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Introduction: The rational development of new therapeutics requires a thorough understanding of how aberrant signalling affects cellular homeostasis and causes human disease. Chemical probes are tool compounds with well-defined mechanism-of-action enabling modulation of, for example, domain-specific protein properties in a temporal manner, thereby complementing other target validation methods such as genetic gain- and loss-of-function approaches.
Areas covered: In this review, the authors summarize recent advances in chemical probe development for emerging target classes such as solute carriers and ubiquitin-related targets and highlight open resources to inform and facilitate chemical probe discovery as well as tool compound selection for target validation and phenotypic screening.
Expert opinion: Chemical probes are powerful tools for drug discovery that have led to fundamental insights into biological processes and have paved the way for the development of first-in-class drugs. Open resources can inform on various aspects of chemical probe development and provide access to data and recommendations on use of chemical probes to catalyse collaborative science and help accelerate drug target identification and validation.
While the sortal constraints associated with Japanese numeral classifiers are well-studied, less attention has been paid to the details of their syntax. We describe an analysis implemented within a broad-coverage HPSG that handles an intricate set of numeral classifier construction types and compositionally relates each to an appropriate semantic representation, using Minimal Recursion Semantics.
Iqbal and Goethe : a note
(2005)
The recourse to Goethe plays an important role in the work of Mohammad Iqbal (1873-1938), one of the few important writers from the Indian subcontinent who knew German literature. Iqbal situates his own writing in the context of western colonial expansion and the corresponding world-historical loss of power of Islam in the East. The recourse to Goethe becomes an import reference point in his work. It enables him to stylise himself as a Messenger of the East in reply to Goethe as a representative of the West. By establishing a comparative cultural constellation with his German predecessor Iqbal affirms a cultural position consisting of a mode of historical complaint and cultural revival.
There are many aspects of Haas' life and experiences in India which deserve greater attention. I would like to refer briefly only to his attempts as a litterateur to come to terms with 'India' as presented in his autobiographical recollection and to some comparative cultural reflections in his essays. Like all reconstructions his autobiographical recollection of India is also a construct in which the site of India as a place of exile is justified by an achieved awareness between conscious individual choice and inevitability. An individual acts out a personal history, the prefiguration of which he only becomes aware of in the form of a subsequent epiphanic realization. Given Haas' literary background, it is not surprising that this is articulated through a literary association.
Four new species of the genus Sokoloviana (Pterolichoidea; Ptiloxenidae) from waders suborder Charadrii (Charadriiformes) are described: Sokoloviana cornuta sp. nov. from the Banded Stilt, Cladorhynchus leucocephalus; Sokoloviana ibidorhynchae sp. nov. from the Ibis-bill, Ibidorhyncha strutersi; Sokoloviana chilensis sp. nov. from the Southern Lapwing, Vanellus chilensis and Sokoloviana vanelli sp. nov. from the Red-wattled Lapwing, Vanellus indicus atronuchalis. A key to all described species is given.
When, some two centuries ago, German Romantics turned their backs on modernity – industrialisation, urbanisation, commerce and secularisation – they turned to ancient India. For them, India exemplified the primordial unity of mankind with this and the afterworld. For sections of the emerging nationalist movement in Germany, found the deployment of India handy to question the cultural hegemony, and eventually break the political dominance, of France. They tried to surpass the French, who claimed the ancient Roman heritage, by claiming an even older heritage for the Germans. Friedrich Schlegel for example suggested that the German language, and not the French, stood in unbroken continuity with ancient Sanskrit. For Romantics such as he, Sanskrit, the oldest surviving Indo-European language, was closest to the language of original divine revelation. This lead Schlegel to romanticise India in a way that stood in marked contrast to the Orientalist clichés current in other parts of Europe at the time. For him, the link between Sanskrit and German made Germany the true oriental self of Europe. The importance of this particular representation of India for the German national movement is underlined by the great number of university chairs that sprang up in the course of the nineteenth century: twenty two in Germany as opposed to only three in the United Kingdom. This paper explores the particular kind of ‘inverse’ Orientalism of the Germans in the context of its recent post-colonial critique.
Pope Benedict XVI’s Regensburg lecture has been exposed by some learned voices of 'the Muslim world' as alluding, by the means of one particular quotation, to age-old stereotypes about Islam being an essentially violent creed in which moderation through reason has no legitimate place, and of representing Muhammadas an evil and inhuman man who preached that Islam should be spread by the sword. While none of these presumably 'Muslim' voices deny that the Pope has the right to express his opinions, even when they are plainly wrong in the face of historic facts that show how Islam and Christianity were spread (or were made to spread) across the world, he is criticised for a host of omissions in terms of intellectual honesty and factual accuracy. These omissions, it is argued here, cast an unfortunate light on the compatibility of scientific and religious rationality much advocated by the Pope in his 12 September 2006 lecture. This flagrant 'performative contradiction' (Habermas) leaves room for speculation about the true aim of the speech. Is Benedict XVI's appeal to theology as a legitimate academic discipline a credible attempt to explicate Roman Catholicism's rightful place in a modern world governed by liberal democracy and ethical-political pluralism, or is it a reflection of a move to restore the age-old, intolerant, anti-scientific, and anti-democratic legacy of the pre-Vatican II Catholic Church?
Based on his studies of the genus Rubus in the Czech Republic, the author describes classification of brambles from Rubus subgen. Rubus in Europe, its recent history, present state, and current problems. In general, the author follows the adherents of "Weberian batology" which in the last 25 years has assumed European responsibility for attempting to ciassify that particular genus. The thesis that not every bramble plant can be inciuded in the ciassification is accepted. The objective reasons for taxonomic difficulties within Rubus subgen. Rubus are connected with special features of taxogenesis of its members, especially with incomplete apomixis, frequent hybridization, splitting of the progeny into different morphotypes, resexualization, transitory existence of segregants, etc. The progress of the evolution of a new taxon in the given taxonomic group can be ranked: individual bush - local type - regional species - species with an extensive distribution area. When classifying a taxon, alongside sufficient morphological characteristics,
great emphasis should be put on the distribution area; its extent can render possible the taxon to be accepted into the classification scheme. On the basis of experience gained from the Czech Republic, the author has accepted some modifications of the scale for acceptance of plants as species. The basic difference is in lowering the low limit of the extent of the distribution area for regional species, to be acceptable for their lnclusion to the classification, i.e. to 20 km in diameter. In contrast to taxa of other plant groups, species of apomictic brambles with more extensive distribution areas are phytogeographically more important than those with small distribution areas. In spite of the use of stricter requirements for the description of new species in Rubus, it appears that many (distinct) species have been neglected until now, and that the number of species in Rubus subgen. Rubus is continuously increasing. The author stresses the necessity of studying the group ser. Glandulosi in Central Europe and points out the usefulness of cooperation with population ecologists to describe the quantitative representation of taxonomically unclassified bramble plants in the field.
Let’s not forget that 1492, one of the first landmarks of Modernity, was both the year of the conquest of the Americas and of the fall or of the Reconquista of Granada, both of inner and outer ethnic cleansing of the nation state; that the national state was a colonial state and is now a securitarian state, that colonialism was the very form of Western Modernity, that the French Revolution itself was colonial, that the leader of the first Black revolutionary independence movement, Toussaint Louverture (Haiti), died in a French prison though inspired by the French Revolution. - No-one has access to reason as whole: there is no such thing as the whole of Reason, or Reason as a whole, or the Totality of reason. Reason is patched up of disconnected bits and pieces that reside at different addresses.
The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.