An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients

An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients

[Ga-68]Ga-THP-Pam: A PET Radiotracer for Imaging Vascular Calcification

[68Ga]Ga-THP-Pam was previously demonstrated to have high affinity towards a number ofcalcium salts while [18F]NaF, the most used PET radiotracer for bone imaging has highaffinity only for hydroxyapatite (the main component of bone mineral).1 It was hypothesisedthat the broad calcium mineral affinity of [68Ga]Ga-THP-Pam may be advantageous indetection of vascular calcification (VC), where the composition of solid calcium mineral maybe more varied than the composition of bone.2 A direct comparison of [68Ga]Ga-THP-Pamand [18F]NaF in a rat model of VC was performed to test this hypothesis

ICT Development in North Korea: Changes and Challenges

Conditions of ICT development in North Korea are among the least known in the world. This paper relies on interviews, documentary material, and other sources to analyze the potentials of and constraints on North Korea's ICT development. We find substantial interest in ICT diffusion at high levels in the government, which has consistently promoted economically focused ICT programs and projects, while severely constraining political uses of ICT. While North Korea can gain substantial benefits from its proximity to South Korea, nonetheless the future of ICT development in North Korea depends on geopolitical circumstances surrounding the Korean Peninsula. Copyright (c) 2005 Massachusetts Institute of Technology.

TECHNOLOGY AND ENTREPRENEURSHIP IN CHINA: Commercialization Reforms in the Science and Technology Sector

A vital component of China's reforms in the area of science and technology (S&T) activities during the last two decades has been improving the commercial exploitation of technology generated in research institutes. This article analyses the various concepts and measures introduced to guide policies for the commercialization of technology as well as various approaches employed by the Chinese government in the light of theories of market-pull innovation and public choice. Copyright 2001 by The Policy Studies Organization.

Greening an international organization: UNIDO’s strategic responses

Environment, Organizational culture, Resource dependency, International organizations, Norm entrepreneurs, UNIDO, F53, L26, Q53,

Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system xc-, is one of the &gt;200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway. </p