CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements

The inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as an attractive target in the treatment of type 2 diabetes. In view of this development, a critical analysis of structural requirements of the DPP-IV inhibitors is envisioned to identify the significant features toward design of selective inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour plots of pyrrolidine based analogues are used to analyze the structural requirements of a DPP-IV active site. The CoMFA model has shown a cross-validated q ² of 0.651 with a non-cross-validated r ² of 0.882 and explained 70.6% variance in the activity of external test compounds. In this, the steric and electrostatic fields have respectively contributed 59.8 and 40.2%, respectively, to the explained activity of the compounds. The CoMSIA model has shown optimum predictivity (cross-validated q ² = 0.661; non-cross-validated r ² = 0.803; external test set’s predictive r ² = 0.706) with four molecular fields namely, steric, electrostatic, hydrogen bond (HB)-donor, and HB-acceptor. The contour plots of molecular fields resulting from these studies have suggested: (i) steric restriction with small electron rich substituent at 2- and 3-position of pyrrolidine ring, (ii) presence of electropositive ring linker between the pyrrolidine head and aryl tail, (iii) presence of electron-rich groups around the aryl tail moiety, and (iv) presence of sulfonamide between the ring linker and aryl tail which would increase DPP-IV binding affinity of the compounds. These findings will help in the design of structurally related/new compounds as potential DPP-IV inhibitors.     

How can nanobiotechnology oversight advance science and industry: examples from environmental,health, and safety studies of nanoparticles (nano-EHS)

Nanotechnology has great potential to transform science and industry in the fields of energy, material, environment, and medicine. At the same time, more concerns are being raised about the occupational health and safety of nanomaterials in the workplace and the implications of nanotechnology on the environment and living systems. Studies on environmental, health, and safety (EHS) issues of nanomaterials have a strong influence on public acceptance of nanotechnology and, eventually, affect its sustainability. Oversight and regulation by government agencies and non-governmental organizations (NGOs) play significant roles in ensuring responsible and environmentally friendly development of nanotechnology. The EHS studies of nanomaterials can provide data and information to help the development of regulations and guidelines. We present research results on three aspects of EHS studies: physico-chemical characterization and measurement of nanomaterials; emission, exposure, and toxicity of nanomaterials; and control and abatement of nanomaterial releases using filtration technology. Measurement of nanoparticle agglomerates using a newly developed instrument, the Universal NanoParticle Analyzer (UNPA), is discussed. Exposure measurement results for silicon nanoparticles in a pilot scale production plant are presented, as well as exposure measurement and toxicity study of carbon nanotubes (CNTs). Filtration studies of nanoparticle agglomerates are also presented as an example of emission control methods.     

In vitro and in vivo mineralization and osseointegration of nanostructured Ti6Al4V

Surface characteristics of the orthopedic implants remarkably affect the corresponding biological responses. In this study, Ti6Al4V alloy was subjected to the surface mechanical attrition treatment (SMAT) in order to achieve favorable surface properties. The SMAT substrates exhibited a highly hydrophilic surface with nanograins about 20–40 nm. Then, the in vitro and in vivo mineralizations were evaluated on the untreated and SMAT processed substrates. The in vitro experimental results showed a significant increase in the deposition of calcium-containing minerals on the SMAT surface both with and without osteoblasts. The in vivo experiments also revealed a higher bone mineral apposition on the SMAT processed implants after 8 and 12 weeks post operation. The well-organized bone formation on the SMAT substrates indicated an enhanced osseointegration on the bone-implant interface. Therefore, it was suggested that the obvious improvements of biomineralization and osseointegration were attributed to the nanostructure features on the SMAT surface, as well as the higher surface hydrophilicity.     

Antibody immobilization on gold nanoparticles coated layer-by-layer with polyelectrolytes

Nanoscale materials are used in the biomedical field for magnetic resonance imaging, protein detection and drug/gene delivery. Gold nanoparticles (AuNPs) are particularly investigated in cancer treatment and imaging. In this study, we described a simple and reliable liquid method to coat AuNPs (diameter: 21 nm) layer-by-layer with alternative cationic polyallylamine and anionic polystyrenesulfonate. The C-terminal amino acid of the antibody directed against anti-bovine serum albumin was activated by EDC/NHS, and then condensed with the amino functions of the external polyallylamine layer. An ELISA test confirmed that the antigen recognition of the bioconjugate antibody was conserved. This AuNP coating and the covalently coupling could be used as a generic process for binding other specific antibodies, particularly those overexpressed in cancer cells and angiogenesis.     

Methoxycarbonyl-terminated hyperbranched poly(amine-ester) as templates for synthesis of silver nanoparticles

Highly stable and spherical silver nanoparticles, stabilized by methoxycarbonyl-terminated hyperbranched poly(amine-ester) (HPAE-COOCH₃), were synthesized in water with reducing AgNO₃/HPAE-COOCH₃ using two methods, viz. NaBH₄ and ultraviolet irradiation. HPAE-COOCH₃ was found to play a key role in the formation of nanoparticles. UV–visible absorption, Transmission electron microscopic (TEM), and Fourier transform infrared spectroscopy (FT-IR) had been used to study the structure and characterization of the silver nanoparticles. The absorption peaks of the silver nanoparticles appear at ~420 nm in UV–visible absorption spectra; average particle size reduced by NaBH₄ is ~30 nm, which is ~10 and ~15 nm, respectively, when ultraviolet irradiation time is 12 and 24 h. FT-IR spectra confirm that there is strong interaction between silver nanoparticles and HPAE-COOCH₃. And silver nanoparticles/HPAE-COOCH₃ aqueous solution can keep stable for more than 3 months.     

Asymptotic formulae for likelihood-based tests of new physics

We describe likelihood-based statistical tests for use in high energy physics for the discovery of new phenomena and for construction of confidence intervals on model parameters. We focus on the properties of the test procedures that allow one to account for systematic uncertainties. Explicit formulae for the asymptotic distributions of test statistics are derived using results of Wilks and Wald. We motivate and justify the use of a representative data set, called the “Asimov data set”, which provides a simple method to obtain the median experimental sensitivity of a search or measurement as well as fluctuations about this expectation.     

Observational constraints on decaying vacuum dark energy model

The decaying vacuum model (DV), treating dark energy as a varying vacuum, has been studied well recently. The vacuum energy decays linearly with the Hubble parameter in the late-times, ρ _Λ (t)∝H(t), and produces the additional matter component. We constrain the parameters of the DV model using the recent data-sets from supernovae, gamma-ray bursts, baryon acoustic oscillations, CMB, the Hubble rate and X-rays in galaxy clusters. It is found that the best fit of the matter density contrast Ω _m in the DV model is much lager than that in ΛCDM model. We give the confidence contours in the Ω _m –h plane up to 3σ confidence level. Besides, the normalized likelihoods of Ω _m and h are presented, respectively.     

Towards Higgs boson production in gluon fusion to NNLO in the MSSM

We consider the Higgs boson production in the gluon-fusion channel to next-to-next-to-leading order within the Minimal Supersymmetric Standard Model. In particular, we present analytical results for the matching coefficient of the effective theory and study its influence on the total production cross section in the limit where the masses of all MSSM particles coincide. For supersymmetric masses below 500 GeV it is possible to find parameters leading to a significant enhancement of the Standard Model cross section, the K-factors, however, change only marginally.     

Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls

Background  

The exact cause of schizophrenia is not known, although several aetiological theories have been proposed for the disease, including developmental or neurodegenerative processes, neurotransmitter abnormalities, viral infection and immune dysfunction or autoimmune mechanisms. Growing evidence suggests that specific cytokines and chemokines play a role in signalling the brain to produce neurochemical, neuroendocrine, neuroimmune and behavioural changes. A relationship between inflammation and schizophrenia was supported by abnormal cytokines production, abnormal concentrations of cytokines and cytokine receptors in the blood and cerebrospinal fluid in schizophrenia. Since the neuropathology of schizophrenia has recently been reported to be closely associated with microglial activation we aimed to determined whether spontaneous or LPS-induced peripheral blood mononuclear cell chemokines and cytokines production is dysregulated in schizophrenic patients compared to healthy subjects. We enrolled 51 untreated first-episode schizophrenics (SC) and 40 healthy subjects (HC) and the levels of MCP-1, MIP-1α, IL-8, IL-18, IFN-γ and RANTES were determined by Elisa method in cell-free supernatants of PBMC cultures.     

WIMP event rates in directional experiments: The diurnal variation signature

The recent WMAP data have confirmed that exotic dark matter together with the vacuum energy (cosmological constant) dominate in the flat Universe. Modern particle theories provide viable cold dark matter candidates with masses in the GeV-TeV region. All such candidates will be called WIMPs (Weakly Interacting Massive Particles). The nature of dark matter can only be unraveled by its direct detection in the laboratory. In this work we present some theoretical elements relevant to the direct dark matter detection experiments, paying particular attention to directional experiments, i.e. experiments in which not only the energy but the direction of the recoiling nucleus is observed. Since the direction of observation is fixed with respect to the Earth, while the Earth is rotating around its axis, in a directional experiment the angle between the direction of observation and the Sun’s direction of motion will change during the day. So, since the event rates sensitively depend on this angle, the observed signal in such experiments will exhibit very interesting and characteristic periodic diurnal variation.