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Millions of tons of waste glass are produced globally. The use of waste glass in concrete is an environmentally friendly solution, contributing to sustainable construction practices. This study investigates the potential of using recycled waste glass powder (RWGP) in foamed concrete nonload bearing wall panels as acoustic barriers. This study investigates the axial and flexural behavior of wall panels constructed with foamed concrete incorporating RWGP. A total of ten 900 mm long and 700 mm wide wall panels of foamed concrete with RWGP reinforced with 7.6 mm diameter steel mesh were cast and tested. Five wall panels were 75 mm thick and reinforced with one layer of steel mesh and the other five wall panels were 120 mm thick and reinforced with two layers of steel mesh. The experimental results exhibited that 120 mm thick wall panels sustained significantly higher peak axial and flexural loads, bending moments, axial deformations at peak axial load and midspan deflections at peak flexural load than 75 mm thick wall panels. The available design codes of masonry structures underestimated the peak axial loads and the bending moments of wall panels by about 9% and 17%, respectively. [ABSTRACT FROM AUTHOR]

Deflection by magnetic or electric field gradients has long been used to analyze or to alter the translational trajectories of neutral gas-phase atoms or molecules. Recent work has developed sources of slow, cold molecular beams that offer means to enhance markedly the attainable deflections, which are inversely proportional to the translational kinetic energy. The sensitivity and resolution can thus be much increased, typically by factors of 102–104. We illustrate ways to exploit this enhanced deflection capability, particularly when balancing electric and magnetic deflections. Chemical scope can be greatly extended by utilizing feeble but ubiquitous interactions, especially the induced electric dipole due to the molecular polarizability and magnetic moments resulting from molecular rotation or nuclear spins. We also examine the effect of non-Maxwellian velocity distributions produced by supersonic expansions or by quantum statistics (pertinent for ultracold beams). Generic plots are provided, employing dimensionless variables, to facilitate the design and interpretation of experiments with deflections amplified by low kinetic energy. [ABSTRACT FROM AUTHOR]

This paper investigates the theoretical conclusions of a numerical analysis. The results are reproduced experimentally using a two-dimensional model in a wave flume. The experimental set-up is conducted by subjecting the model to waves with frequencies ranging from 0.2 to 2 Hz. The heave velocities of the structure and water column are calculated by differentiating the displacement of each with respect to time. The experimental results confirm that the extent of the parametric relationship between the structure heave velocity and oscillating water column heave velocity is linearly related to the power output potential of the system and hence, can be used as a design tool for floating offshore wave energy converters. It has also been determined that the extent of the parametric function is maximised when the forcing frequency is between 90 and 100% of the natural frequency of the water column of the system in question. This shows that the system efficiency is maximised when the waves cause resonance of the water column compared to the ocean wave. [ABSTRACT FROM AUTHOR]

Cost has been traditionally known as a key factor that needs to be considered in the decision making process. Recent awareness in environmental problems has highlighted the need for considering environmental impacts into the process of making choices. However, far too little attention has been paid to reflect the environmental impact and the building cost into the decision making process. As such, this study proposed a method that integrates and considers the environmental cost and building cost in the structural design process. This method takes into account the cost associated with building materials, construction methods and amount of embodied carbon emission during the life cycle of buildings. The current study analysed the effects of two construction systems (Flat slab and waffle slab) and two structural materials (Normal concrete and Ultra-lightweight concrete) on overall costs of a typical high rise concrete structure (15-story office building) in Australia (NS11401.1 2014). The results show that the office building designed with lightweight construction method (waffle slab) and normal concrete (Normal weight) has a lower life cycle cost (50 year lifespan) in comparison with the other design alternatives. It was found that an appropriate selecting of construction forms and type of concrete can save up to 7% of the cost of material consumption, 5% of the total energy consumption expense, and 5% of the CO 2 -e emissions of the building across all five major cities. This study demonstrates a method to quantify the potential impact of Ultra-lightweight concrete has on the life cycle cost and carbon emissions of commercial buildings. The proposed methodology to assess life cycle cost and environmental impact can be used as a supporting tool in selection of efficient construction methods and structural materials over the lifetime of building. [ABSTRACT FROM AUTHOR]

Small-eared shrews of the genusCryptotis(Mammalia: Eulipotyphla: Soricidae) are widespread in the northern Neotropics. Systematic studies of these shrews over the past two decades have revealed previously undocumented morphological and species diversity, resulting in a quadrupling of the number of recognized species. Unfortunately, a small proportion of the species in the genus have been included in molecular phylogenetic studies, and evolutionary relationships within the genus are incompletely known. Traditionally, species have been assigned to four or five morphologically defined ‘species groups’, but tests of the monophyly of some of these groups show weak support and relationships amongst species groups remain somewhat speculative. The largest species group is theC. mexicanusgroup inhabiting Mexico and northern Central America. We studied sequences from mitochondrial cytochrome-b and 16S genes, as well as nuclear ApoB and BRCA1 genes from 22 species ofCryptotis, including 15 species in theC. mexicanusgroup. Our combined analysis shows that theC. goldmanisubgroup is very weakly supported as monophyletic; however, theC. mexicanusgroup as a whole is not monophyletic. Our molecular phylogenetic analyses confirm the distinctiveness of two newly described species (C. celaqueandC. mccarthyi) from isolated highlands of western Honduras and illustrate their relationship with other species formerly considered part of a widespreadC. goodwini. [ABSTRACT FROM PUBLISHER]

One of the main challenges in sustainable design of buildings is to improve the energy efficiency of the building during its lifetime along with reducing the environmental impact of the design. Recent advances in concrete technology offer lower embodied emission through the application of supplementary cementitious materials and recycled aggregates. There are also improvements to thermal properties with the application of admixtures. However, the relationships between the environmental impact (Cradle to Gate) and thermal performance of concrete mix designs have not been researched adequately. The Green House Gas (GHG) emissions associated with each individual concrete component and its production need to be considered with greater refinement. This study correlates the impacts of selecting a concrete mix design in terms of CO 2 -e with resulting thermal conductivity and density at the design stage of buildings. This paper examines 90 concrete mix designs from published literature to identify their embodied emissions and thermal conductivity in order to discuss the relationship between low embodied carbon dioxide equivalents (CO 2 -e) emission alternatives and thermal conductivity. The embodied CO 2 -e of a variety concrete mix designs were quantified by compiling embodied CO 2 -e coefficient for each individual component in the concrete. The results show the variation in embodied CO 2 -e and thermal conductivity of concrete mixes. The application of readily available supplementary cementitious material can reduce embodied CO 2 -e (kg CO 2 -e) by up to 16% in comparison with general practice. Furthermore, the thermal conductivity of concrete mix is influenced by changing the density of aggregates and the proportion of cementitious materials. In completing this work the results obtained from the study are compared with six different inventory databases: ICE (Hammond et al., 2011), Crawford (2011), Alcon (2003), eTool (2014), BPIC (2014) and AusLCI (2013). The comparison identifies some inconsistencies in calculation of embodied CO 2 -e across the different databases. This is attributed to variation in embodied CO 2 -e coefficients and lack of in-depth consideration of the detailed properties of each individual concrete mix design. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) has publicly recognized the importance of improving drug development efficiency, deeming translational biomarkers a top priority. The use of imaging biomarkers has been associated with increased rates of drug approvals. An appropriate level of validation provides a pragmatic way to choose and implement these biomarkers. Standardizing imaging modality selection, data acquisition protocols, and image analysis (in ways that are agnostic to equipment and algorithms) have been key to imaging biomarker deployment. The best known examples come from studies done via precompetitive collaboration efforts, which enable input from multiple stakeholders and data sharing. Digital health technologies (DHTs) provide an opportunity to measure meaningful aspects of patient health, including patient function, for extended periods of time outside of the hospital walls, with objective, sensor‐based measures. We identified the areas where learnings from the imaging biomarker field can accelerate the adoption and widespread use of DHTs to develop novel treatments. As with imaging, technical validation parameters and performance acceptance thresholds need to be established. Approaches amenable to multiple hardware options and data processing algorithms can be enabled by sharing DHT data and by cross‐validating algorithms. Data standardization and creation of shared databases will be vital. Pre‐competitive consortia (public‐private partnerships and professional societies that bring together all stakeholders, including patient organizations, industry, academic experts, and regulators) will advance the regulatory maturity of DHTs in clinical trials. [ABSTRACT FROM AUTHOR]

Presents a study which focused on the rediscovery of the brown sac-wing bat (Balantiopteryx infusca) in Ecuador. Three known species of Balantiopteryx; Materials and methods; Results and discussion.

• A novel method established and tested for realistic analysis of loaded tensegrities. • Robust solution method utilises Rhinoceros 3D, Grasshopper and Kangaroo Physics. • Form-finding coupled with genetic algorithms obtain optimum shape and load capacity. • 600% improvement on previously published load capacities via optimal pretensioning. Tensegrity structures present new possibilities to the field of structural engineering, owing to their ability to efficiently distribute compressive loads associated with their non-orthogonal design. Previous research has shown that when pretensioned, tensegrities exhibit higher resistance to compressive loading. However, over-tensioning can have adverse effects, reducing the tensegrities overall resistance to compressive loading. The geometry of a tensegrity affects how the structure reacts to loading, and the prestress and loading can concurrently affect geometry. This paper uses genetic algorithms to optimize the pretension loads in the cables of a tensegrity to deliver the highest overall vertical load capacity. The results are applied to determine the ultimate load-carrying capacity of tensegrities under a compressive load and determine the optimal aspect ratio at which this is achieved. By optimizing the pretension, the tensegrity can withstand compressive loads up to six times those that have been previously reported in literature. [ABSTRACT FROM AUTHOR]

Characterizes the ternary bismuth sulfide KBi3S5, formed from the reaction of Bi in a K2Sx flux at 300 degrees Celsius. Synthesis and spectroscopy; Description of structure; Thermal analysis; Ion-exchange studies; Solid-state ion exchange reactions with halide salts.

Presents an overview of nuclear medicine and positron emission tomography (PET). Uses of nuclear medicine; Health hazards associated with radiation; Annual effective dose equivalent in the United States; Radionuclides with short half-lives; Majority of radioisotopes used in PET.

Analyzes the characteristics of the quaternary compounds APbPSe4 and A4M(PSe4)2 (M=Pb, Eu) which were yielded from the reaction of Pb and Eu with selenophosphate fluxes made from A2Se/P2Se5/Se (A=K, Rb). Production of two-dimensional [APbPSe4] or one-dimensional [A4M(PSe4)2] compounds; Physical properties of the compounds.

Reports the synthesis, structural characterization and optical, thermal and magnetic properties of a new class of compounds, A2MP2Se6, where A is M, Rb or Cs, M is Mn or Fe and, A2M'2P2Se6, where A is K, M' is Cu or Ag. Magnetic susceptibility measurements; Band gaps; Crystallographic studies.

Examines the structural characterization of Cs2Sb4S8 and CsSbS6 which were synthesized by reacting Sb with a Cs2Sx flux. Thermal analysis data for the complexes.

The article presents information of mammalian species namely Sturnira mordax (S. mordax), bat. S. mordax is a relatively dark-colored medium sized member of Sturnira. Its hind feet are sparsely haired and tip of tragus is bifid or notched in more than 80 percent of individuals. Compared to other stenodermatines, S. mordax tends to be relatively small in lengths of forearm. Pregnant females occur in February, April and August, suggesting that S. mordax may be polyestrus. Many specimen of S. mordax have been taken in moist tropical forests at mid-elevations, averaging 1,257 to 3,000 m.

This data paper presents the experimental investigation of unconfined cold-formed steel double-shear bolted connections where the applied load was stopped at different stages of loading (25% or 65% of the ultimate failure load under monotonic loading) followed by unloading, and finally reloading until failure. A total of 78 bolted connections of cold-formed steel subjected to loading–unloading and reloading conditions with sheet thicknesses ranging from 0.55 to 3.0 mm, bolted with 10, 12, or 16-mm bolts were investigated and compared to the identical specimens subjected to monotonic loading. The failure mode of the specimens tested under both loading conditions was bearing of the inner sheet. The test results show that ultimate capacities obtained from unloading and reloading tests were, on average, lower than those obtained from the monotonic tests. A similar trend was also observed for the displacement corresponding to the ultimate loads. However, the effects of sheet thickness and bolt diameter were found to be less critical. This study establishes a publicly available database of control cases to build the foundation for further study into similar loading regimes. This paper also alludes to several potential use cases for the available data. [ABSTRACT FROM AUTHOR]

Highlights • Trial mixes of foam concrete without and with recycled glass powder are developed. • Effect of cement, foam and recycled glass powder content on foam concrete are investigated. • The compressive strength, plastic density and dry density of foam concrete with recycled glass powder are investigated. Abstract This study investigates the potential of the use of recycled glass powder in foam concrete as a sustainable solution for future construction. The effects of cement and recycled glass powder contents, water to cement ratio and volume of foam on the plastic density, dry density, and compressive strength of foam concrete were investigated. The compressive strength of foam concrete without and with recycled glass powder increased with the increase in the plastic density and dry density of foam concrete. The direct replacement of cement with recycled glass powder (20% by mass) increased the compressive strength of foam concrete. [ABSTRACT FROM AUTHOR]

Minimal research papers have investigated the use of student evaluations on the laboratory, a learning medium usually run by teaching assistants with little control of the content, delivery and equipment. Finding the right mix of teaching assistants for the laboratory can be an onerous task due to the many skills required including theoretical and practical know-how, troubleshooting, safety and class management. Using larger classes with multiple teaching assistants, a team-based teaching (TBT) format may be advantageous. A rigorous three-year study across twenty-five courses over repetitive laboratory classes is analysed using a multi-level statistical model considering students, laboratory classes and courses. The study is used to investigate the effectiveness of the TBT format, and quantify the influence each demonstrator has on the laboratory experience. The study found that TBT is effective and the lead demonstrator most influential, influencing up to 55% of the laboratory experience evaluation. [ABSTRACT FROM AUTHOR]

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. [ABSTRACT FROM AUTHOR]

Describes mixed-valent compounds with all possible coordination geometries for gold. Structure; Optical and thermal properties; Diffuse reflectance spectra; Chain sections.

The conventional safety approach that includes dermal absorption of pharmaceutical or consumer products uses models that are based on intact skin. However, when products are intended for application to skin with a less effective barrier, such as in new-born infants, or in cases where the skin is mildly damaged or diseased, there are instances where absorption through compromised skin is also important. A tape stripping procedure was investigated using dermatomed pig skin to assess if an in vitro model could replicate the typical changes in barrier function observed in humans with compromised skin. The relationship between Trans-Epidermal Water Loss (TEWL), Electrical Resistance (ER) and Tritiated Water Flux (TWF), markers of skin barrier function in OECD 428 studies was investigated. There was a step-wise reduction in ER from normal (control) skin following 5, 10, 15 or 20 tape strips. This was mirrored by increases in both TWF and TEWL. An in vitro experimental protocol using 5 tape strips, ER and dermatomed pig skin provided a rapid, robust and reproducible approach equivalent to the 3–4-fold increases in TEWL observed clinically in compromised skin. [ABSTRACT FROM AUTHOR]

Increased understanding in the area of trafficking behavior of adoptively transferred tumor-specific T cells could help develop better therapeutic protocols. We utilized the DUC18/CMS5 tumor model system in conjunction with a microPET scanner to study the DUC18 T cell distribution pattern in spleens and lymph nodes in live mice. Anti-Thy1.2 antibodies conjugated to 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′-tetraacetic acid (DOTA) and radiolabeled with 64Cu were administered to three groups of BALB-Thy1.1 mice on days 4, 7, or 14 post-DUC18 T cell transfer. We were able to detect the transferred cells in all the major lymph nodes, spleens, and in tumors. Our findings suggest that tumor-specific T cells do not all preferentially localize to the tumors but they also home to all the major lymphoid organs; additionally the number of DUC18 T cells remains relatively constant during and after tumor elimination within each lymphoid organ. [Copyright &y& Elsevier]

Positron emission tomography (PET) provides a powerful means to non-invasively image and quantify protein expression and biochemical changes in living subjects at nano- and picomolar levels. As the field of molecular imaging develops, and as advances in the biochemistry, pharmacology, therapeutics, and molecular biology of disease are made, there is a corresponding increase in the number of clinically relevant, novel disease-associated biomarkers that are brought to the attention of those developing imaging probes for PET. In addition, due to the high specificity of the PET radiotracers being developed, there is a demand for PET cameras with higher sensitivity and resolution. This manuscript reviews advances over the past five years in clinical and pre-clinical PET instrumentation and in new PET probes and imaging methods associated with the latest trends in the molecular imaging of cancer. Included in the PET tracer review is a description of new radioligands for steroid receptors, growth factor receptors, receptor tyrosine kinases, sigma receptors, tumor-associated enzymes, gene reporter probes, markers for tumor hypoxia and metabolism, and sites associated with angiogenesis and cellular proliferation. The use of PET imaging in drug development, including the monitoring of cancer chemotherapy, also is discussed. [ABSTRACT FROM AUTHOR]

Examines the various methods used involving the synthesis of [...-11C]palmitic acid. What the metabolism of fatty acids provides; Procedure of the metabolism; Evaluation of the rate of fatty acid metabolism.

Purpose: Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. Methods: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. Results: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4–20.5%) and 0.496 (0.291–0.644). Conclusion: The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. Trial registration: EudraCT 2016-001110-19 (registered 2016-08-08) [ABSTRACT FROM AUTHOR]

Non-structural components contribute significantly to the lateral stiffness of a cold-formed steel (CFS) building structure, but are cumbersome to model explicitly in the structural analysis. They are therefore commonly ignored in a 3D structural analysis, and their benefits are lost to the design. This paper proposes an efficient modelling method that enables practical and accurate 3D elastic analysis of a multi-storey CFS building structure to study its lateral behaviour within the serviceability limit state. Each shear or gravity wall is represented by an equivalent shear modulus four-node orthotropic shell element, which incorporates the lateral stiffness (or flexibility) contributions of all components including sheathing, braces and fasteners as present in the wall. The equivalent shear modulus is determined from the experimental test of a representative wall panel, or from the analysis of a finely detailed finite element model of the panel. The resulting two-storey building model, which has much fewer degrees of freedom compared to conventional models, is verified against full-scale shake table test results with respect to the natural period, the peak storey drift and the peak floor acceleration at two different construction phases. This paper demonstrates that the proposed modelling method not only saves analysis time considerably through the drastic reduction of degrees of freedom, but also compares favourably against a published modelling method in terms of accuracy and modelling efforts. • Proposes a very efficient modelling method for 3D structural analysis of CFS buildings. • Accounts for the lateral stiffness contributions of non-structural components. • Significantly simpler and more accurate than existing methods. • Verified against independent shake table test results. • Leads to more efficient designs of cold-formed steel buildings. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is characterized by accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles in the brain. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aβ fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling. Further evaluation in an LC-MS/MS “cold tracer” study in rodents revealed high specific binding to BACE1 in brain. Upon radiolabeling, [18F]3 demonstrated favorable brain uptake and high in vivo specificity in nonhuman primate (NHP), suggesting its potential for imaging BACE1 in humans. [ABSTRACT FROM AUTHOR]

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites (ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher. [ABSTRACT FROM AUTHOR]

A new in vitro model based on the electrical resistance properties of the skin barrier has been established in this laboratory. The model utilises a tape stripping procedure in dermatomed pig skin that removes a specific proportion of the stratum corneum , mimicking impaired barrier function observed in humans with damaged skin. The skin penetration and distribution of chemicals with differing physicochemical properties, namely; Benzoic acid, 3-Aminophenol, Caffeine and Sucrose has been assessed in this model. Although, skin penetration over 24 h differed for each chemical, compromising the skin did not alter the shape of the time course profile, although absorption into receptor fluid was higher for each chemical. Systemic exposure (receptor fluid, epidermis and dermis), was marginally higher in compromised skin following exposure to the fast penetrant, Benzoic acid, and the slow penetrant Sucrose. The systemically available dose of 3-Aminophenol increased to a greater extent and the absorption of Caffeine was more than double in compromised skin, suggesting that Molecular Weight and Log P ow , are not the only determinants for assessing systemic exposure under these conditions. Although further investigations are required, this in vitro model may be useful for prediction of dermal route exposure under conditions where skin barrier is impaired. [ABSTRACT FROM AUTHOR]

Introduction: Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [11C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (VND) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated. Methods: For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [11C]GR103545. Seven subjects were scanned before and 75min after oral administration of naltrexone (150mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5h and 8h after an oral dose of PF-04455242 (15mg, n=1 and 30mg, n=5). Metabolite-corrected arterial input functions were measured and all scans were 150min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (VT). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and VND. The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [11C]GR103545 in vivo KD was also estimated. Results: Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that VT was reduced in all regions; thus no suitable reference region is available for the radiotracer. VND was estimated reliably from the occupancy plot of naltrexone blocking (VND=3.4±0.9mL/cm³). The IC50 of PF-04455242 was calculated as 55ng/mL. [11C]GR103545 in vivo KD value was estimated as 0.069nmol/L. Conclusions: [11C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy. [ABSTRACT FROM AUTHOR]

The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique 11C and 18Flabeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood–brain barrier is important for optimal therapeutic outcomes. Our recent publication in Nature Communications employed radiolabeled lorlatinib and positron emission tomography (PET) studies in preclinical models including nonhuman primates (NHPs) that demonstrated high brain permeability of this compound. Our future work with radiolabeled lorlatinib will include advanced PET evaluations in rodent tumor models and normal NHPs with the goal of clinical translation. [ABSTRACT FROM AUTHOR]

Toaccelerate the discovery of novel small molecule central nervoussystem (CNS) positron emission tomography (PET) ligands, we aimedto define a property space that would facilitate ligand design andprioritization, thereby providing a higher probability of successfor novel PET ligand development. Toward this end, we built a databaseconsisting of 62 PET ligands that have successfully reached the clinicand 15 radioligands that failed in late-stage development as negativecontrols. A systematic analysis of these ligands identified a setof preferred parameters for physicochemical properties, brain permeability,and nonspecific binding (NSB). These preferred parameters have subsequentlybeen applied to several programs and have led to the successful developmentof novel PET ligands with reduced resources and timelines. This strategyis illustrated here by the discovery of the novel phosphodiesterase2A (PDE2A) PET ligand 4-(3-[18F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine,[18F]PF-05270430 (5). [ABSTRACT FROM AUTHOR]

[18F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n=5) or bolus-plus-constant-infusion (n=5) of [18F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate VT and BPND. [18F]FPEB was well fitted by the two-tissue compartment model, MA1 (t*=30), and MRTM (using cerebellum white matter as a reference). Highest VT values were observed in the anterior cingulate and caudate, and lowest VT values were observed in the cerebellum and pallidum. For kinetic modeling studies, VT and BPND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [18F]FPEB reduced intersubject variability in VT and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90-120 minutes after the start of injection. [ABSTRACT FROM AUTHOR]

Abstract: [11C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [11C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [11C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [11C]MRB volume of distribution was observed after correction for [11C]MRB plasma free fraction. ATX IC 50 was estimated to be 31±10ng/mL plasma. This corresponds to an effective dose (ED 50) of 0.13mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0–1.5mg/kg). [11C]MRB binding potential BP ND in the thalamus was estimated to be 1.8±0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC 50 estimate obtained using MRTM2 BP ND without arterial blood sampling was 21±3ng/mL (using caudate as the reference region). This study demonstrated that [11C]MRB is suitable for drug occupancy studies of NET. [Copyright &y& Elsevier]

Background/purpose: Oxybenzone is an active ingredient found in sunscreen products that absorbs a broad spectrum of ultraviolet (UV) light, with absorbance peaking in the UVB region and extending into the UVA region. Although the overall incidence of sensitization and irritation associated with oxybenzone in the general population remains unclear, a few studies have reported on the incidence in specific circumstances. However, the relevance of these studies to the general population is limited, because the sample populations reported in these papers generally have consisted of individuals who sought medical attention for pre-existing skin conditions. Therefore, the reported incidence of allergic reactions to oxybenzone in these studies may be overestimated as related to the general population. The objective of this meta-analysis was to determine the safety of oxybenzone in participants recruited from the general population. Methods: The data from 64 unpublished exaggerated use human repeat insult patch tests (HRIPT) and photoallergy (PA) studies sponsored by Schering-Plough HealthCare Products Inc. between 1992 and 2006 were aggregated and analyzed to evaluate the irritancy and sensitization potential of sunscreen products containing oxybenzone at concentrations between 1% and 6%. Results: Forty-eight of 19 570 possible dermal responses were considered to be suggestive of irritation or sensitization; the mean rate of responses across all formulations was 0.26%. Sensitization rates did not correlate significantly with oxybenzone concentration. The available re-challenge data indicated that only eight of these responses were contact allergies from oxybenzone, and the mean rate of contact allergy to oxybenzone was 0.07%. The source of the skin responses was not confirmed for 15 subjects who were lost to follow-up. However, all subjects were given the opportunity to participate in follow-up testing. Conclusion: Our data indicate that sunscreen products formulated with 1–6% oxybenzone do not possess a significant sensitization or irritation potential for the general public. Furthermore, these data suggest that the incidence rate implied in the published literature overestimates the actual incidence of sensitization/irritation due to oxybenzone-containing sunscreen products in the general population. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed as "proof of concept" for a drug development model utilising multitracer serial small animal PET imaging to characterise tumour responses to molecularly targeted therapy. Methods: Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n = 6-8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [18F]fluorodeoxyglucose, [18F]fluoro-L-thymidine, [18F]fluoro-azoazomycinarabinoside or [18F]fluoromisonidazole. Separate cohorts (n = 3) were treated identically and tumours were assessed ex vivo for markers of glucose metabolism, proliferation and hypoxia. Results: During the study period, mean uptake of all PET tracers generally increased for control tumours compared to baseline. In contrast, tracer uptake into CI-1033-treated tumours decreased by 20-60% during treatment. Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline. Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment. Uptake of the hypoxia marker pimonidazole was stable in control tumours but was severely reduced following 7 days of CI-1033 treatment. Conclusion: CI-1033 treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET. The PET findings correlated well with ex vivo biomarkers for each of the cellular processes studied. These results confirm the utility of small animal PET for evaluation of the effectiveness of molecularly targeted therapies and simultaneously definition of specific cellular processes involved in the therapeutic response. [ABSTRACT FROM AUTHOR]

In the K/BxN mouse model of rheumatoid arthritis, the transfer of autoantibodies specific for glucose-6-phosphate isomerase (GPI) into naive mice rapidly induces joint-specific inflammation similar to that seen in human rheumatoid arthritis. The ubiquitous expression of GPI and the systemic circulation of anti-GPI immunoglobulin G (IgG) seem incongruous with the tissue specificity of this disease. By using PET (positron emission tomography), we show here that purified anti-GPI IgG localizes specifically to distal joints in the front and rear limbs within minutes of intravenous injection, reaches saturation by 20 min and remains localized for at least 24 h. In contrast, control IgG does not localize to joints or cause inflammation. The rapid kinetics of anti-GPI IgG joint localization supports a model in which autoantibodies bind directly to pre-existing extracellular GPI in normal healthy mouse joints. [ABSTRACT FROM AUTHOR]

Three fluoro-barbiturates were synthesised, showing in vivo sedative efficacy. One of them, [18F]1a, was synthesised in radiofluorinated form. PET/CT Imaging with [18F]1a identified β-amyloid over-expressing transgenic mice (βA mice) compared to wild type and tau lines. The fluorescent barbiturate 9 was able to label βA plaques in brain sections of βA mice, and co-localise with a fluorescent Zn(ii) indicator. [ABSTRACT FROM AUTHOR]

This paper is concerned with the equivalent static force method for the seismic design of selective storage racks with uplifting baseplates. It proposes a new procedure for determining the effective natural period of such racks in the cross-aisle direction for use in the NZS 1170.5 equivalent static method. The procedure is derived by comparing the base shear results of trialled Rayleigh methods against nonlinear time history analysis results involving 15 upright frame configurations, comprising 5 baseplate types for three, five and seven level racks. The time history analyses use a suite of 44 ground motion records. It is recommended that the effective natural period be computed in the Rayleigh method using nonlinear static analysis with the storage loads included, where the Rayleigh lateral loads create an overturning moment equal to the restoring moment of the storage loads. The proposed procedure leads to more efficient designs of storage racks with uplifting baseplates compared to the conventional procedure based on the use of linear analysis in the Rayleigh method for determining the natural period, but results in more conservative designs compared to the use of nonlinear time history analysis. • First ever study on the equivalent static method for rocking racks. • Includes five baseplate types with very different responses. • Includes a comprehensive set of 44 ground motion records. • A new Rayleigh based method for determining the effective period. • A more efficient seismic design procedure for rocking racks. [ABSTRACT FROM AUTHOR]