160 research outputs found
A Sustainable Water Resources Management Assessment Framework (SWRM-AF) for Arid and Semi-Arid Regions:Part 1: Developing the Conceptual Framework
The evaluation of water resources management practices is essential for water usage decisions in regions with limited water resources. The literature provides numerous assessment frameworks, but many ignore the unique characteristics and conditions of some special arid and semi-arid regions, such as the Gulf Cooperation Council (GCC) countries, which lack any permanent rivers or lakes. Thus, this study, the first in a two-part series, seeks to develop a conceptual Sustainable Water Resources Management Assessment Framework (SWRM-AF). General and particular criteria explain how components and indicators were identified. The conceptual SWRM-AF provided here has four components (environment, economy, society, and infrastructure) and 24 indicators. Almost every indicator has been selected from the literature and is briefly explained and justified. This research presents, possibly for the first time, clear and straightforward directions for evaluating each indicator in colour-coded tables. To create a more holistic framework for arid and semi-arid regions, social indicators like âintervention acceptabilityâ and environmental indicators for assessing the impacts of desalination treatment plants have been added to form a unique framework applicable to such regions. Therefore, the components and indicators of conceptual SWRM-AF could work collectively to aid the process of decision-making. The next phase is validating this framework using a participatory approach
The TNF-Family Receptor DR3 is Essential for Diverse T Cell-Mediated Inflammatory Diseases
SummaryDR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases
Brugia malayi Microfilariae Induce a Regulatory Monocyte/Macrophage Phenotype That Suppresses Innate and Adaptive Immune Responses
Background Monocytes and macrophages contribute to the dysfunction of immune
responses in human filariasis. During patent infection monocytes encounter
microfilariae in the blood, an event that occurs in asymptomatically infected
filariasis patients that are immunologically hyporeactive. Aim To determine
whether blood microfilariae directly act on blood monocytes and in vitro
generated macrophages to induce a regulatory phenotype that interferes with
innate and adaptive responses. Methodology and principal findings Monocytes
and in vitro generated macrophages from filaria non-endemic normal donors were
stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could
show that monocytes stimulated with Mf lysate develop a defined regulatory
phenotype, characterised by expression of the immunoregulatory markers IL-10
and PD-L1. Significantly, this regulatory phenotype was recapitulated in
monocytes from Wuchereria bancrofti asymptomatically infected patients but not
patients with pathology or endemic normals. Monocytes from non-endemic donors
stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and
cytokine production (IFN-Îł, IL-13 and IL-10). IFN-Îł responses were restored by
neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate
expressed high levels of IL-10 and had suppressed phagocytic abilities.
Finally Mf lysate applied during the differentiation of macrophages in vitro
interfered with macrophage abilities to respond to subsequent LPS stimulation
in a selective manner. Conclusions and significance Conclusively, our study
demonstrates that Mf lysate stimulation of monocytes from healthy donors in
vitro induces a regulatory phenotype, characterized by expression of PD-L1 and
IL-10. This phenotype is directly reflected in monocytes from filarial
patients with asymptomatic infection but not patients with pathology or
endemic normals. We suggest that suppression of T cell functions typically
seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in
an IL-10-dependent manner. Together with suppression of macrophage innate
responses, this may contribute to the overall down-regulation of immune
responses observed in asymptomatically infected patients
Evolutionary dynamics of tumor-stroma interactions in multiple myeloma
Cancer cells and stromal cells cooperate by exchanging diffusible factors that sustain tumor growth, a form of frequency-dependent selection that can be studied in the framework of evolutionary game theory. In the case of multiple myeloma, three types of cells (malignant plasma cells, osteoblasts and osteoclasts) exchange growth factors with different effects, and tumor-stroma interactions have been analysed using a model of cooperation with pairwise interactions. Here we show that a model in which growth factors have autocrine and paracrine effects on multiple cells, a more realistic assumption for tumor-stroma interactions, leads to different results, with implications for disease progression and treatment. In particular, the model reveals that reducing the number of malignant plasma cells below a critical threshold can lead to their extinction and thus to restore a healthy balance between osteoclast and osteoblast, a result in line with current therapies against multiple myeloma
Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC-MS) exploiting multistage fragmentation (MS n ). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P < 0.01) or pathogen-based infections of the CNS (P < 0.05) where they were elevated. In plasma, we found that 25-HC (P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophage
Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy
Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1â48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization
Mitochondrial targeted catalase suppresses invasive breast cancer in mice
<p>Abstract</p> <p>Background</p> <p>Treatment of invasive breast cancer has an alarmingly high rate of failure because effective targets have not been identified. One potential target is mitochondrial generated reactive oxygen species (ROS) because ROS production has been associated with changes in substrate metabolism and lower concentration of anti-oxidant enzymes in tumor and stromal cells and increased metastatic potential.</p> <p>Methods</p> <p>Transgenic mice expressing a human catalase gene (mCAT) were crossed with MMTV-PyMT transgenic mice that develop metastatic breast cancer. All mice (33 mCAT positive and 23 mCAT negative) were terminated at 110 days of age, when tumors were well advanced. Tumors were histologically assessed for invasiveness, proliferation and metastatic foci in the lungs. ROS levels and activation status of p38 MAPK were determined.</p> <p>Results</p> <p>PyMT mice expressing mCAT had a 12.5 per cent incidence of high histological grade primary tumor invasiveness compared to a 62.5 per cent incidence in PyMT mice without mCAT. The histological grade correlated with incidence of metastasis with 56 per cent of PyMT mice positive for mCAT showing evidence of pulmonary metastasis compared to 85.4 per cent of PyMT mice negative for mCAT with pulmonary metastasis (p †0.05). PyMT tumor cells expressing mCAT had lower ROS levels and were more resistant to hydrogen peroxide-induced oxidative stress than wild type tumor cells, suggesting that mCAT has the potential of quenching intracellular ROS and subsequent invasive behavior. The metastatic tumor burden in PyMT mice expressing mCAT was 0.1 mm<sup>2</sup>/cm<sup>2 </sup>of lung tissue compared with 1.3 mm<sup>2</sup>/cm<sup>2 </sup>of lung tissue in PyMT mice expressing the wild type allele (p †0.01), indicating that mCAT could play a role in mitigating metastatic tumor progression at a distant organ site. Expression of mCAT in the lungs increased resistance to hydrogen peroxide-induced oxidative stress that was associated with decreased activation of p38MAPK suggesting ROS signaling is dependent on p38MAPK for at least some of its downstream effects.</p> <p>Conclusion</p> <p>Targeting catalase within mitochondria of tumor cells and tumor stromal cells suppresses ROS-driven tumor progression and metastasis. Therefore, increasing the antioxidant capacity of the mitochondrial compartment could be a rational therapeutic approach for invasive breast cancer.</p> <p>Please see related commentary article: <url>http://www.biomedcentral.com/1741-7015/9/62</url></p
Protective Effector Memory CD4 T Cells Depend on ICOS for Survival
Memory CD4 T cells play a vital role in protection against re-infection by pathogens as diverse as helminthes or influenza viruses. Inducible costimulator (ICOS) is highly expressed on memory CD4 T cells and has been shown to augment proliferation and survival of activated CD4 T cells. However, the role of ICOS costimulation on the development and maintenance of memory CD4 T cells remains controversial. Herein, we describe a significant defect in the number of effector memory (EM) phenotype cells in ICOSâ/â and ICOSLâ/â mice that becomes progressively more dramatic as the mice age. This decrease was not due to a defect in the homeostatic proliferation of EM phenotype CD4 T cells in ICOSâ/â or ICOSLâ/â mice. To determine whether ICOS regulated the development or survival of EM CD4 T cells, we utilized an adoptive transfer model. We found no defect in development of EM CD4 T cells, but long-term survival of ICOSâ/â EM CD4 T cells was significantly compromised compared to wild-type cells. The defect in survival was specific to EM cells as the central memory (CM) ICOSâ/â CD4 T cells persisted as well as wild type cells. To determine the physiological consequences of a specific defect in EM CD4 T cells, wild-type and ICOSâ/â mice were infected with influenza virus. ICOSâ/â mice developed significantly fewer influenza-specific EM CD4 T cells and were more susceptible to re-infection than wild-type mice. Collectively, our findings demonstrate a role for ICOS costimulation in the maintenance of EM but not CM CD4 T cells
Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations
Blocking HVEMâLIGHT interactions on T cells reduces the persistence of antigen-specific memory T cell populations after secondary expansion through decreased Akt activity and loss of Bcl-2 expression
Challenges of operational river forecasting
Skillful and timely streamflow forecasts are critically important to water managers and emergency protection services. To provide these forecasts, hydrologists must predict the behavior of complex coupled humanânatural systems using incomplete and uncertain information and imperfect models. Moreover, operational predictions often integrate anecdotal information and unmodeled factors. Forecasting agencies face four key challenges: 1) making the most of available data, 2) making accurate predictions using models, 3) turning hydrometeorological forecasts into effective warnings, and 4) administering an operational service. Each challenge presents a variety of research opportunities, including the development of automated quality-control algorithms for the myriad of data used in operational streamflow forecasts, data assimilation, and ensemble forecasting techniques that allow for forecaster input, methods for using human-generated weather forecasts quantitatively, and quantification of human interference in the hydrologic cycle. Furthermore, much can be done to improve the communication of probabilistic forecasts and to design a forecasting paradigm that effectively combines increasingly sophisticated forecasting technology with subjective forecaster expertise. These areas are described in detail to share a real-world perspective and focus for ongoing research endeavors
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