Type 1 diabetes is a challenging condition to manage for various physiological and behavioural reasons. Regular exercise is important, but management of different forms of physical activity is ...particularly difficult for both the individual with type 1 diabetes and the health-care provider. People with type 1 diabetes tend to be at least as inactive as the general population, with a large percentage of individuals not maintaining a healthy body mass nor achieving the minimum amount of moderate to vigorous aerobic activity per week. Regular exercise can improve health and wellbeing, and can help individuals to achieve their target lipid profile, body composition, and fitness and glycaemic goals. However, several additional barriers to exercise can exist for a person with diabetes, including fear of hypoglycaemia, loss of glycaemic control, and inadequate knowledge around exercise management. This Review provides an up-to-date consensus on exercise management for individuals with type 1 diabetes who exercise regularly, including glucose targets for safe and effective exercise, and nutritional and insulin dose adjustments to protect against exercise-related glucose excursions.
Phosphatase and tensin-homolog deleted on chromosome 10 (PTEN) is a tumor-suppressor protein that regulates phosphatidylinositol 3-kinase (PI3-K) signaling by binding to the plasma membrane and ...hydrolyzing the 3′ phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) to form phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2). Several loss-of-function mutations in PTEN that impair lipid phosphatase activity and membrane binding are oncogenic, leading to the development of a variety of cancers, but information about the membrane-associated state of PTEN remains sparse. We have modeled a membrane-associated state of the truncated PTEN structure bound to PI(3,4,5)P3 via multiscale molecular dynamics simulations. We show that the location of the membrane-binding surface agrees with experimental observations and is robust to changes in lipid composition. The level of membrane interaction is substantially reduced in the phosphatase domain for the triple mutant R161E/K163E/K164E, in line with experimental results. We observe clustering of anionic lipids around the C2 domain in preference to the phosphatase domain, suggesting that the C2 domain is involved in nonspecific interactions with negatively charged lipid headgroups. Finally, our simulations suggest that the oncogenicity of the R335L mutation may be due to a reduction in the interaction of the mutant PTEN with anionic lipids.
Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH) domain is one of the most widespread, ...binding specifically to phosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately 20% anionic lipids within the cytoplasmic leaflet of the plasma membrane. We investigate the mechanism of such recognition via a multiscale procedure combining Brownian dynamics (BD) and molecular dynamics (MD) simulations of the GRP1 PH domain interacting with phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P₃). The interaction of GRP1-PH with PI(3,4,5)P₃ in a zwitterionic bilayer is compared with the interaction in bilayers containing different levels of anionic 'decoy' lipids. BD simulations reveal both translational and orientational electrostatic steering of the PH domain towards the PI(3,4,5)P₃-containing anionic bilayer surface. There is a payoff between non-PIP anionic lipids attracting the PH domain to the bilayer surface in a favourable orientation and their role as 'decoys', disrupting the interaction of GRP1-PH with the PI(3,4,5)P₃ molecule. Significantly, approximately 20% anionic lipid in the cytoplasmic leaflet of the bilayer is nearly optimal to both enhance orientational steering and to localise GRP1-PH proximal to the surface of the membrane without sacrificing its ability to locate PI(3,4,5)P₃ within the bilayer plane. Subsequent MD simulations reveal binding to PI(3,4,5)P₃, forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational framework which addresses lipid recognition within a cell membrane environment, offering a link between structural and cell biological characterisation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The pleckstrin homology (PH) domain of the general receptor for phosphoinositides 1 (GRP1) exhibits specific, high-affinity, reversible binding to phosphatidylinositol (3,4,5)-trisphosphate ...(PI(3,4,5)P3) at the plasma membrane, but the nature and extent of the interaction between this bound complex and the surrounding membrane environment remains unclear. Combining equilibrium and nonequilibrium molecular dynamics (MD) simulations, NMR spectroscopy, and monolayer penetration experiments, we characterize the membrane-associated state of GRP1-PH. MD simulations show loops flanking the binding site supplement the interaction with PI(3,4,5)P3 through multiple contacts with the lipid bilayer. NMR data show large perturbations in chemical shift for these loop regions on binding to PI(3,4,5)P3-containing DPC micelles. Monolayer penetration experiments and further MD simulations demonstrate that mutating hydrophobic residues to polar residues in the flanking loops reduces membrane penetration. This supports a “dual-recognition” model of binding, with specific GRP1-PH-PI(3,4,5)P3 interactions supplemented by interactions of loop regions with the lipid bilayer.
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► Experiment and simulation to investigate the membrane-bound state of GRP1-PH ► GRP1-PH interacts with surrounding lipids in addition to PI(3,4,5)P3 ► Three loop regions near the binding site exhibit protein-lipid contacts ► This suggests a “dual recognition” model of PH binding to membranes
Swimming Escherichia coli cells are propelled by the rotary motion of their flagellar filaments. In the normal swimming pattern, filaments positioned randomly over the cell form a bundle at the ...posterior pole. It has long been assumed that the hook functions as a universal joint, transmitting rotation on the motor axis through up to ∼90° to the filament in the bundle. Structural models of the hook have revealed how its flexibility is expected to arise from dynamic changes in the distance between monomers in the helical lattice. In particular, each of the 11 protofilaments that comprise the hook is predicted to cycle between short and long forms, corresponding to the inside and outside of the curved hook, once each revolution of the motor when the hook is acting as a universal joint. To test this, we genetically modified the hook so that it could be stiffened by binding streptavidin to biotinylated monomers, impeding their motion relative to each other. We found that impeding the action of the universal joint resulted in atypical swimming behavior as a consequence of disrupted bundle formation, in agreement with the universal joint model.
High rate resistive plate chamber for LHC detector upgrades Haddad, Y.; Laktineh, I.; Grenier, G. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
08/2013, Letnik:
718
Journal Article
Recenzirano
Odprti dostop
The limitation of the detection rate of standard bakelite resistive plate chambers (RPCs) used as muon detectors in the LHC experiments has prevented the use of such detectors in the high rate ...regions in both CMS and ATLAS detectors. One alternative to these detectors is RPCs made with low resistivity glass plates (1010Ωcm), a beam test at DESY has shown that such detectors can operate at few thousand Hz/cm2 with high efficiency (>90%).
Introduction: With increasing access to intermittently scanned continuous glucose monitoring (isCGM) , with the FSL, it is essential to understand the effect of TIR and TBR on HbA1c, DRD, and ...resource utilisation in people living with diabetes
Methods: Clinicians from 1NHS UK hospitals submitted FSL user data for16,034 participants, (96% type 1 diabetes) of whom 6859 had follow-up data, collected during routine clinical care and submitted to a web-based secure tool. Linear regression analysis was used to estimate the age, gender and baseline HbA1c adjusted reduction in HbA1c in the TIR categories.
Results: Follow up TIR data were available for 3250 (47%) participants of which, 1241 (38%) reported TIR in line with the international consensus (3.9-mmol/l) . After adjustments for age gender, baseline HbA1c and duration of diabetes follow-up TIR ≥50% was associated with an 0.8% (8.75 mmol/mol) reduction in HbA1c (P<0.0001) and -0.29 reduction in DRD (P<0.0001) , while follow-up TIR ≥70% was associated with a 1.3% (14.mmol/mol) reduction in HbA1c (P<0.0001) and 0.40 reduction (P<0.0001) in DRD vs. those with TIR <50%. With the use of FSL, there was a 67% reduction in hospital admissions due to hypoglycaemia (none in those with TIR≥50) , a 63% reduction in hospital admissions related to hyperglycaemia/DKA and an 85% reduction in paramedic outcalls. The reduction in hospital admissions for hyperglycaemia/DKA and paramedic callouts was independent of the TIR achieved during follow-up. The incidence of severe hypoglycaemia was lower in those with TBR ≤5% as compared to those with TBR >5% (7% vs. 11%) but was not statistically significant (P=0.31) .
Conclusion: In a large cohort of UK FSL users, we demonstrate a significant reduction in HbA1c, diabetes-related distress and resource utilisation which was associated with improved TIR
Disclosure
H.Deshmukh: None. T.Sathyapalan: n/a. B.Pieri: None. E.G.Wilmot: Advisory Panel; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Sanofi, Research Support; Insulet Corporation, Novo Nordisk, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker's Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. N.Shah: None. V.Tsatlidis: None. A.N.Lumb: Advisory Panel; Abbott, Dexcom, Inc., Research Support; Abbott, Novo Nordisk, Speaker's Bureau; Abbott, Dexcom, Inc., Insulet Corporation, Novo Nordisk. R.E.Ryder: None. C.Walton: None.
Funding
NIHR clinical lectureship
A new design of highly granular hadronic calorimeter using Glass Resistive Plate Chambers (GRPCs) with embedded electronics has been proposed for the future International Linear Collider (ILC) ...experiments. It features a 2-bit threshold semi-digital read-out. Several GRPC prototypes with their electronics have been successfully built and tested in pion beams. The design of these detectors is presented along with the test results on efficiency, pad multiplicity, stability and reproducibility.
Glass resistive plate chambers for a semi-digital HCAL Bedjidian, M.; Ianigro, J.-P.; Kieffer, R. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
11/2010, Letnik:
623, Številka:
1
Journal Article
Recenzirano
The Particle Flow Algorithm (PFA) concept is one of the main features of the future ILC experiments. This implies a highly granular hadronic calorimeter. A 1cm2 segmentation can be obtained using ...semi-digital embedded electronics together with an efficient gas detector. The Glass RPC is an excellent candidate that was successfully used in the BELLE experiment. To apply the PFA efficiently it is necessary to reduce the detector dead zones while keeping it as thin as possible. We have designed and constructed very thin GRPCs for which the number and volume of spacers as well as the area of the gas-tight frame are minimized. New resistive coatings were used to reduce cross-talk. Attempts to improve on the high voltage connection were made and novel gas distribution schemes were tested.
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