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Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2′3′-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2′3′-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2′3′-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
This policy note summarizes our assessment of financial sanctions against Russia. We see an increase in sanctions severity starting from (1) the widely discussed SWIFT exclusions, followed by (2) blocking of correspondent banking relationships with Russian banks, including the Central Bank, alongside secondary sanctions, and (3) a full blacklisting of the ‘real’ export-import flows underlying the financial transactions. We assess option (1) as being less impactful than often believed yet sending a strong signal of EU unity; option (2) as an effective way to isolate the Russian banking system, particularly if secondary sanctions are in place, to avoid workarounds. Option (3) represents possibly the most effective way to apply economic and financial pressure, interrupting trade relationships.
Joint Institutional Frameworks in bilateral relations are circumscribed in policy scope, can lack adequate instruments for dynamic adaptation and provide limited access to decision-making processes internal to the contracting parties. Informal governance, the involvement of private actors as well as rules such as equivalence provide avenues to remedy these limits in bilateral relations in sectoral governance. Through bilateral agreements, the scope of territorially bound political authority is expanded. The formalised and institutionalised frameworks and bodies established are, however, frequently accompanied by mechanisms of informal cooperation and special rules either to cover policy fields where no contractual relation exists, to provide for flexible solutions where needed, or to involve both public and private actors that otherwise do not have access to formal decision-making bodies. This SAFE working paper conceptualises formal and informal modes of cooperation and varying actor constellations. It discusses their relevance for the case of bilateral relations between the European Union (EU) and Switzerland in sectoral governance. More specifically, it draws lessons from EU-Swiss sectoral governance of financial and electricity markets for the future relations of the EU with the United Kingdom (UK). The findings suggest that there are distinct governance arrangements across sectors, while the patterns of sectoral governance are expected to look very much alike in the United Kingdom and Switzerland in the years to come. The general takeaway is that Brexit will have repercussions for the EU’s external relations with other third countries, putting ever more emphasis on formal and rule-based approaches, while leaving a need for sector-specific cross border co-operation.
Four new species of limnoterrestrial rhabdocoels (‘Typhloplanidae’ Graff, 1905) are described. One of these – Faunulus nielsi Houben, Proesmans & Artois gen. et sp. nov. – could not be unambiguously placed within an existing genus. Faunulus nielsi most closely resembles species of the genus Adenocerca Reisinger, 1924 but can be clearly distinguished by the position of the testes. The three other new species described are Bryoplana belgica Houben, Proesmans & Artois sp. nov., Hoplopera isis Houben, Proesmans & Artois sp. nov., and Protoplanella leiae Houben, Proesmans & Artois sp. nov. All three belong to the subfamily ‘Protoplanellinae’ Reisinger, 1924 and are distinguished based on a detailed description of the reproductive system. Finally, new data are provided for nine other, known typhloplanids: Adenocerca minima Kolasa, 1981; Chorizogynopora italica Kolasa, 1981; Hoplopera opaca Reisinger, 1924; K. subterranea Reisinger, 1933; Krumbachia virginiana (Kepner & Carter, 1931) Ruebush, 1938; Olisthanellinella rotundula Reisinger, 1924; Prorhynchella minuta Ruebush, 1939; Protoplanella simplex Reisinger, 1924; and Ventrociliella romanae Kolasa, 1977. A detailed comparison of our material of V. romanae to what is described for Bockia deses Reisinger, 1924, leads us to consider the latter a nomen dubium.
The blind and mostly endogean julid genus Stygiiulus Verhoeff, 1929 stat. nov. is reviewed to include ten species: S. ausugi (Manfredi, 1953) comb. nov., S. fimbriatus (Strasser, 1971) comb. et stat. nov., S. gentianae (Strasser, 1971) comb. et stat. nov., S. illyricus (Verhoeff, 1929) comb. nov., S. insularis (Strasser, 1938) comb. nov., S. maximus (Verhoeff, 1929) comb. nov., S. montellensis (Verhoeff, 1930) comb. nov., S. rotundatus (Strasser, 1962) comb. et stat. nov., S. seewaldi (Strasser, 1967) comb. nov., and S. tobias (Berlese, 1886) comb. nov. The distinctiveness of the genus from Typhloiulus is proven by both morphological and molecular data. The monotypic genus Alpityphlus Strasser, 1967 is here treated as a junior subjective synonym of Stygiiulus syn. nov. Stygiiulus fimbriatus comb. et stat. nov. and S. gentianae comb. et stat. nov., originally described as subspecies of S. ausugi comb. nov., are here erected to full species, while the subspecies S. illyricus stygis (Verhoeff, 1933) comb. et syn. nov. is considered to be a junior subjective synonym of the typical S. illyricus comb. nov. Lectotypes are formally designated for S. gentianae comb. et stat. nov. and S. rotundatus comb. et stat. nov., to stabilize the nomenclature of the two species under Article 74.1 of the ICZN. The phylogeny of the genus, its distribution patterns, and the modified mouthparts in some of its species are discussed.
A new species of the gecarcinucid freshwater crab genus, Spiralothelphusa Bott, 1968, is described from the Andhra Pradesh State of South India, with supporting data from mitochondrial cytochrome c oxidase subunit I. This brings the number of known species of Spiralothelphusa to seven, five from India and two from Sri Lanka. The identity of S. wuellerstorfi (Heller, 1862) has remained uncertain because the former lectotype designation was not clear. Bott (1968), while designating a male lectotype of S. wuellerstorfi from the Naturhistorisches Museum Wien, Vienna, Austria, had neither stated the catalogue number nor the size of the specimen. It is now difficult to trace the particular lectotype among several paralectotypes of the depository. A new lectotype is, therefore, designated herein for S. wuellerstorfi, and the species is redescribed. The new species, S. andhra sp. nov., has morphological affinities with S. wuellerstorfi, but can be distinguished from the latter species by the shape of the male telson and outer margin of the non-twisted portion of the male first gonopod. Phylogenetic analyses of the molecular data also corroborate their separation. An illustrated identification key is provided for the species of Spiralothelphusa.
Descriptions of the following 23 species of Macrotomoderus Pic, 1901 new to science, from continental China, are provided as an addition to the recently published review of the genus from China and Taiwan (Telnov 2018): M. angelinii, M. belousovi, M. bicrispus, M. boops, M. bordonii, M. dali, M. daxiangling, M. femoridens, M. hajeki, M. hartmanni, M. hengduan, M. imitator, M. kabaki, M. korolevi, M. lapidarius, M. muli, M. palaung, M. similis, M. tenuis, M. transitans, M. truncatulus, M. usitatus, and M. wudu spp. nov. Additional records are provided for some poorly known species. The identification key to the species of Macrotomoderus from China, the Japanese Archipelago, and Taiwan is herewith significantly supplemented and updated. Biogeographical peculiarities and altitudinal gradient of Macrotomoderus distribution in continental China are briefly discussed.