CT Evaluation of Small-Diameter Coronary Artery Stents: Effect of an Integrated Circuit Detector with Iterative Reconstruction.

PURPOSE: To use suitable objective methods of analysis to assess the influence of the combination of an integrated-circuit computed tomographic (CT) detector and iterative reconstruction (IR) algorithms on the visualization of small (≤3-mm) coronary artery stents. MATERIALS AND METHODS: By using a moving heart phantom, 18 data sets obtained from three coronary artery stents with small diameters were investigated. A second-generation dual-source CT system equipped with an integrated-circuit detector was used. Images were reconstructed with filtered back-projection (FBP) and IR at a section thickness of 0.75 mm (FBP75 and IR75, respectively) and IR at a section thickness of 0.50 mm (IR50). Multirow intensity profiles in Hounsfield units were modeled by using a sum-of-Gaussians fit to analyze in-plane image characteristics. Out-of-plane image characteristics were analyzed with z upslope of multicolumn intensity profiles in Hounsfield units. Statistical analysis was conducted with one-way analysis of variance and the Student t test. RESULTS: Independent of stent diameter and heart rate, IR75 resulted in significantly increased xy sharpness, signal-to-noise ratio, and contrast-to-noise ratio, as well as decreased blurring and noise compared with FBP75 (eg, 2.25-mm stent, 0 beats per minute; xy sharpness, 278.2 vs 252.3; signal-to-noise ratio, 46.6 vs 33.5; contrast-to-noise ratio, 26.0 vs 16.8; blurring, 1.4 vs 1.5; noise, 15.4 vs 21.2; all P < .001). In the z direction, the upslopes were substantially higher in the IR50 reconstructions (2.25-mm stent: IR50, 94.0; IR75, 53.1; and FBP75, 48.1; P < .001). CONCLUSION: The implementation of an integrated-circuit CT detector provides substantially sharper out-of-plane resolution of coronary artery stents at 0.5-mm section thickness, while the use of iterative image reconstruction mostly improves in-plane stent visualization.

Development of a long acting human growth hormone analog suitable for once a week dosing.

Human growth hormone was conjugated to a carrier aldolase antibody, using a novel linker by connecting a disulphide bond in growth hormone to a lysine-94 amine located on the Fab arm of the antibody. The resulting CovX body showed reduced affinity towards human growth hormone receptor, reduced cell-based activity, but improved pharmacodynamic properties. We have demonstrated that this CovX-body, given once a week, showed comparable activity as growth hormone given daily in an in vivo hypophysectomized rat model.

Rapid match-searching for gene silencing assessment.

MOTIVATION: Gene silencing, also called RNA interference, requires reliable assessment of silencer impacts. A critical task is to find matches between silencer oligomers and sites in the genome, in accordance with one-to-many matching rules (G-U matching, with provision for mismatches). Fast search algorithms are required to support silencer impact assessments in procedures for designing effective silencer sequences. RESULTS: The article presents a matching algorithm and data structures specialized for matching searches, including a kernel procedure that addresses a Boolean version of the database task called the skyline search. Besides exact matches, the algorithm is extended to allow for the location-specific mismatches applicable in plants. Computational tests show that the algorithm is significantly faster than suffix-tree alternatives. AVAILABILITY: Source code, executable, data and test results are freely available at ftp://ftp.csiro.au/Horn/RapidMatch.

Low-Power and Ultra-Thin MoS2 Photodetectors on Glass.

Integration of low-power consumer electronics on glass can revolutionize the automotive and transport sectors, packaging industry, smart building and interior design, healthcare, life science engineering, display technologies, and many other applications. However, direct growth of high-performance, scalable, and reliable electronic materials on glass is difficult owing to low thermal budget. Similarly, development of energy-efficient electronic and optoelectronic devices on glass requires manufacturing innovations. Here, we accomplish both by relatively low-temperature (<600 °C) metal-organic chemical vapor deposition growth of atomically thin MoS2 on multicomponent glass and fabrication of low-power phototransistors using atomic layer deposition (ALD)-grown, high-k, and ultra-thin (∼20 nm) Al2O3 as the top-gate dielectric, circumventing the challenges associated with the ALD nucleation of oxides on inert basal planes of van der Waals materials. The MoS2 photodetectors demonstrate the ability to detect low-intensity visible light at high speed and low energy expenditure of ∼100 pico Joules. Furthermore, low device-to-device performance variation across the entire 1 cm2 substrate and aggressive channel length scalability confirm the technology readiness level of ultra-thin MoS2 photodetectors on glass.

Mobility Deception in Nanoscale Transistors: An Untold Contact Story.

Mobility is a critical parameter that is routinely used for benchmarking the performance of field-effect transistors (FETs) based on novel nanomaterials. In fact, mobility values are often used to champion nanomaterials since high-performance devices necessitate high mobility values. The current belief is that the contacts can only limit the FET performance and hence the extracted mobility is an underestimation of the true channel mobility. However, here, such misconception is challenged through rigorous experimental effort, backed by numerical simulations, to demonstrate that overestimation of mobility occurs in commonly used geometries and in nanomaterials for which the contact interface, contact doping, and contact geometry play a pivotal role. In particular, dual-gated FETs based on multilayer MoS2 and WSe2 are used as case studies in order to elucidate and differentiate between intrinsic and extrinsic contact effects manifesting in the mobility extraction. The choice of 2D layered transition metal dichalcogenides (TMDCs) as the semiconducting channel is motivated by their potential to replace and/or coexist with Si-based aging FET technologies. However, the results are equally applicable to nanotube- and nanowire-based FETs, oxide semiconductors, and organic-material-based thin-film FETs.

Early assessment of recurrent glioblastoma response to bevacizumab treatment by diffusional kurtosis imaging: a preliminary report.

PURPOSE: The purpose of this preliminary study is to apply diffusional kurtosis imaging to assess the early response of recurrent glioblastoma to bevacizumab treatment. METHODS: This prospective cohort study included 10 patients who had been diagnosed with recurrent glioblastoma and scheduled to receive bevacizumab treatment. Diffusional kurtosis images were obtained from all the patients 0-7 days before (pre-bevacizumab) and 28 days after (post-bevacizumab) initiating bevacizumab treatment. The mean, 10th, and 90th percentile values were derived from the histogram of diffusional kurtosis imaging metrics in enhancing and non-enhancing lesions, selected on post-contrast T1-weighted and fluid-attenuated inversion recovery images. Correlations of imaging measures with progression-free survival and overall survival were evaluated using Spearman's rank correlation coefficient. The significance level was set at P < 0.05. RESULTS: Higher pre-bevacizumab non-enhancing lesion volume was correlated with poor overall survival (r = -0.65, P = 0.049). Higher post-bevacizumab mean diffusivity and axial diffusivity (D∥, D∥10% and D∥90%) in non-enhancing lesions were correlated with poor progression-free survival (r = -0.73, -0.83, -0.71 and -0.85; P < 0.05). Lower post-bevacizumab axial kurtosis (K∥10%) in non-enhancing lesions was correlated with poor progression-free survival (r = 0.81, P = 0.008). CONCLUSIONS: This preliminary study demonstrates that diffusional kurtosis imaging metrics allow the detection of tissue changes 28 days after initiating bevacizumab treatment and that they may provide information about tumor progression.

Measures of societal risk and their potential use in civil aviation.

This article seeks to clarify the conceptual foundations of measures of societal risk, to investigate how such measures may be used validly in commonly encountered policy contexts, and to explore the application of these measures in the field of civil aviation. The article begins by examining standard measures of societal and individual risk (SR and IR), with attention given to ethical as well as analytical considerations. A comprehensive technical analysis of SR is provided, encompassing scalar risk measures, barrier functions, and a utility-based formulation, and clarifications are offered with respect to the treatment of SR in recent publications. The policy context for SR measures is shown to be critically important, and an extension to a hierarchical setting is developed. The prospects for applying SR to civil aviation are then considered, and some technical and conceptual issues are identified. SR appears to be a useful analytical tool in this context, provided that careful attention is given to these issues.

Engineered optical and electrical performance of rf-sputtered undoped nickel oxide thin films for inverted perovskite solar cells.

Inverted perovskite solar cells incorporating RF sputtered NiO thin films as a hole transport layer and window layer are demonstrated. The electrical and optical properties of the NiO thin films are engineered using varied sputtering conditions. The localized states within bandgap owing to its crystal disorder and nonstoichiometric features affect the transmittance and the optical bandgap of the NiO thin films which in turn influences the Jsc of the perovskite solar cells. In addition, the electrical properties of the NiO thin films can be also varied during sputtering condition affecting the concentration of nickel vacancies and the resulting hole concentration. The conductivity largely originates from the hole concentration relating to the density of states in the NiO thin films which influence the fill factor (FF) of the solar cells. The solar cells fabricated with the NiO thin films made at 4 Pa of deposition pressure show highest performance owing to excellent transmittance and wider bandgap along with moderate conductivity. With further optimization, the perovskite solar cells exhibit ~20 mA/cm2 of Jsc and a 12.4% PCE (11.3% of averaged PCE).

Development of a Non-Invasive Blink Reflexometer.

Qualitative assessments of the blink reflex are used clinically to assess neurological status in critical care, operating room, and rehabilitative settings. Despite decades of literature supporting the use of quantitative measurements of the blink reflex in the evaluation of multiple neurological disorders, clinical adoption has failed. Thus, there remains an unmet clinical need for an objective, portable, non-invasive metric of neurological health that can be used in a variety of settings. We have developed a high-speed videography-based device to trigger, record, and analyze a blink reflex. A pilot study was performed to compare the device's measurements to the published literature of electromyographic measurements, currently the gold standard. The study results indicate that the device is a viable tool to obtain fast, objective, and quantitative metrics of a blink reflex, and has promise as a non-invasive diagnostic assessment of neurological health.

Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/α klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. © 2017 American Society for Bone and Mineral Research.

Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay.

Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.

Blue-shifting of circular Bragg phenomenon by annealing of chiral sculptured thin films.

The wavelength regime of the circular Bragg phenomenon, exhibited by chiral sculptured thin films fabricated using the serial bideposition technique, blue shifts as a result of post-deposition annealing. This blue shift can be attributed to the net effect of three material changes that occur during annealing: a small reduction in helical pitch, an increase in the relative permittivity of the column material changing from amorphous to crystalline, and a density reduction due to columnar thinning from the same amorphous-to-crystalline transition.

Three-year comparison of the content of antioxidant microconstituents and several quality characteristics in organic and conventionally managed tomatoes and bell peppers.

Understanding how the environment and production and cultivation practices influence the composition and quality of food crops is fundamental to the production of high-quality nutritious foods. In this 3-year study, total phenolics, percent soluble solids, ascorbic acid, and the flavonoid aglycones quercetin, kaempferol, and luteolin were measured in two varieties of tomato (Lycopersicon esculentum L. cv. Ropreco and Burbank) and two varieties of bell peppers (Capsicum annuum L. cv. California Wonder and Excalibur) grown by certified organic and conventional practices in a model system. Significantly higher levels of percent soluble solids (17%), quercetin (30%), kaempferol (17%), and ascorbic acid (26%) were found in Burbank tomatoes (fresh weight basis; FWB), whereas only levels of percent soluble solids (10%) and kaempferol (20%) were significantly higher in organic Ropreco tomatoes (FWB). Year-to-year variability was significant, and high values from 2003 influenced the 3-year average value of quercetin reported for organic Burbank tomatoes. Burbank tomatoes generally had higher levels of quercetin, kaempferol, total phenolics, and ascorbic acid as compared to Ropreco tomatoes. Bell peppers were influenced less by environment and did not display cropping system differences.

A method for the fabrication of sculptured thin films of periodic arrays of standing nanorods.

A simple method for the fabrication of sculptured thin films (STFs) of periodic arrays of high-aspect-ratio (20:1) standing nanorods on silicon substrates is described. It is based on oblique evaporation onto periodically arranged arrays of "mini-rod" topography using a rotating sample stage. Recently, it has been shown that these nanostructures can be prepared on relatively large areas and at low cost, making the method suitable for technological applications.

Adenoviral-mediated expression of a kinase-dead mutant of Akt induces apoptosis selectively in tumor cells and suppresses tumor growth in mice.

Akt/protein kinase B is a serine/threonine kinase that plays a critical role in cell survival signaling, and its activation has been linked to tumorigenesis in several human cancers. Up-regulation of Akt, as well as its upstream regulator phosphatidylinositol 3-kinase, has been found in many tumors, and the negative regulator of this pathway, mutated in multiple advanced cancers suppressor (MMAC; also known as phosphatase and tensin homologue deleted on chromosome 10), is a tumor suppressor gene. We have investigated the effects of inhibiting Akt signaling in tumor cells by expression of an Akt kinase-dead mutant in which the two regulatory phosphorylation sites have been mutated to alanines. This mutant, which functions in a dominant negative manner (Akt-DN), was introduced into tumor cells using a replication-defective adenovirus expression system. As controls we used adenoviruses expressing p53, MMAC, beta-galactosidase, and empty virus. We show that in vitro proliferation of human and mouse tumor cells expressing high levels of activated/phosphorylated Akt was inhibited by both Akt-DN and p53, in comparison with control viruses expressing beta-galactosidase. Similarly, Akt-DN mutant expression led to selective induction of apoptosis in tumor cells expressing activated Akt. On the other hand, Akt-DN expression had minimal effect in normal and tumor cells expressing low levels of activated Akt. Expression of MMAC induced selective apoptosis in tumor cell lines in which MMAC is inactivated but not in tumor cells expressing wild-type levels of MMAC. In addition, the growth of tumor cells in a mouse model was also significantly inhibited by intratumoral injection of Akt-DN virus. These studies validate the usefulness of targeting Akt for new drug discovery efforts and suggest that inhibition of Akt may have a selective antitumor effect.

Two-Photon Laser Scanning Stereomicroscopy for Fast Volumetric Imaging.

Bessel beams have been successfully used in two-photon laser scanning fluorescence microscopy to extend the depth of field (EDF), which makes it possible to observe fast events volumetrically. However, the depth information is lost due to integration of fluorescence signals along the propagation direction. We describe the design and implementation of two-photon lasers scanning stereomicroscopy, which allows viewing dynamic processes in three-dimensional (3D) space stereoscopically in real-time with shutter glasses at the speed of 1.4 volumes per second. The depth information can be appreciated by human visual system or be recovered with correspondence algorithms for some cases.

Characterization of empty capsids from a conditionally replicating adenovirus for gene therapy.

As virus vectors for gene therapy approach the goal of successful clinical treatment, it is increasingly necessary for the product to be fully characterized. Empty capsids are perhaps the main extraneous component of recombinant adenovirus (rAd) products that are purified by column chromatography. Two diverse rAd products, one a replication-defective rAd and the other a conditionally replicating rAd, show different protein compositions of their empty capsids. The empty capsid type from the replication-defective rAd carrying the gene for p53 was previously determined to have approximately 1400 copies per particle of pVIII, the precursor to the hexon-associated protein VIII (Vellekamp et al., Hum. Gene Ther. 2001;12:1923-1936). Quantification of this protein is a useful measure of the amount of empty capsids in preparations of this vector. Here we purify and characterize empty capsids from the conditionally replicating rAd. This empty capsid type lacks any appreciable amount of pVIII but contains pVI and multiple forms of the L1 52/55K protein, mostly as disulfidelinked oligomers. Empty capsid from conditionally replicating rAd present new challenges in terms of its quantification, but sodium dodecyl sulfate-polyacrylamide gel electrophoresis densitometry analysis suggests that the amount of this empty capsid in a preparation, like that of rAd p53 empty capsid, declines with increased time of infection. This empty capsid demonstrates heterogeneity by anion-exchange chromatography, electron microscopy, and CsCl density gradient centrifugation.

Highly Efficient and Practical Syntheses of Lavendamycin Methyl Ester and Related Novel Quinolindiones.

The novel 7-(N-formyl-, 7-(N-acetyl-, and 7-(N-isobutyrylamino)-2-methylquinoline-5,8-diones were synthesized in excellent overall yields in three steps via the nitration of the commercially available 8-hydroxy-2-methylquinoline followed by a reduction-acylation step and then oxidation. Acid hydrolysis of 7-(N-acetylamino)-2-methylquinoline-5,8-dione (14a) afforded the novel 7-aminoquinoline-5,8-dione 7 in excellent yields. Due to our efficient preparation of dione 14a, we now report a short and practical method for the total synthesis of the potent antitumor agent lavendamycin methyl ester (1b) with an excellent overall yield.

The Effect of Molecular Weight, PK, and Valency on Tumor Biodistribution and Efficacy of Antibody-Based Drugs.

Poor drug delivery and penetration of antibody-mediated therapies pose significant obstacles to effective treatment of solid tumors. This study explored the role of pharmacokinetics, valency, and molecular weight in maximizing drug delivery. Biodistribution of a fibroblast growth factor receptor 4 (FGFR4) targeting CovX-body (an FGFR4-binding peptide covalently linked to a nontargeting IgG scaffold; 150 kDa) and enzymatically generated FGFR4 targeting F(ab)2 (100 kDa) and Fab (50 kDa) fragments was measured. Peak tumor levels were achieved in 1 to 2 hours for Fab and F(ab)2 versus 8 hours for IgG, and the percentage injected dose in tumors was 0.45%, 0.5%, and 2.5%, respectively, compared to 0.3%, 2%, and 6% of their nontargeting controls. To explore the contribution of multivalent binding, homodimeric peptides were conjugated to the different sized scaffolds, creating FGFR4 targeting IgG and F(ab)2 with four peptides and Fab with two peptides. Increased valency resulted in an increase in cell surface binding of the bivalent constructs. There was an inverse relationship between valency and intratumoral drug concentration, consistent with targeted consumption. Immunohistochemical analysis demonstrated increased size and increased cell binding decreased tumor penetration. The binding site barrier hypothesis suggests that limited tumor penetration, as a result of high-affinity binding, could result in decreased efficacy. In our studies, increased target binding translated into superior efficacy of the IgG instead, because of superior inhibition of FGFR4 proliferation pathways and dosing through the binding site barrier. Increasing valency is therefore an effective way to increase the efficacy of antibody-based drugs.

Drosophila translational elongation factor-1gamma is modified in response to DOA kinase activity and is essential for cellular viability.

Drosophila translational elongation factor-1gamma (EF1gamma) interacts in the yeast two-hybrid system with DOA, the LAMMER protein kinase of Drosophila. Analysis of mutant EF1gamma alleles reveals that the locus encodes a structurally conserved protein essential for both organismal and cellular survival. Although no genetic interactions were detected in combinations with mutations in EF1alpha, an EF1gamma allele enhanced mutant phenotypes of Doa alleles. A predicted LAMMER kinase phosphorylation site conserved near the C terminus of all EF1gamma orthologs is a phosphorylation site in vitro for both Drosophila DOA and tobacco PK12 LAMMER kinases. EF1gamma protein derived from Doa mutant flies migrates with altered mobility on SDS gels, consistent with it being an in vivo substrate of DOA kinase. However, the aberrant mobility appears to be due to a secondary protein modification, since the mobility of EF1gamma protein obtained from wild-type Drosophila is unaltered following treatment with several nonspecific phosphatases. Expression of a construct expressing a serine-to-alanine substitution in the LAMMER kinase phosphorylation site into the fly germline rescued null EF1gamma alleles but at reduced efficiency compared to a wild-type construct. Our data suggest that EF1gamma functions in vital cellular processes in addition to translational elongation and is a LAMMER kinase substrate in vivo.