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Inflammation and tissue remodeling with pathologic fibrosis are common consequences of Th2 responses in the lung and other organs. Interleukin (IL)-13 and transforming growth factor-β1 (TGF-β1) are frequently coexpressed in these responses and are believed to play important roles in the pathogenesis of Th2-induced pathologies. To shed light on the mechanisms of these responses, overexpression transgenic approaches were used to selectively target each of these cytokines to the murine lung. IL-13 proved to be a potent stimulator of eosinophilic inflammation, mucus metaplasia, tissue fibrosis, and alveolar remodeling. CC chemokines, specific chemokine receptors (CCR2, CCR1), adenosine metabolism, vascular endothelial growth factor, and IL-11 contributed to the genesis of these responses. IL-13 also induced tissue fibrosis, at least in part, via its ability to induce and activate TGF-β1. In the TGF-β1 transgenic mouse, epithelial apoptosis preceded the onset of tissue fibrosis and alveolar remodeling. In addition, chemical (Z-VAD-fmk) and genetic (null mutations of early growth response gene 1) interventions blocked apoptosis and ameliorated TGF-β1–induced fibrosis and alveolar restructuring. These studies define an IL-13–TGF-β1 pathway of tissue remodeling that regulates inflammation, mucus metaplasia, apoptosis, vascular responses, and fibrosis in the lung. They also highlight the intimate relationship between apoptosis and fibrosis induced by TGF-β1. By defining the complexities of this pathway, these studies highlight sites at which therapies can be directed to control these important responses.
Fibrosis is an important cause of morbidity and mortality in the lung. This is illustrated in airways disorders such as bronchiolitis obliterans syndrome and asthma, which are characterized by chronic inflammation and subepithelial/airway fibrosis (1, 2). The consequences of these responses are significant because asthma affects approximately 18 million people in the United States, and asthmatic airway remodeling is believed to be an important determinant of disease severity and natural history (1). This is also illustrated in the interstitial lung diseases (ILD), including idiopathic pulmonary fibrosis, scleroderma, and bleomycin lung, where pulmonary fibrosis is a dreaded and sometimes fatal disease endpoint (3). The consequences of these diseases are also significant, with ILD manifesting a prevalence from 3 to 26 per 100,000 per year and undiagnosed ILD occurring at a rate that is 10 times that of recognized disease (3). The mechanisms of tissue fibrosis in these lung disorders are poorly understood.
A chronic Th2-dominated inflammatory response is believed to be the cornerstone of the asthmatic diathesis, and IL-13 is believed to be the key fibrogenic effector in this disorder (4–6). Studies from our laboratory recently demonstrated that IL-13 mediates its fibrogenic effects, at least in part, via its ability to induce and activate transforming growth factor (TGF)-β1 (7). These findings are in accord with and support the "type 2 cytokine hypothesis of fibrosis," which suggests that fibrosis occurs in chronic inflammatory disorders when cytokine balance shifts in a Th2 (Type II) direction (8). In keeping with this hypothesis, IL-13 is also dysregulated in, and may play a critical role in, many interstitial lung disorders, including idiopathic pulmonary fibrosis, scleroderma, radiation-induced pulmonary fibrosis, and bleomycin lung (9–15). TGF-β1 also plays a critical role in the pathogenesis of these and other disorders (7, 16–24).
TGF-β1 family proteins are multifunctional cytokines that play pivotal roles in diverse biologic processes, including the regulation of cell growth and survival, cell and tissue differentiation, development, inflammation, immunity, hematopoiesis, and tissue remodeling and repair. On superficial analysis, TGF-β1 can be accurately described as a healing molecule that manifests antiinflammatory and fibrotic effects while inducing wound healing. This perspective, however, is only partially correct, and the effector profile of TGF-β1 can seem confusing and even contradictory. This is noted in the setting of inflammation where TGF-β1 has important antiinflammatory and immunosuppressive effects in some settings (25, 26) and proinflammatory effects in others (26, 27). This is also seen in oncogenesis, where TGF-β1 can exert potent growth inhibitory effects on tumor cells while enhancing tumor cell migration and invasion. Particularly relevant to the present study are the studies that demonstrate that, in the proper setting, TGF-β1 is essential for wound healing, stimulates matrix molecule deposition and angiogenesis, and is an essential mediator of the pathologic scarring in fibrotic disorders (7, 17, 28–31). On the other hand, TGF-β1 can induce tissue injury (32) and cellular apoptosis, decrease epithelialization, and inhibit wound healing (33–36).
The complexity of TGF-β1 effector function can be attributed to a number of items. First, the effects of TGF-β1 proteins vary with the state of activation and differentiation of the target cell and the presence of other stimuli in the local microenvironment. In addition, it has been demonstrated that TGF-β1 can exert its seemingly antagonistic effects via different effector pathways. This is illustrated in Smad-3 null mutant mice, which manifest enhanced wound healing and epithelialization (33–36). The fact that these responses are perceived to be contradictory may also reflect an inadequate understanding of the events that are required for TGF-β1 to induce its complex tissue phenotypes. Specifically, the kinetics of TGF-β1 induction of its tissue phenotypes are poorly understood, and, in virtually all studies, it has been assumed that each phenotype is a distinct endpoint. The possibility that TGF-β1 may induce one phenotype only if it induces an earlier "different" phenotype has not been considered. As a result, the relationships between endpoints, such as apoptosis and fibrosis, have not been investigated.
IL-13 was discovered as an IL-4–like molecule and was presumed to represent a genetic duplication of this Th2 cytokine. More recently, however, it has become clear that IL-13 and IL-4 differ significantly in their contributions to the Th2 inflammatory response, with IL-13 being a major effector at sites of Th2 inflammation (4, 6). Studies using overexpression (OE) transgenic mice played a major role in this finding. In these studies, the transgenic OE of IL-13 in these animals caused an asthma-like phenotype that included (1) eosinophil-, macrophage-, and lymphocyte-rich inflammation; (2) mucus metaplasia with goblet cell hyperplasia and the hyperproduction of neutral and acidic mucus; and (3) subepithelial fibrosis in the lamina reticularis that extended into the adventitia of the airway. These animals did not have significant abnormalities in baseline airway resistance. They did, however, demonstrate airway hyperresponsiveness on methacholine challenge. These studies demonstrate that IL-13 has the ability to produce many of the pathologies that are characteristic of human asthma (37). In keeping with the role of IL-13 in ILD, prolonged IL-13 elaboration also caused the airway phenotype to spread into the parenchyma. This caused a fibrodestructive disorder and premature death due to respiratory failure (38).
A variety of interventions can be used in transgenic mice to define in vivo the mechanisms that are responsible for the disease-relevant phenotypes that are seen. This can be done with interventions such as antibody neutralization. Powerful results are also obtained by breeding the OE mice with mice with targeted null mutations of downstream genes. This allows one to compare the effects of the transgene in mice with (+/+), (+/−), and (−/−) downstream gene loci. These approaches have been used to characterize major aspects of the IL-13 phenotype.
To define the mechanisms of IL-13–induced inflammation, we characterized the effects of IL-13 on the elaboration of inflammation-generating chemokines and the importance of selected chemokine receptors in the pathogenesis of the IL-13–induced tissue response. Transgenic IL-13 was a potent stimulator of monocyte chemotactic protein (MCP)-1, CCL2, MCP-2 (CCL-8), MCP-3 (CCL-7), and MCP-5 (CCL12). This stimulation was not specific for MCPs because macrophage inhibitory protein (MIP)-1α (CCL3), MIP-1β (CCL4), MIP-2 (CXCL1), MIP-3α (CCL20), thymus- and activation-regulated chemokine (TARC, CCL17), thymus-expressed chemokine (TECK, CCL25), eotaxin (CCL11), eotaxin-2 (CCL24), macrophage-derived chemokine (MDC, CCL22), and C10 (CCL6) were prominently induced. The ability of IL-13 to increase lung size, alveolar size, and lung compliance; to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis; and to cause respiratory failure and death was markedly decreased in CCR2−/− mice, whereas mucus metaplasia was not altered (38). Similar decreases in inflammation, remodeling, and death were noted in IL-13 OE animals with null mutant CCR-1 loci and in IL-13 OE mice treated with neutralizing antibodies against the chemokine C10/CCL6 (39). CCR2 deficiency did not decrease the basal or IL-13–stimulated expression of target matrix metalloproteinases (MMPs) or cathepsins but did increase the levels of mRNA-encoding α1-antitrypsin; tissue inhibitor of metalloproteinase-1, -2, and -4; and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-β1 were diminished in CCR-2−/− animals. Treatment with anti-C10 (or the null mutation of CCR-1) decreased the ability of IL-13 to stimulate the production of MCP-1/CCL2, MIP-1α/CCL3, MMP-2/CXCL1, MMP-9, and cathepsins K, L, and S, and the ability of IL-13 to inhibit α1-antitrypsin. These studies demonstrate that IL-13 is a potent stimulator of a large number of chemokines in the lung and highlight a chemokine cascade in which C10/CCL6 elaboration is required for the induction of MCP-1/CCL2, MIP-1α/CCL3, and proteases (MMP-2 and -9 and cathepsins) and the inhibition of α1-antitrypsin. They also demonstrate that CCR-2 and CCR-1 play critical roles in these IL-13 responses and that CCR-2–mediated alterations in IL-13–induced fibrosis are associated with alterations in the production of TGF-β1.
Vascular remodeling is well described in the asthmatic airway. The mechanisms responsible for the increase in airway vascularity, however, are poorly defined. To address this issue, studies were undertaken to determine if IL-13 regulated the production of vascular regulating growth factors such as vascular endothelial cell growth factor (VEGF). These studies demonstrated that IL-13 is a potent stimulator of VEGF accumulation in the murine lung. Oxidant injury (induced by 100% O2) augmented this inductive response. The 164-amino acid isoform was the major VEGF moiety in bronchoalveolar lavage (BAL) fluid from transgenic mice in room air. The 120- and 188-amino-acid isoforms accumulated in mice during oxidant injury. These studies suggest that VEGF elaboration is a downstream consequence of IL-13 and that VEGF may be responsible for the vascular abnormalities in the asthmatic airway.
To further address this issue, the double-construct, inducible OE system was used to target VEGF165 to the murine airway (40). In these studies, VEGF increased bronchial vascularity and vascular permeability. VEGF also caused mucus metaplasia, airway remodeling, and airway hyperresponsiveness on methacholine challenge.
These studies suggest that VEGF is a multifunctional contributor to asthma pathogenesis. Because respiratory syncytial virus is also a potent stimulator of VEGF elaboration by epithelial cells (41), they also suggest that VEGF may be one of the missing links between the innate immune responses induced by viral infection and the adaptive response that is characteristic of allergen-driven Th2 inflammation.
Tissue fibrosis is a prominent feature in the remodeled asthmatic airway. Because IL-13 is a major effector in airway Th2 responses, studies were undertaken to define the mechanisms by which IL-13 might engender this fibrotic response. We hypothesized that the effects of IL-13 could be mediated by its ability to interact with members of the TGF-β family. To test this hypothesis, we compared the regulation of TGF-β1 in lungs from wild-type mice and mice in which IL-13 OE causes pulmonary fibrosis. IL-13 selectively stimulated TGF-β1 in transgenic animals, and macrophages were a major source of TGF-β1 production and deposition in these tissues. IL-13 also activated TGF-β1 in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-β1 binding protein and increased mRNA encoding urinary plasminogen activator, MMP-9, and CD44. Comparable alterations in thrombospondin-1, integrin β6, and CD36 were not appreciated. TGF-β1 activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in the progeny of crosses of CC10–IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13–induced fibrosis was also significantly ameliorated by treatment with the TGF-β antagonist, soluble TGF–βRII-Fc. These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-β1 in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease and by an MMP-9–dependent and CD44-independent mechanism. Lastly, they demonstrate that the fibrotic effects of IL-13 are mediated, in great extent, via its ability to regulate the TGF-β1 pathway (7).
Elevated levels of adenosine are found in BAL fluid from patients with asthma, and aerosol adenosine exposure induces bronchospasm in patients with asthma and chronic obstructive pulmonary disease but not in normal control subjects. Because adenosine is a nucleoside that is generated in response to cellular stresses such as chronic inflammation, we hypothesized that adenosine accumulation, alterations in adenosine receptor expression, and/or adenosine–IL-13 autoinduction are critical events in the pathogenesis of IL-13–induced tissue pathologies. To test this hypothesis, we characterized the effects of transgenic IL-13 on the levels of adenosine, adenosine deaminase (ADA) enzymatic activity, and the expression of adenosine receptors in the murine lung (42). We also characterized the ability of adenosine to induce IL-13 in lungs from ADA null mutant mice. IL-13 induced a pulmonary inflammatory and remodeling response that eventuated in respiratory failure and death. During this response, IL-13 caused a progressive increase in adenosine accumulation; inhibited ADA enzymatic activity and mRNA accumulation; and augmented the expression of the A1, A2b, and A3 but not the A2a adenosine receptors. IL-13 also induced the production and activation of TGF-β1 in this murine system. ADA enzyme therapy diminished the IL-13–induced increase in adenosine. This alteration inhibited IL-13–induced inflammation and chemokine elaboration and prolonged the survival of IL-13–transgenic animals. ADA enzyme therapy also caused a marked decrease in pulmonary remodeling, a marked decrease in tissue fibrosis, a decrease in alveolar destruction, and a significant decrease in the induction and activation of TGF-β1. Adenosine levels are also markedly increased in lungs from partially ADA null mutant mice. In these mice, the elevated levels of adenosine stimulated the production of IL-13. These studies demonstrate that adenosine is increased and that adenosine signaling is modified in lungs from IL-13 OE transgenic mice. They also demonstrate that this increase in adenosine plays an important role in IL-13–induced inflammation, fibrosis, and alveolar remodeling and demonstrate that these effects are mediated, at least in part, by the ability of adenosine to induce the production and activation of TGF-β1. Last, they demonstrate that IL-13 and adenosine can stimulate one another in an amplification pathway that may contribute to the nature, severity, progression, and chronicity of IL-13–mediated and/or Th2-mediated disorders.
Exaggerated quantities of IL-11 and IL-13 are found in close approximation in asthmatic tissues. We hypothesized that IL-11, signaling via the IL-11Rα–gp-130 receptor complex, plays a key role in IL-13–induced tissue responses. To test this hypothesis, we compared the expression of IL-11, IL-11Rα, and gp130 in lungs from wild-type mice and IL-13 OE transgenic mice. We simultaneously characterized the effects of a null mutation of IL-11Rα on the tissue effects of transgenic IL-13 (43). These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11Rα. They also demonstrate that IL-13 is a potent stimulator of inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death in mice with wild-type IL-11Rα loci and that these alterations are ameliorated in the absence of IL-11Rα. Last, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates CC chemokines, MMPs, mucin genes, and gob 5, and stimulates and activates TGF-β1 via IL-11Rα–dependent pathways. These studies demonstrate that IL-11Rα plays a key role in the pathogenesis of IL-13–induced inflammation and remodeling.
The studies noted previously demonstrate that IL-13 induces tissue fibrosis via its ability to stimulate and activate TGF-β1 (7). They also demonstrate that the alterations in this fibrotic response induced by the manipulation of chemokine receptors, IL-11, and/or adenosine are associated with the proportionate alterations in TGF-β1. These studies led to the hypothesis that TGF-β1 generation and activation can be a major final common pathway of tissue fibrosis in the respiratory tract. To address this hypothesis, studies were undertaken to determine if we could generate airway and parenchymal remodeling and fibrosis by overexpressing TGF-β1. To avoid the vagaries of TGF-β1 activation, we overexpressed bioactive TGF-β1. We initiated these studies using the constitutive transgenic system described by our laboratory (37). With this system, we never got viable transgene-expressing animals. This is in accord with the demonstration that the overexpression of a similar TGF-β1 construct using the surfactant apoprotein-C promoter results in fetal lethality due to a block in branching morphogenesis (44). We followed this with studies using the double transgenic inducible system described by our laboratory. The low level of basal transgene leak in this system was also sufficient to cause fetal lethality. To allow this otherwise fetal lethal transgene to be adequately expressed in the mature murine lung, we developed a novel triple transgenic system based on the tetracycline-controlled transcriptional suppressor (tTS) and the reverse tetracycline transactivator (45). In this system, tTS binds to the transgenic apparatus in transgenic mice on normal water and suppresses gene expression. When the animals are given doxycycline water (dox) the tTS is released, allowing the activating reverse tetracycline transactivator to bind and transgene activation. In the absence of dox, these mice did not express transgenic TGF-β1 on BAL ELISA or lung RNA RT-PCR (35 cycles) evaluations. They did, however, manifest inducibility with transgenic TGF-β1 readily noted after dox administration. These levels were maintained for the duration (up to 3 mo) of dox administration and returned to undetectable levels within 48 h of the removal of dox from the animal's drinking water.
To define the effects of TGF-β1 in the fully formed lung, 6-wk-old, triple-transgene positive [herein referred to as transgene (+)] animals and their transgene (−) littermate controls were randomized to receive normal water or dox. At intervals thereafter, animals were killed, and the lungs were analyzed. These studies revealed a complex phenotype with early apoptosis followed by inflammation, fibrosis, α-smooth muscle actin (+) cell accumulation, and alveolar remodeling. Each is described below.
After as little as 12 h of TGF-β1 induction, a TDT-mediated nick-end labeling (TUNEL) (+) cell death response could be readily appreciated in lungs from transgene (+) but not transgene (−) animals. Many of the TUNEL (+) cells were epithelial cells, as evidenced by their histologic location and by double-labeling experiments. This apoptosis peaked after 48 h of dox administration and decreased despite continuous dox administration and TGF-β1 elaboration. This demonstrates that TGF-β1 induces an early wave of epithelial apoptosis that decreases with continuing TGF-β1 elaboration.
Within 2 d of the administration of dox, a prominent inflammatory response was noted. In BAL, this manifests as an increase in total cell and macrophage recovery. In the tissues, this effect was seen after 2 d and increased in intensity over 10 d. This response was largely due to an increase in macrophages. However, a modest increase in eosinophils could also be appreciated.
The induction of TGF-β1 caused an airway and parenchymal fibrotic response. On trichrome stains, this response could be appreciated after as little as 2 d of dox administration, predominantly in the subepithelial and adventitial regions of the airway. With longer periods of dox administration, this fibrotic response could be appreciated in the parenchyma. In accord with these findings, lung collagen content continued to increase over a 2-mo period of dox administration.
To determine if TGF-β1 caused alterations in myocytes and/or myofibroblasts, α-smooth muscle actin immunohistochemistry was undertaken. Within 10 d of dox administration, a prominent increase in α-smooth muscle actin (+) cells was appreciated. After 1 mo of dox administration, prominent increases in airway muscle mass could be appreciated. At all time points, transmission electron microscopy demonstrated that TGF-β1 increased the accumulation of myofibroblasts and true myocytes.
After prolonged periods of dox administration, alveolar remodeling could be readily appreciated. This response was patchy in nature and associated with alveolar septal thickening and areas of septal rupture. In many areas, it had the appearance of honeycomb lung. It was pronounced enough to be detected via morphometric assessments of chord length (the distance between alveolar walls). Increases in chord length could be appreciated after 7 d of dox administration and were most prominent with longer periods of TGF-β1 elaboration.
To begin to understand the mechanisms by which TGF-β1 induces this phenotype, Affymetrix gene chip analysis was performed using U74 sub A chips and lungs from transgene (+) mice and transgene (−) mice that received dox for 2 d, 5 d, or 1 mo. At each time point, we compared the gene expression in transgene (+) and transgene (−) animals using Gene Spring software (Agilent Inc., Palo Alto, CA). These studies demonstrated that over 2,251 genes and/or expressed sequence tags (ESTs) were altered by at least twofold at any time point. Clustering analysis demonstrated different patterns of regulation with genes that were consistently up-regulated, up-regulated early and then normalized, up-regulated only at the later time points, consistently down-regulated, and inhibited only at early time points. An analysis of these genes revealed a number of interesting findings vis-à-vis the phenotypes that were induced by TGF-β1. Prominent alterations in genes that control cell cycle and apoptosis, genes that induce tissue inflammation, genes that encode extracellular matrix and their synthetic enzymes, genes that encode proteases and antiproteases, genes that encode transcription factors, and genes that encode cytokines and growth factors and integrins were noted. Prominent examples include the up-regulation of proapoptotic molecules (e.g., caspase-7, Bid, and p53) and antiapoptotic molecules (e.g., A1, Bcl-3, p21, and 14-3-3 σ). TGF-β1 was also a potent stimulator of a variety of chemokines, including TARC/CCL17, small inducible cytokine A-2, small inducible cytokine A-9, and eotaxin/CCL11. In addition, the receptors for TARC/CCL17, CCR4, and CCR5 were up-regulated. This provides a logical explanation for the macrophage-rich and eosinophil-rich inflammatory response that is induced by this cytokine. In accord with the fibrotic response that was induced in these animals, TGF-β1 was a potent stimulator of tenascin-C, elastin, fibrilin-1, fibronectin-1, laminin, lysyl oxidase, and a variety of procollagen moieties. In keeping with the patchy alveolar remodeling response, TGF-β1 also had complex effects on proteases and antiproteases with increases in a variety of MMPs (MMP-8, -9, and -12), calpain-1, and antiproteases (plasminogen activator inhibitor type I and tissue inhibitor of metalloproteinase 1). In addition, TGF-β1 was a potent stimulator of its own gene and a variety of other members of the TGF-β1 family, connective tissue growth factor, tumor necrosis factor, insulin-like growth factor 1, and tumor necrosis factor receptor 1. Prominent induction of early growth response gene (EGR)-1 and EGR-2 was noted when transcription factors were analyzed.
To ensure that the results of our gene chip experiments accurately reflected tissue events, confirmatory experiments were performed using a variety of approaches, including ribonuclease protection and real-time reverse transcriptase–polymerase chain reaction (RT-PCR) assays. Seventeen genes were chosen at random, including genes that were up-regulated, down-regulated, and not altered. In all cases, appropriate concordance was noted. These studies highlight the many pathways that are activated by TGF-β1 in this in vivo modeling system. They also provide insights into the mechanisms by which TGF-β1 may be inducing the exciting phenotype that has been noted.
EGR-1 is a potent transcriptional regulator of many of the genes that were altered in our gene chip and mRNA evaluations. We hypothesized that EGR-1 might play an important role in the pathogenesis of the TGF-β1 phenotype. To test this hypothesis, we first used RT-PCR and real-time PCR to define the regulation of EGR-1 in our transgenic system. These studies demonstrated that, after as little as 2 d of dox, increased levels of EGR-1 mRNA could be appreciated in RNA from transgene (+) mice. A similar result was seen with 1 wk of dox administration. EGR-2 and -3 were also induced. The role of EGR-1 was then defined by breeding EGR-1 (−/−) mice (a gift from Dr. T. Milbrandt) (46) and the TGF-β1 OE animals. Using the progeny of these crosses, we were able to compare the phenotypes induced by TGF-β1 in mice with (+/+) and (−/−) EGR-1 loci. The lungs from wild-type mice and transgene (−)/EGR-1(−/−) mice on normal water or dox were virtually identical. In contrast, the TGF-β1 phenotype was markedly altered in EGR-1 (−/−) animals. As previously reported (45), in the absence of EGR-1, the ability of TGF-β1 to stimulate cellular apoptosis was markedly diminished. In the absence of EGR-1, TGF-β1–induced fibrosis on trichrome evaluations, total lung collagen content and alveolar remodeling were also markedly ameliorated. These studies demonstrate that EGR-1 plays a central role in critical aspects of the in vivo TGF-β1 phenotype.
Our studies with EGR-1 null mutant mice demonstrated that an intervention that diminished TGF-β1–induced apoptosis also decreased the ability of TGF-β1 to induce fibrosis and alveolar remodeling. This led to the hypothesis that there is an intimate relationship between the apoptosis and the fibrotic and remodeling phenotypes, with the apoptosis being required to allow the latter phenotypes to be seen. To address this hypothesis, experiments were undertaken in which apoptosis was blocked via a different mechanism, and the effects of this intervention on fibrosis and alveolar remodeling were assessed. In these experiments, transgene (+) and transgene (−) mice were randomized to receive broad-spectrum caspase inhibitor Z-VAD-fmk (intraperitoneally) or vehicle control starting 24 h before the administration of dox. After 10 d of dox administration, the animals were killed, and phenotypic analysis was undertaken. Z-VAD was a potent inhibitor of TGF-β1–induced apoptosis. Z-VAD inhibition of apoptosis was also associated with a marked decrease in tissue fibrosis on trichrome and total lung collagen content evaluations and alveolar remodeling. Thus, in accord with what was noted with EGR-1 null mutant animals, an intervention that blocked apoptosis simultaneously decreased fibrosis and alveolar destruction. When viewed in combination, these studies support the hypothesis that TGF-β1–induced apoptosis is a critical event in the pathogenesis of TGF-β1–induced fibrosis and alveolar destruction. They also demonstrate that TGF-β1 can simultaneously induce injury (apoptosis) and fibrotic responses. One can easily envision how this capacity might work to debride a wound and, by removing marginally viable cells, allow the healing response to take place on a fully healthy wound base.
The reversibility of tissue fibrosis has critical consequences for the natural history of fibrotic pulmonary disorders. Unfortunately, our knowledge of the processes that control reversibility is marginal at best. This is due, in great extent, to the limited ability of the vast majority of animal models to appropriately allow the resolution phase of an injury and repair response to be evaluated. A unique feature of our inducible transgenic system is the clarity with which it allows this sort of analysis to be undertaken. Specifically, in these mice a transgene can be turned "on," and a phenotype can be engendered. The transgene can then be turned "off," and the natural history of the phenotype can be evaluated over time. To accomplish this in our transgenic system, TGF-β1 transgene (+) and transgene (−) mice were randomized to receive normal water or dox for 10 d. At the end of this interval, they were placed on normal water and analyzed at intervals thereafter. Dox administration to transgene (+) mice caused an increase in tissue fibrosis. After 1 mo on normal water, this fibrotic response had significantly decreased. These studies demonstrate that TGF-β1 induces a fibrotic response that is at least partially reversible when overexpressed in the murine lung.
These studies demonstrate that IL-13 is a potent stimulator of inflammation, remodeling, and fibrosis and highlight the important roles that the adenosine system, CCR-2–dependent inflammatory processes, VEGF, and IL-11 play in the generation of these responses (Figure 1). They also highlight the prominent role that TGF-β1 plays in this pathway and the ability of IL-13 to stimulate and activate TGF-β1 (Figure 1). Last, they demonstrate that TGF-β1 induces apoptosis and fibrosis and alveolar remodeling, highlight the role of EGR-1 in this apoptotic response, and demonstrate that TGF-β1–induced apoptosis as a critical prerequisite for its induction of fibrosis and alveolar simplification. Interventions can be envisioned in a number of locations in this pathway to control these important responses.
The authors thank the investigators and organizations that provided the reagents that were used in these studies and Ms. Kathleen Bertier for her administrative assistance.
Supported by National Institutes of Health grants HL-064242, HL-078744, HL-056389, HL-079328, and HL-081639 (J.A.E.).
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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subset: commoncrawl


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The progression of breast cancer is associated with mechanisms that inhibit the antitumor activity of immune system's natural killer (NK) cells, researchers claim.They found that both peripheral and tumor invasive NK cells in breast cancer patients demonstrate altered phenotype and function and that invasive tumors build strong inhibitory microenvironments to escape NK cell antitumor immunity.
The research group was led by a team at Inserm UMR U891 and the Institut Paoli-Calmette in Marseille. Reporting in The Journal of Clinical Investigation, Emilie Mamessier, Ph.D., Daniel Olive, Ph.D., and colleagues, state that their findings highlight the need to develop new breast cancer therapies designed to restore NK cell cytotoxicity to limit or prevent tumor escape from antitumor immunity. Their paper is titled "Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity."
NK cells carry both activating and inhibitory receptors that are triggered during target-cell recognition to respectively induce a positive or negative cell signaling pathway, the researchers explain. Previous research has suggested that breast cancer progression is linked to antitumor immunity efficiency, particularly in relation to NK cells. However, the researchers continue, the precise relationships between NK cells and breast cancer progression in humans has not been studied to date.
The main activating receptors or coreceptors of NK cells include NKG2D and the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, DNAM-1, CD2, NKp80, 2B4, and NTBA. CD16 is a low-affinity receptor that, when cross-linked induces antibody-dependent cellular cytotoxicity (ADCC). Inhibitory receptors include the killer immunoglobulin receptors (KIRs), NKG2A, CD85j, and LAIRs, which are specific for different HLA-class I molecules. This means NK cells should be effective against tumor cells such as breast cancer cells, which have lost or express only low amounts of HLA-class I molecules.
To investigate the relationship between breast cancer and NK cell activity or suppression, Drs. Mamessier, Olive et al. enrolled 121 breast cancer patients at different stages of disease. The patients' tumors were classified as nonvasive (in situ) BCs (Tis) or invasive BCs. Invasive BCs included localized (LOC), locally advanced (LA), and metastatic (M). Patients with benign mammary tumors and healthy donors were included as controls.
An initial evaluation of the expression of 22 different NK receptors on cells from fresh blood samples showed that a number of activating receptors including NKp30, NKG2D, DNAM-1, and 2B4 were downregulated in patients with invasive tumors compared with normal patients and those with Tis tumors. Conversely, the inhibitory receptors NKG2A and CD85j were upregulated in the M group compared with control groups and the Tis group. Analysis of expression data showed that the degree of receptor alteration clearly progressed with tumor stage, notably in the invasive tumors, which demonstrated clear underexpression of activating receptors and overexpression of inhibitory receptors in more advanced stages.
To assess whether receptor expression changes were associated with altered NK cell function, the team assessed the ability of peripheral blood NK (p-NK) cells to kill a target cell, effect degranulation, produce IFN-γ and TNF-α, and mediate ADCC. The results showed that effective killing and degranulation efficiency were altered in the invasive groups compared with the noninvasive groups, and IFN-γ and TNF-α levels were also reduced in the M group.
Interestingly, NK cells from the M group had lost their multifunctionality and either retained degranulating capability or IFN-γ or TNF-α production. NK cells from B and Tis patients were more efficient in mediating ADCC than NK cells from LOC and LA patients, corresponding with their different levels of CD16 expression. Unfortunately not enough p-NK cells from the M group could be obtained to evaluate their ability to mediate ADCC.
The researchers next moved on to evaluate tumor-infiltrating NK (Ti-NK) cells. To identify changes that were specifically tumor-induced rather than just tissue-specific, they compared Ti-NK cells isolated from different LOC and LA breast tumors, with paired p-NK cells and/or with tumor-free NK cells isolated from symmetric normal breast samples (Mt-NK cells).
Analyses suggested the Ti-NK cells were true activated NK cells, but they demonstrated increased expression of inhibitory receptors and decreased expression of activating receptors and cytotoxicity-related molecules when compared with p-NK cells and Mt-NK cells. This strongly suggested the activated Ti-NK cells had poor cytotoxic potential, the authors state.
Further analysis of the expression profiles of the different NK cells showed that while there was a similarity between the profiles of Mt-NK cells and p-NK cells, the Ti-NK cell profiles were heterogeneous. The exception to this was the profile of cells from a group of patients with poor prognosis. Ti-NK cells from these patients showed underexpression of nearly all NK cell receptors.
Ti-NK marker expression was further categorized into three groups according to type of marker. Group I comprised cytotoxic-related effectors, group II comprised receptors involved in NK cell activation, and group III was categorized as molecules related to NK cell maturation markers. When grouped in this way it became evident that downregulation of group I molecules was observed in all Ti-NK cells compared with Mt-NK and p-NK cells, suggesting an alteration induced by the tumor.
The next test was to assess whether compromised Ti-NK cells were still capable of carrying out a helper function. CD107 functional assays comparing paired Ti-NK and p-NK cells showed that Ti-NK cells were activated more slowly, had a decreased degranulation potential, displayed strong alterations of IFN-γ and TNF-α production, and were unable to mediate ADCC.
Having confirmed the compromised state of NK cells in cancer, the team turned to look at the expression of NK cell ligands on breast tumor cells. They found that breast tumors expressed heterogeneous levels of ligands for NK cell receptors, particularly with respect to HLA ligands and NKp30-ligand. Breast cancer cells also frequently expressed high levels of DHAM-1-L and NKG2D-L.
"Most importantly," the team continues, "we found deregulated transcriptional expression of NK cell ligands in a large set of breast cancers compared with healthy mammary tissues previously profiled using DNA microarrays, suggesting that an editing process was indeed involved."
The researchers went on to show that the tumor environment was at least in part responsible for the NK cell changes. Exposure of normal NK cells to tumor breast tumor supernatants induced changes in NK cell receptors that mirrored those observed on Ti-NK cells.
Moreover, when p-NK cells were exposed to the supernatants and then used in cytotoxic assays, there was a marked suppression of all NK cell functions, particularly IFN-γ secretion, compared with nonexposed p-NK cells. "These results suggest that soluble factors released by tumors (epithelial or stromal components) affect both NK cell phenotype and functions," they state.
Analysing tumor supernatant levels of soluble factors known to be increased in other cancers and to alter lymphocyte functions demonstrated a positive correlation with NKG2A expression but a negative correlation with molecules related to NK cell cytotoxicity, the researchers state. The highest negative correlations were obtained with TGF-β1 and PGE2, while TGF-β1 also displayed the highest correlation with the Nottingham Prognostic Index (NPI), showing that more aggressive breast tumors contain more TGF-β1-producing cells. In fact, blocking TGF-β1 in tumor supernatants partially restored NK cell functionality by about 20%.
As a final test to show that NK cell alterations are tumor induced, the researchers looked at the phenotypes of p-NK cells from former invasive breast cancer patients who had undergone surgery more than five years ago and had not relapsed since. The NK cells from these ex-patients expressed similar levels of Kp30, CD16, NKG2D, and NKG2A receptors as individuals with benign breast tumors. These receptors were respectively up- and downregulated compared with matched NK cells isolated from the breast cancer groups, "indicating that a normal NK cell phenotype was restored after tumor removal."
The overall results indicate that "invasive breast tumors induce self tolerance in NK cells, resulting in attenuated malignant cell immunogenicity and the creation of a multifaceted immunosuppressive microenvironment that blunts NK cells' cytotoxicity and prevents their final maturation process," the authors conclude.
The data suggests that at least four mechanisms are associated with the ability of invasive breast cancers to escape from NK cell antitumor immunity: the modulation of NK surface receptors associated with invasive tumor characteristics and a poor prognosis; changes in the protein and mRNA profiles of NK cell ligands on breast cancer cells; the reversitibility of Ti-NK cell alteration, which suggests that the tumor induces its own tolerance to NK cell antitumor activity; and the impact of the tumor microenvironment on the final maturation of NK cells in tissues.
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MDMA (commonly known as the empathogen "ecstasy") is classified as a Schedule 1 drug, which is reserved for compounds with no accepted medical use and a high abuse potential. Two researchers from Stanford, however, call for a rigorous scientific exploration of MDMA's effects to identify precisely how the drug works, the data from which could be used to develop therapeutic compounds.Do you agree that ecstasy should be studied for its potential therapeutic benefits?
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Guide to Computer Forensics and Investigations Paperback – Sep 3 2003
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About the Author
Amelia Phillips is a graduate of the Massachusetts Institute of Technology and has worked for more than 30 years in government, private industry, and academics. She has designed distance education classes and e-commerce, computer forensics, and network security programs at several community colleges. Amelia is Chair of the Pure and Applied Science Division at Highline Community College, a Fulbright Scholar, and a recent PhD in computer security.
Bill Nelson has been a computer forensics examiner for a Fortune 50 company for the past 12 years and has developed high-tech investigation programs for professional organizations and colleges. His previous experience includes AFIS software engineering and reserve police work.
Frank Enfinger, from Suquamish, Washington, is a tenured faculty member at North Seattle Community College and a Computer Forensics Specialist with a local police department. He holds a degree in Computer Science.
Christopher Steuart is one of the founders and the staff attorney for IT Forensics.com. Previously, he was an information systems security specialist for a Fortune 50 company and the United States government. Chris resides in Seattle, Washington.
Customer Reviews
Top Customer Reviews
The information regarding digital signatures is incorrect. Much of the information regarding partitions is incorrect. The information in regards to boot structures and MACS is scant, and what is there has been copied from existing web pages. Only enough information on NT and the MFT to confuse and confound.
The exercises are hard to follow, and even suggest using a different operating system if they do not work. The examiner cannot switch the operating system on the drive being examined - this is ridiculous.
The book is written with the primary audience of law enforcement. If a law enforcement officer were to have this book as their only education in computer forensics, their testimony would never stand up. I truly doubt that the material covered is sufficient to allow one to pass the IACIS certification.
A competent forensic examiner would not use this book other than as a reference for using DriveSpy.
p. 11: "Until 1993, the laws defining computer crimes did not exist. To this day, many have yet to be tested in court." HUH????? The fed.s proposed the first one in 1977, Florida and Arizona passed the first two computer crime statutes in 1978, and the feds finally got theirs through (18 USC 1029 & 1030) in 1986.
In another place, they talk about commmercial forensics software only being available recently, which ignores the decades of work done by experts using Norton's DiskEdit (still in use today). They barely mention Dan Mares, who wrote some of the first forensics tools, and is still doing so.
They don't really explain what their relationship is with a particular vendor whose software and hardware products are covered in detail.... and their description of the IACIS certification process is out of date. IACIS (an organization to which I belong and from which I received my computer forensics certification) has not endorsed this book.
It covers boot structures, forensic tools, evidence reporting, and all the way to being an expert witness.
I also use this book to teach a condensed version of the subject at Cal State Fullerton Extended Education.
Hope this info help!
Most recent customer reviews
As a new examiner, I found this book somewhat useful, but I thought the book was edited horribly. It looks to me as though the publisher hired an English major to edit a Computer... Read morePublished on May 19 2004 by Jim
The majority of exercises do not work. I found myself having to create exercises for my students to follow so I switched books. Read morePublished on April 22 2004
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text: Posted May 29, 2014 BvB have signed Ciro Immobile who was the Serie A top scorer for €19.5m. What a steal considering he is only 24 and they have done a good job replacing Lewa by acquiring Adrian Ramos as well. Sent from my iPhone using CarolinaHuddle Giroud was top scorer in League 1 and Arsenal got him for £10m. I tho it was a steal too. Share this post Link to post Share on other sites


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Chihuahuas in a cage
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at Snapchat (View all jobs) Los Angeles, CA Over 100 million people use Snapchat every day to Snap with family, watch Stories from friends, see events from around the world, and explore expertly-curated content from top publishers. In short, we are a passionate team working hard6/27/2016 Los Angeles, CA Save This Job
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Salvation Army Soldier Wins Miss Congeniality!
Monday, March 26, 2012
The following was contributed by guest blogger Teresa Engel, Director of Communications and Marketing at The Salvation Army Portland Metro – Cascade Divisional Headquarters.
Several thrift store outfits made a flashy comeback on Saturday, March 10th when Mrs. Lauralee Balash, Mrs. Portland 2012, who is a soldier and a volunteer leader at The Salvation Army Portland Tabernacle, competed for the title wearing outfits she found at her local Salvation Army Family Store.


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I've seen a lot of mocks with both Spiller and McClain both there at #13.
Honestly, I am completely on the fence on this one. I would love to have Willis and McClain in the middle (historically-special LB Corps), but I do NOT want to see Spiller in Seattle.
I would personally take Spiller and hope McClain falls.


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Rupee Surges to One-Month High After Fed; Bonds Rally
India's rupee surged to the highest level in more than a month after the U.S. Federal Reserve unexpectedly refrained from cutting stimulus that has buoyed emerging-market assets. Bonds and stocks rallied.
The Federal Open Market Committee said yesterday it wants to see more evidence of a recovery in the world's largest economy before tapering monthly bond purchases of $85 billion. Economists surveyed by Bloomberg had forecast a reduction of $5 billion. The FOMC is concerned the rapid tightening of financial conditions in recent months could damp growth, Fed Chairman Ben S. Bernanke said at a press conference in Washington.
"The surprising Fed decision is naturally supportive of risk appetite in emerging markets" and "the effect on the current account-deficit countries could be larger," Koon Chow, head of emerging-market strategy at Barclays Plc in London, wrote in an e-mailed note. "As their currencies rally, some of the priced-in expectations of aggressive monetary tightening may be unwound as well, with local bonds enjoying a lift."
The rupee climbed 2.6 percent to 61.7750 per dollar in Mumbai, the strongest level since Aug. 16, according to prices from local banks compiled by Bloomberg. It rose as high as 61.6450 intraday.
The yield on the 7.16 percent Indian sovereign notes due May 2023 slumped 18 basis points, or 0.18 percentage point, to 8.19 percent, according to the central bank's trading system. That's the lowest level since Aug. 8. The 30-stock S&P BSE Sensex of local shares soared 3.4 percent to 20,646.64, its highest close since November 2010, with lenders leading the advance.
Fed Outlook
The Fed left unchanged its outlook that its target interest rate will remain near zero "at least as long as" unemployment exceeds 6.5 percent, so long as the outlook for inflation is no higher than 2.5 percent, according to a statement. The U.S. will release jobless claims and existing home sales reports later today.
Overseas funds have reduced holdings of Indian debt by more than $10 billion since May 22, when Bernanke first flagged a potential paring of asset purchases.
The Reserve Bank of India will review policy tomorrow after government data this week showed wholesale-price inflation unexpectedly rose to a six-month high of 6.1 percent in August. Governor Raghuram Rajan will leave the benchmark repurchase rate unchanged at 7.25 percent, according to all 36 economists surveyed by Bloomberg.
'Breathing Space'
"There is likely to be some positive outcome for the rupee" from the Fed's decision, which "provides some breathing space for domestic policy makers to address the key issues of current-account deficit and fiscal," Kotak Mahindra Bank Ltd. economists including Madhavi Arora wrote in a note. "The RBI will likely use the space provided to strengthen its forex position and keep the lid on the depreciation pressure by maintaining status quo on interest rates."
One-month implied volatility in the rupee, a measure of expected moves in the exchange rate used to price options, slumped 192 basis points to 17.73 percent, the most since Sept. 10, data compiled by Bloomberg show. The rate surged 214 basis points in the past two days, the biggest such advance since Aug. 28, when the currency sank to a record 68.845 to a dollar.
Three-month onshore rupee forwards jumped 2.2 percent to 63.43 per dollar, data compiled by Bloomberg show. Offshore non-deliverable contracts climbed 2.6 percent to 63.52. Forwards are agreements to buy or sell assets at a set price and date. Non-deliverable contracts are settled in dollars.


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[edit] Background
This game is the sequel to Critical Mass and Chain Reaction. Duke, after discovering the future, came back to the present for fixing things and change what he saw. Unfortunately for him, his mission went wrong, sending him in a new trip in time. The problem is that Duke will land during World War II. Will Duke change History?


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Jawbone UP and Airbnb iOS apps get all new features, revamped designsA pair of app updates on Wednesday brought new wellness tracking tools and a refreshed look to Jawbone's UP fitness system, while community-rooted travel marketplace Airbnb received a more comprehensive makeover complete with rebranding.
Jawbone UP
With its UP and UP24 wrist-worn wearables, Jawbone is a major player in the trend toward harvesting and processing so-called "quantified self" data. A new update to the UP by Jawbone app features a tweaked user interface to support new data tools for weight management and food intake.
With the new software, users now have the ability to set goals for weight and calorie intake. The revamped UI allows quick logging of logging of food, entire meals and a breakout category for water consumption. Data is laid out in a graphical chart format
Jawbone has also built out its database of restaurant menus and common food pairings, to which users can add customized frequent meals. In addition, a new "Food Score" feature assigns a single number to a dish based on its healthiness.
Combined with the UP or UP24 wristband, both of which track activity throughout the day, Jawbone's app is able to keep tabs on a user's health metrics with minimal interaction.
UP by Jawbone is a free 72.3MB app that requires either the UP or UP24 wristband to access all features.
While much of the hype surrounding Airbnb's new rebranding effort has focused on a new abstractly sexual logo, the redesigned app and website are perhaps more worthy of attention.
The community-based short-term accommodation marketplace refreshed its app design to include larger photos, a "flatter" user interface in line with iOS 7 and easy-to-read fonts. A new feature called "Discover" lets users filter rent-ready spaces by theme and specific locations.
Airbnb's usual tools for listing and reserving places to stay are still present in the update, as are information boxes about a location's surroundings. Renters can also access host profiles from an accommodation's main page.
Aside from the app and Web redesign, Airbnb is also allowing hosts and travelers to riff on the new logo — dubbed "Belo" — with a free 28.9MB download from the App Store.
On Topic: App Store
- Apple's iOS App Store now generating 4x revenues per app vs Android Google Play
- Pixelmator image editor gets powerful selection tools in iOS app update
- Pokemon Go update fixes login problems, sponsored game content coming soon
- European expansion of Pokemon Go commences with launch in Germany
- Pokemon GO is earning Apple's App Store 3x as much money as Nintendo


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I know what nightmare means,it is bad dream during sleeping.I would like know how we experience it. Do we see it, my sentence make sense?
Last night I've seen very bad nightmare.
I know what nightmare means,it is bad dream during sleeping.I would like know how we experience it. Do we see it, my sentence make sense?
It may sound boring, but the verb we most often associate with nightmare is simply have.
You can see the prevalence of this usage in this Ngram.
This other Ngram shows the most common words that are put in front of "a nightmare." Most are prepositions; the top verbs are had and was. I'm guessing most of those uses of was are probably more figurative usages of the word, such as:
You might say you "saw something in a dream", or a nightmare. But when speaking about just generally experiencing it, you would say you "had a bad dream" or "had a nightmare".
You would not say "Last night I saw a bad dream", nor "Last night I saw a nightmare" when referring to the experience of dreaming.
The only way you would say "Last night I saw a nightmare" would be if you were speaking figuratively--that while awake, you'd seen something that was very bad--as if it were from a nightmare.
You 'see' nightmares and dreams because a dream (or a nightmare) is like a movie, played by our sub-conscience. So yes, we "see" dreams and nightmares. I'm not an expert on that, however, I can help you with the sentence construction. I'm afraid your sentence is incorrect, try:
Also, 'nightmares' are negative dreams. So you don't have to mention 'bad' along with it. It becomes redundant. Optionally, you could also say:
But when we talk about dreams and nightmares, you generally use "had".
As Martin Luther Kings said: "I have a dream.." and not "I see a dream.."
One thing missing from the answers is the point that "seeing" implies perception with one's eyes. Since phenomena such as dreams, visions, hallucinations and nightmares are perceived with the mind's "eye" (a misleadingly corporealized abstraction), "seeing" does not apply.
That said, a sentence like "I see nightmares in my waking life." is perfectly valid (syntactically and semantically), however, as someone above mentioned, that usage of "nightmare" is figurative and the implication is that you see (with your eyes) material things/scenes that have a nightmarish quality. So the rule still holds.
On rereading the above answers, I realize that Varun KN was alluding to this point but didn't quite get there.
You can't say you saw a dream or a nightmare but could suggest that the dream had a visual element by saying
Here is the definition I am thinking of:
In proper English:
I know what the word "nightmare" means ... it is a bad dream. [Dreams occur while sleeping, so there's no need to mention that.] I would like to know how to refer to the experience: Do we see it? Does that sentence make sense?
Answer: In English, we talk about having experiences. we have dreams and nightmares, accidents, lucky breaks, epiphanies, realizations, etc. We talk about seeing the content of dreams and nightmares, e.g., "I had a nightmare in which I saw monsters eating people alive."
A nightmare is more than visuals. It's an experience, as you say. Therefore, besides the already mentioned
you can also say
A number of words fit in this category, e.g. endure can also be used here.


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I'm interested in software tool, which can fill up my database based on parameters with some random data.
Doesn't matter if it is something based on desktop application, online tool
What it should fulfill:
- Filling models based on HABTM, hasMany, belongsTo, ... relations
- Accept MAX and MIN values for number types
- Accept number of generated items in specific models
- Multi-platform (if desktop-application it means written in Java or some script language)
- Testing design (layouts filled with long texts)
- Testing performance of Application/API/Server-Side
- Testing data-type security, allocations, ...
- ...
Is there anything usable in moment? I'm not able to find anything


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Beach hotels in Hastings
Search for Beach hotels in Hastings
Trending now in Hastings
- Most bookedRadisson Aquatica Resort Barbados
275 people looked at this hotel in the last hour
Most recent review
"Excellent customer service ( front desk staff, restaurant staff, and housekeeping as well)!!! Great hotel at great price. Would stay here again."
A Traveller, Jun 2016, US
219 people looked at this hotel in the last hour
Most recent review
"Check in at the hotel was a little slow but assume that was because everyone arrived from the same flight around the same time. Other than that, hotel was very nice, it was clean, room was nice and beach area also very nice. The food was a little pricey for my taste but I'm also use to an all-i..."
M, Jun 2016, US
187 people looked at this hotel in the last hour
Most recent review
"Stayed 4 days/3 nights in early June. Hotel staff was very accommodating, polite and responsive. Was our first stay in Barbados but we thought the location of Accra was really good - walking distance to some fantastic restaurants, handy little store in the mall across the street, etc."
C, Jun 2016, US
100 people looked at this hotel in the last hour
Most recent review
"The property here is amazing. The location to crane beach is unbeatable. The staff is so friendly and welcoming. Rooms are spacious, AC works great, and bathrooms are big. The restaurants at the property are ok, surprisingly we thought the Italian restaurant had the better food. The room service ..."
A Traveller, Jun 2016, US
71 people looked at this hotel in the last hour
Most recent review
"Though I just had a one night stopover, in transit, I received a very warm welcome from the staff and a very pleasant room. It was on the top floor, with wonderful sea views overlooking the lovely beach. The room was well equipped and very clean. It also featured a large modern bathroom, fridg..."
M, Jun 2016, CA
68 people looked at this hotel in the last hour
Most recent review
"We knew there would be renovation noise when we booked so I won't complain about the noise....will be even better when the work is completed. Decent pool and sun lounging area. The main beach is which is larger is very close but the small secluded beach was fine for paddling to cool down. Staff..."
A Traveller, Jun 2016, GB
51 people looked at this hotel in the last hour
Most recent review
"Overall all went well. The room was surprisingly comfortable and the swimming pool was amazingly clean and warm. The food side would be my only criticism if I really had one. Also no tea making facilities in the rooms. Remember we are British and we love our tea. There was a problem with receptio..."
A Traveller, Sep 2015, GB
50 people looked at this hotel in the last hour
Most recent review
"Handy for the airport. We stayed on way to and from Dominica. Nice rooms and pool area. Restaurant a little pricey but good quality food and great service. Banana pancakes are a must!"
A Traveller, Jun 2016, GB
39 people looked at this hotel in the last hour
Most recent review
"I stayed there May 12th - 15th 2016. Amazing location in the heart of the night life, this hotel is located on the beach so each morning as you wake you can go for a swim. Food is delicious Caribbean flavor well seasoned. Staff treated us with utmost respect and was pleasant everyday. "
A Traveller, May 2016, US
38 people looked at this hotel in the last hour
Most recent review
"Easy access to all that is needed for an enjoyable vacation. "
A Traveller, May 2016, US
Explore Hastings
Looking to enjoy a bit of sun and surf in Hastings, stay at a great hotel, and earn free nights while you're at it? Well, we're here to do our best to help.
Hotels.com has 10 Hastings beach hotels for you to compare and find the perfect mix of price, amenities, and location. With prices starting at just $75/night, we try to make it as easy as possible to work within any budget on beaches across Barbados.
So how popular are beach hotels in Hastings right now? In the last hour, we've had 5 bookings. The most popular choices were:
1. Sugar Bay Barbados - All Inclusive
2. The Soco Hotel - All Inclusive
3. South Beach Hotel
4. South Ocean Villa 402
5. Accra Beach Hotel & Spa
We highly recommend booking now, so you can make sure we can get you the best room available!
When is the best time to go to the beach?
Obviously, the busiest times to hit the beach are going to be major holidays and weekends - especially in between Memorial Day and Labor Day. So if you're looking to save a few bucks (or just avoid the crowds!), your best bet is going to be a weekday or an off-peak time. As a general rule, September is a great time to plan a beach getaway if you're able - most kids are back in school and the weather and water are both still warm enough to make sure you're getting the full sun and sand experience.
How do I find the best beach hotel for me in Hastings?
We try to offer as many ways as possible to help you find the perfect room. First, you can take a quick look at our Top 10 Trending Beach Hotels in Hastings to the right. These are great option if you're in a hurry and just looking for a popular location.
Another great way to narrow your search is to use our search tool to filter by amenity, location, star-rating, etc. After you narrow down your list based on your particular needs, take the time to use the reviews provided by our hotel guests. These are people that have actually stayed in Hastings so be sure to use their experiences to determine if the room you're considering is right for you (not only do we use our customer's hotel reviews, we also use Expedia's and TripAdvisor's!).
We also try to show off our hotel partners that are doing a great job for our customers, so be sure to check out the beach hotels that our verified guests have rated as the best in Hastings for:
1. Cleanliness: Sugar Bay Barbados - All Inclusive
2. Service: South Ocean Villa 402
3. Comfort: Sugar Bay Barbados - All Inclusive
4. Condition: Sugar Bay Barbados - All Inclusive
And as always, at Hotels.com we strive to make it as easy as possible to save money on every booking. We offer our Best Price Guarantee on most bookings. Plus we offer 3 more ways to save:
1. Hotels.com Rewards - Stay 10 nights, get 1 free*
2. Hotels.com Deals & Discounts - Search over 10,000 deals!
3. Hotels.com promo codes - All our official coupon and discount codes in one place.


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|"Vinod Kumar Vavilapalli (JIRA)" <j...@apache.org>
|[jira] Updated: (HADOOP-2775) [HOD] Put in place unit test framework for HOD
|Wed, 13 Feb 2008 05:04:07 GMT
[ https://issues.apache.org/jira/browse/HADOOP-2775?page=com.atlassian.jira.plugin.system.issuetabpanels:all-tabpanel ] Vinod Kumar Vavilapalli updated HADOOP-2775: -------------------------------------------- Attachment: patch_unittesting.1 Reattaching. Including license headers in each file. > [HOD] Put in place unit test framework for HOD > ---------------------------------------------- > > Key: HADOOP-2775 > URL: https://issues.apache.org/jira/browse/HADOOP-2775 > Project: Hadoop Core > Issue Type: Test > Components: contrib/hod > Affects Versions: 0.16.0 > Reporter: Hemanth Yamijala > Assignee: Vinod Kumar Vavilapalli > Fix For: 0.17.0 > > Attachments: patch_unittesting, patch_unittesting.1 > > > HOD does not have any unit tests in place currently. This issue is to decide on a framework that would be effective for our python code base. Something on the lines of pyUnit would be good. The fix should put in place any dependencies needed for running the tests, and should also define some tests that demonstrate how to write further tests. We would not be defining a complete unit test suite for the entire code base right now, but would incrementatlly add tests as changes are made. -- This message is automatically generated by JIRA. - You can reply to this email to add a comment to the issue online.
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Allure of the Seas Cruise Review by ejt2011: Allure of the Seas Review
Overall Member Rating
Allure of the Seas Review
Destination: Western Caribbean
Embarkation: Fort Lauderdale (Port Everglades)
Just recently finished our sailing with Allure of the Seas for the October 16th 2011 sailing. Here is my review being as objective as possible:
- Food in main dining room was of low quality. Lackluster dish presentation, bland tasting food, and limited menu. We ended up tired of going there and skipped the same at the end.
- Food in specialty restaurants were of great quality, great presentation, and very tasty, especially Chops Grille! Highly recommended. If you have the money I would skip the main dining all together.
- Having sailed in other cruises, including other RC ships, we found most shows to be boring. Chicago though was very good.
- Although the Cruise had several entertainment options and activities, we found these completely lacking, especially for a ship that spends 3 days at sea. One does really get bored. Being a couple in their 30's and early 40's, we found most activities and entertainment targeted to an older population, specifically american, More for a ship carrying such a culturally diverse crowd. For a ship with so many bars were one would expect a lively nightlife, these were dead most of the time. Our sailing unfortunately was filled with rainy days and many cancelled outdoor activities. Although we understand that weather is unexpected, there should have been a plan B for indoor entertainment.
- Not all was dissapointing, beautiful cruise ship, so many different places to be and see, excellent ambience, Central Park is beautiful, Promenade is awesome.
In sum, beautiful ship with lots of potential to correct the flaws. But so far not worth the higher premium. Never feels cramped until you need help or get in an elevator. Less
Published 10/20/11
Read more Allure of the Seas cruise reviews >>
Read Cruise Critic's Allure of the Seas Review >>
Cabin review: D5 Superior Ocean View Stateroom with Balcony
Read All Superior Ocean View Stateroom with Balcony (D5) Reviews >>
NCL is not for us.
Overall Good Time
Worse Cruise Ever
RCI comes off as only caring a...
Great for Teenagers; Didn't li...
Too Much that Is Not Good (Dir...
Very new experience for old sa...
Great Cruise
The captain did an excellent j...
Short Cruise on a Small ship, ...
Great for a First Time
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Hi, Very nive macro. I also interesting in butterfly. Do yoy remember which lens you used and what was the f stop. Ercan
Hello my dear friends!
Thank you your visit, and your kind comments.
I am glad that you like my photograph.
Best wishes from Germany, Christian.
Photo taken in Bergheim, Germany


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- Port of Dover advice for customers this weekend
- Traffic Update
- Car wrecks, water rescues and chemical spills
- Union Street Swing Bridge Reopened
- Plain sailing for the Port of Dover Community Regatta
- Port of Dover Statement - Last Weekend's Travel Situation
- UPDATE: Port of Dover - French Border Control
- Dover Western Docks Revival project achieves sustainability excellence award
- Goodwin Sands Marine Licence Application Open Meeting
- Open Letter from Port Chief Executive
- Infrastructure investment crucial for UK #economy & increasing #employment #GoodwinSands marine licence application https://t.co/8Ee8SveSQZ
- #DoverWesternDocksRevival central to UK #economy = 17% of #British trade: #GoodwinSands #marine licence application https://t.co/8Ee8SveSQZ
- Please follow @PoD_travelnews for regular #travel updates.
- TRAVEL UPDATE Roads leading to #PortofDover are clear & there are no queues in the #port. Please follow @PoD_travelnews for regular updates.
- Find out what @wildlifetrusts are doing around the coast this #nationalmarineweek https://t.co/L1cF1TiBQh https://t.co/tZVLvrJOqF
Welcome to the Port of Dover
Originally established in 1606, the principal activities of the Dover Harbour Board (DHB) are to administer and maintain the Port of Dover and its facilities and to develop resources to meet future demands.
The Port of Dover is Europe's busiest ferry port, a vital international gateway for the movement of passengers and trade. It is also an award-winning cruise port, the second busiest in the UK and hosts some of the world's most prestigious cruise lines. Other successful businesses include a cargo terminal, a top award-winning marina and several niche activities. The business mix is diverse.
Who Are We?
29th Jul 2016
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Goodwin Sands Aggregate Dredging Environmental Statement: Volume I , Volume II , Volume III and the Marine Licence Application .
QUITE SIMPLY: The commitment is to be the Best Port in the World for the benefit of our customers and community


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Laura Govan Against "Hoes"
We found out from our interview with Shaunie O' Neal that the Govan sisters weren't returning to "Basketball Wives LA." We thought it was because the Govan's constantly butt heads with producer Shaunie O' Neal, but Laura says it's because VH1 added "hoes" to the cast, ie: Draya.
Well Draya responded and thinks Laura is a little bitter because she is no longer on the show, which is being shot as we read. We agree. Laura have a seat.
The Best Celeb Style Moments Of The Week [9-25 to 10-02]
16 photos Launch gallery


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I dunno, seems like a lesser number of players with a balanced loadout and using teamwork could take out more than their number of wheeled shotgunners, but those grenades seem like the cincher. I didn't realize grenades caused an AOE disorient effect. At the very least you can knock out all the enemy bases so that their teammates couldn't simply mop them up.
A good commander really helps too. I could usually identify the base being used by looking at movement speed and patterns.
When I played comm I tended to be very specific in how I vectored my teammates, it was quite fun to hear how the game was unfolding. Making sure to keep my teammates near cover so they could quickly retreat while reinforcements were vectored in around the sides.
One big problem with the Commander map system was that the maps didn't provide enough terrain information, especially height information. It just displayed impassable areas, so I didn't know if my guys were fighting uphill or downhill.
I suspect I'll be buying Chromehounds 2 if they're smart enough to fix all of its problems and add more teamwork oriented parts. I was hoping for things like NA contact relays, or NA extenders, or even a waypoint system that can be used in game to direct units.


text:
BATON ROUGE -- The LSU men's basketball team looks to rebound from Thursday night's setback at Georgia when the Tigers host Auburn, Saturday afternoon in a 3 p.m. matinee game at the Pete Maravich Assembly Center.
Click here for the original story.
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Email this article from PlasticsNews.com
Schulman may boost its bid for Ferro
AKRON, OHIO — A. Schulman Inc.'s bid for Ferro Corp. is featured in this week's Material Insights video. Also featured this week are the fines and settlements surrounding Dow Chemical Co., as well as a prediction of higher growth for the biopolymers markets.
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The Beautiful Homes Of America's Tech Titans
After learning of Steve Jobs' soon-to-be demolished historic home, and Mark Zuckerberg's life as a month-to-month renter, we decided to see what other types of real estate today's tech titans like to call home.
Here's where some of the biggest (and richest) tech-industry moguls take a break from their web-ruled world and turn to a place they call home.
Read the original article on Zillow. Copyright 2010. Follow Zillow on Twitter.
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