BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions

Investigations into brain function and disease depend on the precise classification of neural cell types. Cells of the oligodendrocyte lineage differ greatly in their morphology, but accurate identification has thus far only been possible for oligodendrocyte progenitor cells and mature oligodendrocytes in humans. We find that breast carcinoma amplified sequence 1 (BCAS1) expression identifies an oligodendroglial subpopulation in the mouse and human brain. These cells are newly formed, myelinating oligodendrocytes that segregate from oligodendrocyte progenitor cells and mature oligodendrocytes and mark regions of active myelin formation in development and in the adult. We find that BCAS1+ oligodendrocytes are restricted to the fetal and early postnatal human white matter but remain in the cortical gray matter until old age. BCAS1+ oligodendrocytes are reformed after experimental demyelination and found in a proportion of chronic white matter lesions of patients with multiple sclerosis (MS) even in a subset of patients with advanced disease. Our work identifies a means to map ongoing myelin formation in health and disease and presents a potential cellular target for remyelination therapies in MS

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date

An innovative, efficient current-fed push-pull grid connectable inverter for distributed generation systems

Environmentally friendly power sources such as photovoltaic solar cells, small scale wind turbines and fuel cells are particularly suitable for distributed generation systems, but typically produce a relatively low magnitude DC voltage output that can vary significantly as operating conditions change. Hence a power electronic inverter is required to condition this output into a more conventional constant magnitude AC supply voltage. Such an inverter should be light weight, low cost, efficient, and provide galvanic isolation between the source and the AC output/grid connection. It is also often preferable that the inverter draws constant DC current from the input energy source, which means it must smooth out the double-fundamental-frequency energy flow of a single phase AC load connection. These requirements can be met with a double conversion system incorporating a high frequency DC-DC step up converter to produce a relatively constant high voltage DC output from the varying DC input, and a high voltage DC-AC inverter and filter to produce the final AC output

Automated Strategies for Specializing Constraint Logic Programs

We consider the problem of specializing constraint logic programs w.r.t. constrained queries. We follow a transformational approach based on rules and strategies. The use of the rules ensures that the specialized program is equivalent to the initial program w.r.t. a given constrained query. The strategies guide the application of the rules so to derive an efficient specialized program. In this paper we address various issues concerning the development of an automated transformation strategy. In particular, we consider the problems of when and how we should unfold, replace constraints, introduce generalized clauses, and apply the contextual constraint replacement rule. We propose a solution to these problems by adapting to our framework various techniques developed in the field of constraint programming, partial evaluation, and abstract interpretation. In particular, we use: (i) suitable solvers for simplifying constraints, (ii) well-quasi-orders for ensuring the termination of the unfoldings and for activating clause generalizations, and (iii) widening operators for ensuring the termination of the generalization process

Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis

Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2(+) monocytes are required for both. Depleting CCR2(+) monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2(+) monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS