Stimulus configuration and context effects in perceptual organization in schizophrenia.

Two studies assessed perceptual organization in schizophrenia to determine (a) whether inpatient and outpatient groups with poor premorbid schizophrenia have comparable levels of perceptual organization deficit; and (b) whether the deficit could be eliminated by task manipulations. In Study 1, inpatients demonstrated clear evidence of a perceptual organization deficit, whereas outpatients performed similarly to the control groups. In Study 2, a performance pattern that operationally defined a perceptual organization deficit was eliminated by a task manipulation thought to aid in context processing. The perceptual organization deficit is most pronounced in actively symptomatic patients with poor premorbid schizophrenia, and the deficit reflects, in part, deficient top-down influences to basic perceptual processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Development of Small‐Molecule Trypanosoma brucei N‐Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode

The enzyme N‐myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high‐throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X‐ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X‐ray crystallography/structure‐based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000‐fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.     

Determination of the distribution of infectious viruses in aerosol particles using water-based condensational growth technology and a bacteriophage MS2 model

Inhalation of aerosols containing pathogenic viruses can result in morbidity, in some cases leading to mortality. The objective of this study was to develop a model for assessing how infectious viruses might distribute in airborne particles using bacteriophage MS2 as a surrogate for human viruses. Particle deposition in the respiratory system is size-dependent, and small virus-containing particles can be inhaled deeply into the lower lungs, potentially leading to more severe respiratory disease manifestations. Laboratory-generated virus-containing particles were size-selected by a differential mobility analyzer and then collected by the newly introduced Super-Efficient Sampler for Influenza Virus. The number of infectious and total viruses per particle as a function of particle size varied with the spraying medium: it approximated a cubic exponential value scaling for deionized (DI) water, a quartic exponential value for artificial saliva (AS), and between quadratic and cubic exponential value for beef extract solution (BES). The survivability of MS2 did not change significantly with particle size for DI water and BES, while that for AS was maximum at 120?nm. Viruses could be homogeneously distributed or aggregated inside or on the surface of the particles, depending on the composition of the spraying medium.

Copyright © 2019 American Association for Aerosol Research     

Dual-labeled glucose binding protein for ratiometric measurements of glucose

Highly sensitive glucose monitoring has potential applications in conditions where the glucose levels are below the detection limit of currently available technology. Examples include bioprocess monitoring of bacterial cultures and measurement of minute amounts of human interstitial fluid extracted by iontophoresis. Here we describe a ratiometric glucose sensor capable of measuring micromolar levels of glucose. This sensor is based on an E. coli glucose binding protein (GBP) labeled with two fluorophores. The L255C mutant of GBP was labeled with the environment-sensitive fluorophore, acrylodan, at the cysteine mutation and a long-lived metal ligand complex of ruthenium (ruthenium bis(2,2'-bipyridyl)-1, 10-phenanthroline-9-isothiocyanate) at the N-terminal. The acrylodan emission is quenched in the presence of glucose while the ruthenium emission remained constant, thereby serving as a reference. The sensitivity of the sensor is in the micromolar range (K(d) = 0.4-1.4 microM). Thus, it is possible to measure glucose concentrations at micromolar levels and higher (with dilution). Calculations of the fluorescence energy-transfer efficiency between acrylodan and ruthenium gave an approximate distance of 25 A between the two fluorophores, consistent with X-ray crystallographic data. The effect of temperature on glucose binding was measured and analyzed. Maximum signal changes and apparent binding constants increase with temperature. The enthalpy change for glucose binding as calculated from the apparent binding constants is approximately 43.1 kJ/mol. In addition to ratiometric measurements, the presence of the long-lived ruthenium metal ligand complex allows for low-cost modulation-based sensing.     

The formation of MgZnO luminescent ceramics

Mg_xZn_1−xO is a promising alloy system with UV-tunable bandgap. The alloy can have the hexagonal or cubic structure depending on the composition x and growth conditions. We present studies of the optical and material properties of Mg_0.1Zn_0.9O and Mg_0.6Zn_0.4O sintered ceramics. The rationale for choosing these compositions is that alloys of both the wurtzite and the cubic phases, respectively, can be investigated. To study the alloying dynamics for the optimization of light emission, the properties as a function of annealing temperature in the range of 600–1,100 °C were investigated via micro-photoluminescence, X-ray diffraction, and imaging techniques. For the Mg_0.1Zn_0.9O it was found that a threshold temperature of ~900 °C is required in order to initiate the formation of the solid solution with the wurtzite structure. At the elevated temperature regime, the photoluminescence energy for this ceramic sample shifted from 3.25 to 3.5 eV, while the ceramic retained the wurtzite structure. The Mg_0.6Zn_0.4O was found to have a sequence of phases: initially the alloy formed with the wurtzite structure, and then a transition into the NaCl cubic structure took place. Similar to the Mg_0.1Zn_0.9O, a threshold temperature of ~900 °C was required in order to initiate the alloying process. At that temperature regime an alloy was formed with the wurtzite structure, and its photoluminescence energy was ~3.25 eV. At ~1,100 °C the alloy was found to undergo a phase transition from wurtzite to cubic structure. The photoluminescence energy at that temperature was considerably shifted into the UV-range of 4 eV.     

Protein surface mapping using diethylpyrocarbonate with mass spectrometric detection

The reliability and information content of diethylpyrocarbonate (DEPC) as a covalent probe of protein surface structure has been improved when used appropriately with mass spectrometric detection. Using myoglobin, cytochrome c, and beta-2-microglobulin as model protein systems, we demonstrate for the first time that DEPC can modify Ser and Thr residues in addition to His and Tyr residues. This result expands the capability of DEPC as a structural probe because about 25% of the sequence of the average protein can now be covered using this covalent labeling reagent. In addition, we establish a new approach based on mass spectrometry to ensure the structural integrity of proteins during amino acid-specific covalent labeling reactions. This approach involves monitoring the extent of modification as a function of reagent concentration and allows any small-scale or local perturbations caused by the covalent label to be readily identified and avoided. Results indicate that these dose-response plots are much more reliable and generally applicable probes of possible protein structural changes than fluorescence or circular dichroism spectroscopies. These dose-response plots also provide a means of quantitatively comparing the reactivity of each modified residue. On the basis of comparisons to known X-ray crystal structures, we find that the solvent accessibility of the reactive atom in the side chain and the presence of a nearby charged residue most affect modification rates. Finally, this improved surface mapping method has been used to determine the effect of Cu(II) binding on the structure of beta-2-microglobulin. Results confirm that Cu(II) binds His31, but not any of the other three His residues, and changes the solvent accessibility of residues near His31 and near the N-terminus.     

Telephone-administered cognitive–behavioral therapy for the treatment of depressive symptoms in multiple sclerosis.

This study examined the efficacy of an 8-week telephone-administered cognitive- behavioral therapy (CBT) for the treatment of depressive symptomatology in multiple sclerosis (MS) patients. The treatment, Coping with MS (CMS), included a patient workbook designed to structure the treatment, provide visual aids, and help with homework assignments. Thirty-two patients with MS, who scored at least 15 on the Profile of Mood States Depression-Dejection scale, were randomly assigned to either the telephone CMS or to a usual-care control (UCC) condition. Depressive symptomatology decreased significantly in the CNIS condition compared with the UCC condition. Furthermore, adherence to interferon beta-1a, a disease-modifying medication for the treatment of MS, was significantly better at the 4-month follow-up among patients who received CMS as compared with those in the UCC condition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)