Dog ownership and physical activity: A review of the evidence

Background: Dog walking is a strategy for increasing population levels of physical activity (PA). Numerous cross-sectional studies of the relationship between dog ownership and PA have been conducted. The purpose was to review studies comparing PA of dog owners (DO) to nondog owners (NDO), summarize the prevalence of dog walking, and provide recommendations for research. Methods: A review of published studies (1990-2010) examining DO and NDO PA and the prevalence of dog walking was conducted (N = 29). Studies estimating the relationship between dog ownership and PA were grouped to create a pointestimate using meta-analysis. Results: Most studies were conducted in the last 5 years, were cross-sectional, and sampled adults from Australia or the United States. Approximately 60% of DO walked their dog, with a median duration and frequency of 160 minutes/week and 4 walks/week, respectively. Meta-analysis showed DO engage in more walking and PA than NDO and the effect sizes are small to moderate (d = 0.26 and d = 0.16, respectively). Three studies provided evidence of a directional relationship between dog ownership and walking. Conclusions: Longitudinal and interventional studies would provide stronger causal evidence for the relationship between dog ownership and PA. Improved knowledge of factors associated with dog walking will guide intervention research

Mitotic phosphorylation by NEK6 and NEK7 reduces microtubule affinity of EML4 to promote chromosome congression

EML4 is a microtubule-associated protein that promotes microtubule stability. We investigated its regulation across the cell cycle and found that EML4 was distributed as punctate foci along the microtubule lattice in interphase but exhibited reduced association with spindle microtubules in mitosis. Microtubule sedimentation and cryo-electron microscopy with 3D reconstruction revealed that the basic N-terminal domain of EML4 mediated its binding to the acidic C-terminal tails of α- and β-tubulin on the microtubule surface. The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. Meanwhile, constitutive activation of NEK6 or NEK7 reduced EML4 association with interphase microtubules. Together, these data support a model in which NEK6- and NEK7- dependent phosphorylation promotes dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression

Gender incongruence of adolescence and adulthood: acceptability and clinical utility of the World Health Organization’s proposed ICD-11 criteria

The World Health Organization (WHO) is currently updating the tenth version of their diagnostic tool, the International Classification of Diseases (ICD, WHO, 1992). Changes have been proposed for the diagnosis of Transsexualism (ICD-10) with regard to terminology, placement and content. The aim of this study was to gather the opinions of transgender individuals (and their relatives/partners) and clinicians in the Netherlands, Flanders (Belgium) and the United Kingdom regarding the proposed changes and the clinical applicability and utility of the ICD-11 criteria of ‘Gender Incongruence of Adolescence and Adulthood’ (GIAA). A total of 628 participants were included in the study: 284 from the Netherlands (45.2%), 8 from Flanders (Belgium) (1.3%), and 336 (53.5%) from the UK. Most participants were transgender people (or their partners/relatives) (n = 522), 89 participants were healthcare providers (HCPs) and 17 were both healthcare providers and (partners/relatives of) transgender people. Participants completed an online survey developed for this study. Most participants were in favor of the proposed diagnostic term of ‘Gender Incongruence’ and thought that this was an improvement on the ICD-10 diagnostic term of ‘Transsexualism’. Placement in a separate chapter dealing with Sexual- and Gender-related Health or as a Z-code was preferred by many and only a small number of participants stated that this diagnosis should be excluded from the ICD-11. In the UK, most transgender participants thought there should be a diagnosis related to being trans. However, if it were to be removed from the chapter on “psychiatric disorders”, many transgender respondents indicated that they would prefer it to be removed from the ICD in its entirety. There were no large differences between the responses of the transgender participants (or their partners and relatives) and HCPs. HCPs were generally positive about the GIAA diagnosis; most thought the diagnosis was clearly defined and easy to use in their practice or work. The duration of gender incongruence (several months) was seen by many as too short and required a clearer definition. If the new diagnostic term of GIAA is retained, it should not be stigmatizing to individuals. Moving this diagnosis away from the mental and behavioral chapter was generally supported. Access to healthcare was one area where retaining a diagnosis seemed to be of benefit

Discovery of a first-in-class small molecule antagonist against the adrenomedullin-2 receptor: structure–activity relationships and optimization

Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM2 receptors would be therapeutically valuable, inhibition of AM1 receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structure–activity relationships that has led to the development of first-in-class AM2 receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM1 receptor. These results highlight the therapeutic potential of AM2 antagonists

Discovery of a first-in-class potent small molecule antagonist against the adrenomedullin-2 receptor

The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumour progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same orphan G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). CLR with RAMP2 forms an adrenomedullin-1 receptor and CLR with RAMP3 forms an adrenomedullin-2receptor. Recent research suggests that selective blockade of adrenomedullin-2 receptors would be valuable therapeutically. Here we describe the design, synthesis and characterization of potent small molecule adrenomedullin-2 receptor antagonists with 1,000-foldselectivity over the adrenomedullin-1 receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties and inhibit xenograft tumour growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anti-cancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers

Homologs of genes and anonymous loci on human Chromosome 13 map to mouse Chromosomes 8 and 14

To enhance the comparative map for human Chromosome (Chr) 13, we identified clones for human genes and anonymous loci that cross-hybridized with their mouse homologs and then used linkage crosses for mapping. Of the clones for four genes and twelve anonymous loci tested, cross-hybridization was found for six, COL4A1, COL4A2, D13S26, D13S35, F10, and PCCA. Strong evidence for homology was found for COL4A1, COL4A2, D13S26, D13S35, and F10, but only circumstantial homology evidence was obtained for PCCA. To genetically map these mouse homologs ( Cf10, Col4a1, Col4a2, D14H13S26, D8H13S35 , and Pcca-rs ), we used interspecific and intersubspecific mapping panels. D14H13S26 and Pcca-rs were located on the distal portion of mouse Chr 14 extending by ∼30 cM the conserved linkage between human Chr 13 and mouse Chr 14, assuming that Pcca-rs is the mouse homolog of PCCA. By contrast, Cf10, Col4a1, Col4a2 , and D8H13S35 mapped near the centromere of mouse Chr 8, defining a new conserved linkage. Finally, we identified either a closely linked sequence related to Col4a2 , or a recombination hot-spot between Col4a1 and Col4a2 that has been conserved in humans and mice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47022/1/335_2004_Article_BF00352413.pd

The Drosophila melanogaster Genetic Reference Panel

A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics

The evolution of language: a comparative review

For many years the evolution of language has been seen as a disreputable topic, mired in fanciful "just so stories" about language origins. However, in the last decade a new synthesis of modern linguistics, cognitive neuroscience and neo-Darwinian evolutionary theory has begun to make important contributions to our understanding of the biology and evolution of language. I review some of this recent progress, focusing on the value of the comparative method, which uses data from animal species to draw inferences about language evolution. Discussing speech first, I show how data concerning a wide variety of species, from monkeys to birds, can increase our understanding of the anatomical and neural mechanisms underlying human spoken language, and how bird and whale song provide insights into the ultimate evolutionary function of language. I discuss the ‘‘descended larynx’ ’ of humans, a peculiar adaptation for speech that has received much attention in the past, which despite earlier claims is not uniquely human. Then I will turn to the neural mechanisms underlying spoken language, pointing out the difficulties animals apparently experience in perceiving hierarchical structure in sounds, and stressing the importance of vocal imitation in the evolution of a spoken language. Turning to ultimate function, I suggest that communication among kin (especially between parents and offspring) played a crucial but neglected role in driving language evolution. Finally, I briefly discuss phylogeny, discussing hypotheses that offer plausible routes to human language from a non-linguistic chimp-like ancestor. I conclude that comparative data from living animals will be key to developing a richer, more interdisciplinary understanding of our most distinctively human trait: language