149 research outputs found
Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition
No full textPMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
The Sustainable Refurbishment of BK City
No full textClimate change - and particularly its long term-implications - has become the greatest challenge that scientists and politicians have to face. The building sector worldwide and, more specifically, the existing building stock, have been identified as major contributors to both global energy consumption and environmental damage. This study aims at investigating the most appropriate measures for the refurbishment of the Architecture building of TU Delft (BK City) that, currently, lacks sufficient energy conservation measures and is characterized by its obsolete fabric and outdated building services systems. Moreover, the final proposals take into account the historical value of the building, along with its most essential features. The first part of the study is a theoretical approach to the problem that starts by defining the content of the terms ‘sustainability’, ‘refurbishment’ and ‘historic buildings’. Next, a framework of the ‘sustainable refurbishment of historic buildings’ in terms of legal, ethical and procedural aspects, is outlined, as well as the range of possible refurbishment measures that can be applied within this framework. After having analyzed the extent and severity of the problem with specific reference to Europe, this section ends by highlighting the potential of refurbishment and by providing a brief summary of the current status of well-known refurbishment policies in four European countries. The second part of the study is an investigation of the case-study building. Necessary information concerning the context of BK City is presented, ranging from climatic and geographical data, to specific information on the building, its history and its performance in terms of building physics. Here, the distinguishing features of the building are identified, as well as the permissible interventions. With regards to building physics, it is pointed out that the weaknesses of the building are, mainly, the out-dated exterior envelope and mechanical equipment, which result in a poor indoor climate, despite the excessively high energy consumption. The information in this section is essential for the development of the refurbishment strategies. Before elaborating on the refurbishment alternatives, an investigation is carried out to cluster all possible measures in 8 categories and cite relevant showcases and good practice examples of previously refurbished buildings. The most appropriate of these measures form the three proposed refurbishment Strategies of this Thesis, that range from basic interventions, such as cavity wall insulation, to more sophisticated solutions, as is the use of fuel cells. Advantages and disadvantages, application guidelines and market availability for each measure are provided. The objective of the last section is to evaluate the impact of a selection of the aforementioned measures. For this purpose, a model is provided that allows the static calculation of the heating and cooling demands that will keep the indoor climate of the building at comfort levels. The results of these calculations are further analyzed and discussed. The conclusions suggest that the existing building is wasteful in its use of energy resources and, thus, huge possibilities lie in its refurbishment, even if only moderate measures are applied.Structural and Building EngineeringDesign and ConstructionCivil Engineering and Geoscience
Towards the design of tools for the organization of the stochastic
No full textThis paper reports on one aspect of the ongoing doctoral research of the first named author. This study builds on prior work, which identified that students of age 11 years had sound intuitions for short-term randomness but had few tools for articulating patterns in longer-term randomness. This previous work did however identify the construction of new causal meanings for distribution when they interacted with a computer-based microworld. Through a design research methodology, we are building new microworlds that aspire to capture how students might use knowledge about the deterministic to explain probability distribution as an emergent phenomenon. In this paper, we report on some insights gained from early iterations and show how we have embodied these ideas into a new microworld, not yet tested with students
Differences in self and proxy assessments regarding motivation, quality of life and care dependency of people with dementia considering a technology-based intervention
No full textBackground: Self-reported assessments of people with dementia (PwD) are sparsely used in research, which may be due to the progressive impairment of cognitive functioning and higher time expenditures for assessments. Proxy assessments by healthcare professionals or relatives are often used instead. The aim was to investigate whether a technology-based intervention significantly influences self and proxy assessments of PwD’s quality of life (QoL), motivation, and care dependency. Method: Data from the RCT of the project AMIGO were used. 32 community-dwelling people with mild to moderate dementia and their relatives received either a humanoid social robot combined with a tablet-based dementia training (IG) or a tablet-based dementia training only (CG). Self and proxy versions of three standardized measurements (AES, DEMQoL, PAS) assessing motivation, QoL, and care dependency were used and analyzed using descriptive statistics and Wilcoxon signed-rank tests. Result: Compared with proxy assessments by relatives, PwD rated themselves better in all outcomes, regardless of group allocation or time points. At baseline, the median differences (MD) differed significantly between self and proxy assessments in IG and CG participants regarding PwDs’ motivation (16.0, p<0.001; 9.0, p<0.001) and care dependency (11.0, p = 0.014; 7.0, p = 0.002), while for QoL this was only the case in the CG (11.0, p = 0.035) and not in the IG (5.0, p = 0.139). After intervention, all outcomes in the IG and CG were significantly differently rated by PwD and relatives demonstrated by the MD for motivation (8.0, p<0.001; 12.0, p = 0.0101), QoL (16.0, p = 0.0023; 16.5, p = 0.030) and care dependency (12.0, p = 0.006; 4.5, p = 0.019). Conclusion: There are significant differences of assessments between relatives and PwD, which could be due to a reduced illness insight of PwD, different foci of PwD and relatives on scale domains (e.g., psychosocial, physical), or an influence of relatives' attitudes and burden. However, QoL in the IG was not perceived differently at baseline, but after the intervention. This finding as well as the significant increase of self-reported QoL, but the non-significant proxy evaluation in the main study, highlight the PwDs’ ability to assess themselves and the necessity to involve them in research evaluations
Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90–Client Interactions
No full textProtein folding quality control in cells requires the activity of a class of proteins known as molecular chaperones. Heat shock protein-90 (Hsp90), a multidomain ATP driven molecular machine, is a prime representative of this family of proteins. Interactions between Hsp90, its co-chaperones, and client proteins have been shown to be important in facilitating the correct folding and activation of clients. Hsp90 levels and functions are elevated in tumor cells. Here, we computationally predict the regions on the native structures of clients c-Abl, c-Src, Cdk4, B-Raf and Glucocorticoid Receptor, that have the highest probability of undergoing local unfolding, despite being ordered in their native structures. Such regions represent potential ideal interaction points with the Hsp90-system. We synthesize mimics spanning these regions and confirm their interaction with partners of the Hsp90 complex (Hsp90, Cdc37 and Aha1) by Nuclear Magnetic Resonance (NMR). Designed mimics selectively disrupt the association of their respective clients with the Hsp90 machinery, leaving unrelated clients unperturbed and causing apoptosis in cancer cells. Overall, selective targeting of Hsp90 protein–protein interactions is achieved without causing indiscriminate degradation of all clients, setting the stage for the development of therapeutics based on specific chaperone:client perturbation
Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM
No full textThe human R2TP complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) is an HSP90 co-chaperone required for the maturation of several essential multiprotein complexes, including RNA polymerase II, small nucleolar ribonucleoproteins, and PIKK complexes such as mTORC1 and ATR-ATRIP. RUVBL1-RUVBL2 AAA-ATPases are also primary components of other essential complexes such as INO80 and Tip60 remodelers. Despite recent efforts, the molecular mechanisms regulating RUVBL1-RUVBL2 in these complexes remain elusive. Here, we report cryo-EM structures of R2TP and show how access to the nucleotide-binding site of RUVBL2 is coupled to binding of the client recruitment component of R2TP (PIH1D1) to its DII domain. This interaction induces conformational rearrangements that lead to the destabilization of an N-terminal segment of RUVBL2 that acts as a gatekeeper to nucleotide exchange. This mechanism couples protein-induced motions of the DII domains with accessibility of the nucleotide-binding site in RUVBL1-RUVBL2, and it is likely a general mechanism shared with other RUVBL1-RUVBL2-containing complexes.Funding:
This work was supported by the Spanish Ministry of Science, Innovation and
Universities (MCIU/AEI) and cofunded by the European Regional Development Fund (ERDF)
[SAF2014-52301-R (to O.L.), SAF2017-82632-P (to O.L.), BFU2017-87316-P (to R.F.-L.), and
BES-2015-071348 (to C.F.R.)], a Wellcome Trust Senior Investigator award (095605/Z/11/Z), and
Award Enhancement Grant (095605/Z/11/A) (to L.H.P.). We thank E.
Hesketh and R.
Thompson
for help at the Astbury Centre for Structural Molecular Biology (Leeds, UK) and J.
Boskovic for
help at the CNIO Electron Microscopy Unit. We acknowledge the help of A.L.-Perrote (CNIO) for
RUVBL1-RUVBL2 cloning and purification.
Author contributions
: O.L. and H.M.-H. designed
the cryo-EM experiments. M.P. expressed and purified the RPAP3-PIH1D1 complex and
discussed results. H.M.-H. purified RUVBL1-RUVBL2 and performed the pull-down experiments,
assembled the complex, performed cryo-EM, and collected and processed the data to solve/
obtain the cryo-EM maps. R.F.-L. helped design the data collection and processing strategy.
C.F.R. built all the atomic models and discussed results. O.L. supervised cryo-EM processing
and the research. O.L. wrote the manuscript and prepared all figures. L.H.P., C.P., and M.P.
discussed results and reviewed the manuscript. O.L. directed the work.
Competing interests:
The authors declare that they have no competing interests.
Data and materials availability:
All data needed to evaluate the conclusions in the paper are present in the paper and/or the
Supplementary Materials. Additional data related to this paper may be requested from the
authors. The cryo-EM maps and the models have been deposited in the Electron Microscopy
Data Bank (EMDB) with accession codes EMD-4552, EMD-4553, EMD-4554, EMD-4555,
EMD-4556, and EMD-4557 for the cryo-EM maps and PDB ID 6QI8 and 6QI9 for the models.S
Intramedullary spinal cord primitive neuroectodermal tumor presenting with hydrocephalus
No full textSpinal primitive neuroectodermal tumors are exceedingly rare. Herewith, we present the first case of an intramedullary spinal cord tumor associated with hydrocephalus in a 2-month-old boy that presented with left hemiparesis. The patient had been diagnosed on prenatal ultrasound with enlarged ventricular system. At his current admission, a brain magnetic resonance imaging (MRI) revealed hydrocephalus and an intramedullary lesion extending from the second cervical to the first thoracic vertebrae. Dissemination of the tumor was revealed intracranially and in the spinal canal. After a ventriculoperitoneal shunt placement a radical resection of the tumor was performed, however some small tumor remnants could not be safely removed. Postoperative there was no neurologic deterioration. The tumor was diagnosed as a central nervous system primitive neuroectodermal tumor (World Health Organization grade IV). Spinal intramedullary primitive neuroectodermal tumors are extremely rare. In such rare tumors, multiinstitutional studies are needed for treatment guidelines to be established. © The Author(s) 2013
Director trades, profitability and market efficiency: New evidence
No full textWe investigate if directors of Australian companies can generate abnormal returns on their reported trades, if these abnormal returns are significant enough to be mimicked by outsiders, and if insider trades have an effect on returns of other investors. We find that insiders take advantage of their private information in stocks of larger corporations, but generally do not in medium and small capitalization firms, indicating that the insiders are attracted to the liquidity and a greater presence of uninformed traders in large stocks. We find that outsiders can make profitable trades net of transaction costs by following insiders’ sale trades in large and medium size firms, otherwise tracking insider trades result in net losses for outsiders. They accumulate on average a net abnormal profit of 4.17 % after a year following insiders sale trades. We propose that market quality can be improved with public access to good quality aggregated data on reported director insider trades
A simplified rate dependent model of forming and wrinkling of pre-impregnated woven composites
No full textA simplified finite element model is developed and validated for the forming/
draping of pre-impregnated woven composites, incorporating the effects of
wrinkling and strain rate dependence. The model development builds upon previous
work on simulation of fabric draping using a truss representation of the woven
material. Tows are modelled by stiff elastic bar elements, and the non-linear
rate dependent shear behaviour is incorporated in elastic-viscoplastic elements
that follow an appropriate phenomenological constitutive model. Wrinkling due to
tow buckling is simulated by allowing the deactivation of tow elements that
undergo compressive deformation. The model convergence is tested and its
validity is checked against experimental results from the forming of pre-
impregnated woven carbon hemispheres. It is found that the model reproduces
successfully experimental measurements of shear and wrinkling with a relative
error of approximately 4%, while solution times are kept below 60 s on a
conventional PC. These features allow potential iterative use of the model
within a process optimisation scheme. The sensitivity of the process outcome to
process parameters such as blank holder force and forming speed is investigated
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