440 research outputs found
Structure of S. aureus HPPK and discovery of a new inhibitor
The first structural and biophysical data on the folate pathway enzyme and drug target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), from the pathogenic bacterium Staphylococcus aureus is presented. HPPK is the second essential enzyme in the folate biosynthesis pathway, responsible for catalysing pyrophosphoryl transfer from cofactor (ATP) to the substrate (6-hydroxymethyl- 7,8-dihydropterin, HMDP). In-silico screening led to the discovery of a substrate competitive inhibitor, San1, which was subsequently co-crystallised with HPPK. A 1.65 Å resolution x-ray structure showed this to bind at the pterin site sharing many of the key intermolecular interactions of the substrate. ITC and SPR measurements yielded an equilibrium binding constant, Kd, of ~13 μM for San1. An IC50 of ~12 μM was determined by means of a new convenient tri-enzyme-coupled spectrophotometric assay. ITC and SPR further showed that the San1 inhibitor has no requirement for magnesium or ATP cofactor for competitive binding to the substrate site. According to 15N heteronuclear NMR measurements, the fast motion of the pterin loop (L2) is partially dampened in the ternary complex between SaHPPK, HMDP and , -methylene adenosine 5-triphosphate (AMPCPP), but the ATP loop (L3) remains mobile on the μs timescale. In contrast, for the SaHPPK/San1/AMPCPP ternary complex, loop L2 becomes rigid on the fast timescale and loop L3 becomes more ordered which are supported by a large entropic penalty associated with San1 binding as revealed by ITC. Backbone assignments and chemical shift perturbations implicate the sulphur in San1 as a likely important loop L2/L3 stabilizing mediato
RIDME distance measurements using Gd(iii) tags with a narrow central transition
Methods based on pulse electron paramagnetic resonance allow measurement of the electron-electron dipolar coupling between two spin labels. Here we compare the most popular technique, Double Electron-Electron Resonance (DEER or PELDOR), with the dead-time free 5-pulse Relaxation-Induced Dipolar Modulation Enhancement (RIDME) method for Gd(iii)-Gd(iii) distance measurements at W-band (94.9 GHz, ≈3.5 T) using Gd(iii) tags with a small zero field splitting (ZFS). Such tags are important because of their high EPR sensitivity arising from their narrow central transition. Two systems were investigated: (i) a rigid model compound with an inter-spin distance of 2.35 nm, and (ii) two mutants of a homodimeric protein, both labeled with a DOTA-based Gd(iii) chelate and characterized by an inter-spin distance of around 6 nm, one having a narrow distance distribution and the other a broad distribution. Measurements on the model compound show that RIDME is less sensitive to the complications arising from the failure of the weak coupling approximation which affect DEER measurements on systems characterized by short inter-spin distances between Gd(iii) tags having a narrow central transition. Measurements on the protein samples, which are characterized by a long inter-spin distance, emphasize the complications due to the appearance of harmonics of the dipolar interaction frequency in the RIDME traces for S > 1/2 spin systems, as well as enhanced uncertainties in the background subtraction. In both cases the sensitivity of RIDME was found to be significantly better than DEER. The effects of the experimental parameters on the RIDME trace are discussed.This research was supported by the Israeli Science Foundation
(grant 334/14) and was made possible in part by the historic
generosity of the Harold Perlman Family (D. G.). We also
acknowledge the Australian Research Council for a Discovery
grant to G. O. and B. G. (DP150100383) and a Future Fellowship
to B. G. (FT130100838). D. G. holds the Erich Klieger professorial
chair in Chemical Physics
An ultracold molecular beam for testing fundamental physics
We use two-dimensional transverse laser cooling to produce an ultracold beam
of YbF molecules. Through experiments and numerical simulations, we study how
the cooling is influenced by the polarization configuration, laser intensity,
laser detuning and applied magnetic field. The ultracold part of the beam
contains more than molecules per shot and has a temperature
below 200 K, and the cooling yields a 300-fold increase in the brightness
of the beam. The method can improve the precision of experiments that use
molecules to test fundamental physics. In particular, the beam is suitable for
measuring the electron electric dipole moment with a statistical precision
better than e cm.Comment: 25 pages, 14 figures. Trajectory simulations added and results
compared to experiment; other minor revision
The personal benefits of musicking for people living with dementia:a thematic synthesis of the qualitative literature
This review aimed to explore the psychological, social and emotional benefits of music activities for people living with dementia through a systematic review of qualitative literature. Eighteen studies were identified that covered a wide range of music programmes for people with dementia, with the majority of programmes focusing on active musical participation. A thematic synthesis revealed four key benefits of music engagement for people with dementia, namely: Taking Part, Being Connected, Affirming Identity and Immersion “in the moment”. Overall, engaging with music was seen to have a number of psychological, social and emotional benefits for people with dementia. However, only seven studies actively included people with dementia in the research process. Going forward, it would appear essential that people with dementia are encouraged to take a more active role in research exploring musical experiences and that a heightened emphasis is placed upon participatory approaches to knowledge generation. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group
Čvrsta disperzija meloksikama: faktorijalno dizajnirani dozirani pripravak za gerijatrijsku populaciju
The objective of the present work was to improve the dissolution properties of the poorly water-soluble drug meloxicam by preparing solid dispersions with hydroxyethylcellulose (HEC), mannitol and polyethylene glycol (PEG) 4000 and to develop a dosage form for geriatric population. Differential scanning calorimetry, X–ray diffractometry, Fourier transform infrared spectroscopy and scanning electron microscopy were used to investigate the solid-state physical structure of the prepared solid dispersions. Higher in vitro dissolution of solid dispersions was recorded compared to their corresponding physical mixtures and the pure drug. PEG 4000 in 1:9 drug to carrier ratio exhibited the highest drug release (100.2%), followed by mannitol (98.2%) and HEC (89.5%) in the same ratio. Meloxicam-PEG 4000 solid dispersion was formulated into suspension and optimization was carried out by 23 factorial design. Formulations containing higher levels of methyl cellulose and higher levels of either sodium citrate or Tween 80 exhibited the highest drug release.Cilj rada bio je poboljšati topljivost meloksikama u vodi pripravom čvrstih disperzija s hidroksietilcelulozom (HEC), manitolom i polietilen glikolom 4000 (PEG 4000) te razviti dozirani pripravaka za gerijatrijsku populaciju. Za ispitivanje fizičke strukture pripravljenih čvrstih disperzija korištene su diferencijalna pretražna kalorimetrija, difraktometrija rentgentskim zrakama, FTIR i pretražna elektronska mikroskopija. Čvrste disperzije su u in vitro uvjetima pokazale bolju topljivost u odnosu na fizičku smjesu i čistu ljekovitu tvar. Najbolje oslobađanje lijeka (100,2%). postignuto je iz disperzija s PEG 4000 (omjer ljekovite tvari i nosača 1:9). Slijede manitol (98,2%) i HEC (89,5%) (isti omjer meloksikama i polimera). Čvrsta disperzija meloksikama s PEG 4000 prevedena je u suspenziju te optimirana 23 faktorijalnim dizajnom. Najbolje oslobađanje ljekovite tvari postignuto je iz pripravaka koji sadrže veći udio etilceluloze i natrijevog citrata, odnosno Tween 80
Ultra-fast intramolecular vibronic coupling revealed by RIXS and RPES maps of an aromatic adsorbate on TiO2(110)
Two-dimensional resonant inelastic x-ray scattering (RIXS) and resonant photoelectron spectroscopy (RPES) maps are presented for multilayer and monolayer coverages of an aromatic molecule (bi-isonicotinic acid) on the rutile TiO2(110) single crystal surface. The data reveals ultra-fast intramolecular vibronic coupling upon core-excitation from the N 1s orbital into the lowest unoccupied molecular orbital (LUMO) derived resonance. In the RIXS measurements this results in the splitting of the participator decay channel into a purely elastic line which disperses linearly with excitation energy, and a vibronic coupling channel at constant emission energy. In the RPES measurements the vibronic coupling results in a linear shift in binding energy of the participator channel as the excitation is tuned over the LUMO-derived resonance. Localisation of the vibrations on the molecule on the femtosecond timescale results in predominantly inelastic scattering from the core-excited state in both the physisorbed multilayer and the chemisorbed monolayer
Geologically constrained evolutionary geomechanical modelling of diapir and basin evolution: a case study from the Tarfaya basin, West African coast
We systematically incorporate burial history, sea floor geometry and tectonic loads from a sequential kinematic restoration model into a 2D evolutionary geomechanical model that simulates the formation of the Sandia salt diapir, Tarfaya basin, NW African Coast. We use a poro-elastoplastic description for the sediment behaviour and a viscoplastic description for the salt. Sedimentation is coupled with salt flow and regional shortening to determine the sediment porosity and strength and to capture the interaction between salt and sediments. We find that temporal and spatial variation in sedimentation rate is a key control on the kinematic evolution of the salt system. Incorporation of sedimentation rates from the kinematic restoration at a location east of Sandia leads to a final geomechanical model geometry very similar to that observed in seismic reflection data. We also find that changes in the variation of shortening rates can significantly affect the present-day stress state above salt. Overall, incorporating kinematic restoration data into evolutionary models provides insights into the key parameters that control the evolution of geologic systems. Furthermore, it enables more realistic evolutionary geomechanical models, which, in turn, provide insights into sediment stress and porosity
Playful, Curious, Creative, Equitable : Exploring Opportunities for AI Technologies with Older Adults
There has recently been much discussion around OpenAI, Generative AI, use of chatbots and the use of other immersive technologies in the mainstream. These developments have much to offer to older adults in terms of playful, accessible and creative ways to engage with technology in everyday life. In this workshop, we are interested in developing a research agenda for HCI research with older adults to explore, enjoy, build new and extend existing interactions with such technologies. What are the possibilities they offer simply for introducing creativity, playfulness, enjoyment and ‘fun’ for older adults in everyday life? Or are there other goals that older adults want to achieve using them, such as new ways of socially engaging with their grandchildren, developing hobbies and knowledge, or simply making their lives easier? Can these tools empower older adults to explore various interaction modalities to help them achieve their goals? Finally, what are the new ways that these tools can be used to engage with older adults in the research and design of new emerging technologies? In this workshop, we will aim to generate discussion, develop a community and a roadmap for older adults’ use of technology that is playful, curious, creative and equitable. We will focus on five themes for the role of such technologies: (i) for enabling expression and creativity, (ii) as a catalyst for experience and action, (iii) for enabling reflection and awareness, (iv) for communication and (v) supporting the design process for (re) inventing new products and avenues for use. This workshop will feature co-creation and exploration of research methods and technologies, with panel and multidisciplinary discussions bringing together researchers who are interested in designing for and with older adults. We will explore new technology interactions including AI and immersive technologies within HCI; discussing methods, opportunities, and challenges in using these technologies and leveraging them for ideation, and form a multidisciplinary community for future synergies and collaborations
Human mucosal associated invariant T cells detect bacterially infected cells
Control of infection with Mycobacterium tuberculosis (Mtb) requires Th1-type immunity, of which CD8+ T cells play a unique role. High frequency Mtb-reactive CD8+ T cells are present in both Mtb-infected and uninfected humans. We show by limiting dilution analysis that nonclassically restricted CD8+ T cells are universally present, but predominate in Mtbuninfected individuals. Interestingly, these Mtb-reactive cells expressed the Va7.2 T-cell receptor (TCR), were restricted by the nonclassical MHC (HLA-Ib) molecule MR1, and were activated in a transporter associated with antigen processing and presentation (TAP) independent manner. These properties are all characteristics of mucosal associated invariant T cells (MAIT), an "innate" T-cell population of previously unknown function. These MAIT cells also detect cells infected with other bacteria. Direct ex vivo analysis demonstrates that Mtb-reactive MAIT cells are decreased in peripheral blood mononuclear cells (PBMCs) from individuals with active tuberculosis, are enriched in human lung, and respond to Mtb-infected MR1-expressing lung epithelial cells. Overall, these findings suggest a generalized role for MAIT cells in the detection of bacterially infected cells, and potentially in the control of bacterial infection. © 2010 Gold et al
X-ray absorption spectroscopy systematics at the tungsten L-edge
A series of mononuclear six-coordinate tungsten compounds spanning formal oxidation states from 0 to +VI, largely in a ligand environment of inert chloride and/or phosphine, has been interrogated by tungsten L-edge X-ray absorption spectroscopy. The L-edge spectra of this compound set, comprised of [W<sup>0</sup>(PMe<sub>3</sub>)<sub>6</sub>], [W<sup>II</sup>Cl<sub>2</sub>(PMePh<sub>2</sub>)<sub>4</sub>], [W<sup>III</sup>Cl<sub>2</sub>(dppe)<sub>2</sub>][PF<sub>6</sub>] (dppe = 1,2-bis(diphenylphosphino)ethane), [W<sup>IV</sup>Cl<sub>4</sub>(PMePh<sub>2</sub>)<sub>2</sub>], [W<sup>V</sup>(NPh)Cl<sub>3</sub>(PMe<sub>3</sub>)<sub>2</sub>], and [W<sup>VI</sup>Cl<sub>6</sub>] correlate with formal oxidation state and have usefulness as references for the interpretation of the L-edge spectra of tungsten compounds with redox-active ligands and ambiguous electronic structure descriptions. The utility of these spectra arises from the combined correlation of the estimated branching ratio (EBR) of the L<sub>3,2</sub>-edges and the L<sub>1</sub> rising-edge energy with metal Z<sub>eff</sub>, thereby permitting an assessment of effective metal oxidation state. An application of these reference spectra is illustrated by their use as backdrop for the L-edge X-ray absorption spectra of [W<sup>IV</sup>(mdt)<sub>2</sub>(CO)<sub>2</sub>] and [W<sup>IV</sup>(mdt)<sub>2</sub>(CN)<sub>2</sub>]<sup>2–</sup> (mdt<sup>2–</sup> = 1,2-dimethylethene-1,2-dithiolate), which shows that both compounds are effectively W<sup>IV</sup> species. Use of metal L-edge XAS to assess a compound of uncertain formulation requires: 1) Placement of that data within the context of spectra offered by unambiguous calibrant compounds, preferably with the same coordination number and similar metal ligand distances. Such spectra assist in defining upper and/or lower limits for metal Z<sub>eff</sub> in the species of interest; 2) Evaluation of that data in conjunction with information from other physical methods, especially ligand K-edge XAS; 3) Increased care in interpretation if strong π-acceptor ligands, particularly CO, or π-donor ligands are present. The electron-withdrawing/donating nature of these ligand types, combined with relatively short metal-ligand distances, exaggerate the difference between formal oxidation state and metal Z<sub>eff</sub> or, as in the case of [W<sup>IV</sup>(mdt)<sub>2</sub>(CO)<sub>2</sub>], add other subtlety by modulating the redox level of other ligands in the coordination sphere
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