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Covalent inhibition has become more accepted in the past two decades, as illustrated by the clinical approval of several irreversible inhibitors designed to covalently modify their target. Elucidation of the structure-activity relationship and potency of such inhibitors requires a detailed kinetic evaluation. Here, we elucidate the relationship between the experimental read-out and the underlying inhibitor binding kinetics. Interactive kinetic simulation scripts are employed to highlight the effects of in vitro enzyme activity assay conditions and inhibitor binding mode, thereby showcasing which assumptions and corrections are crucial. Four stepwise protocols to assess the biochemical potency of (ir)reversible covalent enzyme inhibitors targeting a nucleophilic active site residue are included, with accompanying data analysis tailored to the covalent binding mode. Together, this will serve as a guide to make an educated decision regarding the most suitable method to assess covalent inhibition potency. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.
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.
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.
The (mis)management of rapport amongst groups in Niger Delta (ND) communities has become a significant issue, which Ahmed Yerima's Hard Ground (HG) depicts as having the capacity to aid or control the conflicts in the region. Linguistic studies on Yerima's drama from the perspective of pragmatics have tended to use pragmatic acts to identify the discourse value of proverbs and functions of characters' utterances but have not accounted for the politeness strategies utilised for rapport management, especially in conflict situations. This article, drawing on a rapport management model of politeness and aspects of speech act discourse, identifies the face, sociality rights, and interactional goals that characterise the conflict-motivated dialogues sampled in HG, and reveals the rapport management (RM) strategies through which these are managed in the text. Three conflict situations can be observed as prompting different RM strategies: cause-effect identification (CEI), militancy support (MSP), and disagreement (DSG) situations. CEI is marked by incriminating (involving eliciting and informing acts) and exonerating (including complimenting and acknowledging acts) strategies; MSP is indexed by strategies of persuasion (realised with face-enhancing/threatening acts), whereas DSG is typified by requesting (featuring explicit head acts and alerters) and blaming strategies (including insulting and threatening, aggravating moves). Generally, the requesting, blaming, and exonerating strategies are largely used by the ND youth in HG to probe, threaten, or disagree on specific issues, while the incriminating and persuasion strategies are mainly employed by the women to indict, influence, and predict future actions. The study of RM in the conflict situations depicted in the play sheds light on the often neglected cause of conflicts in contemporary Africa.
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.
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.
Meadowbird populations in The Netherlands are under great pressure. Recently, predation is named increasingly
often as one of the key factors in contributing to the declines. A four-year research project (2001-2005) aimed to
collect (as yet mostly nonexisting) data to provide a factual basis for this discussion. A country-wide inventory based
on data for wader nests found by volunteers who mark nests for their protection from grazing/mowing indicated that
above-average predation losses are found predominantly in the half-open landscapes of northern and eastern Netherlands,
but also locally in the low-lying open grasslands which are the key areas for meadowbirds. Nest predation has increased in recent years, but the same is true for agricultural losses, at least in areas where no nest-protection takes
place. At a local scale, predation losses vary greatly from area to area and from year to year. Temperature loggers in nest showed that diurnal and nocturnal predators contribute equally in total predation losses up to 50%, but higher predation losses are mainly caused by nocturnal predators. As many as 10 animal species were identified as nest predators
on nests under surveillance with video cameras. Chick survival, investigated using radiotelemetry, was very low. About 60-80% were lost by predation, 5-15% by agricultural activities and 10-15% to all kind of other losses. At least 15
predator species were implied, with an apparently larger share taken by birds (notably Buzzard (16%) and Grey Heron
(7-18%)) than mammals, with one exception: stoat (16%). Of the most-discussed predator species, Carrion Crows were
W. Teunissen et al. Osnabrücker Naturwiss. Mitt. 32 2006
138 remarkably rarely involved in both nest and chick predation, while Red Foxes take a large toll of clutches in some areas, but not in others. Of all losses during the reproductive cycle about 75% and 60% was due to predation in Lapwing and Black-tailed Godwit respectively. Predation on chicks by birds had the largest effect on total breeding success, but at the same time elimination of this loss factor (if at all possible) alone would not be sufficient to establish a self-sustaining population. Predation seems to have become a factor of importance in some areas, in combination with already existing other losses. Our findings suggest that solutions to predation problems probably have to be found in locally/regionally targeted, specific action on multiple fronts rather than countrywide measures.
Human impacts on the landscape have increased the penalties for Black-tailed Godwits laying their eggs too late, especially in the very intensive agricultural landscapes of The Netherlands. Thus, godwits have experienced a dramatic change of their fitness landscape, because the advance in mowing date made late clutches worthless destroying either eggs or chicks. To determine the driving forces of the recent population decline we study the individual variation in timing of breeding with respect to reproductive success in a population unaffected by mowing. Our results show that even in a low intensity agricultural area it is very important for godwits to breed early in the season.
Black-tailed Godwits (Limosa limosa) have been declining for decades in The Netherlands and so far this has not been slowed by conservation measures. A new form of agri-environment scheme was tried out in 2003-2005 at 6 sites where a ‘grassland mosaic’ (200-300 ha) was created by collectives of farmers through a diverse use of fields including postponed and staggered mowing, (early) grazing, creating ‘refuge strips’ during mowing, and active nest protection. We measured breeding success of godwits in each of the experimental sites and nearby, paired controls. Breeding success was higher (0.28 chicks fledged / pair) in mosaics than in controls, but due to lower agricultural nest losses only. Chick survival was 11 % in both mosaics and controls. The amount of late-mown and other grassland suitable for chicks hardly differed between treatments during the fledging period, mainly due to rainfall delaying postponed mowing in all sites. Chick survival was however positively correlated with site variation in the amount of high grass (>18 cm). Breeding success was high enough to compensate for adult mortality (ca. 0.6) in only one mosaic site. Chick survival was lower than in previous Godwit studies, indicating that additional loss factors have increased. Predation (50-80 % of chicks, mostly by birds) is a candidate, but changes in the suitability of late-mown grassland (insect abundance and sward density in grass monocultures) may also play a role. Consequently a higher management investment is needed to achieve a self-sustaining population.
In this study, we report the results of a long-term investigation on changes in population size and fledging success of Northern Lapwing on Wangerooge, a German Wadden Sea island. This population is increasing over a period of 34 years in contrast to numerous populations in North-western Europe. The reproductive success however declines over time and also with population density. Both effects cannot be considered separately due to autocorrelation. However, it is noted that the population on Wangerooge is not sustained by local recruitment only. This outcome is even more alarming as coastal areas and islands are considered as rare high quality meadow bird habitats. According to the present results Wangerooge cannot be considered as a source habitat for Northern Lapwings in North-western Germany.