Miracle-dz/UniFAR-FTUs huggingface dataset:
Ecto-5′-Nucleotidase (CD73) Attenuates Allograft Airway Rejection through Adenosine 2A Receptor Stimulation

There are multiple drivers of leukocyte recruitment in lung allografts that contribute to lymphocytic bronchitis (LB) and bronchiolitis obliterans (BO). The innate mechanisms driving (or inhibiting) leukocyte trafficking to allografts remain incompletely understood. This study tested the hypothesis that CD73 (ecto-5′nucleotidase), an enzyme that catalyzes the conversion of AMP to adenosine, is a critical negative regulator of LB and BO. Implantation of tracheal allografts from wild type (WT) mice into CD73−/− recipients revealed a striking increase in airway luminal obliteration at 7 d (62 ± 4% and 47 ± 5% for CD73−/− and WT allograft recipients, respectively; p = 0.046). There was also a concordant increase in CD3+ lymphocytic infiltration (523 ± 41 cells and 313 ± 43 cells for CD73−/− and WT allograft recipients, respectively; p = 0.013). Because real-time PCR revealed a 43-fold upregulation of mRNA for the adenosine A2A receptor (A2AR) in WT allografts compared with WT isografts (p = 0.032), additional experiments were performed to determine whether the protective effect of CD73 was due to generation of adenosine and its stimulation of the A2AR. Treatment of WT recipients with an A2AR agonist significantly reduced CD3+ lymphocyte infiltration and airway luminal obliteration; similar treatment of CD73−/− recipients rescued them from LB and airway obliteration. These data implicate CD73 acting through adenosine generation and its stimulation of the A2AR as a critical negative modulator of lymphocyte recruitment into airway allografts. The CD73/adenosine axis might be a new therapeutic target to prevent BO.
SP1-Dependent Induction of CD39 Facilitates Hepatic Ischemic Preconditioning

Ischemia/reperfusion injury (IRI) of the liver is an important cause of hepatic dysfunction. Ischemic preconditioning (IP) is associated with adenosine-mediated tissue protection from subsequent IRI. Extracellular nucleotides (e.g., ATP) represent the main source for extracellular adenosine. Therefore, we hypothesized that phosphohydrolysis of ATP/ADP via the ectonucleoside triphosphate diphosphohydrolase-1 (CD39), conversion of ATP/ADP to AMP, mediates IP-dependent liver protection. We found that hepatic IP was associated with significant induction of CD39 transcript, heightened protein expression, and improved outcomes after IRI. Targeted gene deletion or pharmacological inhibition of CD39 abolished hepatoprotection by IP as measured by serum markers of liver injury or histology. Therapeutic studies to mimic IP with i.p. apyrase (a soluble ectonucleoside triphosphate diphosphohydrolase, NTPDase) in the absence of IP attenuated hepatic injury after IRI. In additional in vivo studies, small interfering RNA treatment was used to achieve repression of the transcription factor Sp1, known to be implicated in CD39 transcriptional regulation. In fact, Sp1 small interfering RNA treatment was associated with attenuated CD39 induction and increased hepatic injury in vivo. Our data suggest a Sp1-dependent regulatory pathway for CD39 during hepatic IP. These studies reveal a novel role of CD39 in hepatic protection and suggest soluble apyrase for the treatment of liver ischemia.
Knowledge management with focus on the innovation process in collaborative networking companies

Knowledge lies at the very heart of innovation. A company's ability to create, store and transfer knowledge about technologies, customer needs and the innovation process itself may well determine success in bringing new products or services to the market. Yet, little is known as to how companies treat these issues in practice. This paper presents the results of a research project assessing practices and challenges for innovation-oriented knowledge management within four global technology-based companies in Switzerland. Results are discussed from both company-internal and external network perspectives. For company-internal knowledge management, broad differences in terms of both practices and challenges were found between the companies mainly because of different ways of implementing the innovation process and very different company cultures. Common issues included poor implementation of post-project reviews as well as a need for better integrating market and customer knowledge into all stages of the innovation process. For the external perspective, a more homogenous picture emerged where companies network with different partners throughout the innovation process and where knowledge creation and transfer were substantially greater for long-term partnerships.
Myeloid PTEN Promotes Inflammation but Impairs Bactericidal Activities during Murine Pneumococcal Pneumonia

Phosphatidylinositol 3-kinase has been described as an essential signaling component involved in the chemotactic cell influx that is required to eliminate pathogens. At the same time, PI3K was reported to modulate the immune response, thus limiting the magnitude of acute inflammation. The precise role of the PI3K pathway and its endogenous antagonist phosphatase and tensin homolog deleted on chromosome 10 (PTEN) during clinically relevant bacterial infections is still poorly understood. Utilizing mice lacking myeloid cell-specific PTEN, we studied the impact of PTEN on the immune response to Streptococcus pneumoniae. Survival analysis disclosed that PTEN-deficient mice displayed less severe signs of disease and prolonged survival. The inflammatory response to S. pneumoniae was greatly reduced in macrophages in vitro and in vivo. Unexpectedly, neutrophil influx to the lungs was significantly impaired in animals lacking myeloid-cell PTEN, whereas the additional observation of improved phagocytosis by alveolar macrophages lacking PTEN ultimately resulted in unaltered lung CFUs following bacterial infection. Together, the absence of myeloid cell-associated PTEN and consecutively enhanced PI3K activity dampened pulmonary inflammation, reduced neutrophil influx, and augmented phagocytic properties of macrophages, which ultimately resulted in decreased tissue injury and improved survival during murine pneumococcal pneumonia.
CRBT customer churn prediction: can data mining techniques work?

Coloring Ring Back Tone (CRBT) is one of the most successful Value-added (VAD) services in China telecommunication operators. Under fierce competition conditions, CRBT customer churn has significantly decreased the profits of operators. Thus churn management has become a major focus to retain subscribers via satisfying their needs under resource constraints. One of the challenges is that churn prediction specific to this business is not available in existing literature. Through empirical evaluation, this study analyse the features of CRBT, compare various data mining techniques that can assign a 'propensity to churn' to each CRBT subscriber. The results indicate that our models can achieve satisfactory prediction effectiveness by using customer demographics, billing and service usage information. At the same time, we find some new symptoms different from existing telecom churn literature, and try to explain them, and point out which predictors are needed to intensively monitor by telecom operators.
Physical exercise and psychological health of rural left-behind children: An experiment from China

Background How to promote the health (especially mental health) growth of left-behind children has become a hot social issue. Physical exercise is usually considered as a positive role in improving the physical and mental health of children, which can be considered to be integrated into the living environment of left-behind children. Objective To discuss the changes of left-behind children in psychological health before and after the exercise-based intervention, thus providing a practical approach to improve the psychological growth of this disadvantaged group. Methods An exercise-based social intervention experiment was designed and conducted in a township middle school in China, and 200 left-behind children with relatively low psychological health participated in the experiment. Results Physical exercise had positive effects on rural left-behind children’s sense of hope, self-esteem, self-efficiency, and self-concept, and it seems that the positive effects are durative due to the optimization of living environment. There was no significant difference in the psychological promotion effect of different programs (football and table tennis) on left-behind children. Hope, self-esteem, and self-efficiency significantly mediated the relationship between physical exercise and self-concept of left-behind children. Conclusion Physical exercise contributes to promoting the development of rural left-behind children’s positive psychology such as hope, self-esteem, self-efficiency, and thus relieving the negative psychology caused by long-term parental-child separation and improving self-concept.
Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1α, a transcriptional regulator of the immune response. Mclk1 encodes a mitochondrial protein that is necessary for ubiquinone biosynthesis. Heterozygote Mclk1+/− mutant mice are long-lived despite increased mitochondrial ROS and decreased energy metabolism. In this study, Mclk1+/− mutant mice in the C57BL/6J background displayed increased basal and induced expression of HIF-1α in liver and macrophages in association with elevated expression of inflammatory cytokines, in particular TNF-α. Mutant macrophages showed increased classical and decreased alternative activation, and mutant mice were hypersensitive to LPS. Consistent with these observations in vivo, knock-down of Mclk1 in murine RAW264.7 macrophage-like cells induced increased mitochondrial ROS as well as elevated expression of HIF-1α and secretion of TNF-α. We used an antioxidant peptide targeted to mitochondria to show that altered ROS metabolism is necessary for the enhanced expression of HIF-1α, which, in turn, is necessary for increased TNF-α secretion. These findings provide in vivo evidence for the action of mitochondrial ROS on HIF-1α activity and demonstrate that changes in mitochondrial function within physiologically tolerable limits modulate the immune response. Our results further suggest that altered immune function through a limited increase in HIF-1α expression can positively impact animal longevity.
International Conference on Computational Science , ICCS 2013 A tool for selecting the right target machine for Parallel Scientific Applications

Analyzing and predicting performance in parallel applications is a great challenge for scientific programmers due to its complexity. Analyzing parallel application behavior is not a trivial process and it requires spending a large amount of time and effort to understand the behavior of the application algorithms during execution. We have developed PAS2P toolkit from PAS2P methodology. This methodology strives to characterize the behavior of MPI applications to identify and extract representative phases and create a signature, which will be used to analyze the application behavior and predict its execution time in different target systems. Applying this methodology is a non-trivial process for users, for this reason we have developed the proposal toolkit, which allows users to make the whole process, from creating a signature to executing it on target systems, in user-space in an easy and fully automatic way. PAS2P toolkit has been validated, making clear the advantages of the signature, with its execution time being much lower than the whole application execution time (around 7% of the total execution time), with a high quality prediction of around 96%.
Mutational Analyses Reveal that the Staphylococcal Immune Evasion Molecule Sbi and Complement Receptor 2 (CR2) Share Overlapping Contact Residues on C3d: Implications for the Controversy Regarding the CR2/C3d Cocrystal Structure

We recently characterized an interaction between the Staphylococcus aureus immune evasion molecule Staphylococcus aureus binder of Ig (Sbi) and complement C3, an interaction mediated primarily through the binding of C3d(g) to Sbi domain IV. Events related to these studies prompted us to investigate via mutagenesis the binding interface of C3d for Sbi domain IV (Sbi-IV), as well as to revisit the controversial issue of the complement receptor 2 (CR2) binding site of C3d. Specifically, we had shown that Sbi domains III and IV fragment binding to C3dg inhibited the latter’s binding to CR2. Moreover, a published cocrystal structure of C3d bound to complement inhibitory C-terminal domain of extracellular fibrinogen-binding protein (Efb-C), a structural and functional homolog of Sbi-IV, showed Efb-C binding to a region on the concave face of C3d previously implicated in CR2 binding by our mutagenesis data but not confirmed in the CR2(short consensus repeat [SCR]1–2):C3d cocrystal structure. We have now analyzed by surface plasmon resonance the binding of a series of variant C3dg molecules to biosensor-bound Sbi-IV or CR2(SCR1–2). We found that mutations to the concave face acidic pocket of C3d significantly affected binding to both Sbi-IV and CR2, although there was divergence in which residues were most important in each case. By contrast, no binding defects were seen for mutations made to the sideface of C3d implicated from the cocrystal structure to be involved in binding CR2(SCR1–2). The results with Sbi-IV suggest a mode of binding highly similar to that visualized in the Efb-C:C3d complex. The results with CR2 confirm our earlier mapping studies and cast even further doubt on the physiologic relevance of the complex visualized in the C3d:CR2 cocrystal.
Inhibitor of NF-κB Kinases α and β Are Both Essential for High Mobility Group Box 1-Mediated Chemotaxis

Inhibitor of NF-κB kinases β (IKKβ) and α (IKKα) activate distinct NF-κB signaling modules. The IKKβ/canonical NF-κB pathway rapidly responds to stress-like conditions, whereas the IKKα/noncanonical pathway controls adaptive immunity. Moreover, IKKα can attenuate IKKβ-initiated inflammatory responses. High mobility group box 1 (HMGB1), a chromatin protein, is an extracellular signal of tissue damage-attracting cells in inflammation, tissue regeneration, and scar formation. We show that IKKα and IKKβ are each critically important for HMGB1-elicited chemotaxis of fibroblasts, macrophages, and neutrophils in vitro and neutrophils in vivo. By time-lapse microscopy we dissected different parameters of the HMGB1 migration response and found that IKKα and IKKβ are each essential to polarize cells toward HMGB1 and that each kinase also differentially affects cellular velocity in a time-dependent manner. In addition, HMGB1 modestly induces noncanonical IKKα-dependent p52 nuclear translocation and p52/RelB target gene expression. Akin to IKKα and IKKβ, p52 and RelB are also required for HMGB1 chemotaxis, and p52 is essential for cellular orientation toward an HMGB1 gradient. RAGE, a ubiquitously expressed HMGB1 receptor, is required for HMGB1 chemotaxis. Moreover, IKKβ, but not IKKα, is required for HMGB1 to induce RAGE mRNA, suggesting that RAGE is at least one IKKβ target involved in HMGB1 migration responses, and in accord with these results enforced RAGE expression rescues the HMGB1 migration defect of IKKβ, but not IKKα, null cells. Thus, proinflammatory HMGB1 chemotactic responses mechanistically require the differential collaboration of both IKK-dependent NF-κB signaling pathways.
Integrin αMβ2 Clustering Triggers Phosphorylation and Activation of Protein Kinase Cδ that Regulates Transcription Factor Foxp1 Expression in Monocytes

Integrins are type I membrane and heterodimeric (αβ) cell adhesion receptors. Intracellular signals triggered by ligand-bound integrins are important for cell growth, differentiation, and migration. Integrin αMβ2 plays key roles in myeloid cell adhesion, phagocytosis, and degranulation. In this study, we show that protein kinase C (PKC) δ is involved in αMβ2 signaling. In human monocytic U937 cells and peripheral blood monocytes, αMβ2 clustering induced PKCδ translocation to the plasma membrane, followed by Tyr311 phosphorylation and activation of PKCδ by the src family kinases Hck and Lyn. Interestingly, αMβ2-induced PKCδ Tyr311 phosphorylation was not mediated by the tyrosine kinase Syk, which is a well reported kinase in β2 integrin signaling. Analysis of the β2 cytoplasmic tail showed that the sequence Asn727-Ser734 is important in αMβ2-induced PKCδ Tyr311 phosphorylation. It has been shown that αMβ2 clustering regulates the expression the transcription factor Foxp1 that has a role in monocyte differentiation. We show that Foxp1 expression was reduced in monocytes that were allowed to adhere to human microvascular endothelial cells. However, the expression of Foxp1 was not affected in monocytes that were treated with PKCδ-targeting small interfering RNA, suggesting that PKCδ regulates Foxp1 expression. These results demonstrate a role of PKCδ in αMβ2-mediated Foxp1 regulation in monocytes.
Relative Over-Reactivity of Human versus Chimpanzee Lymphocytes: Implications for the Human Diseases Associated with Immune Activation

Although humans and chimpanzees share >99% identity in alignable protein sequences, they differ surprisingly in the incidence and severity of some common diseases. In general, humans infected with various viruses, such as HIV and hepatitis C virus, appear to develop stronger reactions and long-term complications. Humans also appear to suffer more from other diseases associated with over-reactivity of the adaptive immune system, such as asthma, psoriasis, and rheumatoid arthritis. In this study, we show that human T cells are more reactive than chimpanzee T cells to a wide variety of stimuli, including anti-TCR Abs of multiple isotypes, l-phytohemagglutin, Staphylococcus aureus superantigen, a superagonist anti-CD28 Ab, and in MLRs. We also extend this observation to B cells, again showing a human propensity to react more strongly to stimuli. Finally, we show a relative increase in activation markers and cytokine production in human lymphocytes in response to uridine-rich (viral-like) ssRNA. Thus, humans manifest a generalized lymphocyte over-reactivity relative to chimpanzees, a finding that is correlated with decreased levels of inhibitory sialic acid-recognizing Ig-superfamily lectins (Siglecs; particularly Siglec-5) on human T and B cells. Furthermore, Siglec-5 levels are upregulated by activation in chimpanzee but not human lymphocytes, and human T cell reactivity can be downmodulated by forced expression of Siglec-5. Thus, a key difference in the immune reactivity of chimp and human lymphocytes appears to be related to the differential expression of Siglec-5. Taken together, these data may help explain human propensities for diseases associated with excessive activation of the adaptive immune system.
Ethanol Upregulates Glucocorticoid-Induced Leucine Zipper Expression and Modulates Cellular Inflammatory Responses in Lung Epithelial Cells

Alcohol abuse is associated with immunosuppressive and infectious sequelae. Particularly, alcoholics are more susceptible to pulmonary infections. In this report, gene transcriptional profiles of primary human airway epithelial cells exposed to varying doses of alcohol (0, 50, and 100 mM) were obtained. Comparison of gene transcription levels in 0 mM alcohol treatments with those in 50 mM alcohol treatments resulted in 2 genes being upregulated and 16 genes downregulated by at least 2-fold. Moreover, 0 mM and 100 mM alcohol exposure led to the upregulation of 14 genes and downregulation of 157 genes. Among the upregulated genes, glucocorticoid-induced leucine zipper (GILZ) responded to alcohol in a dose-dependent manner. Moreover, GILZ protein levels also correlated with this transcriptional pattern. Lentiviral expression of GILZ small interfering RNA in human airway epithelial cells diminished the alcohol-induced upregulation, confirming that GILZ is indeed an alcohol-responsive gene. Gene silencing of GILZ in A549 cells resulted in secretion of significantly higher amounts of inflammatory cytokines in response to IL-1β stimulation. The GILZ-silenced cells were more resistant to alcohol-mediated suppression of cytokine secretion. Further data demonstrated that the glucocorticoid receptor is involved in the regulation of GILZ by alcohol. Because GILZ is a key glucocorticoid-responsive factor mediating the anti-inflammatory and immunosuppressive actions of steroids, we propose that similar signaling pathways may play a role in the anti-inflammatory and immunosuppressive effects of alcohol.
Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response to Francisella tularensis Live Vaccine Strain

An inadequate innate immune response appears to contribute to the virulence of Francisella tularensis following pulmonary infection. Studies in mice suggest that this poor response results from suppression of proinflammatory cytokine production early during infection, but the mechanisms involved are not understood. PI3K is known to regulate proinflammatory cytokine expression, but its exact role (positive versus negative) is controversial. We sought to clarify the role of PI3K in regulating proinflammatory signaling and cytokine production during infection with F. tularensis live vaccine strain (LVS). In this study, we demonstrate that the induction of TNF and IL-6 expression by LVS in mouse bone marrow-derived macrophages was markedly enhanced when PI3K activity was inhibited by either of the well-known chemical inhibitors, wortmannin or LY294002. The enhanced cytokine expression was accompanied by enhanced activation of p38 MAPK and ERK1/2, both of which were critical for LVS-induced expression of TNF and IL-6. LVS-induced MAPK activation and cytokine production were TLR2- and MyD88- dependent. PI3K/Akt activation was MyD88-dependent, but was surprisingly TLR2-independent. LVS infection also rapidly induced MAPK phosphatase-1 (MKP-1) expression; PI3K and TLR2 signaling were required. Peak levels of MKP-1 correlated closely with the decline in p38 MAPK and ERK1/2 phosphorylation. These data suggest that infection by LVS restrains the TLR2-triggered proinflammatory response via parallel activation of PI3K, leading to enhanced MKP-1 expression, accelerated deactivation of MAPKs, and suppression of proinflammatory cytokine production. This TLR2-independent inhibitory pathway may be an important mechanism by which Francisella suppresses the host’s innate immune response.