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Berlin Brandenburg

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  • JSTOR Archival Journals  (7,494)
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  • 1
    Language: English
    In: Journal of Conflict Resolution, February 2013, Vol.57(1), pp.143-168
    Description: This article provides evidence for a particular channel through which sustained terrorism in rural areas may affect growth in developing countries. Using micro-level data from agricultural surveys during the period of insurgency in Punjab (India), I find significant negative effects of terrorism on the level of investment in long-term agricultural technology, but effects are small and insignificant for short-term investment. The presence of a major terrorist incident in a district in a year reduces long-term fixed investment by around 17 percent after controlling for district fixed-effects, time trends, district trends, and other farm-level controls. These negative effects are greater for richer farmers and those living in bordering districts. This results in a farmer losing close to 4 percent of his income annually because of the insurgency.
    Keywords: Terrorism ; Investment ; Punjab ; Social Sciences (General) ; International Relations ; Law
    ISSN: 0022-0027
    E-ISSN: 1552-8766
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 14 July 2015, Vol.112(28), pp.8579-83
    Description: The variable domains of Ig and T-cell receptor genes in vertebrates are assembled from gene fragments by the V(D)J recombination process. The RAG1-RAG2 recombinase (RAG1/2) initiates this recombination by cutting DNA at the borders of recombination signal sequences (RSS) and their neighboring gene segments. The RAG1 protein is also known to contain a ubiquitin E3 ligase activity, located in an N-terminal region that is not strictly required for the basic recombination reaction but helps to regulate recombination. The isolated E3 ligase domain was earlier shown to ubiquitinate one site in a neighboring RAG1 sequence. Here we show that autoubiquitination of full-length RAG1 at this specific residue (K233) results in a large increase of DNA cleavage by RAG1/2. A mutational block of the ubiquitination site abolishes this effect and inhibits recombination of a test substrate in mouse cells. Thus, ubiquitination of RAG1, which can be promoted by RAG1's own ubiquitin ligase activity, plays a significant role in governing the level of V(D)J recombination activity.
    Keywords: Diversification ; Immunoglobulin ; Ubiquitin ; Ubiquitination ; V(D)J Recombination ; Homeodomain Proteins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Article
    Article
    BMJ Publishing Group Ltd and Institute of Medical Ethics
    Language: English
    In: Journal of Medical Ethics, 28 June 2013, Vol.39(6), p.359
    Description: In this article, I examine children's reported experiences with stimulant drug treatments for attention deficit hyperactivity disorder in light of bioethical arguments about the potential threats of psychotropic drugs to authenticity and moral agency. Drawing on a study that involved over 150 families in the USA and the UK, I show that children are able to report threats to authenticity, but that the majority of children are not concerned with such threats. On balance, children report that stimulants improve their capacity for moral agency, and they associate this capacity with an ability to meet normative expectations. I argue that although under certain conditions stimulant drug treatment may increase the risk of a threat to authenticity, there are ways to minimise this risk and to maximise the benefits of stimulant drug treatment. Medical professionals in particular should help children to flourish with stimulant drug treatments, in good and in bad conditions.
    Keywords: Children ; Neuroethics ; Psychiatry ; Psychopharmacology ; Open Access ; Editor'S Choice
    ISSN: 0306-6800
    ISSN: 03066800
    E-ISSN: 1473-4257
    E-ISSN: 14734257
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  • 4
    In: Genes, Chromosomes and Cancer, December 2014, Vol.53(12), pp.999-1007
    Description: Small cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. These cancers are deficient in glucocorticoid receptor () expression, and therefore, resistant to glucocorticoids. Overexpression of the both in vivo and in vitro leads to apoptotic cell death suggesting that loss of is favorable for cancer growth. Indeed, the promoter is silenced in SCLC cells by methylation. We now show that treatment of the SCLC cell line (DMS79) cells with the demethylating agent, 5‐aza‐2′‐deoxycytidine (5‐aza), results in significant endogenous re‐expression of both α and the ligand‐independent . The gene has a complex promoter region comprising nine alternative promoters, the proximal seven of which lie within a CpG island. The endogenous re‐expression seen is attributed to the constitutive promoters 1B and 1C and 1J but predominantly 1F, which we show to be heavily methylated in SCLC cells. Flow cytometric analysis using the apoptotic marker, Annexin V, shows that this endogenous re‐expression is sufficient to drive the SCLC cells to apoptosis. Apoptotic induction is specific to re‐expression as cotreatment with 5‐aza and the antagonist, RU486 prevented apoptosis. Of the three functional GR domains (the DNA binding domain, ligand binding domain, and transactivation domain), we identified that the transactivation domain is essential for apoptosis in SCLC. The discovery that endogenous re‐expression of the GR in SCLC cells is sufficient to induce apoptotic cell death by reversing a cancer‐driven DNA methylation effect may lead to the development of novel adjunct therapies. © 2014 Wiley Periodicals, Inc.
    Keywords: Lung Cancer – Analysis ; Methylation – Analysis ; Glucocorticoids – Analysis ; Apoptosis – Analysis ; Steroids (Organic Compounds) – Analysis;
    ISSN: 1045-2257
    E-ISSN: 1098-2264
    E-ISSN: 10916490
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  • 5
    Language: English
    In: Science (New York, N.Y.), 02 September 2011, Vol.333(6047), pp.1254-6
    Description: In our view, synthetic biology is an extension of the continuum of genetic science that has been used safely for more than 40 years by the biotechnology industry in the development of commercial products. Examples of synthetic biology use by biotechnology companies illustrate the potential to substantially reduce research and development time and to increase speed to market. Improvements in the speed and cost of DNA synthesis are enabling scientists to design modified bacterial chromosomes that can be used in the production of renewable chemicals, biofuels, bioproducts, renewable specialty chemicals, pharmaceutical intermediates, fine chemicals, food ingredients, and health care products. Regulatory options should support innovation and commercial development of new products while protecting the public from potential harms.
    Keywords: Biotechnology ; Government Regulation ; Synthetic Biology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 18 August 2015, Vol.112(33), pp.10431-6
    Description: Infertility is a prevalent health issue, affecting ∼15% of couples of childbearing age. Nearly one-half of idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. Traditional methods for studying inheritance, such as genome-wide association studies and linkage analyses, have been confounded by the genetic and phenotypic complexity of reproductive processes. Here we describe an association- and linkage-free approach to identify segregating infertility alleles, in which CRISPR/Cas9 genome editing is used to model putatively deleterious nonsynonymous SNPs (nsSNPs) in the mouse orthologs of fertility genes. Mice bearing "humanized" alleles of four essential meiosis genes, each predicted to be deleterious by most of the commonly used algorithms for analyzing functional SNP consequences, were examined for fertility and reproductive defects. Only a Cdk2 allele mimicking SNP rs3087335, which alters an inhibitory WEE1 protein kinase phosphorylation site, caused infertility and revealed a novel function in regulating spermatogonial stem cell maintenance. Our data indicate that segregating infertility alleles exist in human populations. Furthermore, whereas computational prediction of SNP effects is useful for identifying candidate causal mutations for diverse diseases, this study underscores the need for in vivo functional evaluation of physiological consequences. This approach can revolutionize personalized reproductive genetics by establishing a permanent reference of benign vs. infertile alleles.
    Keywords: Crispr/Cas9 ; Cyclin ; Genome Editing ; Meiosis ; Spermatogenesis ; Mutation ; Polymorphism, Single Nucleotide ; Infertility, Female -- Genetics ; Infertility, Male -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 May 2013, Vol.110(22), pp.8960-5
    Description: Establishment and maintenance of apico-basolateral trafficking pathways are critical to epithelial homeostasis. Loss of polarity and trafficking fidelity are thought to occur as a consequence of transformation; however, here we report that selective mistrafficking of the epidermal growth factor receptor (EGFR) ligand epiregulin (EREG) from the basolateral to the apical cell surface drives transformation. Normally, EREG is preferentially delivered to the basolateral surface of polarized Madin-Darby canine kidney cells. EREG basolateral trafficking is regulated by a conserved tyrosine-based basolateral sorting motif in its cytoplasmic domain (YXXΦ: Y(156)ERV). Both Y156 and V159 are required for basolateral sorting of EREG, because Y156A and V159G substitutions redirect EREG to the apical cell surface. We also show that basolateral sorting of EREG is adaptor protein 1B-independent. Apical mistrafficking of EREG has a distinctive phenotype. In contrast to transient EGFR tyrosine phosphorylation after basolateral EREG stimulation, apical EREG leads to prolonged EGFR tyrosine phosphorylation, which may be related, at least in part, to a lack of negative regulatory Y1045 phosphorylation and subsequent ubiquitylation. Notably, Madin-Darby canine kidney cells stably expressing apically mistrafficked EREG form significantly larger, hyperproliferative, poorly differentiated, and locally invasive tumors in nude mice compared with WT EREG-expressing cells.
    Keywords: Epithelial Transformation ; Growth Factor Trafficking ; Protein Sorting ; Receptor Tyrosine Kinase ; Cell Polarity -- Physiology ; Cell Transformation, Neoplastic -- Metabolism ; Epidermal Growth Factor -- Metabolism ; Epithelial Cells -- Physiology ; Signal Transduction -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 04 March 2014, Vol.111(9), pp.3389-94
    Description: Proline utilization A (PutA) proteins are bifunctional peripheral membrane flavoenzymes that catalyze the oxidation of L-proline to L-glutamate by the sequential activities of proline dehydrogenase and aldehyde dehydrogenase domains. Located at the inner membrane of Gram-negative bacteria, PutAs play a major role in energy metabolism by coupling the oxidation of proline imported from the environment to the reduction of membrane-associated quinones. Here, we report seven crystal structures of the 1,004-residue PutA from Geobacter sulfurreducens, along with determination of the protein oligomeric state by small-angle X-ray scattering and kinetic characterization of substrate channeling and quinone reduction. The structures reveal an elaborate and dynamic tunnel system featuring a 75-Å-long tunnel that links the two active sites and six smaller tunnels that connect the main tunnel to the bulk medium. The locations of these tunnels and their responses to ligand binding and flavin reduction suggest hypotheses about how proline, water, and quinones enter the tunnel system and where L-glutamate exits. Kinetic measurements show that glutamate production from proline occurs without a lag phase, consistent with substrate channeling and implying that the observed tunnel is functionally relevant. Furthermore, the structure of reduced PutA complexed with menadione bisulfite reveals the elusive quinone-binding site. The benzoquinone binds within 4.0 Å of the flavin si face, consistent with direct electron transfer. The location of the quinone site implies that the concave surface of the PutA dimer approaches the membrane. Altogether, these results provide insight into how PutAs couple proline oxidation to quinone reduction.
    Keywords: X-Ray Crystallography ; Membrane Association ; Proline Catabolism ; Models, Molecular ; Protein Conformation ; Bacterial Proteins -- Chemistry ; Benzoquinones -- Metabolism ; Geobacter -- Enzymology ; Membrane Proteins -- Chemistry ; Metabolic Networks and Pathways -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 14 February 2012, Vol.109(7), pp.2184-5
    Description: Author contributions: H.S.M. wrote the paper.
    Keywords: Endogenous Retroviruses -- Genetics ; Gene Products, Env -- Physiology ; Placentation -- Physiology ; Pregnancy Proteins -- Physiology ; Viral Envelope Proteins -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 September 2015, Vol.112(35), pp.10956-61
    Description: Bacterial growth and morphogenesis are intimately coupled to expansion of peptidoglycan (PG), an extensively cross-linked macromolecule that forms a protective mesh-like sacculus around the cytoplasmic membrane. Growth of the PG sacculus is a dynamic event requiring the concerted action of hydrolases that cleave the cross-links for insertion of new material and synthases that catalyze cross-link formation; however, the factors that regulate PG expansion during bacterial growth are poorly understood. Here, we show that the PG hydrolase MepS (formerly Spr), which is specific to cleavage of cross-links during PG expansion in Escherichia coli, is modulated by proteolysis. Using combined genetic, molecular, and biochemical approaches, we demonstrate that MepS is rapidly degraded by a proteolytic system comprising an outer membrane lipoprotein of unknown function, NlpI, and a periplasmic protease, Prc (or Tsp). In summary, our results indicate that the NlpI-Prc system contributes to growth and enlargement of the PG sacculus by modulating the cellular levels of the cross-link-cleaving hydrolase MepS. Overall, this study signifies the importance of PG cross-link cleavage and its regulation in bacterial cell wall biogenesis.
    Keywords: Meps ; Nlpi-Prc ; Bacterial Morphogenesis ; Peptidoglycan ; Regulated Proteolysis ; Morphogenesis ; Escherichia Coli -- Growth & Development ; N-Acetylmuramoyl-L-Alanine Amidase -- Metabolism ; Peptidoglycan -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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