Miracle-dz/UniFAR-FTUs huggingface dataset:
Elucidation of the biochemical basis for a clinical drug–drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha

Abstract 1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778 875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778 875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778 875 (1.0 mg QD) on days 5–12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778 875. Subjects in group B (n = 29) received CP-778 875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5–12. 3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778 875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778 875. CP-778 875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4. Inhibition of organic anion transporting polypeptide 1B1 by CP-778 875 (IC50 = 2.14 ±0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778 875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.
Re-evaluation of the role of P-glycoprotein in in vitro drug permeability studies with the bovine brain microvessel endothelial cells

Abstract 1. Currently available in vitro blood-brain barrier models all have recognized restrictions. In addition to leakiness, inconsistent data about P-glycoprotein mediated efflux limit the attractiveness of the primary bovine brain microvessel endothelial cells (BBMECs). Therefore, we re-evaluated the role of P-glycoprotein mediated efflux with two culture conditions in BBMECs for prediction of drug permeability of potential P-glycoprotein substrates. 2. BBMECs were monocultured on filters on petri dishes and on filter inserts, and expression and localization of P-glycoprotein were compared by using western blot and confocal microscopy, respectively. The functionality of P-glycoprotein was assessed by using cellular uptake, calcein-AM and bidirectional transport assays. 3. P-glycoprotein expression was higher in BBMECs cultured on filter inserts decreasing the permeability of digoxin and paclitaxel, but not the permeability of vinblastine. However, the monocultured BBMECs were not able to demonstrate efflux in the bidirectional transport assays. Under certain culture conditions, occludin may not be correctly located, perhaps explaining in part the leakiness of BBMECs. 4. In conclusion, BBMECs, despite possessing a functional P-glycoprotein, under certain culture conditions may not be a suitable in vitro model for the bidirectional transport assays and for predicting the permeability of drugs and xenobiotics that are potential P-glycoprotein substrates.
Prototypic Long Pentraxin PTX3 Is Present in Breast Milk, Spreads in Tissues, and Protects Neonate Mice from Pseudomonas aeruginosa Lung Infection

Newborns and infants present a higher susceptibility to infection than adults, a vulnerability associated with deficiencies in both the innate and adaptive immune systems. Innate immune receptors are sensors involved in the recognition and elimination of microbes that play a pivotal role at the interface between innate and adaptive immunity. Pentraxin 3 (PTX3), the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against selected pathogens. Because neonates are generally resistant to these pathogens, we suspected that PTX3 may be provided by a maternal source during the early life times. We observed that human colostrum contains high levels of PTX3, and that mammary epithelial cell and CD11b+ milk cells constitutively produce PTX3. Interestingly, PTX3 given orally to neonate mice was rapidly distributed in different organs, and PTX3 ingested during lactation was detected in neonates. Finally, we observed that orally administered PTX3 provided protection against Pseudomonas aeruginosa lung infection in neonate mice. Therefore, breastfeeding constitutes, during the early life times, an important source of PTX3, which actively participates in the protection of neonates against infections. In addition, these results suggest that PTX3 might represent a therapeutic tool for treating neonatal infections and support the view that breastfeeding has beneficial effects on the neonates’ health.
Open for business: emerging business models in open source software

Open source software (OSS) has come of age, and a number of maturing business models allow OSS companies to make a profit even when their product is distributed for free. This article considers the dynamics of value creation fuelling the proliferation of OSS and examines the business model factors that enable value capture. After interviewing leaders from over 20 OSS firms and organisations through early 2006, we found that three factors were consistently important in defining a vendor’s adoption of a given business model: software licence choice, which takes into account intellectual property ownership; management of developer communities; and the unique features of the markets and product categories in which the vendor participates. Considering these factors, we characterise seven business models. One striking finding is that it is rare to find business-model purity. The majority of firms in our sample are pursuing either blended business models or multiple models simultaneously.
G Protein–Coupled Receptor Kinase 6 Deficiency Promotes Angiogenesis, Tumor Progression, and Metastasis

G protein–coupled receptor kinases (GRKs) phosphorylate the activated form of G protein–coupled receptors leading to receptor desensitization and downregulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis, and wound healing. In this study, we investigate the role of GRK6 in tumorigenesis using murine models of human lung cancer. Mice deficient in GRK6 (GRK6−/−) exhibited a significant increase in Lewis lung cancer growth and metastasis relative to control littermates (GRK6+/+). GRK6 deletion had no effect on the expression of proangiogenic chemokine or vascular endothelial growth factor, but upregulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs, and microvessel density. Because β-arrestin-2–deficient (βarr2−/−) mice exhibited increased Lewis lung cancer growth and metastasis similar to that of GRK6−/−, we developed a double GRK6−/−/βarr2−/− mouse model. Surprisingly, GRK6−/−/βarr2−/− mice exhibited faster tumor growth relative to GRK6−/− or βarr2−/− mice. Treatment of the mice with anti-CXCR2 Ab inhibited tumor growth in both GRK6−/− and GRK6−/−/βarr2−/− animals. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression, and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment, thereby promoting angiogenesis and metastasis. Because GRK6−/−/βarr2−/− showed greater tumor growth relative to GRK6−/− or βarr2−/− mice, the data further suggest that CXCR2 couples to different mechanisms to mediate tumor progression and metastasis.
Pro-Apoptotic Protein Noxa Regulates Memory T Cell Population Size and Protects against Lethal Immunopathology

Memory T cells form a highly specific defense layer against reinfection with previously encountered pathogens. In addition, memory T cells provide protection against pathogens that are similar, but not identical to the original infectious agent. This is because each T cell response harbors multiple clones with slightly different affinities, thereby creating T cell memory with a certain degree of diversity. Currently, the mechanisms that control size, diversity, and cross-reactivity of the memory T cell pool are incompletely defined. Previously, we established a role for apoptosis, mediated by the BH3-only protein Noxa, in controlling diversity of the effector T cell population. This function might positively or negatively impact T cell memory in terms of function, pool size, and cross-reactivity during recall responses. Therefore, we investigated the role of Noxa in T cell memory during acute and chronic infections. Upon influenza infection, Noxa−/− mice generate a memory compartment of increased size and clonal diversity. Reinfection resulted in an increased recall response, whereas cross-reactive responses were impaired. Chronic infection of Noxa−/− mice with mouse CMV resulted in enhanced memory cell inflation, but no obvious pathology. In contrast, in a model of continuous, high-level T cell activation, reduced apoptosis of activated T cells rapidly led to severe organ pathology and premature death in Noxa-deficient mice. These results establish Noxa as an important regulator of the number of memory cells formed during infection. Chronic immune activation in the absence of Noxa leads to excessive accumulation of primed cells, which may result in severe pathology.
Discovery of T Cell Epitopes Implementing HLA-Peptidomics into a Reverse Immunology Approach

T cell recognition of minor histocompatibility Ags (MiHA) plays an important role in the graft-versus-tumor effect of allogeneic stem cell transplantation. Selective infusion of T cells reactive for hematopoiesis-restricted MiHA presented in the context of HLA class I or II molecules may help to separate the graft-versus-tumor effects from graft-versus-host disease effects after allogeneic stem cell transplantation. Over the years, increasing numbers of MiHA have been identified by forward immunology approaches, and the relevance of these MiHA has been illustrated by correlation with clinical outcome. As the tissue distribution of MiHA affects the clinical outcome of T cell responses against these Ags, it would be beneficial to identify additional predefined MiHA that are exclusively expressed on hematopoietic cells. Therefore, several reverse immunology approaches have been explored for the prediction of MiHA. Thus far, these approaches frequently resulted in the identification of T cells directed against epitopes that are not naturally processed and presented. In this study we established a method for the identification of biologically relevant MiHA, implementing mass spectrometry–based HLA-peptidomics into a reverse immunology approach. For this purpose, HLA class I binding peptides were eluted from transformed B cells, analyzed by mass spectrometry, and matched with a database dedicated to identifying polymorphic peptides. This process resulted in a set of 40 MiHA candidates that were evaluated in multiple selection steps. The identification of LB-NISCH-1A demonstrated the technical feasibility of our approach. On the basis of these results, we present an approach that can be of value for the efficient identification of MiHA or other T cell epitopes.
Technology transfer offices as a nexus within the triple helix: the progression of the university's role

The prospect of increased revenue and spillovers has influenced the mission of the university to reflect an increasingly commercial orientation. This paper focuses on university commercialisation in three countries (Ireland, New Zealand and the USA), through 58 semi-structured interviews with technology transfer officers and a quantitative assessment of university patenting trajectories. Using interviews with technology transfer office executives and university patent applications as proxies for commercial orientation, the study uncovers explanations to the heterogeneous commercial orientation apparent in all three regions. Findings indicate that path dependency; university leadership; technology transfer office scale and connectivity are critical determinants of commercial orientation. The paper concludes by surmising how path dependency might strongly dictate the other determinants and outlines some implications for literature and policy development.
PGE2 Induces Macrophage IL-10 Production and a Regulatory-like Phenotype via a Protein Kinase A–SIK–CRTC3 Pathway

The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE2, in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A–dependent pathway. Both TLR agonists and PGE2 promote the phosphorylation of the transcription factor CREB on Ser133. However, although CREB regulates IL-10 transcription, the mutation of Ser133 to Ala in the endogenous CREB gene did not prevent the ability of PGE2 to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser343, inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE2 on IL-10 production.
TNFR2 Is Critical for the Stabilization of the CD4+Foxp3+ Regulatory T Cell Phenotype in the Inflammatory Environment

Several lines of evidence indicate the instability of CD4+Foxp3+ regulatory T cells (Tregs). We have therefore investigated means of promoting the stability of Tregs. In this study, we found that the proportion of Tregs in mouse strains deficient in TNFR2 or its ligands was reduced in the thymus and peripheral lymphoid tissues, suggesting a potential role of TNFR2 in promoting the sustained expression of Foxp3. We observed that upon in vitro activation with plate-bound anti-CD3 Ab and soluble anti-CD28 Ab, Foxp3 expression by highly purified mouse Tregs was markedly downregulated. Importantly, TNF partially abrogated this effect of TCR stimulation and stabilized Foxp3 expression. This effect of TNF was blocked by anti-TNFR2 Ab, but not by anti-TNFR1 Ab. Furthermore, TNF was not able to maintain Foxp3 expression by TNFR2-deficient Tregs. In a mouse colitis model induced by transfer of naive CD4 cells into Rag1−/− mice, the disease could be inhibited by cotransfer of wild-type Tregs, but not by cotransfer of TNFR2-deficient Tregs. Furthermore, in the lamina propria of the colitis model, most wild-type Tregs maintained Foxp3 expression. In contrast, an increased number of TNFR2-deficient Tregs lost Foxp3 expression. Thus, our data clearly show that TNFR2 is critical for the phenotypic and functional stability of Tregs in the inflammatory environment. This effect of TNF should be taken into account when designing future therapy of autoimmunity and graft-versus-host disease by using TNF inhibitors.
10,000 Steps Rockhampton : evaluation of a whole community approach to improving population levels of physical activity

Objectives: To describe the effectiveness of a multi-strategy physical activity (PA) intervention. Methods: Self-report data from random samples were collected prior to and following intervention. Social marketing, healthcare provider, and environmental strategies were concurrently implemented with a central coordinating theme of “10,000 Steps Rockhampton. ” Results: There was evidence of significant project reach and awareness. The downward trend in PA seen in the comparison community (48.3% to 41.9% “active”) was not evident in Rockhampton. Women were the “early adopters” in this project; with an increase of 5% (95% CI: –0.6, 10.6) in the percent categorized as “active” (compared with decreases among women in the comparison community and among men in both communities). Conclusions: High levels of project awareness, combined with modest increases in activity levels in women, demonstrate initial project effects. Longer term interventions, focusing on sustainable individual, social, and environmental change.
Fibrosis and Subsequent Cytopenias Are Associated with Basic Fibroblast Growth Factor–Deficient Pluripotent Mesenchymal Stromal Cells in Large Granular Lymphocyte Leukemia

Cytopenias occur frequently in systemic lupus erythematosus, rheumatoid arthritis, Felty’s syndrome, and large granular lymphocyte (LGL) leukemia, but the bone marrow microenvironment has not been systematically studied. In LGL leukemia (n = 24), retrospective analysis of bone marrow (BM) histopathology revealed severe fibrosis in 15 of 24 patients (63%) in association with the presence of cytopenias, occurrence of autoimmune diseases, and splenomegaly, but was undetectable in control cases with B cell malignancies (n = 11). Fibrosis severity correlated with T cell LGL cell numbers in the BM, but not in the periphery, suggesting deregulation is limited to the BM microenvironment. To identify fibrosis-initiating populations, primary mesenchymal stromal cultures (MSCs) from patients were characterized and found to display proliferation kinetics and overabundant collagen deposition, but displayed normal telomere lengths and osteoblastogenic, chondrogenic, and adipogenic differentiation potentials. To determine the effect of fibrosis on healthy hematopoietic progenitor cells (HPCs), bioartificial matrixes from rat tail or purified human collagen were found to suppress HPC differentiation and proliferation. The ability of patient MSCs to support healthy HSC proliferation was significantly impaired, but could be rescued with collagenase pretreatment. Clustering analysis confirmed the undifferentiated state of patient MSCs, and pathway analysis revealed an inverse relationship between cell division and profibrotic ontologies associated with reduced basic fibroblast growth factor production, which was confirmed by ELISA. Reconstitution with exogenous basic fibroblast growth factor normalized patient MSC proliferation, collagen deposition, and HPC supportive function, suggesting LGL BM infiltration and secondary accumulation of MSC-derived collagen is responsible for hematopoietic failure in autoimmune-associated cytopenias in LGL leukemia.
The Validity of Reporting Willingness to Use a Supervised Injecting Facility on Subsequent Program Use among People Who Use Injection Drugs

Background: Innovative health programs for injection drug users (IDUs), such as supervised injecting facilities (SIFs), are often preceded by evaluations of IDUs’ willingness to use the service. The validity of these surveys has not been fully evaluated. We sought to determine whether measures of willingness collected prior to the opening of a Canadian SIF accurately predicted subsequent use of the program. Methods: Data were derived from a prospective cohort of IDUs. The sample size for this study was 640 IDUs. Using multivariate logistic regression, it was assessed if a history of reporting willingness to use the program, were it available, was associated with subsequent use. In sub-analysis restricted to individuals who had a history of reported willingness, we used multivariate longitudinal analysis to identify factors associated with not attending the SIF. Results: Among 442 IDUs, 72% of those who reported initial willingness to use a SIF later attended the program, and a prior willingness to use a SIF significantly predicted later attendance (adjusted odds ratio = 1.67). In sub-analyses restricted to those who had a history of reporting willingness to use the SIF, not using the program was predicted by not frequenting the neighborhood where the SIF was located. Conclusion: Our findings indicate that reported willingness measures collected from IDUs regarding potential SIF program participation prior to its opening independently predicted later attendance even when variables that were likely determinants of willingness were adjusted for. These data suggest that willingness measures are reasonably valid tools for planning the delivery of health services among IDU populations.
Noradrenergic Neurons Regulate Monocyte Trafficking and Mortality during Gram-Negative Peritonitis in Mice

Effective host defense requires a robust, yet self-limited response to pathogens. A poorly calibrated response can lead to either bacterial dissemination due to insufficient inflammation or organ injury due to excessive inflammation. Recent evidence suggests that the cholinergic anti-inflammatory reflex helps calibrate the immune response. However, the influence of peripheral noradrenergic neurons, which are primarily sympathetic neurons, in regulating immunity remains incompletely characterized. Using a model of 6-hydroxydopamine–mediated noradrenergic nerve ablation, we show that elimination of noradrenergic neurons improves survival during Klebsiella pneumoniae peritonitis (67 versus 23%, p < 0.005) in mice. The survival benefit results from enhanced MCP-1–dependent monocyte recruitment and a subsequent decrease in bacterial loads. Splenectomy eliminated both the survival benefit of 6-hydroxydopamine and monocyte recruitment, suggesting that monocytes recruited to the peritoneum originate in the spleen. These results suggest that noradrenergic neurons regulate the immune response through two pathways. First, sympathetic nerve-derived norepinephrine directly restrains MCP-1 production by peritoneal macrophages during infection. Second, norepinephrine derived from the vagally innervated splenic nerve regulates splenic monocyte egress. Removal of these two modulators of the immune response enhances antibacterial immunity and improves survival. These results may have implications for how states of catecholamine excess influence the host response to bacterial infections.
Functional Social Support within a Medical Supervised Outpatient Treatment Program

Background: This study examined functional social support (FSS) and its impact on treatment outcome in alcohol-dependent outpatients treated with supervised disulfiram. Method: FSS was assessed cross-sectionally in 46 severe alcohol-dependent patients participating in a close-meshed biopsychosocial treatment program. The FSS was measured with the Medical Outcome Study Social Support Survey. Results: We found significantly higher FSS levels in patients with a current partnership. No significant influence was found of the FSS on days until relapse and retention time. However, FSS was positively correlated with cumulative abstinence. In comparison with another patient sample, it can be shown that the patients of the close-meshed biopsychosocial treatment program seemed to perceive more FSS, presumably through the higher frequency of the outpatient treatment contacts. Conclusion: High FSS is associated with a current partnership and with a higher cumulative time of abstinence through close professional supervision. A better understanding of the underlying mechanisms of social relationships in alcohol-dependent patients would probably help to improve treatment outcome in the future.