Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle.

Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of hereditary sensory motor neuropathy, is caused by mutations of mitofusin-2 (MFN2). Mitofusin-2 is a GTPase required for fusion of mitochondrial outer membranes, repair of damaged mitochondria, efficient mitochondrial energetics, regulation of mitochondrial-endoplasmic reticulum calcium coupling and axonal transport of mitochondria. We knocked T105M MFN2 preceded by a loxP-flanked STOP sequence into the mouse Rosa26 locus to permit cell type-specific expression of this pathogenic allele. Crossing these mice with nestin-Cre transgenic mice elicited T105M MFN2 expression in neuroectoderm, and resulted in diminished numbers of mitochondria in peripheral nerve axons, an alteration in skeletal muscle fiber type distribution, and a gait abnormality

Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model.

Multiple sclerosis (MS) is characterized by central nervous system (CNS) inflammation, demyelination, and axonal degeneration. CXCL10 (IP-10), a chemokine for CXCR3+ T cells, is known to regulate T cell differentiation and migration in the periphery, but effects of CXCL10 produced endogenously in the CNS on immune cell trafficking are unknown. We created floxed cxcl10 mice and crossed them with mice carrying an astrocyte-specific Cre transgene (mGFAPcre) to ablate astroglial CXCL10 synthesis. These mice, and littermate controls, were immunized with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide) to induce experimental autoimmune encephalomyelitis (EAE). In comparison to the control mice, spinal cord CXCL10 mRNA and protein were sharply diminished in the mGFAPcre/CXCL10fl/fl EAE mice, confirming that astroglia are chiefly responsible for EAE-induced CNS CXCL10 synthesis. Astroglial CXCL10 deletion did not significantly alter the overall composition of CD4+ lymphocytes and CD11b+ cells in the acutely inflamed CNS, but did diminish accumulation of CD4+ lymphocytes in the spinal cord perivascular spaces. Furthermore, IBA1+ microglia/macrophage accumulation within the lesions was not affected by CXCL10 deletion. Clinical deficits were milder and acute demyelination was substantially reduced in the astroglial CXCL10-deleted EAE mice, but long-term axon loss was equally severe in the two groups. We concluded that astroglial CXCL10 enhances spinal cord perivascular CD4+ lymphocyte accumulation and acute spinal cord demyelination in MOG peptide EAE, but does not play an important role in progressive axon loss in this MS model

Building brand reputation through third party endorsement : Fair Trade in British Chocolate

This article looks at the evolution of the British chocolate industry from the 1860s to the 1960s, a period during which it was dominated by Quaker businesses: Cadbury, Rowntree, and their predecessor, Fry. It provides evidence of early forms of fair trade by these Quaker businesses, showing that, before the fair trade movement took off in the 1970s, they contributed to social change and to improvement in living standards and long-term sustainable economic growth in developing countries. This article argues that when the mechanisms for enforcing food standards were weak and certification bodies did not exist, the Religious Society of Friends acted as an indirect independent endorser, reinforcing the imagery and reputation of the Quaker-owned brands and associating them both with purity and quality and with honest and fair trading

Adolescent Loneliness and Social Skills:Agreement and Discrepancies Between Self-, Meta-, and Peer-Evaluations

Contains fulltext : 160961.pdf (publisher's version ) (Open Access)Lonely adolescents report that they have poor social skills, but it is unknown whether this is due to an accurate perception of a social skills deficit, or a biased negative perception. This is an important distinction, as actual social skills deficits require different treatments than biased negative perceptions. In this study, we compared self-reported social skills evaluations with peer-reported social skills and meta-evaluations of social skills (i.e., adolescents' perceptions of how they believe their classmates evaluate them). Based on the social skills view, we expected negative relations between loneliness and these three forms of social skills evaluations. Based on the bias view, we expected lonely adolescents to have more negative self- and meta-evaluations compared to peer-evaluations of social skills. Participants were 1342 adolescents (48.64 % male, M age = 13.95, SD = .54). All classmates rated each other in a round-robin design to obtain peer-evaluations. Self- and meta-evaluations were obtained using self-reports. Data were analyzed using polynomial regression analyses and response surface modeling. The results indicated that, when self-, peer- and meta-evaluations were similar, a greater sense of loneliness was related to poorer social skills. Loneliness was also related to larger discrepancies between self- and peer-evaluations of loneliness, but not related to the direction of these discrepancies. Thus, for some lonely adolescents, loneliness may be related to an actual social skills deficit, whereas for others a biased negative perception of one's own social skills or a mismatch with the environment may be related to their loneliness. This implies that different mechanisms may underlie loneliness, which has implications for interventions.11 p

Correction: Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle.

[This corrects the article DOI: 10.1371/journal.pone.0167573.]

Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle.

Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of hereditary sensory motor neuropathy, is caused by mutations of mitofusin-2 (MFN2). Mitofusin-2 is a GTPase required for fusion of mitochondrial outer membranes, repair of damaged mitochondria, efficient mitochondrial energetics, regulation of mitochondrial-endoplasmic reticulum calcium coupling and axonal transport of mitochondria. We knocked T105M MFN2 preceded by a loxP-flanked STOP sequence into the mouse Rosa26 locus to permit cell type-specific expression of this pathogenic allele. Crossing these mice with nestin-Cre transgenic mice elicited T105M MFN2 expression in neuroectoderm, and resulted in diminished numbers of mitochondria in peripheral nerve axons, an alteration in skeletal muscle fiber type distribution, and a gait abnormality

Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle

Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of hereditary sensory motor neuropathy, is caused by mutations of mitofusin-2 (MFN2). Mitofusin-2 is a GTPase required for fusion of mitochondrial outer membranes, repair of damaged mitochondria, efficient mitochondrial energetics, regulation of mitochondrial-endoplasmic reticulum calcium coupling and axonal transport of mitochondria. We knocked T105M MFN2 preceded by a loxP-flanked STOP sequence into the mouse Rosa26 locus to permit cell type-specific expression of this pathogenic allele. Crossing these mice with nestin-Cre transgenic mice elicited T105M MFN2 expression in neuroectoderm, and resulted in diminished numbers of mitochondria in peripheral nerve axons, an alteration in skeletal muscle fiber type distribution, and a gait abnormality

Neuronopathy in the Motor Neocortex in a Chronic Model of Multiple Sclerosis

We provide evidence of cortical neuronopathy in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis, an established model of chronic multiple sclerosis. To investigate phenotypic perturbations in neurons in this model, we used apoptotic markers and immunohistochemistry with antibodies to NeuN and other surrogate markers known to be expressed by adult pyramidal Layer V somas, including annexin V, encephalopsin, and Emx1. We found no consistent evidence of chronic loss of Layer V neurons but detected both reversible and chronic decreases in the expression of these markers in conjunction with evidence of cortical demyelination and presynaptic loss. These phenotypic perturbations were present in, but not restricted to, the neocortical Layer V. We also investigated inflammatory responses in the cortex and subcortical white matter of the corpus callosum and spinal dorsal funiculus and found that those in the cortex and corpus callosum were delayed compared with those in the spinal cord. Inflammatory infiltrates initially included T cells, neutrophils, and Iba1-positive microglia/macrophages in the corpus callosum, whereas only Iba1-positive cells were present in the cortex. These data indicate that we have identified a new temporal pattern of subtle phenotypic perturbations in neocortical neurons in this chronic multiple sclerosis model

Conditional Ablation of Astroglial CCL2 Suppresses CNS Accumulation of M1 Macrophages and Preserves Axons in Mice with MOG Peptide EAE

Current multiple sclerosis (MS) therapies only partially prevent chronically worsening neurological deficits, which are largely attributable to progressive loss of CNS axons. Prior studies of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide), a model of MS, documented continued axon loss for months after acute CNS inflammatory infiltrates had subsided, and massive astroglial induction of CCL2 (MCP-1), a chemokine for CCR2(+) monocytes. We now report that conditional deletion of astroglial CCL2 significantly decreases CNS accumulation of classically activated (M1) monocyte-derived macrophages and microglial expression of M1 markers during the initial CNS inflammatory phase of MOG peptide EAE, reduces the acute and long-term severity of clinical deficits and slows the progression of spinal cord axon loss. In addition, lack of astroglial-derived CCL2 results in increased accumulation of Th17 cells within the CNS in these mice, but also in greater confinement of CD4(+) lymphocytes to CNS perivascular spaces. These findings suggest that therapies designed to inhibit astroglial CCL2-driven trafficking of monocyte-derived macrophages to the CNS during acute MS exacerbations have the potential to significantly reduce CNS axon loss and slow progression of neurological deficits