743 research outputs found
Crystal Structure of the PIM2 Kinase in Complex with an Organoruthenium Inhibitor
BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1
The Course of Habituation of the Proboscis Extension Reflex Can Be Predicted by Sucrose Responsiveness in Drosophila
The proboscis extension reflex (PER) is triggered when insects’ gustatory receptors contact appetitive stimuli, so it provides a behavioral readout for perceptual encoding of tastants. Research on the experience dependent modulation of PER in Drosophila has been hindered by the difficulty of obtaining reliable measures of memory-driven change in PER probability in the background of larger changes induced by physiological state. In this study, we showed that the course of PER habituation can be predicted by the degree of sucrose responsiveness in Drosophila. We assessed early response parameters, including the number of proboscis extensions and labellar movements in the first five trials, the trial to start responding, and the trial to make the first stop to quantify responsiveness, which predicted the upcoming pattern of both the short-term and 1 hour memory of PER habituation for individual flies. The cAMP signaling pathway mutant rutabaga displayed deficits in attunement of perceptual salience of sucrose to physiological demands and stimulus-driven sensitization
Emergent complex neural dynamics
A large repertoire of spatiotemporal activity patterns in the brain is the
basis for adaptive behaviour. Understanding the mechanism by which the brain's
hundred billion neurons and hundred trillion synapses manage to produce such a
range of cortical configurations in a flexible manner remains a fundamental
problem in neuroscience. One plausible solution is the involvement of universal
mechanisms of emergent complex phenomena evident in dynamical systems poised
near a critical point of a second-order phase transition. We review recent
theoretical and empirical results supporting the notion that the brain is
naturally poised near criticality, as well as its implications for better
understanding of the brain
Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.
A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions
Dental therapists in general dental practice. A literature review and case study analysis to determine what works, why, how and in what circumstances
Introduction
In the United Kingdom, policy and guidance changes regarding the role of Dental Therapists (DTs) were implemented in recent years with a view to changing dental care to a more preventive‐focussed, teamwork approach. However, success in the adoption of this model of working has been varied.
Aims
Adopting a realist approach, our aim was, to examine the use of DTs in general dental practices in Wales, exploring what works, why, how and in what circumstances.
Materials and Methods
The research comprised two stages. (i) A structured literature search, dual‐coding papers for high‐level factors describing the conditions or context(s) under which the mechanisms operated to produce outcomes. From this, we derived theories about how skill‐mix operates in the general dental service. (ii) Six case studies of general dental practices (three with a Dental Therapist/three without a Dental Therapist) employing a range of skill‐mix models incorporating semi‐structured interviews with all team members. We used the case studies/interviews to explore and refine the theories derived from the literature.
Results
Eighty‐four papers were coded. From this coding, we identified seven theories which reflected factors influencing general dental practices within three broad contexts: the dental practice as a business, as a healthcare provider, and as a workplace. We tested these theories in interviews with 38 dental team members across the six care studies. As a result, we amended five of the theories.
Conclusion
Our analysis provides theory about outcomes that DTs may facilitate and the mechanisms that may assist the work of DTs within different contexts of general dental practice
Primordial Black Holes: sirens of the early Universe
Primordial Black Holes (PBHs) are, typically light, black holes which can
form in the early Universe. There are a number of formation mechanisms,
including the collapse of large density perturbations, cosmic string loops and
bubble collisions. The number of PBHs formed is tightly constrained by the
consequences of their evaporation and their lensing and dynamical effects.
Therefore PBHs are a powerful probe of the physics of the early Universe, in
particular models of inflation. They are also a potential cold dark matter
candidate.Comment: 21 pages. To be published in "Quantum Aspects of Black Holes", ed. X.
Calmet (Springer, 2014
CP-31398, a putative p53-stabilizing molecule tested in mammalian cells and in yeast for its effects on p53 transcriptional activity
BACKGROUND: CP-31398 is a small molecule that has been reported to stabilize the DNA-binding core domain of the human tumor suppressor protein p53 in vitro. The compound was also reported to function as a potential anti-cancer drug by rescuing the DNA-binding activity and, consequently, the transcription activation function of mutant p53 protein in mammalian tissue culture cells and in mice. RESULTS: We performed a series of gene expression experiments to test the activity of CP-31398 in yeast and in human cell cultures. With these cell-based assays, we were unable to detect any specific stimulation of mutant p53 activity by this compound. Concentrations of CP-31398 that were reported to be active in the published work were highly toxic to the human H1299 lung carcinoma and Saos-2 cell lines in our experiments. CONCLUSION: In our experiments, the small molecule CP-31398 was unable to reactivate mutant p53 protein. The results of our in vivo experiments are in agreement with the recently published biochemical analysis of CP-31398 showing that this molecule does not bind p53 as previously claimed, but intercalates into DNA
The SOCS-Box of HIV-1 Vif Interacts with ElonginBC by Induced-Folding to Recruit Its Cul5-Containing Ubiquitin Ligase Complex
The HIV-1 viral infectivity factor (Vif) protein recruits an E3 ubiquitin ligase complex, comprising the cellular proteins elongin B and C (EloBC), cullin 5 (Cul5) and RING-box 2 (Rbx2), to the anti-viral proteins APOBEC3G (A3G) and APOBEC3F (A3F) and induces their polyubiquitination and proteasomal degradation. In this study, we used purified proteins and direct in vitro binding assays, isothermal titration calorimetry and NMR spectroscopy to describe the molecular mechanism for assembly of the Vif-EloBC ternary complex. We demonstrate that Vif binds to EloBC in two locations, and that both interactions induce structural changes in the SOCS box of Vif as well as EloBC. In particular, in addition to the previously established binding of Vif's BC box to EloC, we report a novel interaction between the conserved Pro-Pro-Leu-Pro motif of Vif and the C-terminal domain of EloB. Using cell-based assays, we further show that this interaction is necessary for the formation of a functional ligase complex, thus establishing a role of this motif. We conclude that HIV-1 Vif engages EloBC via an induced-folding mechanism that does not require additional co-factors, and speculate that these features distinguish Vif from other EloBC specificity factors such as cellular SOCS proteins, and may enhance the prospects of obtaining therapeutic inhibitors of Vif function
Auditory temporal resolution and evoked responses to pulsed sounds for the Yangtze finless porpoises (Neophocaena phocaenoides asiaeorientalis)
Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology 197 (2011): 1149-1158, doi:10.1007/s00359-011-0677-y.Temporal cues are important for some forms of auditory processing, such as
echolocation. Among odontocetes (toothed whales, dolphins, and porpoises), it has been
suggested that porpoises may have temporal processing abilities which differ from other
odontocetes because of their relatively narrow auditory filters and longer duration echolocation
signals. This study examined auditory temporal resolution in two Yangtze finless porpoises
(Neophocaena phocaenoides asiaeorientalis) using auditory evoked potentials (AEPs) to
measure: (i) rate following responses and modulation rate transfer function for 100 kHz centered
pulse sounds and (ii) hearing thresholds and response amplitudes generated by individual pulses
of different durations. The animals followed pulses well at modulation rates up to 1250 Hz, after
which response amplitudes declined until extinguished beyond 2500 Hz. The subjects had
significantly better hearing thresholds for longer, narrower-band pulses similar to porpoise
echolocation signals compared to brief, broadband sounds resembling dolphin clicks. Results
indicate that the Yangtze finless porpoise follows individual acoustic signals at rates similar to
other odontocetes tested. Relatively good sensitivity for longer duration, narrow-band signals
suggests that finless porpoise hearing is well-suited to detect their unique echolocation signals.The work was supported by the Office of Naval Research, a WHOI
Mellon Joint Initiatives Award , the Chinese National Natural Science Foundation (grant No:
30730018) and the Institute of Hydrobiology of the Chinese Academy of Sciences2012-09-1
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