25 research outputs found
The HIPK2/CDC14B-MeCP2 axis enhances the spindle assembly checkpoint block by promoting cyclin B translation
Mitotic perturbations activate the spindle assembly checkpoint (SAC) that keeps cells in prometaphase with high CDK1 activity. Prolonged mitotic arrest is eventually bypassed by gradual cyclin B decline followed by slippage of cells into G without chromosome segregation, a process that promotes cell transformation and drug resistance. Hitherto, the cyclin B1 decay is exclusively defined by mechanisms that involve its proteasomal degradation. Here, we report that hyperphosphorylated HIPK2 kinase accumulates in mitotic cells and phosphorylates the Rett syndrome protein MeCP2 at Ser, a regulation that is counteracted by CDC14B phosphatase. MeCP2 phosphorylation leads to the enhanced translation of cyclin B1, which is important for cells with persistent SAC activation to counteract the proteolytic decline of cyclin B1 and therefore to suspend mitotic slippage. Hence, the HIPK2/CDC14B-MeCP2 axis functions as an enhancer of the SAC-induced mitotic block. Collectively, our study revises the prevailing view of how cells confer a sustainable SAC
What is an emerging technology?
There is considerable and growing interest in the emergence of novel technologies, especially from the policy-making perspective. Yet as an area of study, emerging technologies lacks key foundational elements, namely a consensus on what classifies a technology as âemergentâ and strong research designs that operationalize central theoretical concepts. The present paper aims to fill this gap by developing a definition of âemerging technologiesâ and linking this conceptual effort with the development of a framework for the operationalisation of technological emergence. The definition is developed by combining a basic understanding of the term and in particular the concept of âemergenceâ with a review of key innovation studies dealing with definitional issues of technological emergence. The resulting definition identifies five attributes that feature in the emergence of novel technologies. These are: (i) radical novelty, (ii) relatively fast growth, (iii) coherence, (iv) prominent impact, and (v) uncertainty and ambiguity. The framework for operationalising emerging technologies is then elaborated on the basis of the proposed attributes. To do so, we identify and review major empirical approaches (mainly in, although not limited to, the scientometric domain) for the detection and study of emerging technologies (these include indicators and trend analysis, citation analysis, co-word analysis, overlay mapping, and combinations thereof) and elaborate on how these can be used to operationalise the different attributes of emergence
Shelled pteropods in peril: Assessing vulnerability in a high CO2 ocean
The impact of anthropogenic ocean acidification (OA) on marine ecosystems is a vital concern facing marine scientists and managers of ocean resources. Euthecosomatous pteropods (holoplanktonic gastropods) represent an excellent sentinel for indicating exposure to anthropogenic OA because of the sensitivity of their aragonite shells to the OA conditions less favorable for calcification. However, an integration of observations, experiments and modelling efforts is needed to make accurate predictions of how these organisms will respond to future changes to their environment. Our understanding of the underlying organismal biology and life history is far from complete and must be improved if we are to comprehend fully the responses of these organisms to the multitude of stressors in their environment beyond OA. This review considers the present state of research and understanding of euthecosomatous pteropod biology and ecology of these organisms and considers promising new laboratory methods, advances in instrumentation (such as molecular, trace elements, stable isotopes, palaeobiology alongside autonomous sampling platforms, CT scanning and high-quality video recording) and novel field-based approaches (i.e. studies of upwelling and CO2 vent regions) that may allow us to improve our predictive capacity of their vulnerability and/or resilience. In addition to playing a critical ecological and biogeochemical role, pteropods can offer a significant value as an early-indicator of anthropogenic OA. This role as a sentinel species should be developed further to consolidate their potential use within marine environmental management policy making
Association of biofilm formation and cytotoxic potential with multidrug resistance in clinical isolates of Pseudomonas aeruginosa
Multidrug resistant (MDR) Pseudomonas aeruginosa having strong biofilm potential and virulence factors are a
serious threat for hospitalized patients having compromised immunity. In this study, 34 P. aeruginosa isolates of
human origin (17 MDR and 17 non-MDR clinical isolates) were checked for biofilm formation potential in enriched
and minimal media. The biofilms were detected using crystal violet method and a modified software package
of the automated VideoScan screening method. Cytotoxic potential of the isolates was also investigated on
HepG2, LoVo and T24 cell lines using automated VideoScan technology. Pulse field gel electrophoresis revealed
10 PFGE types in MDR and 8 in non-MDR isolates. Although all isolates showed biofilm formation potential,
strong biofilm formation was found more in enriched media than in minimal media. Eight MDR isolates showed
strong biofilm potential in both enriched and minimal media by both detection methods. Strong direct correlation
between crystal violet and VideoScan methods was observed in identifying strong biofilm forming isolates. High
cytotoxic effect was observed by 4 isolates in all cell lines used while 6 other isolates showed high cytotoxic effect
on T24 cell line only. Strong association of multidrug resistance was found with biofilm formation as strong biofilms
were observed significantly higher in MDR isolates (p-value < 0.05) than non-MDR isolates. No significant
association of cytotoxic potential with multidrug resistance or biofilm formation was found (p-value > 0.05). The
MDR isolates showing significant cytotoxic effects and strong biofilm formation impose a serious threat for hospitalized
patients with weak immune system
Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures: Versatile Warheads To Address a Catalytic Dyad
Crystallography is frequently used
as follow-up method to validate
hits identified by biophysical screening cascades. The capacity of
crystallography to directly screen fragment libraries is often underestimated,
due to its supposed low-throughput and need for high-quality crystals.
We applied crystallographic fragment screening to map the protein-binding
site of the aspartic protease endothiapepsin by individual soaking
experiments. Here, we report on 41 fragments binding to the catalytic
dyad and adjacent specificity pockets. The analysis identifies already
known warheads but also reveals hydrazide, pyrazole, or carboxylic
acid fragments as novel functional groups binding to the dyad. A remarkable
swapping of the S1 and S1âČ pocket between structurally related
fragments is explained by either steric demand, required displacement
of a well-bound water molecule, or changes of trigonal-planar to tetrahedral
geometry of an oxygen functional group in a side chain. Some warheads
simultaneously occupying both S1 and S1âČ are promising starting
points for fragment-growing strategies