Suchergebnisse

PMCID: PMC3993263 Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.02774-13. ; Antimicrobials targeting cell wall biosynthesis are generally considered inactive against nonreplicating bacteria. Paradoxically, we found that under nonpermissive growth conditions, exposure of Mycobacterium bovis BCG bacilli to such antimicrobials enhanced their survival. We identified a transcriptional regulator, RaaS (for regulator of antimicrobial-assisted survival), encoded by bcg1279 (rv1219c) as being responsible for the observed phenomenon. Induction of this transcriptional regulator resulted in reduced expression of specific ATP-dependent efflux pumps and promoted long-term survival of mycobacteria, while its deletion accelerated bacterial death under nonpermissive growth conditions in vitro and during macrophage or mouse infection. These findings have implications for the design of antimicrobial drug combination therapies for persistent infectious diseases, such as tuberculosis. ; The study was supported by the Wellcome Trust (GM 081396/Z/06/Z, WT097828MF); BBSRC (O.T., D.I.Y., and M.Y.; P15165); European Union "New Medicines for TB—NM4TB" (LSHP-CT-2005-018923); Ministerio de Educación y Ciencia, Spain (G.T.; 2005/0565); the Schlumberger Foundation (A.S.); and the French Infrastructure for Integrated Structural Biology (M.C.G.; ANR-10-INSB-05-01). ; Peer-reviewed ; Publisher Version

Background: Tau is a microtubule associated protein that regulates the stability of microtubules and the microtubule-dependent axonal transport. Its hyperphosphorylated form is one of the hallmarks of Alzheimer's disease and other tauopathies and the major component of the paired helical filaments that form the abnormal proteinaceous tangles found in these neurodegenerative diseases. It is generally accepted that the phosphorylation extent of tau is the result of an equilibrium in the activity of protein kinases and phosphatases. Disruption of the balance between both types of enzyme activities has been assumed to be at the origin of tau hyperphosphorylation and the subsequent toxicity and progress of the disease. Objective: We explore the possibility that, beside the phosphatase action on phosphorylated tau, the catalytic subunit of PKA catalyzes both tau phosphorylation and also tau dephosphorylation, depending on the ATP/ADP ratio. Methods: We use the shift in the relative electrophoretic mobility suffered by different phosphorylated forms of tau, as a sensor of the catalytic action of the enzyme. Results: The results are in agreement with the long-known thermodynamic reversibility of the phosphorylation reaction (ATP + Protein = ADP+Phospho-Protein) catalyzed by PKA and many other protein kinases. Conclusion: The results contribute to put the compartmentalized energy state of the neuron and the mitochondrial-functions disruption upstream of tau-related pathologies. ; Spanish Government PGC2018 096177-B_100

Background: Tau is a microtubule associated protein that regulates the stability of microtubules and the microtubule-dependent axonal transport. Its hyperphosphorylated form is one of the hallmarks of Alzheimer's disease and other tauopathies and the major component of the paired helical filaments that form the abnormal proteinaceous tangles found in these neurodegenerative diseases. It is generally accepted that the phosphorylation extent of tau is the result of an equilibrium in the activity of protein kinases and phosphatases. Disruption of the balance between both types of enzyme activities has been assumed to be at the origin of tau hyperphosphorylation and the subsequent toxicity and progress of the disease. Objective: We explore the possibility that, beside the phosphatase action on phosphorylated tau, the catalytic subunit of PKA catalyzes both tau phosphorylation and also tau dephosphorylation, depending on the ATP/ADP ratio. Methods: We use the shift in the relative electrophoretic mobility suffered by different phosphorylated forms of tau, as a sensor of the catalytic action of the enzyme. Results: The results are in agreement with the long-known thermodynamic reversibility of the phosphorylation reaction (ATP + Protein = ADP+Phospho-Protein) catalyzed by PKA and many other protein kinases. Conclusion: The results contribute to put the compartmentalized energy state of the neuron and the mitochondrial-functions disruption upstream of tau-related pathologies ; Financial support has been provided by a grant from the Spanish Government PGC2018 096177-B-100

AbstractThe objective of this article is to examine the shift in the intergenerational mobility of Indian immigrant entrepreneurs in Australia. Based on a qualitative methodology, this article reports on the differences in the entrepreneurial attitudes of push and pull and the aptitudes of social and human capital between pre 2000 and post 2000 immigrant entrepreneurs. The findings suggest that the post 2000 Indian migrant entrepreneurs in Australia are mostly pull motivated, have higher qualifications than the pre 2000 arrivals, speak better English, have professional educational qualifications relevant to their business, and operate predominantly in the service sector. They take fewer years to get into business and are less dependent on immigrant social capital resources than pre 2000 arrivals. The study proposes that, compared with social capital resources, human capital resource have a greater impact on entrepreneurial propensity in the case of second generation Indian migrant entrepreneurs in Australia.
Policy Implications


This research has implication for Australian immigration policy, labour laws and settlement services of migrants. It recommends successful implementation of policies and durable solutions for Indian immigrants in the labour market in Australia.

The Australian Government will be assisted in examining and identifying future options for the intake of temporary and permanent migrants that improve the income, wealth and living standards of Australian citizens, improve the budgets and balance sheets of Australian governments, minimize administration and compliance costs associated with immigration, and provide pathways both for Australian citizens to be altruistic towards foreigners, and for Australia's international responsibilities and obligations to foreign residents to be met. Improvements in the labour laws would promote the effective integration of Indian immigrants into society.

Further, Indians in the USA have contributed immensely to the entrepreneurial spirit due to the government support for migrant SMEs and the small business venture funds. The Australian government can replicate this policy, reduce restriction on employment opportunities and enhance entrepreneurship for all migrants.

Organic electronic ion pumps (OEIPs) are versatile tools for electrophoretic delivery of substances with high spatiotemporal resolution. To date, OEIPs and similar iontronic components have been fabricated using thin-film techniques and often rely on laborious, multistep photolithographic processes. OEIPs have been demonstrated in a variety of in vitro and in vivo settings for controlling biological systems, but the thin-film form factor and limited repertoire of polyelectrolyte materials and device fabrication techniques unnecessarily constrain the possibilities for miniaturization and extremely localized substance delivery, e.g., the greater range of pharmaceutical compounds, on the scale of a single cell. Here, we demonstrate an entirely new OEIP form factor based on capillary fibers that include hyperbranched polyglycerols (dPGs) as the selective electrophoretic membrane. The dPGs enable electrophoretic channels with a high concentration of fixed charges and well-controlled cross-linking and can be realized using a simple one-pot fluidic manufacturing protocol. Selective electrophoretic transport of cations and anions of various sizes is demonstrated, including large substances that are difficult to transport with other OEIP technologies. We present a method for tailoring and characterizing the electrophoretic channels fixed charge concentration in the operational state. Subsequently, we compare the experimental performance of these capillary OEIPs to a computational model and explain unexpected features in the ionic current for the transport and delivery of larger, lower-mobility ionic compounds. From this model, we are able to elucidate several operational and design principles relevant to miniaturized electrophoretic drug delivery technologies in general. Overall, the compactness of the capillary OEIP enables electrophoretic delivery devices with probelike geometries, suitable for a variety of ionic compounds, paving the way for less-invasive implantation into biological systems and for healthcare applications. ; Funding Agencies|Swedish Foundation for Strategic Research; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009-00971]; Onnesjo Foundation; Knut and Alice Wallenberg Foundation

© 2014 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US. Background.ZNRD1 was identified as a host protein required for the completion of the human immunodeficiency virus (HIV) lifecycle in a genome-wide screen using small interfering RNA gene silencing. Subsequently, a genome-wide association study (GWAS) of host determinants for HIV-1 disease identified an association of single nucleotide polymorphisms (SNPs) in the ZNRD1 region with CD4+T-cell depletion. Methods.We investigated the effects of SNPs in the ZNRD1 region on human immunodeficiency virus type 1 (HIV-1) infection and progression to clinical outcomes in 5 US-based HIV-1 longitudinal cohorts consisting of men who have sex with men, males with hemophilia, and injection drug users (IDUs) (n = 1865). SNP function was evaluated by electrophoretic mobility shift assay and promoter luciferase assay. Results.A haplotype in the ZNRD1 gene showed significant association with a 35% decreased risk of HIV-1 acquisition (OR = 0.65, 95% CI,. 47-.89), independent of HLA-C rs9264942, in European Americans. The SNP rs3132130 tagging this haplotype, located in the ZNRD1 5′ upstream region, caused a loss of nuclear factor binding and decrease in ZNRD1 promoter activity. ZNRD1 variants also affected HIV-1 disease progression in European- and African-American cohorts. Conclusions.This study provides novel evidence that ZNRD1 polymorphism may confer host resistance to HIV-1 acquisition.

Tomasz Janasz demonstrates that digital technologies and new mobility concepts can lead to a reduction of the automobiles in urban areas by a factor of 10. The book features two vivid case studies of such digital mobility concepts: TwoGo by SAP and smexx. The author proposes six prototypes of business models for 'Shared Automobility Services'. Janasz offers also the 'Transformative Literacy' for designing sustainable urban mobility systems of the future. The author elaborates on the socio-political patterns of urban mobility by presenting the case of the City of Basel (Switzerland). He proposes the framework of 'Integrated Sustainable Urban Mobility' to explain how to overcome car dependence in cities. Contents New Mobility Concepts Autonomous Vehicles Digital Technologies Business Models Policy Interventions for Sustainable Mobility Target Groups Researchers in the fields of innovation management, sustainability, and future urban transportation systems Practitioners in the fields of urban mobility, automotive industry, digital technologies, and business model design The Author Dr. Tomasz Janasz is a business consultant for digital innovation and transformation at a German multinational software corporation. His focus lies on digital business models for the Internet of Things with the main interest in designing efficient urban mobility systems. Series Editors The book series Advances in Information Systems and Business Engineering is edited by Prof. Dr. Ulrike Baumöl, Prof. Dr. Jan vom Brocke and Prof. Dr. Reinhard Jung.--