Orphan G protein-coupled receptors MrgA1 and MrgC11 are distinctively activated by RF-amide-related peptides through the G{alpha}q/11 pathway

MrgA1 and MrgC11 belong to a recently identified family of orphan G-protein coupled receptors, called mrgs (mas-related genes). They are only expressed in a specific subset of sensory neurons that are known to detect painful stimuli. However, the precise physiological function of Mrg receptors and their underlying mechanisms of signal transduction are not known. We therefore have screened a series of neuropeptides against human embryonic kidney (HEK) 293 cells that stably express either MrgA1 or MrgC11 to identify ligands and/or agonists. MrgA1- or MrgC11-specific agonists stimulated dose-dependent increases in intracellular free Ca2+ in a pertussis toxin-insensitive manner, but failed to alter basal or forskolin-stimulated levels of intracellular cAMP. Furthermore, studies using embryonic fibroblasts derived from various G{alpha} protein knockout mice demonstrated that both the MrgA1 and MrgC11 receptors are coupled to the G{alpha}q/11 signaling pathway. Screening of neuropeptides identified surrogate agonists, most of these peptides included a common C-terminal -RF(Y)G or -RF(Y) amide motif. Structure-function studies suggest that endogenous ligands of Mrg receptors are likely to be RF(Y)G and/or RF(Y) amide-related peptides and that postprocessing of these peptides may serve to determine Mrg receptor-ligand specificity. The differences in ligand specificity also suggest functional diversity amongst the Mrg receptors

Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.

This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic

Profound vision loss impairs psychological well-being in young and middle-aged individuals.

PurposeThe aim of this study was to evaluate the effects of profound vision loss on psychological well-being in adolescents, young adults, and middle-aged adults with regard to mood, interpersonal interactions, and career-related goals. In addition, we assessed the significance of the resources that may be used to enhance psychological well-being in cases of profound vision loss, and in particular, examined the utility of low vision aids and the role of the ophthalmologist as a provider of emotional support.MethodsA questionnaire was issued to individuals aged 13-65 years with profound vision loss resulting from Leber's hereditary optic neuropathy (LHON). Depression prevalence was evaluated with questions regarding major depressive disorder symptomatology. Participants appraised the effects of vision loss on their interpersonal interactions and career goals by providing an impact rating (IR) on a 21-point psychometric scale from -10 to +10. Social well-being index was defined as the average of interpersonal IR and career IR. Subjects were additionally asked about the use of low vision aids and sources of emotional support.ResultsA total of 103 participants (mean age =26.4±11.2 years at LHON diagnosis; mean ± standard deviation) completed the questionnaire. Nearly half (49.5%) met the depression criteria after vision loss. Negative impacts on interpersonal interactions (median IR = -5) and career goals (median IR = -6) were observed; both ratings were worse (P<0.001) for depressed versus nondepressed subjects. Older age at diagnosis corresponded to higher depression prevalence and increased incidence of negative interpersonal IR and career IR. Sixty-eight percent of subjects used electronic vision aids; controlling for age, social well-being index was higher among these individuals than for those who did not use electronic aids (P=0.03). Over half of the participants (52.4%) asserted that they derived emotional support from their ophthalmologist.ConclusionProfound vision loss in adolescents, young adults, and middle-aged adults is associated with significant negative psychological and psychosocial effects, which are influenced by age and use of electronic vision aids. Ophthalmologists, in addition to managing vision loss, may serve an important role in the emotional adaptation of these patients

Gravitational collapse of thick domain walls

Numerical simulations are performed of the gravitational collapse of a scalar field with a \lambda \phi^4 potential. Comparisons are made with the thin shell approximation.Comment: 10 pages, 5 figure

Investigating photoexcitation-induced mitochondrial damage by chemotherapeutic corroles using multimode optical imaging

We recently reported that a targeted, brightly fluorescent gallium corrole (HerGa) is highly effective for breast tumor detection and treatment. Unlike structurally similar porphryins, HerGa exhibits tumor-targeted toxicity without the need for photoexcitation. We have now examined whether photoexcitation further modulates HerGa toxicity, using multimode optical imaging of live cells, including two-photon excited fluorescence, differential interference contrast (DIC), spectral, and lifetime imaging. Using two-photon excited fluorescence imaging, we observed that light at specific wavelengths augments the HerGa-mediated mitochondrial membrane potential disruption of breast cancer cells in situ. In addition, DIC, spectral, and fluorescence lifetime imaging enabled us to both validate cell damage by HerGa photoexcitation and investigate HerGa internalization, thus allowing optimization of light dose and timing. Our demonstration of HerGa phototoxicity opens the way for development of new methods of cancer intervention using tumor-targeted corroles

Finding Home: Policy Options for Addressing Homelessness in Canada

Finding Home aims to fill a gap in the information available on homelessness by providing an easily accessible collection of the best Canadian research and policy analysis on homelessness.Social Sciences and Humanities Research Council of Canad

Optically induced forces and torques:Interactions between nanoparticles in a laser beam

Distinctive optical forces and torques arise between nanoparticles irradiated by intense laser radiation. These forces, associated with a pairwise process of stimulated scattering, prove to enable the possibility of producing significant modifications to both the form and magnitude of interparticle forces, with additional contributions arising in the case of dipolar materials. Moreover, such forces have the capacity to generate unusual patterns of nanoscale response, entirely controlled by the input beam characteristics- principally the optical frequency, intensity, and polarization. Based on quantum electrodynamical theory, a general result is secured for the laser-induced force under arbitrary conditions, incorporating both static and dynamic coupling mechanisms. Specific features of the results are identified for pairs of particles with prolate cylindrical symmetry, e.g., carbon nanotubes, where it is shown that the laser-induced forces and torques are sensitive functions of the pair spacing and orientation, and the laser beam geometry; significantly, they can be either repulsive or attractive according to conditions. For nanoparticles trapped in a Laguerre-Gaussian laser beam the results also reveal additional and highly distinctive torques that suggest further possibilities for nanomanipulation with light. The paper concludes with a discussion on several potential applications of such forces. © 2005 The American Physical Society

Callous-Unemotional Traits among Children and Adolescents in Asian Cultures: A Systematic Review

Considerable evidence now exists for callous and unemotional (CU) traits as markers for a high-risk pathway to child and adolescent conduct problems implicating unique risk processes and treatment needs, but research has been limited largely to Western countries. We review the evidence base related to CU traits in Asian countries that has emerged in recent years, with respect to four key questions. Specifically, are higher CU traits among Asian children and adolescents associated with (1) increased severity of conduct problems; (2) similar neurodevelopmental and neurocognitive correlates as reported in Western countries; (3) similar environmental risk factors as reported in Western countries; and (4) poorer treatment outcomes? A systematic search identified 28 studies that have reported on child and adolescent CU traits in Asian countries. Consistent with Western samples, CU traits were associated with individual risk factors including atypical neural activation during cognitive tasks and poor empathy, as well as parenting risk factors. CU traits were also positively associated with most measures of conduct problems. Differences from findings in Western samples, however, emerged for areas such as correlates of reactive aggression and delinquent peer influence. Treatment has been investigated in only one study to date and is therefore a high priority for future research. The limitations of existing evidence are addressed along with key directions for future cross-cultural research, including measurement research with children and adolescents.</p

Callous-Unemotional Traits among Children and Adolescents in Asian Cultures: A Systematic Review

Considerable evidence now exists for callous and unemotional (CU) traits as markers for a high-risk pathway to child and adolescent conduct problems implicating unique risk processes and treatment needs, but research has been limited largely to Western countries. We review the evidence base related to CU traits in Asian countries that has emerged in recent years, with respect to four key questions. Specifically, are higher CU traits among Asian children and adolescents associated with (1) increased severity of conduct problems; (2) similar neurodevelopmental and neurocognitive correlates as reported in Western countries; (3) similar environmental risk factors as reported in Western countries; and (4) poorer treatment outcomes? A systematic search identified 28 studies that have reported on child and adolescent CU traits in Asian countries. Consistent with Western samples, CU traits were associated with individual risk factors including atypical neural activation during cognitive tasks and poor empathy, as well as parenting risk factors. CU traits were also positively associated with most measures of conduct problems. Differences from findings in Western samples, however, emerged for areas such as correlates of reactive aggression and delinquent peer influence. Treatment has been investigated in only one study to date and is therefore a high priority for future research. The limitations of existing evidence are addressed along with key directions for future cross-cultural research, including measurement research with children and adolescents.</p