Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Role for Interleukin-27 (IL-27) as Mediator of Intestinal Epithelial Barrier Protection Mediated via Differential Signal Transducer and Activator of Transcription (STAT) Protein Signaling and Induction of Antibacterial and Anti-inflammatory Proteins*

Background: IL-27 is a Th17 cell-inhibiting cytokine. Results: IL-27 activates differential STAT signaling in intestinal epithelial cells resulting in increased epithelial restitution, induction of antibacterial genes (DMBT1 and IDO1), and growth inhibition of intestinal bacteria. Conclusion: IL-27 mediates epithelial barrier protection and antibacterial responses. Significance: We identified novel functions of IL-27, including epithelial restitution and a major role in the host response to intestinal bacteria. The role of the Th17 cell inhibiting cytokine IL-27 in the pathogenesis of inflammatory bowel disease is contradictory. Its effects on the intestinal barrier have so far not been investigated, which was the aim of this study. We show that intestinal epithelial cells (IEC) express both IL-27 receptor subunits IL-27RA and gp130. The IL-27 receptor expression is up-regulated in intestinal inflammation and during bacterial infection. IL-27 activates ERK and p38 MAPKs as well as Akt, STAT1, STAT3, and STAT6 in IEC. IL-27 significantly enhances cell proliferation and IEC restitution. These functions of IL-27 are dependent on the activation of STAT3 and STAT6 signaling pathways. As analyzed by microarray, IL-27 modulates the expression of 428 target genes in IEC (316 up and 112 down; p < 0.05). IL-27 as well as its main target genes are up-regulated in colonic tissue and IEC isolated from mice with dextran sulfate sodium (DSS)-induced colitis. The IL-27-induced expression of the anti-bacterial gene deleted in malignant brain tumor 1 (DMBT1) is mediated by p38 and STAT3 signaling, whereas the activation of the anti-inflammatory and anti-bacterial gene indoleamine 2,3-dioxygenase (IDO1) is dependent on STAT1 signal transduction. IL-27-induced indoleamine 2,3-dioxygenase enzymatic activity leads to growth inhibition of intestinal bacteria by causing local tryptophan depletion. For the first time, we characterize IL-27 as a mediator of intestinal epithelial barrier protection mediated via transcriptional activation of anti-inflammatory and antibacterial target genes.
Characterization of Heparin-binding Site of Tissue Transglutaminase

Background: TG2 is a multifunctional matrix protein and cross-linking enzyme. Results: Identification and mutation of its heparan sulfate (HS)-binding site blocks matrix deposition of TG2 as do inhibitors of syndecan shedding. Conclusion: Coordinated binding to cell surface heparan sulfates facilitates TG2 cell surface trafficking and deposition into the ECM. Significance: Blocking heparan sulfate binding provides an avenue for regulating the pathological roles of the enzyme. Tissue transglutaminase (TG2) is a multifunctional Ca2+-activated protein cross-linking enzyme secreted into the extracellular matrix (ECM), where it is involved in wound healing and scarring, tissue fibrosis, celiac disease, and metastatic cancer. Extracellular TG2 can also facilitate cell adhesion important in wound healing through a nontransamidating mechanism via its association with fibronectin, heparan sulfates (HS), and integrins. Regulating the mechanism how TG2 is translocated into the ECM therefore provides a strategy for modulating these physiological and pathological functions of the enzyme. Here, through molecular modeling and mutagenesis, we have identified the HS-binding site of TG2 202KFLKNAGRDCSRRSSPVYVGR222. We demonstrate the requirement of this binding site for translocation of TG2 into the ECM through a mechanism involving cell surface shedding of HS. By synthesizing a peptide NPKFLKNAGRDCSRRSS corresponding to the HS-binding site within TG2, we also demonstrate how this mimicking peptide can in isolation compensate for the RGD-induced loss of cell adhesion on fibronectin via binding to syndecan-4, leading to activation of PKCα, pFAK-397, and ERK1/2 and the subsequent formation of focal adhesions and actin cytoskeleton organization. A novel regulatory mechanism for TG2 translocation into the extracellular compartment that depends upon TG2 conformation and the binding of HS is proposed.
Regulation of Arginine Acquisition and Virulence Gene Expression in the Human Pathogen Streptococcus pneumoniae by Transcription Regulators ArgR1 and AhrC

Background: Arginine is a key amino acid in cellular metabolism in bacteria. Results: ArgR1 and AhrC mediate arginine-dependent expression of arginine acquisition and virulence genes in the human pathogen Streptococcus pneumoniae. Conclusion: Arginine regulation in S. pneumoniae significantly differs from that in other model bacteria. Significance: Understanding metabolic regulation increases insights into the molecular pathogenesis of S. pneumoniae. In this study, we investigated for the first time the transcriptional response of the human pathogen Streptococcus pneumoniae to fluctuating concentrations of arginine, an essential amino acid for this bacterium. By means of DNA microarray analyses, several operons and genes were found, the expression of which was affected by the concentration of arginine in the medium. Five of the identified operons were demonstrated to be directly repressed in the presence of high arginine concentrations via the concerted action of the ArgR-type regulators ArgR1 and AhrC. These ArgR1/AhrC targets encompass the putative amino acid transport genes artPQ, abpA, abpB, and aapA; the arginine biosynthetic genes argGH; and the virulence genes aliB and lmB/adcAII-phtD encoding an oligopeptide-binding lipoprotein and cell surface Zn2+-scavenging units, respectively. In addition, the data indicate that three of the amino acid transport genes encode an arginine ATP-binding cassette transporter unit required for efficient growth during arginine limitation. Instead of regulating arginine biosynthetic and catabolic genes as has been reported for other Gram-positive bacteria, our findings suggest that the physiological function of ArgR1/AhrC in S. pneumoniae is to ensure optimal uptake of arginine from the surrounding milieu.
Modulation of l-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids*

Background: The endogenous l-α-lysophosphatidylinositol activates GPR55. Results: Structural analogues of SR141716A act both as agonists alone and as inhibitors of l-α-lysophosphatidylinositol. Certain CB2 receptor agonists also modulate GPR55 activity. Conclusion: Certain cannabinoids can both activate GPR55 and attenuate l-α-lysophosphatidylinositol-mediated phosphorylated ERK1/2 activation. This has mechanistic implications for the antinociceptive effects of certain CB2 agonists. Significance: Cannabinoid ligands have complex interactions with the l-α-lysophosphatidylinositol/GPR55 signaling system. GPR55 is activated by l-α-lysophosphatidylinositol (LPI) but also by certain cannabinoids. In this study, we investigated the GPR55 pharmacology of various cannabinoids, including analogues of the CB1 receptor antagonist Rimonabant®, CB2 receptor agonists, and Cannabis sativa constituents. To test ERK1/2 phosphorylation, a primary downstream signaling pathway that conveys LPI-induced activation of GPR55, a high throughput system, was established using the AlphaScreen® SureFire® assay. Here, we show that CB1 receptor antagonists can act both as agonists alone and as inhibitors of LPI signaling under the same assay conditions. This study clarifies the controversy surrounding the GPR55-mediated actions of SR141716A; some reports indicate the compound to be an agonist and some report antagonism. In contrast, we report that the CB2 ligand GW405833 behaves as a partial agonist of GPR55 alone and enhances LPI signaling. GPR55 has been implicated in pain transmission, and thus our results suggest that this receptor may be responsible for some of the antinociceptive actions of certain CB2 receptor ligands. The phytocannabinoids Δ9-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.
Analysis of teamwork in an NHS community trust: an empirical study

The following paper describes the results of an empirical investigation into four different types of teamworking within an inner-city National Health Service (NHS) community trust in the UK. The four kinds of team were: (1) single-disciplinary (e.g. district nursing teams, health visiting teams); (2) multidisciplinary (a group of professionals working within a clinic or health centre); (3) management (e.g. planning and development teams); and (4) primary health care (a group of health professionals and support staff arranged around a general practice or set of practices). The present study involved a survey of 259 members of 30 teams. Nineteen of the teams were multidisciplinary clinic or health centre teams. Six of the teams were primary health care teams, two were single-disciplinary teams, and three were NHS management teams. Team members were surveyed during team building workshops with the Team Climate Inventory (TCI: Anderson & West, 1994) which measured team climate on four levels: participative sa.
Huntington disease: families' experiences of healthcare services.

AIM This paper is a report of a study of the perceptions of family caregivers regarding the availability and adequacy of health and social care services for their family member with Huntington disease, and to compare findings from these reports in United Kingdom and United States of America samples. BACKGROUND Huntington disease is an inherited neurodegenerative condition. Family members often take responsibility for care of relatives with long-term conditions. Studies have demonstrated there are both positive and negative outcomes for carers. METHODS During 2006 and 2007, respondents from the United Kingdom (n = 108) and the United States (n = 119) who were caring for a relative affected with Huntington disease completed the Community Health Care Services Scale to identify areas of concern and the extent to which specific issues bothered carers. Data were analysed using statistical tests including chi-square, t-tests and factor analysis. Results were compared between carers in the two cohorts. RESULTS Three main factors were derived: 'community resources', 'individualized care' and 'knowledge of Huntington disease'. Carers had concerns about the knowledge of healthcare professionals providing care and thought that there were insufficient services to support them and the affected person. There were different challenges for carers when the affected person had a long-term neurodegenerative condition because these carers were also likely to have responsibilities for earning and caring for children. CONCLUSION Comprehensive facilities and resources are needed to support families affected by long-term complex conditions. Healthcare professionals need to be aware of the health needs of carers as well as those of the affected person.
α-Catenin Uses a Novel Mechanism to Activate Vinculin*

Background: In cell-matrix adhesions, vinculin is activated by talin and actin, but the identity of the ligand that activates vinculin in cell-cell adhesions is unknown. Results:α-Catenin activates vinculin and the A50I talin-binding mutant of vinculin. Conclusion: These data suggest that α-catenin employs a novel mechanism to activate vinculin. Significance: These findings explain how vinculin is differentially activated in cell-cell and cell-matrix adhesions. Vinculin, an actin-binding protein, is emerging as an important regulator of adherens junctions. In focal-adhesions, vinculin is activated by simultaneous binding of talin to its head domain and actin filaments to its tail domain. Talin is not present in adherens junctions. Consequently, the identity of the ligand that activates vinculin in cell-cell junctions is not known. Here we show that in the presence of F-actin, α-catenin, a cytoplasmic component of the cadherin adhesion complex, activates vinculin. Direct binding of α-catenin to vinculin is critical for this event because a point mutant (α-catenin L344P) lacking high affinity binding does not activate vinculin. Furthermore, unlike all known vinculin activators, α-catenin binds to and activates vinculin independently of an A50I substitution in the vinculin head, a mutation that inhibits vinculin binding to talin and IpaA. Collectively, these data suggest that α-catenin employs a novel mechanism to activate vinculin and may explain how vinculin is differentially recruited and/or activated in cell-cell and cell-matrix adhesions.
Biobank participation and returning research results: Perspectives from a deliberative engagement in South Side Chicago

To be respectful of the public, biobank guiding principles and operations should be responsive to and inclusive of the values and beliefs of their participants. In an effort to increase knowledge and inform institutional policies, we conducted a deliberative engagement of individuals from two healthcare facilities in South Side Chicago that serve different socioeconomic communities to consider biobank policies regarding return of research results. We recruited primary caregivers of children receiving care at either a Federally Qualified Health Center or a university‐based practice to attend two full‐day deliberative engagement sessions, which included four educational presentations followed by focus group discussions. Surveys were administered to assess attitudes before and after the engagement, and an evaluation was conducted to assess the deliberative engagement process. All 45 participants self‐identified as African‐American. Focus group themes included: (1) overall interest in biobank participation, broad consent, and recontact; (2) root causes of distrust and potential biobank strategies to facilitate trust; (3) perceived positive and negative aspects of receiving research results; and (4) strong interest in receiving and managing their children's research results. Survey data indicated the same degree of interest in receiving results about themselves as about their children. Pre‐ and post‐session findings showed mainly non‐significant attitudinal changes in level of interest in biobank participation and return of research results, although there was a decrease in level of concern regarding identification from research data. Our findings reveal shared community insights important in facilitating relationships and policy discussions between biobank researchers and research participants. © 2012 Wiley Periodicals, Inc.
Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone*

Background: Mineralocorticoid aldosterone controls ENaC-mediated Na+ reabsorption in the distal nephron. Results: Ang II stimulates production of reactive oxygen species to stimulate ENaC, and this effect is preserved when mineralocorticoids are high. Conclusion: Ang II directly controls ENaC activity and expression in murine distal nephrons. Significance: Ang II may have a specific role in regulation of sodium handling in the distal nephron during variations in dietary Na+ intake. Dietary salt intake controls epithelial Na+ channel (ENaC)-mediated Na+ reabsorption in the distal nephron by affecting status of the renin-angiotensin-aldosterone system (RAAS). Whereas regulation of ENaC by aldosterone is generally accepted, little is known about whether other components of RAAS, such as angiotensin II (Ang II), have nonredundant to aldosterone-stimulatory actions on ENaC. We combined patch clamp electrophysiology and immunohistochemistry in freshly isolated split-opened distal nephrons of mice to determine the mechanism and molecular signaling pathway of Ang II regulation of ENaC. We found that Ang II acutely increases ENaC Po, whereas prolonged exposure to Ang II also induces translocation of α-ENaC toward the apical membrane in situ. Ang II actions on ENaC Po persist in the presence of saturated mineralocorticoid status. Moreover, aldosterone fails to stimulate ENaC acutely, suggesting that Ang II and aldosterone have different time frames of ENaC activation. AT1 but not AT2 receptors mediate Ang II actions on ENaC. Unlike its effect in vasculature, Ang II did not increase [Ca2+]i in split-opened distal nephrons as demonstrated using ratiometric Fura-2-based microscopy. However, application of Ang II to mpkCCDc14 cells resulted in generation of reactive oxygen species, as probed with fluorescent methods. Consistently, inhibiting NADPH oxidase with apocynin abolished Ang II-mediated increases in ENaC Po in murine distal nephron. Therefore, we concluded that Ang II directly regulates ENaC activity in the distal nephron, and this effect complements regulation of ENaC by aldosterone. We propose that stimulation of AT1 receptors with subsequent activation of NADPH oxidase signaling pathway mediates Ang II actions on ENaC.
Dissecting the Obesogenic Environment of a Psychiatric Setting: Client Perspectives

This qualitative study asked individuals with schizophrenia to identify environmental factors in a psychiatric facility that influence their diet, physical activity, and ultimately weight. Participants took photographs of environmental elements they perceived to be obesogenic within the hospital and then participated in a semi-structured interview during which they were asked about the identified environmental elements. The Analysis Grid for Environments Linked to Obesity (ANGELO) framework was used for the analysis of data. Participants recommended individual and environmental approaches to address obesity. The ANGELO framework is a useful tool for identifying obesogenic factors, a process that can inform environmental interventions in psychiatric settings.
Informing on prenatal screening for Down syndrome prior to conception. An empirical and ethical perspective

In most Western countries, information on prenatal screening for Down syndrome is provided in the first‐trimester of pregnancy. The purpose of this study was to examine whether this information should additionally be provided before pregnancy to improve the informed decision‐making process. In an empirical study, we obtained data from pregnant women with respect to their preferences regarding information on prenatal screening preconceptionally. Questionnaire data (n = 510) showed that 55.7% of responding women considered participating in prenatal screening for Down syndrome before pregnancy. 28.0% of women possessed information on prenatal screening preconceptionally. 84.6% preferred not to receive information preconceptionally in retrospect. In an ethical analysis, we elaborated on these preferences by weighing pros and cons. We considered two arguments against the provision of information on prenatal screening preconceptionally: women's preference to receive information in a step‐by‐step manner, and the risk of providing a directive message. We identified three reasons supporting its provision preconceptionally: the likelihood of making an informed decision could, firstly, be increased by “unchaining” the initial information from possible subsequent decisions, and, secondly, by providing women sufficient time to deliberate. Thirdly, the probability of equal access to prenatal screening may increase. To conclude with, we propose to incorporate an information offer on prenatal screening for Down syndrome in preconception care consultations. By offering information, instead of providing information, prospective parents are enabled to either accept or decline the information, which respects both their right to know and their right not‐to‐know. © 2012 Wiley Periodicals, Inc.
Infection control in clinical placements: experiences of nursing and midwifery students.

AIM This paper is a report of a study of the experiences of nursing and midwifery students in relation to infection control in their clinical placements and how these affect their learning. BACKGROUND Compliance with infection control precautions has been found to be low in many areas. Reasons for non-compliance include factors relevant to nursing and midwifery students, such as lack of knowledge and lack of a positive role model. However, there is little in the literature about how students experience infection control in placements and how this affects their own practice. METHODS Semi-structured interviews were undertaken in 2009 with 40 nursing and midwifery students. Analysis of transcripts was by Framework analysis. FINDINGS Students identified practices that they had observed and benchmarked these against what they had been taught at university and what was demonstrated by staff perceived as positive role models. Observing inappropriate practice affected student practice both positively and negatively. Students were reluctant to report poor practice due to fear of failing placements and not wanting to be identified negatively by staff. Students believed that practice supported by theory was important to provide them with a rationale for their activities and to support any complaints that they had. CONCLUSION Poor practice in clinical placements can have a negative impact on student learning and practice and may therefore have implications for the practice of future nurses and midwives. In order to maintain patient safety, there needs to be more support for students who wish to identify poor practice.
Interaction with ErbB4 Promotes Hypoxia-inducible Factor-1α Signaling*

Background: HIF-1α can be regulated by both VHL-dependent and VHL-independent mechanisms. Results: ErbB4 directly interacts with HIF-1α and promotes its stability and signaling in vitro and in vivo. Conclusion: The interaction between HIF-1α and ErbB4 is a biologically significant mechanism to promote HIF-1α activity. Significance: A novel VHL-independent mechanism promoting HIF-1α signaling is described. The receptor-tyrosine kinase ErbB4 was identified as a direct regulator of hypoxia-inducible factor-1α (HIF-1α) signaling. Cleaved intracellular domain of ErbB4 directly interacted with HIF-1α in the nucleus, and stabilized HIF-1α protein in both normoxic and hypoxic conditions by blocking its proteasomal degradation. The mechanism of HIF stabilization was independent of VHL and proline hydroxylation but dependent on RACK1. ErbB4 activity was necessary for efficient HRE-driven promoter activity, transcription of known HIF-1α target genes, and survival of mammary carcinoma cells in vitro. In addition, mammary epithelial specific targeting of Erbb4 in the mouse significantly reduced the amount of HIF-1α protein in vivo. ERBB4 expression also correlated with the expression of HIF-regulated genes in a series of 4552 human normal and cancer tissue samples. These data demonstrate that soluble ErbB4 intracellular domain promotes HIF-1α stability and signaling via a novel mechanism.