Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, D9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/ kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes

Negative Regulation of Bone Formation by the Transmembrane Wnt Antagonist Kremen-2

Wnt signalling is a key pathway controlling bone formation in mice and humans. One of the regulators of this pathway is Dkk1, which antagonizes Wnt signalling through the formation of a ternary complex with the transmembrane receptors Krm1/2 and Lrp5/6, thereby blocking the induction of Wnt signalling by the latter ones. Here we show that Kremen-2 (Krm2) is predominantly expressed in bone, and that its osteoblast-specific over-expression in transgenic mice (Col1a1-Krm2) results in severe osteoporosis. Histomorphometric analysis revealed that osteoblast maturation and bone formation are disturbed in Col1a1-Krm2 mice, whereas bone resorption is increased. In line with these findings, primary osteoblasts derived from Col1a1-Krm2 mice display a cell-autonomous differentiation defect, impaired canonical Wnt signalling and decreased production of the osteoclast inhibitory factor Opg. To determine whether the observed effects of Krm2 on bone remodeling are physiologically relevant, we analyzed the skeletal phenotype of 24 weeks old Krm2-deficient mice and observed high bone mass caused by a more than three-fold increase in bone formation. Taken together, these data identify Krm2 as a regulator of bone remodeling and raise the possibility that antagonizing KRM2 might prove beneficial in patients with bone loss disorders

The effect of multiple internal representations on context rich instruction

This paper presents n-coding, a theoretical model of multiple internal mental representations. The n-coding construct is developed from a review of cognitive and imaging studies suggesting the independence of information processing along different modalities: verbal, visual, kinesthetic, social, etc. A study testing the effectiveness of the n-coding construct in an algebra-based mechanics course is presented. Four sections differing in the level of n-coding opportunities were compared. Besides a traditional instruction section used as a control group, each of the remaining three treatment sections were given context rich problems following the 'cooperative group problem solving' approach which differed by the level of n-coding opportunities designed into their laboratory environment. To measure the effectiveness of the construct, problem solving skills were assessed as was conceptual learning using the Force Concept Inventory. However, a number of new measures taking into account students' confidence in concepts were developed to complete the picture of student learning. Results suggest that using the developed n-coding construct to design context rich environments can generate learning gains in problem solving, conceptual knowledge and concept-confidence.Comment: Submitted to the American Journal of Physic

Model International Mobility Convention

While people are as mobile as they ever were in our globalized world, the movement of people across borders lacks global regulation. This leaves many refugees in protracted displacement and many migrants unprotected in irregular and dire situations. Meanwhile, some states have become concerned that their borders have become irrelevant. International mobility—the movement of individuals across borders for any length of time as visitors, students, tourists, labor migrants, entrepreneurs, long-term residents, asylum seekers, or refugees—has no common definition or legal framework. To address this key gap in international law, and the growing gaps in protection and responsibility that are leaving people vulnerable, the "Model International Mobility Convention" proposes a framework for mobility with the goals of reaffirming the existing rights afforded to mobile people (and the corresponding rights and responsibilities of states) as well as expanding those basic rights where warranted. In 213 articles divided over eight chapters, the Convention establishes both the minimum rights afforded to all people who cross state borders as visitors, and the special rights afforded to tourists, students, migrant workers, investors and residents, forced migrants, refugees, migrant victims of trafficking and migrants caught in countries in crisis. Some of these categories are covered by existing international legal regimes. However, in this Convention these groups are for the first time brought together under a single framework. An essential feature of the Convention is that it is cumulative. This means, for the most part, that the chapters build on and add rights to the set of rights afforded to categories of migrants covered by earlier chapters. The Convention contains not only provisions that afford rights to migrants and, to a lesser extent, States (such as the right to decide who can enter and remain in their territory). It also articulates the responsibilities of migrants vis-à-vis States and the rights and responsibilities of different institutions that do not directly respond to a right held by migrants

Appraising the Qualities of Social Work Students’ Theoretical Knowledge: A Qualitative Exploration

Van Bommel, M., Boshuizen, H. P. A., & Kwakman, K. (2012). Appraising the qualities of social work students' theoretical knowledge: A qualitative exploration. Vocations and Learning, 5, 277-295. doi:10.1007/s12186-012-9078-9Higher professional education aims to prepare students for entering practice with an adequate theoretical body of knowledge. In constructivist programmes, authentic learning contexts and self-directed learning are assumed to support knowledge learning and the transition from education to practice. Through an in-depth exploration, this case study aimed at defining and assessing the qualities of social work students’ theoretical knowledge at initial qualification. Participants were final-year bachelor’s students (n=18) in a constructivist professional programme of social work. Students’ knowledge concerning a real-life practical case was elicited through an interview and a form of concept mapping. A six-step procedure was used for a qualitative appraisal of students’ knowledge with the assistance of seven expert teachers. During this procedure an instrument for analysing knowledge qualities was developed, comprising 13 aspects representing four features of expert knowledge: extent, depth, structure, and critical control. Results showed that 13 students received high appraisals for their knowledge extent and depth. Only 4 students received high appraisals for knowledge structure and critical control. 5 Students who received overall lower appraisals seemed inhibited to show their knowledge qualities by preoccupations with self-concerns about their own professional role. Conclusion is that the majority of students needs more learning support for knowledge structure and critical control than offered by their constructivist programme. Further research is needed into the personal factors that influence students’ theoretical knowledge learning and which knowledge qualities can be reached by young adults in a four year educational programme.Hogeschool Arnhem Nijmege

The Evolutionary Genetics and Emergence of Avian Influenza Viruses in Wild Birds

We surveyed the genetic diversity among avian influenza virus (AIV) in wild birds, comprising 167 complete viral genomes from 14 bird species sampled in four locations across the United States. These isolates represented 29 type A influenza virus hemagglutinin (HA) and neuraminidase (NA) subtype combinations, with up to 26% of isolates showing evidence of mixed subtype infection. Through a phylogenetic analysis of the largest data set of AIV genomes compiled to date, we were able to document a remarkably high rate of genome reassortment, with no clear pattern of gene segment association and occasional inter-hemisphere gene segment migration and reassortment. From this, we propose that AIV in wild birds forms transient “genome constellations,” continually reshuffled by reassortment, in contrast to the spread of a limited number of stable genome constellations that characterizes the evolution of mammalian-adapted influenza A viruses

Continuous and Periodic Expansion of CAG Repeats in Huntington's Disease R6/1 Mice

Huntington's disease (HD) is one of several neurodegenerative disorders caused by expansion of CAG repeats in a coding gene. Somatic CAG expansion rates in HD vary between organs, and the greatest instability is observed in the brain, correlating with neuropathology. The fundamental mechanisms of somatic CAG repeat instability are poorly understood, but locally formed secondary DNA structures generated during replication and/or repair are believed to underlie triplet repeat expansion. Recent studies in HD mice have demonstrated that mismatch repair (MMR) and base excision repair (BER) proteins are expansion inducing components in brain tissues. This study was designed to simultaneously investigate the rates and modes of expansion in different tissues of HD R6/1 mice in order to further understand the expansion mechanisms in vivo. We demonstrate continuous small expansions in most somatic tissues (exemplified by tail), which bear the signature of many short, probably single-repeat expansions and contractions occurring over time. In contrast, striatum and cortex display a dramatic—and apparently irreversible—periodic expansion. Expansion profiles displaying this kind of periodicity in the expansion process have not previously been reported. These in vivo findings imply that mechanistically distinct expansion processes occur in different tissues

Enhanced Brain Disposition and Effects of Δ9-Tetrahydrocannabinol in P-Glycoprotein and Breast Cancer Resistance Protein Knockout Mice

The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ9-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (−/−), Abcg2 (−/−) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (−/−) and Abcg2 (−/−) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (−/−) mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis

Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes