A nonsense mutation in Myelin Protein Zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function

Protein Zero (P0) is the major structural protein in peripheral myelin and mutations in the Myelin Protein Zero (Mpz) gene produce wide ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin. We find that P0Q215X does not elicit an unfolded protein response, which is a key mechanism for other pathogenic MPZ mutations, but is instead in part aberrantly trafficked to non-myelin plasma membranes and induces defects in radial sorting of axons by Schwann cells (SC). We show that the loss of the C-terminal YAML motif is responsible for P0 mislocalisation, as its addition is able to restore correct P0Q215X trafficking in vitro. Lastly, we show that P0Q215X acts through dose-dependent gain of abnormal function, as wildtype P0 is unable to rescue the hypomyelination phenotype. Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies

Contract for health care under the Civil Code

i Název diplomové práce v anglickém jazyce Contract for health care under the Civil Code Abstract This master thesis discusses a contract for health care under the Civil Code. A contract for health care was established as a new nominate contract type on the 1st of January 2014, as the Civil Code Act 89/2012 Sb. became effective. Considering the importance and wide use of the contract, it is staggering how the public knowledge about this topic is insufficiently low. The aim of this thesis is to generally introduce the topic and analyse its individual aspects. The thesis also draws attention to potential interpretation issues and legislative imperfections or ambiguities. The theoretical angle is suitably being supported by practical examples, which contribute to the overall understanding of the topic as well as make the explanation clearer. This paper gives an elementary explanation of relations between the Civil Code as a general act and special acts. To provide the best possible picture of the contract type, author likewise mentions a brief historical background and relevant elementary international law relations. Thereto the thesis includes an excursus to the English law, specifically to a patient's consent. Regarding the contract for health care under the Civil Code itself, the paper gives an..

Real-Time Framework for Energy Management System of a Smart Microgrid Using Multiagent Systems

This paper presents a framework to analyze the problem of real-time management of Smart Grids. For this purpose, the energy management is integrated with the power system through a telecommunication system. The use of Multiagent Systems (MAS) leads the proposed algorithm to find the best-integrated solution, taking into consideration the operating scenario and the system characteristics. With this framework it was possible to evaluate the design of the energy management and the impact of the algorithm developed in the MAS. In the same way, the data sent from the power system to be used for energy management have a direct impact on his behavior. The proposed framework is tested with the help of a microgrid, so the results may be replicated