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991.
Sandra Berger-Müller Atsushi Sugie Fumio Takahashi Gaia Tavosanis Satoko Hakeda-Suzuki Takashi Suzuki 《PloS one》2013,8(12)
A hallmark of the central nervous system is its spatial and functional organization in synaptic layers. During neuronal development, axons form transient contacts with potential post-synaptic elements and establish synapses with appropriate partners at specific layers. These processes are regulated by synaptic cell-adhesion molecules. In the Drosophila visual system, R7 and R8 photoreceptor subtypes target distinct layers and form en passant pre-synaptic terminals at stereotypic loci of the axonal shaft. A leucine-rich repeat transmembrane protein, Capricious (Caps), is known to be selectively expressed in R8 axons and their recipient layer, which led to the attractive hypothesis that Caps mediates R8 synaptic specificity by homophilic adhesion. Contradicting this assumption, our results indicate that Caps does not have a prominent role in synaptic-layer targeting and synapse formation in Drosophila photoreceptors, and that the specific recognition of the R8 target layer does not involve Caps homophilic axon-target interactions. We generated flies that express a tagged synaptic marker to evaluate the presence and localization of synapses in R7 and R8 photoreceptors. These genetic tools were used to assess how the synaptic profile is affected when axons are forced to target abnormal layers by expressing axon guidance molecules. When R7 axons were mistargeted to the R8-recipient layer, R7s either maintained an R7-like synaptic profile or acquired a similar profile to r8s depending on the overexpressed protein. When R7 axons were redirected to a more superficial medulla layer, the number of presynaptic terminals was reduced. These results indicate that cell-surface molecules are able to dictate synapse loci by changing the axon terminal identity in a partially cell-autonomous manner, but that presynapse formation at specific sites also requires complex interactions between pre- and post-synaptic elements. 相似文献
992.
Stefan Balabanov Thomas Wilhelm Simone Venz Gunhild Keller Christian Scharf Heike Pospisil Melanie Braig Christine Barett Carsten Bokemeyer Reinhard Walther Tim H. Brümmendorf Andreas Schuppert 《PloS one》2013,8(1)
In drug discovery, the characterisation of the precise modes of action (MoA) and of unwanted off-target effects of novel molecularly targeted compounds is of highest relevance. Recent approaches for identification of MoA have employed various techniques for modeling of well defined signaling pathways including structural information, changes in phenotypic behavior of cells and gene expression patterns after drug treatment. However, efficient approaches focusing on proteome wide data for the identification of MoA including interference with mutations are underrepresented. As mutations are key drivers of drug resistance in molecularly targeted tumor therapies, efficient analysis and modeling of downstream effects of mutations on drug MoA is a key to efficient development of improved targeted anti-cancer drugs. Here we present a combination of a global proteome analysis, reengineering of network models and integration of apoptosis data used to infer the mode-of-action of various tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cell lines expressing wild type as well as TKI resistance conferring mutants of BCR-ABL. The inferred network models provide a tool to predict the main MoA of drugs as well as to grouping of drugs with known similar kinase inhibitory activity patterns in comparison to drugs with an additional MoA. We believe that our direct network reconstruction approach, demonstrated on proteomics data, can provide a complementary method to the established network reconstruction approaches for the preclinical modeling of the MoA of various types of targeted drugs in cancer treatment. Hence it may contribute to the more precise prediction of clinically relevant on- and off-target effects of TKIs. 相似文献
993.
Christina R?hr Martin Kerick Axel Fischer Alexander Kühn Karl Kashofer Bernd Timmermann Andriani Daskalaki Thomas Meinel Dmitriy Drichel Stefan T. B?rno Anja Nowka Sylvia Krobitsch Alice C. McHardy Christina Kratsch Tim Becker Andrea Wunderlich Christian Barmeyer Christian Viertler Kurt Zatloukal Christoph Wierling Hans Lehrach Michal R. Schweiger 《PloS one》2013,8(7)
MiRNAs are discussed as diagnostic and therapeutic molecules. However, effective miRNA drug treatments with miRNAs are, so far, hampered by the complexity of the miRNA networks. To identify potential miRNA drugs in colorectal cancer, we profiled miRNA and mRNA expression in matching normal, tumor and metastasis tissues of eight patients by Illumina sequencing. We validated six miRNAs in a large tissue screen containing 16 additional tumor entities and identified miRNA-1, miRNA-129, miRNA-497 and miRNA-215 as constantly de-regulated within the majority of cancers. Of these, we investigated miRNA-1 as representative in a systems-biology simulation of cellular cancer models implemented in PyBioS and assessed the effects of depletion as well as overexpression in terms of miRNA-1 as a potential treatment option. In this system, miRNA-1 treatment reverted the disease phenotype with different effectiveness among the patients. Scoring the gene expression changes obtained through mRNA-Seq from the same patients we show that the combination of deep sequencing and systems biological modeling can help to identify patient-specific responses to miRNA treatments. We present this data as guideline for future pre-clinical assessments of new and personalized therapeutic options. 相似文献
994.
Pauline Scherdel Jean-Fran?ois Salaün Marie-No?lle Robberecht-Riquet Laura Reali Gabriella Páll Elke J?ger-Roman Manuel Praena Crespo Marilena Moretto Margareta Seher-Zupan?i? Sigurlaug Agustsson the European Confederation of Primary Care Paediatricians research group Martin Chalumeau 《PloS one》2013,8(8)
Objective
We aimed to study current practices in growth monitoring by European primary care paediatricians and to explore their perceived needs in this field.Methods
We developed a cross-sectional, anonymous on-line survey and contacted primary care paediatricians listed in national directories in the 18 European countries with a confederation of primary care paediatricians. Paediatricians participated in the survey between April and September 2011.Results
Of the 1,198 paediatricians from 11 European countries (response rate 13%) who participated, 29% used the 2006 World Health Organization Multicentre Growth Reference Study growth charts, 69% used national growth charts; 61% used software to draw growth charts and 79% did not use a formal algorithm to detect abnormal growth on growth charts. Among the 21% of paediatricians who used algorithms, many used non-algorithmic simple thresholds for height and weight and none used the algorithms published in the international literature. In all, 69% of paediatricians declared that a validated algorithm to monitor growth would be useful in daily practice. We found important between-country variations.Conclusion
The varied growth-monitoring practices declared by primary care paediatricians reveals the need for standardization and evidence-based algorithms to define abnormal growth and the development of software that would use such algorithms. 相似文献995.
Wenli Zhang Manish Solanki Nadine Müther Melanie Ebel Jichang Wang Chuanbo Sun Zsuzsanna Izsvak Anja Ehrhardt 《PloS one》2013,8(10)
Recombinant adeno-associated viral (AAV) vectors have been shown to be one of the most promising vectors for therapeutic gene delivery because they can induce efficient and long-term transduction in non-dividing cells with negligible side-effects. However, as AAV vectors mostly remain episomal, vector genomes and transgene expression are lost in dividing cells. Therefore, to stably transduce cells, we developed a novel AAV/transposase hybrid-vector. To facilitate SB-mediated transposition from the rAAV genome, we established a system in which one AAV vector contains the transposon with the gene of interest and the second vector delivers the hyperactive Sleeping Beauty (SB) transposase SB100X. Human cells were infected with the AAV-transposon vector and the transposase was provided in trans either by transient and stable plasmid transfection or by AAV vector transduction. We found that groups which received the hyperactive transposase SB100X showed significantly increased colony forming numbers indicating enhanced integration efficiencies. Furthermore, we found that transgene copy numbers in transduced cells were dose-dependent and that predominantly SB transposase-mediated transposition contributed to stabilization of the transgene. Based on a plasmid rescue strategy and a linear-amplification mediated PCR (LAM-PCR) protocol we analysed the SB100X-mediated integration profile after transposition from the AAV vector. A total of 1840 integration events were identified which revealed a close to random integration profile. In summary, we show for the first time that AAV vectors can serve as template for SB transposase mediated somatic integration. We developed the first prototype of this hybrid-vector system which with further improvements may be explored for treatment of diseases which originate from rapidly dividing cells. 相似文献
996.
Fabrice E. Graf Philipp Ludin Tanja Wenzler Marcel Kaiser Reto Brun Patient Pati Pyana Philippe Büscher Harry P. de Koning David Horn Pascal M?ser 《PLoS neglected tropical diseases》2013,7(10)
The predominant mechanism of drug resistance in African trypanosomes is decreased drug uptake due to loss-of-function mutations in the genes for the transporters that mediate drug import. The role of transporters as determinants of drug susceptibility is well documented from laboratory-selected Trypanosoma brucei mutants. But clinical isolates, especially of T. b. gambiense, are less amenable to experimental investigation since they do not readily grow in culture without prior adaptation. Here we analyze a selected panel of 16 T. brucei ssp. field isolates that (i) have been adapted to axenic in vitro cultivation and (ii) mostly stem from treatment-refractory cases. For each isolate, we quantify the sensitivity to melarsoprol, pentamidine, and diminazene, and sequence the genomic loci of the transporter genes TbAT1 and TbAQP2. The former encodes the well-characterized aminopurine permease P2 which transports several trypanocides including melarsoprol, pentamidine, and diminazene. We find that diminazene-resistant field isolates of T. b. brucei and T. b. rhodesiense carry the same set of point mutations in TbAT1 that was previously described from lab mutants. Aquaglyceroporin 2 has only recently been identified as a second transporter involved in melarsoprol/pentamidine cross-resistance. Here we describe two different kinds of TbAQP2 mutations found in T. b. gambiense field isolates: simple loss of TbAQP2, or loss of wild-type TbAQP2 allele combined with the formation of a novel type of TbAQP2/3 chimera. The identified mutant T. b. gambiense are 40- to 50-fold less sensitive to pentamidine and 3- to 5-times less sensitive to melarsoprol than the reference isolates. We thus demonstrate for the first time that rearrangements of the TbAQP2/TbAQP3 locus accompanied by TbAQP2 gene loss also occur in the field, and that the T. b. gambiense carrying such mutations correlate with a significantly reduced susceptibility to pentamidine and melarsoprol. 相似文献
997.
998.
Yahaya Adam Giuliano Cecchi Patrick M. Kgori Tanguy Marcotty Charles I. Mahama Martin Abavana Benita Anderson Massimo Paone Raffaele Mattioli Jérémy Bouyer 《PLoS neglected tropical diseases》2013,7(3)
Background
An integrated strategy of intervention against tsetse flies was implemented in the Upper West Region of Ghana (9.62°–11.00° N, 1.40°–2.76° W), covering an area of ≈18,000 km2 within the framework of the Pan-African Tsetse and Trypanosomosis Eradication Campaign. Two species were targeted: Glossina tachinoides and Glossina palpalis gambiensis.Methodology/Principal Findings
The objectives were to test the potentiality of the sequential aerosol technique (SAT) to eliminate riverine tsetse species in a challenging subsection (dense tree canopy and high tsetse densities) of the total sprayed area (6,745 km2) and the subsequent efficacy of an integrated strategy including ground spraying (≈100 km2), insecticide treated targets (20,000) and insecticide treated cattle (45,000) in sustaining the results of tsetse suppression in the whole intervention area. The aerial application of low-dosage deltamethrin aerosols (0.33–0.35 g a.i/ha) was conducted along the three main rivers using five custom designed fixed-wings Turbo thrush aircraft. The impact of SAT on tsetse densities was monitored using 30 biconical traps deployed from two weeks before until two weeks after the operations. Results of the SAT monitoring indicated an overall reduction rate of 98% (from a pre-intervention mean apparent density per trap per day (ADT) of 16.7 to 0.3 at the end of the fourth and last cycle). One year after the SAT operations, a second survey using 200 biconical traps set in 20 sites during 3 weeks was conducted throughout the intervention area to measure the impact of the integrated control strategy. Both target species were still detected, albeit at very low densities (ADT of 0.27 inside sprayed blocks and 0.10 outside sprayed blocks).Conclusions/Significance
The SAT operations failed to achieve elimination in the monitored section, but the subsequent integrated strategy maintained high levels of suppression throughout the intervention area, which will contribute to improving animal health, increasing animal production and fostering food security. 相似文献999.
1000.
Barbara A. Rath Kaveh Pouran Yousef David K. Katzenstein Robert W. Shafer Christof Schütte Max von Kleist Thomas C. Merigan 《PloS one》2013,8(4)