Inside-out activation of integrins is mediated via the binding of talin and kindlin to integrin β-subunit cytoplasmic tails. The kindlin FERM domain is interrupted by a pleckstrin homology (PH) ...domain within its F2 subdomain. Here, we present data confirming the importance of the kindlin-1 PH domain for integrin activation and its x-ray crystal structure at a resolution of 2.1 Å revealing a C-terminal second α-helix integral to the domain but found only in the kindlin protein family. An isoform-specific salt bridge occludes the canonical phosphoinositide binding site, but molecular dynamics simulations display transient switching to an alternative open conformer. Molecular docking reveals that the opening of the pocket would enable potential ligands to bind within it. Although lipid overlay assays suggested the PH domain binds inositol monophosphates, surface plasmon resonance demonstrated weak affinities for inositol 3,4,5-triphosphate (Ins(3,4,5)P3; KD ∼100 μm) and no monophosphate binding. Removing the salt bridge by site-directed mutagenesis increases the PH domain affinity for Ins(3,4,5)P3 as measured by surface plasmon resonance and enables it to bind PtdIns(3,5)P2 on a dot-blot. Structural comparison with other PH domains suggests that the phosphate binding pocket in the kindlin-1 PH domain is more occluded than in kindlins-2 and -3 due to its salt bridge. In addition, the apparent affinity for Ins(3,4,5)P3 is affected by the presence of PO4 ions in the buffer. We suggest the physiological ligand of the kindlin-1 PH domain is most likely not an inositol phosphate but another phosphorylated species.
Kindlins are essential co-activators with talin of integrins.
Kindlin-1 PH domain is necessary for integrin activation and has low affinity for PtdInsP species partly determined by a salt bridge across its binding pocket.
The PH domain is necessary to kindlins, localizing them to integrins, and displays subtle structural variations having major functional effects.
Targeting of kindlins partly depends on their PH domains.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Power-pulsed readout potentially offers a solution to the problem of high power consumption of the electronics for detectors at the future International Linear Collider (ILC) experiments. A 33 x 50 ...cm super(2) Glass Resistive Plate Chamber (GRPC) equipped with a power-pulsed electronics board offering 1 cm super(2) lateral segmentation was successfully tested in a 3-Tesla magnet. A significant reduction in power consumption with no deterioration of the detector performance was obtained when the power-pulsing mode was applied. This result shows that highly granular calorimeters for ILC experiments are not only an attractive but also a realistic option.
People with type 1 diabetes want to enjoy the benefits of sport and exercise, but management of diabetes in this context is complex. An understanding of the physiology of exercise in health, and ...particularly the control of fuel mobilization and metabolism, gives an idea of problems that may arise in managing diabetes for sport and exercise.
Exercise is complicated both by hypoglycaemia and hyperglycaemia in particular circumstances. Recent data demonstrate both early and late hypoglycaemia associated with endurance exercise and also give new insights into fuel use during exercise in diabetes. These data also provide potential explanations for the reduction in maximal exercise capacity sometimes observed in people with diabetes, although it should be noted that this observation is by no means universal.
Advances in the understanding of exercise physiology allow the development of management strategies that aim to help athletes with diabetes achieve appropriate metabolic control during exercise. These metabolic strategies, coupled with observations from each athlete's own experience, give a basis for individualized advice that will help athletes with diabetes to fulfil their full potential.
The study of astronomical objects using electromagnetic radiation involves four basic observational approaches: imaging, spectroscopy, photometry (accurate counting of the photons received) and ...polarimetry (measurement of the polarizations of the observed photons). In contrast to observations at other wavelengths, a lack of sensitivity has prevented X-ray astronomy from making use of polarimetry. Yet such a technique could provide a direct picture of the state of matter in extreme magnetic and gravitational fields, and has the potential to resolve the internal structures of compact sources that would otherwise remain inaccessible, even to X-ray interferometry. In binary pulsars, for example, we could directly 'see' the rotation of the magnetic field and determine if the emission is in the form of a 'fan' or a 'pencil' beam. Also, observation of the characteristic twisting of the polarization angle in other compact sources would reveal the presence of a black hole. Here we report the development of an instrument that makes X-ray polarimetry possible. The factor of 100 improvement in sensitivity that we have achieved will allow direct exploration of the most dramatic objects of the X-ray sky.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
16.
Progress with micro-pattern gas detectors Bellazzini, R; Spandre, G; Lumb, N
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2002, Volume:
478, Issue:
1
Journal Article
Peer reviewed
Open access
Micro-pattern gas detectors are position-sensitive proportional counters whose sense electrodes are constructed using micro-electronics, thin-film or advanced PCB techniques. The feature size ...attainable using these methods is of the order of a few microns and the detectors demonstrate excellent spatial resolution and fast charge collection.
We review recent progress on micro-pattern gas detectors for tracking and other cross-disciplinary applications, focussing on design principles, performance and limitations. A short list of interesting applications is discussed.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
17.
The WELL detector Bellazzini, R; Bozzo, M; Brez, A ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/1999, Volume:
423, Issue:
1
Journal Article
Peer reviewed
Open access
We introduce the WELL detector, a new type of position-sensitive gas proportional counter produced using advanced Printed Circuit Board (PCB) technology. The WELL is based on a thin kapton foil, ...copper-clad on both sides. Charge amplifying micro-wells are etched into the first metal and kapton layers. These end on a micro-strip pattern which is defined on the second metal plane. The array of micro-strips is used for read-out to obtain 1-D positional information. First results from our systematic assessment of this device are reported.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The limitation of the detection rate of standard bakelite resistive plate chambers (RPC) used as muon detector in LHC experiments is behind the absence of such detectors in the high η regions in both ...CMS and ATLAS detectors. RPCs made with low resistivity glass plates (10 10 Ω.cm) could be an adequate solution to equip the high TJ regions extending thus both the trigger efficiency and the physics performance. Different beam tests with single and multi-gap configurations using the new glass have shown that such detectors can operate at few thousands Hzlcm 2 with high efficiency(>90%).
What is the real gas gain of a standard GEM? Bellazzini, R.; Brez, A.; Gariano, G. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/1998, Volume:
419, Issue:
2-3
Journal Article
Peer reviewed
Open access
We have observed very high gains (up to 7000) from GEMs with ‘standard’ parameters (kapton thickness 50μm, pitch 120μm, copper hole diameter 65μm, kapton hole diameter 30μm). This was achieved using ...GEMs coupled to a simple array of copper read-out strips. From the measurements of the current on all the electrodes, we conclude that the high observed gains are fully attributable to electron multiplication in the holes of the mesh, and not to electronics related effects as had been previously suggested. Furthermore, we report that this large gain may only be fully exploited when the field in the second GEM gap is high. The effect on the gain of coupling a GEM to another charge amplifying device was investigated using a GEM–PMGC combination.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A new concept of high granularity hadronic calorimeter using thin Glass Resistive Plate Chambers (GRPCs) as sensitive medium with embedded semi-digital readout electronics is under development within ...the CALICE collaboration. CALICE calorimeters are intended to be used in the future linear collider experiments. To validate this new concept a prototype of 1 m is being conceived. Several GRPCs as large as 1 m were built with a new design, reducing the dead zones and improving the gas distribution system. The GRPCs were tested with an electronics board of the same size. A readout board containing 144 64-channel ASICs was conceived and built for this purpose.
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