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In this paper, we consider the general problem of the simulation of highly reliable systems operating in the presence of Gaussian noise. Our methodology uses importance sampling which has been shown to be a particularly effective method in the general discipline of rare-event simulation. The methods we propose are optimal in a certain sense, i.e., they are efficient. We also give a new class of simulation distributions that are universally efficient in the sense that they depend only on a single scalar parameter, regardless of the dimensionality of the underlying system or of the error sets to be simulated. Index Terms--Gaussian noise, importance sampling, Monte Carlo simulation.

Wireless sensor networks are expected to be one of the key enabling technologies in the next 10 years. Protocols for such networks should be highly flexible in order to adapt to topology changes due to node mobility. In this article we focus on strategies for management of node mobility in clustered wireless sensor networks based on IEEE 802.15.4/ZigBee standards. Taking into account that modification of the cluster structure leads to performance degradation of the network reconfiguration strategies, help in avoiding long reconnection times or missing connections is required. In our work we propose a combination of proactive and reactive reconfiguration strategies to reorganize clustered structures with node mobility, leading to increased connectivity, faster reconnection times after connection loss, and building energy-efficient compact cluster-tree topologies. [ABSTRACT FROM PUBLISHER]

Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a "safe harbor" site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6-9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

We have successfully generated and characterized a stable packaging cell line for HIV-1-based vectors. To allow safe production of vector, a minimal packaging construct carrying only the coding sequences of the HIV-1 gag-pol, tat, and rev genes was stably introduced into 293G cells under the control of a Tet(o) minimal promoter. 293G cells express the chimeric Tet(R)/VP16 trans-activator and contain a tetracycline-regulated vesicular stomatitis virus protein G (VSV-G) envelope gene. When the cells were grown in the presence of tetracycline the expression of both HIV-1-derived and VSV-derived packaging functions was suppressed. On induction, approximately 50 ng/ml/24 hr of Gag p24 equivalent of vector was obtained. After introduction of the transfer vector by serial infection, vector could be collected for several days with a transduction efficiency similar or superior to that of vector produced by transient transfection both for dividing and growth-arrested cells. The vector could be effectively concentrated to titers reaching 10(9) transducing units/ml and allowed for efficient delivery and stable expression of a GFP transgene in the mouse brain. The packaging cell line and all vector producer clones described here were shown to be free from replication-competent recombinants, and from recombinants between packaging and vector constructs that transfer the viral gag-pol genes. The packaging cell line and the assays developed will advance lentiviral vectors toward the stringent requirements of clinical applications.

In the Department of Obstetrics and Gynaecology of the Wilhelm-Pieck-University Rostock 215 women were treated with altogether 510 hydrotubations because of tubar sterility. 154 patients with altogether 392 hydrotubations could be analysed. Hydrotubations were performed ambulatory, praeovulatory, using the pertubation device by means of double ballon cathether partly in combination with the Speck-test. 35 of the 154 patients treated because of tubar sterility by means of hydrotubation and conception may be suspected in 5 cases. The rate of complications following hydrotubation is 1.5%. The use of hydrotubation can be recommended because of the technically easy administration and the wide therapeutical scale (cleaning of the tube, fimbriolysis, antiphlogistic effect on the tubal mucosa, stimulation of ciliar activity, desobliteration, neuroreflective induction of ovulation) especially as an additional treatment in the field of diagnosis and therapy of the pathological tubal factor.