimensional (2D) cell cultures. To close the gap between 2D cell cultures and in vivo tissues, three-dimensional (3D) cell cultures such as spheroids or embryoid bodies were developed. To fully take advantage of the third dimension, imaging techniques are essential. The emerging field of "image-based systems biology" exploits the information in images and builds a connection between experimental and theoretical investigation of biological processes. Such interdisciplinary approaches strongly depend on the development of protocols to establish 3D cell cultures, innovations in sample preparation, well-suited imaging techniques and quantitative segmentation methods.
Although 3D cell cultures and image-based systems biology provide a great potential, 2D methods are still not completely replaced by 3D methods. This is mainly due to methodical and technical hurdles. Therefore, this thesis provides a significant contribution to overcome these hurdles and to further develop 3D cell cultures. I established computational and experimental methods related to 3D aggregates and investigated fundamental, cellular processes such as adhesion, growth and differentiation.
The automatic segmentation method "PAS" and "LoS" were developed in the context of this thesis. They extract essential biological properties such as the projected area or features of cell nuclei from 2D or 3D images of 3D aggregates. Both algorithms show their accuracy robustly over image data from different samples and different microscopes. In addition, the superior performance of PAS and LoS was proven in a comparison with state-of-the-art methods.
The PAS approach served as an essential basis for investigating cellular processes such as adhesion and growth which are tightly regulated to contribute to tissue integrity. These processes are involved in the formation of spheroids. The temporally resolved data of spheroid formation of three mammary epithelial cell lines revealed differences in their formation dynamics as well as in the onset of spheroid formation phases (aggregation, compaction and growth). Despite these differences, adhesion- and growth-associated proteins such as E-cadherin, actin, microtubules, and the focal adhesion kinase show similar importance in a particular phase. Notably, certain proteins (e.g. E-Cadherin) contribute differently to spheroid formation of cells from different cell types in terms of cell adhesion and growth. Overall, analyses of the individual phases of spheroid formation revealed the temporal coordination of fundamental tissue-specific processes. The results contribute to a better understanding of the maintenance and disruption of tissue integrity.
An important but yet unknown process is how cells accomplish to arrange themselves against the gravitational force to form a spheroid. Live imaging with light sheet-based microscopy provides the best solution for a temporally and in particular spatially resolved investigation of spheroid formation. Although the imaging possibilities increase with this particular microscopy technique, available sample preparation methods are rare. Therefore, I have significantly optimized "agarose beaker" as preparation method for 3D long-term imaging of spheroid formation. The data show that upward movement of the cells takes place early. This movement is initiated in the centre of the initially flat cell layer. Subsequently, the cells move from the periphery of the cell layer toward the centre. Cells rearrange within the spheroid which is followed by growth. It is very likely that 3D aggregates form by adopting an energetically favoured, spherical shape by increasing cell-cell or cell-matrix contacts.
Besides the knowledge gained from the examination of the self-assembly process in different contexts, fully formed cellular aggregates can serve as basis to investigate differentiation processes. Differentiation guide cell fate specification during early embryonic development (i.e. preimplantation) and is not fully understood yet. Due to the lack of an in vitro system for preimplantation, I have developed "blastoids". These are 3D multicellular aggregates of mouse embryonic stem cells which represent important phases of preimplantation and beyond. In qualitative and quantitative analyses, a strong similarity was proven between blastoids and the inner cell mass of in vivo mouse embryos. Further results strongly suggest that both, the cell number and the trophectoderm play a subordinate role for cell fate decision during preimplantation. Furthermore, 3D neighbourhood analyses have shown that both, blastoids and mouse embryos, do not show a random "salt-and-pepper" pattern during differentiation. Instead, they show a yet unknown local clustering of cells with identical fates, suggesting local cell interactions that influence cell fate decision. Furthermore, the data indicate that the maturation of the epiblast in the later stages of preimplantation is initiated by an interaction between cells of the epiblast and the primitive endoderm.
Using image-based systems biology, I have investigated fundamental cellular processes such as adhesion, growth and differentiation in the context of tissue integrity and early embryonic development using 3D cellular aggregates. This highly interdisciplinary work is a major contribution to 3D cell biology and demonstrates how cells bind and interact within a complex system. The main methods developed in this thesis as well as the biological findings can be used not only in further biological but also in medical and pharmacological studies. They have the potential to advance our understanding of complex biological systems and to provide new opportunities for practical applications.
Acute myeloid leukemia (AML) is a clonal malignancy of hematopoietic stem cells (HSCs) characterized by expansion of myeloid blasts in the bone marrow. It has been shown that autophagy is a degradative process, which delivers cytoplasmic components to lysosomes to prevent malignant transformation by maintaining HSC integrity. Besides its function as a bulk degradation machinery to recycle cytoplasmic components during limited energy supply, autophagy also serves as an intracellular quality control mechanism. Selective autophagy requires autophagy receptors such as p62 to specifically bridge the targeted cargos into autophagosomes. p62 is known as a central signaling hub involved in pro-oncogenic signaling pathways and autophagic degradation pathways. However, little is known about the role of p62 as a selective autophagy receptor in AML. This study aims to elucidate the precise function of p62 as an autophagy receptor in leukemia development and maintenance.
In silico analysis revealed that high p62 expression was significantly associated with poor overall survival of adult patients with de novo AML, suggesting that p62 may promote leukemia maintenance. To address the functional role of p62 in leukemia, genome editing by CRISPR/Cas9 was used to knockout p62 in four human AML cell lines. Importantly, p62 loss reduced cell proliferation in all four cell lines. This observation could be transferred to a murine leukemia cell model in which leukemic transformation of lineage-depleted bone marrow (ldMBM) cells was induced by overexpression of the human transcriptional coactivator MN1. Knockdown of p62 by shRNA in MN1-driven leukemia cells impaired proliferation and decreased colony forming ability without altering apoptosis. This indicates that p62 is crucial for leukemia proliferation in vitro. To further characterize the role of p62 in leukemia development and maintenance a murine AML transplantation model was established. Therefore, ldMBM cells isolated from WT and p62-/- mice were transduced with MN1 and transplanted into lethally irradiated mice. As expected, all mice developed fatal myeloid proliferation. Notably, p62 loss in MN1-driven leukemia significantly prolonged survival in mice and caused a more immature phenotype. Consistent with the in vitro results, ex vivo analysis of p62-/- leukemic cells displayed decreased colony-forming ability, although p62 loss did not affect composition and function of HSCs. Moreover, re-transplantation of primary MN1-driven leukemia cells attenuated leukemia progression upon p62 loss. These findings support a decisive role of p62 in leukemia development and maintenance.
To gain molecular insight into the function of p62 during myeloid transformation an interactome analysis of murine MN1-driven leukemia cells was performed. This revealed first that p62 predominantly interacts with mitochondrial proteins and second that inhibition of autophagic degradation causes accumulation of p62-bound mitochondria. This leads to the first assumption that loss of p62 may provoke mitochondrial accumulation with increasing mitochondrial damage and second that p62 may mediate degradation of mitochondria by mitophagy. Indeed, in the absence of p62, accumulation of dysfunctional mitochondria was detected by morphological changes of the mitochondria, increased mitochondrial ROS and impaired mitochondrial respiration capacity. Furthermore, induction of PINK1/Parkin-independent mitophagy revealed that loss of p62 caused impaired degradation of mitochondrial proteins and reduced translocation of damaged mitochondria into autophagosomes. Taken together, p62 is required for effective degradation of dysfunctional mitochondria by mitophagy in AML.
Due to the fact that p62 is a multifunctional protein, rescue experiments with different mutants of p62 were performed to clarify if p62-mediated mitophagy contributes to leukemia proliferation. Notably, the autophagy-deficient mutant (disabled to bind autophagosomes) reduced cell growth and colony-forming ability to the same extent as knockdown of p62, as the clustering-deficient mutant (disabled to form aggregates) displayed an intermediate phenotype. Strikingly, only the autophagy-deficient mutant failed to rescue mitophagy.
In conclusion, this study demonstrates the prominent role of p62 as a selective autophagy receptor for mitochondrial quality control which contributes to leukemia development and maintenance. Therefore, targeting selective autophagy opens new venues in the treatment of AML.
The pyrrolobenzodiazepine tilivalline (1) was originally identified in the human gut pathobiont Klebsiella oxytoca, the causative agent of antibiotic-associated hemorrhagic colitis. Here we show the identification of tilivalline and analogs thereof in the entomopathogenic bacterium Xenorhabdus eapokensis as well as the identification of its biosynthesis gene cluster encoding a bimodular non-ribosomal peptide synthetase. Heterologous expression of both genes in E. coli resulted in the production of 1 and from mutasynthesis and precursor directed biosynthesis 11 new tilivalline analogs were identified in X. eapokensis. These results allowed the prediction of the tilivalline biosynthesis being similar to that in K. oxytoca.
Im Kindes- und Jugendalter gehoert das Rhabdomyosarkom zu den haeufigsten Weichteilsarkomen. Bisher belaeuft sich das Therapieverfahren auf chirurgische Entfernung, gefolgt von Chemotherapie, bzw. bei nicht-operablen Faellen auf Radiotherapie und Chemotherapie, jedoch haben sich die Ueberlebenschancen fuer Patienten mit einer Erkrankung in metastasiertem oder rezidiviertem Stadium trotz intensiver Forschung ueber mehrere Jahrzehnte hinweg kaum gebessert und bleiben bei unter 30%. Neue therapeutische Strategien versuchen das Immunsystem des Patienten zu modulieren und dieses gezielter oder aggressiver gegen Tumorzellen zu machen. Nebst direkter Injektion von Zytokinen oder Antikoerpern bietet die adoptive Immunzelltherapie einen vielversprechenden Ansatz. In der vorliegenden Arbeit lag der Fokus auf Natuerlichen Killer- (NK) Zellen, da diese ein hohes zytotoxisches Potential gegenueber Tumorzellen aufweisen. Eine der groessten Herausforderungen der NK-Zellforschung ist die Breitstellung ausreichender Mengen an NK-Zellen mit optimaler antitumoraler Funktion fuer den klinischen Einsatz. Viele aktuell erprobte NK-Zellexpansionsstrategien basieren auf der Verwendung von Hilfs- oder Feeder-Zellen (Versorgerzellen), die jedoch vor der Applikation in Patienten aus dem finalen Produkt entfernt werden muessen. In der vorliegenden Arbeit sollten Feeder-zellfreie NK-Zellexpansionsprotokolle unter Verwendung von Gammakettenzytokinen getestet werden.
Interleukin (IL-) 15 erwies sich dabei vor allem fuer die Vermehrung der NK-Zellen als besonders foerderlich. Im Vergleich dazu fielen die Expansionsraten mit IL-2 oder IL-21 geringer aus. Interessanterweise wurde der expansionsfoerdernde Effekt von IL-15 durch dauerhafte Anwesenheit von IL-21 im Kulturmedium gehemmt. Ein kurzer, dreitaegiger IL-21-Boost am Ende der Expansionsphase wirkte sich wiederum positiv auf die NK-Zellexpansionsraten aus. Zudem zeigte sich durch IL-21 ein vermehrtes Auftreten von NK-Zellen des reiferen CD16posCD56dim Phaenotyps, der die zytotoxische Funktion vermittelt. Bei Degranulationsuntersuchungen wurden eine IL-21-induzierte Exozytoseaktivitaet und die vermehrte Ausschuettung von Perforin und Granzym B, welche Apoptose in den Zielzellen ausloesen, beobachtet. Vor allem der dreitaegige Boost mit IL-21 bewirkte eine gesteigerte Zytotoxizitaet gegenueber Tumorzellen, insbesondere gegenueber Rhabdomyosarkomzellen.
Auf dieser Grundlage bot es sich an fuer die NK-Zellexpansion ein Zwei-Phasen-Protokoll anzuwenden, bestehend aus einer initialen Proliferationsphase mit IL-15 und einem anschliessendem IL-21-Boost, durch den die antitumorale Funktionalitaet der NK-Zellen gesteigert wurde. Dieses IL-15+21boost-Protokoll wurde mit anderen Kombinationen aus den Gammakettenzytokinen IL-2, IL-15 und IL-21 verglichen und stellte sich hinsichtlich der NK-Zellexpansionsraten, der Degranulationskapazitaet und der damit verbundenen Zytotoxizitaet als den anderen Protokollen ueberlegen heraus.
Zytokinexpandierte NK-Zellen zeigten eine hoehere Rezeptorexpression an ihren Oberflaechen als unstimulierte Zellen. Die Expansion mit dem IL-15+21boost-Protokoll bewirkte die hoechste Dichte des Todesrezeptors TRAIL, jedoch auch der inhibitorischen KIR2D-Rezeptorfamilie. Fuer andere Oberflaechenmarker ergab sich jeweils eine mittlere Expressionsdichte verglichen mit dem IL-15- bzw. dem IL-15+21-Expansionsprotokoll. Die Sekretion von proinflammatorischen Zytokinen wie Interferon-gamma (IFN-g) und Tumor-Nekrose-Faktor-alpha (TNF-a) wurde zudem verstaerkt durch IL-21 angeregt, aber ebenso die Sekretion des immunsupprimierenden IL-10.
Weiter wurden die zytoinexpandierten NK-Zellen zur UEberpruefung ihrer in vivo Funktionalitaet anhand eines praeklinischen Xenograftmodells unter Verwendung von NOD SCID IL-2-Rgamma-/- (NSG) Maeusen und der Technologie der in-vivo-Biolumineszenzbildgebung getestet. Dabei konnte beobachtet werden, dass die NK-Zellen das Wachstum luciferaseexprimierender humaner Rhabdomyosarkome verlangsamten. Die Wirksamkeit der IL-15+21boost-expandierten NK-Zellen zeigte sich vor allem in einem kombinierten Ansatz, bei dem die Tumore zunaechst mit ionisierender Strahlung behandelt wurden und residuale Rhabdomyosarkomzellen anschliessend durch den adoptiven Transfer von humanen NK-Zellen in ihrem Wachstum gehemmt waren, solange die NK-Zelltherapie andauerte. Somit stellte sich die Kombination aus Bestrahlung und NK-Zelltransfer als wirksamer im Einsatz gegen Rhabdomyosarkome heraus als die alleinige Behandlung der Tumore durch Radiotherapie.
Zusammengefasst konnte in dieser Arbeit ein NK-Zellexpansionsprotokoll entwickelt werden, dass durch den ausschliesslichen Einsatz von Gammakettenzytokinen zu einem funktionalen NK-Zellprodukt fuehrte, welches auch in vivo lytische Aktivitaet gegenueber Rhabdomyosarkomzellen aufwies.