Applications of Click Chemistry in Radiopharmaceutical Development

Click chemistry, a concept that employs only practical and reliable transformations for compound synthesis, has made a significant impact in several areas of chemistry, including material sciences and drug discovery. The present article describes the use of click chemistry for the development of radiopharmaceuticals. Target templated in situ click chemistry was used for lead generation. The 1,2,3-triazole moiety was found to improve the pharmacokinetic properties of certain radiopharmaceuticals. The reliable Cu(i)-catalyzed click reaction was employed for radiolabeling of peptidic compounds without the need for protecting groups. In summary, the click chemistry approach for the discovery, optimization and labeling of new radiotracers, represents a very powerful tool for radiopharmaceutical development

Application of response surface techniques to helicopter rotor blade optimization procedure

In multidisciplinary optimization problems, response surface techniques can be used to replace the complex analyses that define the objective function and/or constraints with simple functions, typically polynomials. In this work a response surface is applied to the design optimization of a helicopter rotor blade. In previous work, this problem has been formulated with a multilevel approach. Here, the response surface takes advantage of this decomposition and is used to replace the lower level, a structural optimization of the blade. Problems that were encountered and important considerations in applying the response surface are discussed. Preliminary results are also presented that illustrate the benefits of using the response surface

An efficient numerical approach to modeling the effects of particle shape on rubble-pile dynamics

We present an approach for the inclusion of non-spherical constituents in high-resolution N-body discrete element method (DEM) simulations. We use aggregates composed of bonded spheres to model non-spherical components. Though the method may be applied more generally, we detail our implementation in the existing N-body code pkdgrav. It has long been acknowledged that non-spherical grains confer additional shear strength and resistance to flow when compared with spheres. As a result, we expect that rubble-pile asteroids will also exhibit these properties and may behave differently than comparable rubble piles composed of idealized spheres. Since spherical particles avoid some significant technical challenges, most DEM gravity codes have used only spherical particles, or have been confined to relatively low resolutions. We also discuss the work that has gone into improving performance with non-spherical grains, building on pkdgrav's existing leading-edge computational efficiency among DEM gravity codes. This allows for the addition of non-spherical shapes while maintaining the efficiencies afforded by pkdgrav's tree implementation and parallelization. As a test, we simulated the gravitational collapse of 25,000 non-spherical bodies in parallel. In this case, the efficiency improvements allowed for an increase in speed by nearly a factor of three when compared with the naive implementation. Without these enhancements, large runs with non-spherical components would remain prohibitively expensive. Finally, we present the results of several small-scale tests: spinup due to the YORP effect, tidal encounters, and the Brazil-nut Effect. In all cases, we find that the inclusion of non-spherical constituents has a measurable impact on simulation outcomes.Comment: 35 pages, 8 figure

Classification of Human Retinal Microaneurysms Using Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography

Purpose. Microaneurysms (MAs) are considered a hallmark of retinal vascular disease, yet what little is known about them is mostly based upon histology, not clinical observation. Here, we use the recently developed adaptive optics scanning light ophthalmoscope (AOSLO) fluorescein angiography (FA) to image human MAs in vivo and to expand on previously described MA morphologic classification schemes. Methods. Patients with vascular retinopathies (diabetic, hypertensive, and branch and central retinal vein occlusion) were imaged with reflectance AOSLO and AOSLO FA. Ninety-three MAs, from 14 eyes, were imaged and classified according to appearance into six morphologic groups: focal bulge, saccular, fusiform, mixed, pedunculated, and irregular. The MA perimeter, area, and feret maximum and minimum were correlated to morphology and retinal pathology. Select MAs were imaged longitudinally in two eyes. Results. Adaptive optics scanning light ophthalmoscope fluorescein angiography imaging revealed microscopic features of MAs not appreciated on conventional images. Saccular MAs were most prevalent (47%). No association was found between the type of retinal pathology and MA morphology (P = 0.44). Pedunculated and irregular MAs were among the largest MAs with average areas of 4188 and 4116 μm2, respectively. Focal hypofluorescent regions were noted in 30% of MAs and were more likely to be associated with larger MAs (3086 vs. 1448 μm2, P = 0.0001). Conclusions. Retinal MAs can be classified in vivo into six different morphologic types, according to the geometry of their two-dimensional (2D) en face view. Adaptive optics scanning light ophthalmoscope fluorescein angiography imaging of MAs offers the possibility of studying microvascular change on a histologic scale, which may help our understanding of disease progression and treatment response

Trends and biases in the listing and recovery planning for threatened species: an Australian case study

Many countries rely on formal legislation to protect and plan for the recovery of threatened species. Even though the listing procedures in threatened species legislation are designed to be consistent for all species there is usually a bias in implementing the laws towards charismatic fauna and flora, which leads to uneven allocation of conservation efforts. However, the extent of bias in national threatened species lists is often unknown. Australia is a good example: the list of threatened species under the Environmental Protection and Biological Conservation Act has not been reviewed since 2000, when it was first introduced. We assessed how well this Act represents threatened species across taxonomic groups and threat status, and whether biases exist in the types of species with recovery plans. We found that birds, amphibians and mammals have high levels of threatened species (12-24%) but < 6% of all reptiles and plants and < 0.01% of invertebrates and fish are considered threatened. Similar taxonomic biases are present in the types of species with recovery plans. Although there have been recent improvements in the representation of threatened species with recovery plans across taxonomic groups, there are still major gaps between the predicted and listed numbers of threatened species. Because of biases in the listing and recovery planning processes many threatened species may receive little attention regardless of their potential for recovery: a lost opportunity to achieve the greatest conservation impact possible. The Environmental Protection and Biological Conservation Act in Australia needs reform to rectify these biases

A combined hard x-ray photoelectron spectroscopy and electrical characterisation study of metal/SiO2/Si(100) metal-oxide-semiconductor structures

Combined hard x-ray photoelectron spectroscopy (HAXPES) and electrical characterisation measurements on identical Si based metal-oxide-semiconductor structures have been performed. The results obtained indicate that surface potential changes at the Si/SiO2 interface due to the presence of a thin Al or Ni gate layer can be detected with HAXPES. Changes in the Si/SiO2 band bending at zero gate voltage and the flat band voltage for the case of Al and Ni gate layers derived from the silicon core levels shifts observed in the HAXPES spectra are in agreement with values derived from capacitance-voltage measurements. (C) 2012 American Institute of Physics. (http://dx.doi.org/10.1063/1.4770380

Pain communication through body posture:the development and validation of a stimulus set

This study reports the creation and validation of a stimulus set of affective body postures that includes pain. Pain can be communicated nonverbally through facial expressions, vocalisations, and bodily movements. Most studies have focussed on the facial display of pain, whereas there is little research on postural display. Stimulus sets for facial and vocal expressions of pain have been developed, but there is no equivalent for body‐based expressions. Reported here is the development of a new stimulus set of dynamic body postures that communicate pain and basic emotions. This stimulus set is designed to facilitate research into the bodily communication of pain. We report a 3‐phase development and validation study. First 16 actors performed affective body postures for pain, as well as happiness, sadness, fear, disgust, surprise, anger, and neutral expressions. Second, 20 observers independently selected the best image stimuli based on the accuracy of emotion identification and valence/arousal ratings. Third, to establish reliability, this accuracy and valence rating procedure was repeated with a second independent group of 40 participants. A final set of 144 images with good reliability was established and is made available. Results demonstrate that pain, along with basic emotions, can be communicated through body posture. Cluster analysis demonstrates that pain and emotion are recognised with a high degree of specificity. In addition, pain was rated as the most unpleasant (negative valence) of the expressions, and was associated with a high level of arousal. For the first time, specific postures communicating pain are described. The stimulus set is provided as a tool to facilitate the study of nonverbal pain communication, and its possible uses are discussed

Physical and social environmental characteristics of physical activity for Mexican-origin children: examining differences between school year and summer perceptions

BACKGROUND: Colonias are substandard residential areas along the U.S.-Mexico border. Families of Mexican-origin living in colonias face health burdens characterized by environmental and socioeconomic hardships. Mexican Americans and low-income families, including colonias children, do not frequently participate in physical activity despite the known link to disease risk reduction. For colonias children, schools are the most commonly reported location for physical activity. School closures and extreme temperatures during summer months create a need to explore seasonal differences in environmental supports and barriers in this population. The purpose of this study was to examine the effect of seasonality on perceived environmental barriers, opportunities, and social support for physical activity among colonias children. As a secondary aim, mother-child discordance for each factor was analyzed. METHODS: Promotora-researchers recruited mother-child dyads (n=101 dyads, n=202 participants) from colonias in Hidalgo County, Texas. Mothers and children were separately administered surveys at two time points to capture perceived barriers, opportunities, and social support for physical activity (school-year: February-May; summertime: July-August). Summative scores for each outcome were calculated and three multilevel longitudinal models for continuous outcomes were examined; children were nested within households. Mother-child discordance was measured using Cohen’s Kappa statistic. RESULTS: Physical activity barriers and environmental opportunities (household and neighborhood) increased from school-year to summer by 1.16 and 2.83 points respectively (p≤0.01), after adjusting for covariates. Significant predictors of increased barriers included household income of >$900/month and having more household members. Children of mothers with significant others who were employed part-time or full-time saw significant decreases in barriers. Mother-child agreement of barriers, environmental opportunities, and social support across seasons was slight to fair (range: median κ=0.047 to κ=0.262). CONCLUSIONS: These results suggest a complex relationship between dimensions of economic hardship (employment status, household income, etc…) and perceived opportunities and barriers of children’s physical activity engagement during the school-year and summer. In this study, both barriers and opportunities increased from school-year to summer, further demonstrating that interactions among these characteristics need to be better understood and addressed when considering physical activity initiatives for colonias and other Mexican-American children, specifically during summer when school-based physical activity resources are unavailable

Genetic Interactions between Doublecortin and Doublecortin-like Kinase in Neuronal Migration and Axon Outgrowth

SummaryAlthough mutations in the human doublecortin gene (DCX) cause profound defects in cortical neuronal migration, a genetic deletion of Dcx in mice produces a milder defect. A second locus, doublecortin-like kinase (Dclk), encodes a protein with similar “doublecortin domains” and microtubule stabilization properties that may compensate for Dcx. Here, we generate a mouse with a Dclk mutation that causes no obvious migrational abnormalities but show that mice mutant for both Dcx and Dclk demonstrate perinatal lethality, disorganized neocortical layering, and profound hippocampal cytoarchitectural disorganization. Surprisingly, Dcx−/y;Dclk−/− mutants have widespread axonal defects, affecting the corpus callosum, anterior commissure, subcortical fiber tracts, and internal capsule. Dcx/Dclk-deficient dissociated neurons show abnormal axon outgrowth and dendritic structure, with defects in axonal transport of synaptic vesicle proteins. Dcx and Dclk may directly or indirectly regulate microtubule-based vesicle transport, a process critical to both neuronal migration and axon outgrowth