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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 20 March 2018, Vol.115(12), pp.E2859-E2868
    Description: Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth. Here, we used individual nucleotide-resolution cross-linking and immunoprecipitation (iCLIP) to determine the RNA interactome of hnRNP R in motoneurons. We identified ∼3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the noncoding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus and also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R, and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK-deletion mutants, we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the PTEF-B complex involved in transcriptional regulation. These results propose a role for 7SK as an essential interactor of hnRNP R to regulate its function in axon maintenance.
    Keywords: 7sk ; Axon ; Hnrnp R ; Iclip ; Motoneuron ; Axons -- Physiology ; Heterogeneous-Nuclear Ribonucleoproteins -- Metabolism ; Motor Neurons -- Physiology ; RNA, Small Nuclear -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Angewandte Chemie International Edition, 04 January 2010, Vol.49(1), pp.121-124
    Description: : Threonine aldolases (‐TA, ‐TA) have now been found to accept donors other than glycine. In a simple asymmetric biocatalytic aldol reaction alanine, serine, and cysteine reacted with a range of simple acceptor aldehydes to yielded α‐substituted serine derivatives (see scheme; PLP=pyridoxal phosphate).
    Keywords: Aldol Reaction ; Aldolases ; Amino Acids ; Biocatalysis
    ISSN: 1433-7851
    E-ISSN: 1521-3773
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(4), p.e0124056
    Description: Threonine aldolases catalyze the pyridoxal phosphate (PLP) dependent cleavage of threonine into glycine and acetaldehyde and play a major role in the degradation of this amino acid. In nature, L- as well as D-specific enzymes have been identified, but the exact physiological function of D-threonine aldolases (DTAs) is still largely unknown. Both types of enantio-complementary enzymes have a considerable potential in biocatalysis for the stereospecific synthesis of various β-hydroxy amino acids, which are valuable building blocks for the production of pharmaceuticals. While several structures of L-threonine aldolases (LTAs) have already been determined, no structure of a DTA is available to date. Here, we report on the determination of the crystal structure of the DTA from Alcaligenes xylosoxidans (AxDTA) at 1.5 Å resolution. Our results underline the close relationship of DTAs and alanine racemases and allow the identification of a metal binding site close to the PLP-cofactor in the active site of the enzyme which is consistent with the previous observation that divalent cations are essential for DTA activity. Modeling of AxDTA substrate complexes provides a rationale for this metal dependence and indicates that binding of the β-hydroxy group of the substrate to the metal ion very likely activates this group and facilitates its deprotonation by His193. An equivalent involvement of a metal ion has been implicated in the mechanism of a serine dehydratase, which harbors a metal ion binding site in the vicinity of the PLP cofactor at the same position as in DTA. The structure of AxDTA is completely different to available structures of LTAs. The enantio-complementarity of DTAs and LTAs can be explained by an approximate mirror symmetry of crucial active site residues relative to the PLP-cofactor.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Forensic Science International, 10 January 2000, Vol.107(1-3), pp.169-179
    Description: The Bavarian State Bureau of Investigation in Munich has the exclusive responsibility for investigation of criminal acts. One considerable expertise is that of hair analysis. According to the legal system in Germany, there is a special interest when some clients' hair tested positive for illicit drugs. An accused with a lot of drugs in his hair will be treated as a supposed addict and will be guaranteed extenuating circumstances. The instrumentation used for hair analysis is a powerful analytical tool: a Varian 3400 gas chromatograph linked to a Finnigan Tandem-MS (TSQ 700). The methanol extraction method is used for the detection of illegal drugs and metabolites: amphetamine, methamphetamine, MDA, MDMA (ecstasy), MDE, MBDB, methadone, THC, EDDP (metabolite of methadone), cocaine, benzoylecgonine, cocaethylene, opiates (dihydrocodeine, codeine, heroin, 6-monoacetylmorphine, morphine, acetylcodeine). For the detection of 9-carboxy-THC by negative chemical ionization the hair sample is hydrolyzed under alkaline conditions. Solid-phase extraction is used for clean-up. The LOQ for the determination of 11-nor- Delta -9-tetrahydrocannabinol-9-carboxylic-acid is 0.16 pg/mg hair. An unsurpassed combination for rendering an expert opinion based on hair analysis may be: a forensic expert using diligence and experience, coupled with the performance of a sophisticated analytical instrument.
    Keywords: Hair Analysis ; Gc/MS/MS ; Illicit Drugs ; 9-Carboxy-Thc ; Public Health
    ISSN: 0379-0738
    E-ISSN: 1872-6283
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  • 5
    Language: English
    In: BBA - Proteins and Proteomics, December 2014, Vol.1844(12), pp.2298-2305
    Description: The crystal structure of a putative protease from (ppBat) suggested the presence of a zinc ion in each protomer of the dimer as well as a flavin in the dimer interface. Since the chemical identity of the flavin and the exact mode of binding remained unclear, we have determined the crystal structure of ppBat in complex with riboflavin. The obtained structure revealed that the isoalloxazine ring is sandwiched between two tryptophan residues (Trp164) from both chains and adopts two alternate orientations with the N(10)-ribityl side chain protruding from the binding site in opposite directions. In order to characterize the zinc-binding site, we generated two single variants and one double variant in which the two coordinating cysteine residues (Cys74 and Cys111) were replaced by alanine. All three variants were unable to bind zinc demonstrating that both cysteine residues are essential for binding. Moreover, the lack of zinc binding also resulted in drastically reduced thermal stability (11–15 °C). A similar effect was obtained when wild-type protein was incubated with EDTA supporting the conclusion that the zinc-binding site plays an important structural role in ppBat. On the other hand, attempts to identify proteolytic activity failed suggesting that the zinc may not act as a catalytic center in ppBat. Structurally similar zinc binding motives in other proteins were also found to play a structural rather than catalytic role and hence it appears that neither the flavin nor the zinc binding sites possess a catalytic function in ppBat.
    Keywords: Flavin ; Zinc ; X-Ray Crystallography ; Thermal Stability ; Microcalorimetry ; Redox Potential ; Chemistry ; Anatomy & Physiology
    ISSN: 1570-9639
    E-ISSN: 1878-1454
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  • 6
    Language: English
    In: Aquacultural Engineering, 2015, Vol.68, p.19(9)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.aquaeng.2015.07.003 Byline: David C. Love, Michael S. Uhl, Laura Genello Abstract: * Inputs and outputs of a small-scale raft aquaponics system were measured. * Edible plants require fewer inputs than fish and are the profit center. * Small-scale aquaponics needs further study related to resource use. Author Affiliation: (a) Johns Hopkins Center for a Livable Future, Johns Hopkins University, Baltimore, MD, USA (b) Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA (c) Department of Geography and Environmental Engineering, Johns Hopkins University, Baltimore, MD, USA Article History: Received 8 January 2015; Revised 29 July 2015; Accepted 29 July 2015
    Keywords: Aquaculture – Usage ; Water Use – Usage
    ISSN: 0144-8609
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: BMC Research Notes, Oct 31, 2011, Vol.4, p.470
    Description: Background Mechanical forces are known to alter the expression of genes, but it has so far not been reported whether they may influence the fidelity of nucleus-based processes. One experimental approach permitting to address this question is the application of cyclic stretch to cultured human fibroblasts. As a marker for the precision of nucleus-based processes, the number of errors that occur during co-transcriptional splicing can then be measured. This so-called splicing noise is found at low frequency in pre-mRNA splicing. Findings The amount of splicing noise was measured by RT-qPCR of seven exon skips from the test genes AATF, MAP3K11, NF1, PCGF2, POLR2A and RABAC1. In cells treated by altered uniaxial cyclic stretching for 18 h, a uniform and significant increase of splicing noise was found for all detectable exon skips. Conclusion Our data demonstrate that application of cyclic stretch to cultured fibroblasts correlates with a reduced transcriptional fidelity caused by increasing splicing noise.
    Keywords: Fibroblasts -- Genetic Aspects ; Fibroblasts -- Physiological Aspects ; Fibroblasts -- Research ; Rna Splicing -- Research ; Transcription (Genetics) -- Research
    ISSN: 1756-0500
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: BMC Research Notes, Oct 31, 2011, Vol.4, p.470
    Description: Background Mechanical forces are known to alter the expression of genes, but it has so far not been reported whether they may influence the fidelity of nucleus-based processes. One experimental approach permitting to address this question is the application of cyclic stretch to cultured human fibroblasts. As a marker for the precision of nucleus-based processes, the number of errors that occur during co-transcriptional splicing can then be measured. This so-called splicing noise is found at low frequency in pre-mRNA splicing. Findings The amount of splicing noise was measured by RT-qPCR of seven exon skips from the test genes AATF, MAP3K11, NF1, PCGF2, POLR2A and RABAC1. In cells treated by altered uniaxial cyclic stretching for 18 h, a uniform and significant increase of splicing noise was found for all detectable exon skips. Conclusion Our data demonstrate that application of cyclic stretch to cultured fibroblasts correlates with a reduced transcriptional fidelity caused by increasing splicing noise.
    Keywords: Fibroblasts -- Genetic Aspects ; Fibroblasts -- Physiological Aspects ; Fibroblasts -- Research ; Rna Splicing -- Research ; Transcription (Genetics) -- Research
    ISSN: 1756-0500
    Source: Cengage Learning, Inc.
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  • 9
    Language: English
    In: Methods, 15 April 2017, Vol.118-119, pp.60-72
    Description: CLIP-seq experiments are currently the most important means for determining the binding sites of RNA binding proteins on a genome-wide level. The computational analysis can be divided into three steps. In the first pre-processing stage, raw reads have to be trimmed and mapped to the genome. This step has to be specifically adapted for each CLIP-seq protocol. The next step is peak calling, which is required to remove unspecific signals and to determine bona fide protein binding sites on target RNAs. Here, both protocol-specific approaches as well as generic peak callers are available. Despite some peak callers being more widely used, each peak caller has its specific assets and drawbacks, and it might be advantageous to compare the results of several methods. Although peak calling is often the final step in many CLIP-seq publications, an important follow-up task is the determination of binding models from CLIP-seq data. This is central because CLIP-seq experiments are highly dependent on the transcriptional state of the cell in which the experiment was performed. Thus, relying solely on binding sites determined by CLIP-seq from different cells or conditions can lead to a high false negative rate. This shortcoming can, however, be circumvented by applying models that predict additional putative binding sites.
    Keywords: Clip-Seq Data Analysis ; Peak Calling ; Rbp Binding Models ; Rbp Binding Site Prediction ; Chemistry ; Anatomy & Physiology
    ISSN: 1046-2023
    E-ISSN: 1095-9130
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  • 10
    Language: English
    In: Forensic Science International, July 2018, Vol.288, pp.223-226
    Description: Drugs which are commonly smoked or sniffed (e.g. cocaine), can contaminate hair through smoke or dust; therefore testing for metabolites, especially hydroxy metabolites, is highly recommended. The presence of hydroxy metabolites in street-cocaine (COC) has been discussed. To check if detection of hydroxy metabolites definitely proves ingestion, the presence of these metabolites in street COC samples has to be checked. It is expected that the more hydrophilic hydroxy metabolites of COC are incorporated into the hair-matrix to a lesser extent. For this study 576 COC positive hair samples (≥0.1 ng COC/mg hair) were analysed by LC–MS/MS for benzoylecgonine (BE), norcocaine (NC), cocaethylene (CE), -, - and -hydroxy COC ( -, -, -OH-COC), - and -hydroxy BE ( -, -OH-BE), and - and -hydroxy NC ( -, -OH-NC). The results were compared with the respective metabolite/COC concentration ratios in 146 street COC samples, confiscated by the Bavarian police. Peak areas were used to estimate BE/COC, NC/COC, CE/COC and hydroxy metabolites/COC. Similar metabolic ratios were found for -OH-COC in 88% of the samples, but for -OH-COC and -OH-COC only in 5.1% and 6.8%, respectively. Notably, and OH-BE as well as and OH-NC could not be identified from seized samples. We propose that area ratios exceeding the ratios of street COC more than twice or identification of OH-BE and OH-NC enable to differentiate COC consumption from contamination. Using these criteria, consumption of the drug could be proven in 92% of COC positive samples. As detection of - and -hydroxy metabolites using the above mentioned criteria is a reliable tool to distinguish between ingestion and external contamination, it is recommended to implement their measurement into daily routine work.
    Keywords: Cocaine ; Hair Testing ; Hydroxy Metabolites ; Public Health
    ISSN: 0379-0738
    E-ISSN: 1872-6283
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