Peptide binding to HLA-DP proteins at pH 5.0 and pH 7.0:a quantitative molecular docking study

Background: HLA-DPs are class II MHC proteins mediating immune responses to many diseases. Peptides bind MHC class II proteins in the acidic environment within endosomes. Acidic pH markedly elevates association rate constants but dissociation rates are almost unchanged in the pH range 5.0 - 7.0. This pH-driven effect can be explained by the protonation/deprotonation states of Histidine, whose imidazole has a pKa of 6.0. At pH 5.0, imidazole ring is protonated, making Histidine positively charged and very hydrophilic, while at pH 7.0 imidazole is unprotonated, making Histidine less hydrophilic. We develop here a method to predict peptide binding to the four most frequent HLA-DP proteins: DP1, DP41, DP42 and DP5, using a molecular docking protocol. Dockings to virtual combinatorial peptide libraries were performed at pH 5.0 and pH 7.0. Results: The X-ray structure of the peptide - HLA-DP2 protein complex was used as a starting template to model by homology the structure of the four DP proteins. The resulting models were used to produce virtual combinatorial peptide libraries constructed using the single amino acid substitution (SAAS) principle. Peptides were docked into the DP binding site using AutoDock at pH 5.0 and pH 7.0. The resulting scores were normalized and used to generate Docking Score-based Quantitative Matrices (DS-QMs). The predictive ability of these QMs was tested using an external test set of 484 known DP binders. They were also compared to existing servers for DP binding prediction. The models derived at pH 5.0 predict better than those derived at pH 7.0 and showed significantly improved predictions for three of the four DP proteins, when compared to the existing servers. They are able to recognize 50% of the known binders in the top 5% of predicted peptides. Conclusions: The higher predictive ability of DS-QMs derived at pH 5.0 may be rationalised by the additional hydrogen bond formed between the backbone carbonyl oxygen belonging to the peptide position before p1 (p-1) and the protonated ε-nitrogen of His 79β. Additionally, protonated His residues are well accepted at most of the peptide binding core positions which is in a good agreement with the overall negatively charged peptide binding site of most MHC proteins. © 2012 Patronov et al.; licensee BioMed Central Ltd.

Stock index reaction to large price changes:evidence frommajor Asian stock indexes

We examine the short-term price behavior of ten Asian stock market indexes following large price changes or “shocks”. Under the standard OLS regression, there is stronger support for return continuations particularly following positive and negative price shocks of less than 10% in absolute size. The results under the GJR-GARCH method provide stronger support for market efficiency, especially for large price shocks. For example, for the Hong Kong stock index, negative shocks of less than -5% but more than -10% generate a significant one day cumulative abnormal return (CAR) of-0.754% under the OLS method, but an insignificant CAR of 0.022% under the GJR-GARCH. We find no support for the uncertainty information hypothesis. Furthermore, the CARs following the period after the Asian financial crisis adjust more quickly to price shocks.

Strain-facilitated process for the lift-off of a Si layer of less than 20 nm thickness

We report a process for the lift-off of an ultrathin Si layer. By plasma hydrogenation of a molecular-beam-epitaxy-grown heterostructure of SiSb-doped-SiSi, ultrashallow cracking is controlled to occur at the depth of the Sb-doped layer. Prior to hydrogenation, an oxygen plasma treatment is used to induce the formation of a thin oxide layer on the surface of the heterostructure. Chemical etching of the surface oxide layer after hydrogenation further thins the thickness of the separated Si layer to be only 15 nm. Mechanisms of hydrogen trapping and strain-facilitated cracking are discussed. © 2005 American Institute of Physics.

Faster radial strain relaxation in InAs-GaAs core-shell heterowires

The structure of wurtzite and zinc blende InAs-GaAs (001) core-shell nanowires grown by molecular beam epitaxy on GaAs (001) substrates has been investigated by transmission electron microscopy. Heterowires with InAs core radii exceeding 11 nm, strain relax through the generation of misfit dislocations, given a GaAs shell thickness greater than 2.5 nm. Strain relaxation is larger in radial directions than axial, particularly for shell thicknesses greater than 5.0 nm, consistent with molecular statics calculations that predict a large shear stress concentration at each interface corner. © 2012 American Institute of Physics.

Melting and solidification of Zinc-Aluminium alloys

Following a scene-setting introduction are detailed reviews of the relevant scientific principles, thermal analysis as a research tool and the development of the zinc-aluminium family of alloys. A recently introduced simultaneous thermal analyser, the STA 1500, its use for differential thermal analysis (DTA) being central to the investigation, is described, together with the sources of support information, chemical analysis, scanning electron microscopy, ingot cooling curves and fluidity spiral castings. The compositions of alloys tested were from the binary zinc-aluminium system, the ternary zinc-aluminium-silicon system at 30%, 50% and 70% aluminium levels, binary and ternary alloys with additions of copper and magnesium to simulate commercial alloys and five widely used commercial alloys. Each alloy was shotted to provide the smaller, 100mg, representative sample required for DTA. The STA 1500 was characterised and calibrated with commercially pure zinc, and an experimental procedure established for the determination of DTA heating curves at 10°C per minute and cooling curves at 2°C per minute. Phase change temperatures were taken from DTA traces, most importantly, liquidus from a cooling curve and solidus from both heating and cooling curves. The accepted zinc-aluminium binary phase diagram was endorsed with the added detail that the eutectic is at 5.2% aluminium rather than 5.0%. The ternary eutectic trough was found to run through the points, 70% Al, 7.1% Si, 545°C; 50% Al, 3.9% Si, 520°C; 30% Al, 1.4% Si, 482°C. The dendrite arm spacing in samples after DTA increased with increasing aluminium content from 130m at 30% to 220m at 70%. The smallest dendrite arm spacing of 60m was in the 30% aluminium 2% silicon alloy. A 1kg ingot of the 10% aluminium binary alloy, insulated with Kaowool, solidified at the same 2°C per minute rate as the DTA samples. A similar sized sand casting was solidified at 3°C per minute and a chill casting at 27°C per minute. During metallographic examination the following features were observed: heavily cored phase which decomposed into ' and '' on cooling; needles of the intermetallic phase FeAl4; copper containing ternary eutectic and copper rich T phase.

Compact sensors based on cascaded single-mode-multimode-single-mode fiber structures

Concatenated single-mode-multimode-single-mode (SMS) structures are demonstrated as functional sensing platforms. The devices are fabricated by periodically inserting micrometric sections of multimode optical fiber (MMF) in a single-mode fiber (SMF). The periodic change of the core diameter produces a single strong resonant transmission notch, tunable in the wavelength range from 1200 to 1600 nm. It was found that the position of the notch changed with temperature and refractive index. The devices introduced here are highly compact (length less than 5 mm), simple to fabricate and robust; hence, they are adequate for diverse sensing applications. © 2013 The Japan Society of Applied Physics.

High-accuracy discrimination of Parkinson’s Disease participants from healthy controls using smartphones

Objective: To test the practicality and effectiveness of cheap, ubiquitous, consumer-grade smartphones to discriminate Parkinson’s disease (PD) subjects from healthy controls, using self-administered tests of gait and postural sway. Background: Existing tests for the diagnosis of PD are based on subjective neurological examinations, performed in-clinic. Objective movement symptom severity data, collected using widely-accessible technologies such as smartphones, would enable the remote characterization of PD symptoms based on self-administered, behavioral tests. Smartphones, when backed up by interviews using web-based videoconferencing, could make it feasible for expert neurologists to perform diagnostic testing on large numbers of individuals at low cost. However, to date, the compliance rate of testing using smart-phones has not been assessed. Methods: We conducted a one-month controlled study with twenty participants, comprising 10 PD subjects and 10 controls. All participants were provided identical LG Optimus S smartphones, capable of recording tri-axial acceleration. Using these smartphones, patients conducted self-administered, short (less than 5 minute) controlled gait and postural sway tests. We analyzed a wide range of summary measures of gait and postural sway from the accelerometry data. Using statistical machine learning techniques, we identified discriminating patterns in the summary measures in order to distinguish PD subjects from controls. Results: Compliance was high all 20 participants performed an average of 3.1 tests per day for the duration of the study. Using this test data, we demonstrated cross-validated sensitivity of 98% and specificity of 98% in discriminating PD subjects from healthy controls. Conclusions: Using consumer-grade smartphone accelerometers, it is possible to distinguish PD from healthy controls with high accuracy. Since these smartphones are inexpensive (around $30 each) and easily available, and the tests are highly non-invasive and objective, we envisage that this kind of smartphone-based testing could radically increase the reach and effectiveness of experts in diagnosing PD.

The SECURE study:long-term safety of Ranibizumab 0.5 mg in neovascular age-related macular degeneration

Objective - To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). Design - Twenty-four–month, open-label, multicenter, phase IV extension study. Participants - Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. Methods - Ranibizumab 0.5 mg administered at the investigator's discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigator's opinion). Main Outcome Measures - Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections. Results - Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline. Conclusions - The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigator's discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment.