564 research outputs found
The structure of the ternary Eg5–ADP–ispinesib complex
No full textThe human kinesin Eg5 is responsible for bipolar spindle formation during early mitosis. Inhibition of Eg5 triggers the formation of monoastral spindles, leading to mitotic arrest that eventually causes apoptosis. There is increasing evidence that Eg5 constitutes a potential drug target for the development of cancer chemotherapeutics. The most advanced Eg5-targeting agent is ispinesib, which exhibits potent antitumour activity and is currently in multiple phase II clinical trials. In this study, the crystal structure of the Eg5 motor domain in complex with ispinesib, supported by kinetic and thermodynamic binding data, is reported. Ispinesib occupies the same induced-fit pocket in Eg5 as other allosteric inhibitors, making extensive hydrophobic interactions with the protein. The data for the Eg5-ADP-ispinesib complex suffered from pseudo-merohedral twinning and revealed translational noncrystallographic symmetry, leading to challenges in data processing, space-group assignment and structure solution as well as in refinement. These complications may explain the lack of available structural information for this important agent and its analogues. The present structure represents the best interpretation of these data based on extensive data-reduction, structure-solution and refinement trials
PIJ912612 Supplemental Material - Supplemental material for A molecular dynamics-based investigation on tribological properties of functionalized graphene reinforced thermoplastic polyurethane nanocomposites
No full textSupplemental material, PIJ912612 Supplemental Material for A molecular dynamics-based investigation on tribological properties of functionalized graphene reinforced thermoplastic polyurethane nanocomposites by Animesh Talapatra and Debasis Datta in Proceedings of the Institution of Mechanical Engineers, Part J: Journal of Engineering Tribology</p
Microscopic understanding of domain formation in Gd-Fe thin films
No full textWe report a systematic study of the role of film thickness on the formation of magnetic domains in Gd-Fe thin films. The films having thickness up to 33 nm show no visible domain contrast, whereas the evolution of magnetic domain starts at a thickness of 50 nm. For 100 nm thick films, meandering stripe domains with long range correlation are observed with strong magnetic contrast, which symbolize the perpendicular magnetic anisotropy in the film. Our experimental result has also been complemented with 3D micromagnetic simulation
COVID-19: An advisory for a radiation oncology department pertinent to the multidisciplinary team
No full textExtramedullary haematopoiesis causing spinal cord compression: A rare presentation with excellent outcome
No full textExtramedullary haematopoiesis (EMH) as a cause of spinal cord compression in patients with thalassaemia major is very rare. Treatment of EMH includes the use of radiotherapy, hypertransfusion, laminectomy and chemotherapy in the form of hydroxyurea We report a presentation of progressive paraparesis due to a sacral mass in a 7 year old child undergoing repeated blood transfusions for thalassaemia major who had a dramatic improvement in symptoms after radiotherapy. A standard recommendation regarding the radiation dose required is not available but a dose of 20Gy delivered over 10 fractions seems to be effective and well tolerated
Characterization of an ultra-high temperature ceramic composite (UHTCC) by ultrasonic testing
No full textThe ultra high temperature ceramic composites (UHTCC) are of interest for hypersonic vehicle leading edge. The ultrasonic testing is one of the widely used non-destructive testing (NDT) for the material characterization. The aim of investigations described in this article is measurement of the mechanical properties of two ceramic composite by pulse-echo ultrasonic testing. These two samples (ZrB2-20%ZrC-20%SiC-5%Si3N4 and ZrB2 -20%SiC- 5%Si3N4) were fabricated by hot pressing into 25mm diameter and 4mm thickness discs. The measurements were performed using pulse echo ultrasonic technique and ultrasonic transducers with the frequencies 5.0 MHz. It was determined that the velocity of ultrasonic longitudinal and shear waves varies when the frequency is changing. Ultrasound velocity measurements were used to evaluate mechanical properties of UHTCC. These composites were prepared from ZrB2, SiC, ZrC and Si3N4 by ball milling and hot pressing.http://dx.doi.org/10.5755/j01.u.66.2.527Superaukštų temperatūrų keraminiai kompozitai yra naudojami viršgarsinių lėktuvų priekinėse briaunose. Ultragarsiniai bandymai yra plačiai naudojami neardomajam medžiagų charakterizavimui. Straipsnyje aprašytų tyrimų tikslas buvo dviejų keraminių kompozitų mechaninių savybių matavimas impulsiniu ultragarsiniu aido metodu. Tuo tikslu buvo pagaminti du 25 mm diametro ir 4 mm storio bandiniai (ZrB2-20%ZrC-20%SiC-5%Si3N4 ir ZrB2 -20%SiC- 5%Si3N4) karšto presavimo metodu. Matavimai buvo atlikti impulsiniu aido metodu, naudojant 5 MHz dažnio ultragarsinius keitiklius. Buvo rasta, kad išilginių ir skersinių ultragarso bangų greitis priklauso nuo dažnio.http://dx.doi.org/10.5755/j01.u.66.2.52
Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors
No full textThe thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design
Parthenolide and a new germacranolide, 11,13-dehydrolanuginolide, from Michelia lanuginosa
No full textAn Ab Initio Investigation of Thermoelastic Phase Transformations in Transition Metal Alloys
No full textThe energy pathways associated with the martensitic transformation in shape memory alloys (SMAs), though the focus of extensive research over the past decades, are still unclear. In this work, we use a ���rst-principles approach within the frame-work of density functional theory, as implemented in the Vienna ab initio simulation package (VASP), to model the transformation in transition metal alloys by tracking atomic motion via shear, shu���e and distortion during the transformation. We build a framework to investigate the f.c.c-h.c.p transformation in Co-based binary alloys which may be applied to ternary alloys as well. In the Co2NiGa Heusler system, by applying the Burgers transformation, we found a low-energy phase with orthorhombic symmetry (O) phase which is lower in energy than the experimentally observed L10. By performing a detailed analysis of the transformation paths (Burgers and Bain) taking into account perturbations on the ground state, it is seen that a phase selection problem exists: the ultimate crystal structure that the system transforms into, depends on the path that the system prefers. When coming from high temperature, the accessible path is that corresponding to the Bain transformation. Finally, we present a complete and unique 4-parameter model to describe the B2 ��� B19���transformation in Ni ��� Ti. We eliminate the possibility of the B19 phase being an intermediate phase in the transformation and show that it is in fact a barrier-less transformation. Crystallographic analysis of intermediate states shows that the B2 ��� B19���path follows a known crystallographic path
Magnetic anisotropy studies in magnetostrictive Fe-Co thin films
No full textStructural, magnetic and magnetostrictive behavior of Fe-Co thin films grown on Si substrates has been investigated. Structural studies indicated that the films are polycrystalline in nature with body centered cubic type structure. Magnetostriction was found to decrease with increase in film thicknesses. Magnetization studies exhibited predominant in-plane magnetic anisotropy for all the films. In addition to this, films grown with higher thicknesses also showed presence of out-of-plane magnetic anisotropy co-existing with in-plane magnetic components. This observation was further validated through magnetic microscopy studies. Presence of competing anisotropies has been found to be the reason for the decrease in the magnetostriction with change in film thicknesses
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