Hemodynamic Regulation of Inflammation at the Endothelial-Neutrophil Interface

Arterial shear stress can regulate endothelial phenotype. The potential for anti-inflammatory effects of shear stress on TNFα-activated endothelium was tested in assays of cytokine expression and neutrophil adhesion. In cultured human aortic endothelial cells (HAEC), arterial shear stress of 10 dyne/cm2 blocked by \u3e 80% the induction by 5 ng/ml TNFα of interleukin-8 (IL-8) and IL-6 secretion (50% and 90% reduction, respectively, in the presence of nitric oxide synthase antagonism with 200 μM nitro-L-arginine methylester, L-NAME). Exposure of TNFα-stimulated HAEC to arterial shear stress for 5 hr also reduced by 60% (P &#; 0.001) the conversion of neutrophil rolling to firm arrest in a venous flow assay conducted at 1 dyne/cm2. Also, neutrophil rolling lengths at 1 dyne/cm2 were longer when TNFα-stimulated HAEC were presheared for 5 hr at arterial stresses. In experiments with a synthetic promoter that provides luciferase induction to detect cis interactions of glucocorticoid receptor (GR) and NFκB, shear stress caused a marked 40-fold induction of luciferase in TNFα-treated cells, suggesting a role for GR pathways in the anti-inflammatory actions of fluid shear stress. Hemodynamic force exerts anti-inflammatory effects on cytokine activated endothelium by attenuation of cytokine expression and neutrophil firm arrest

Emotional Mental Imagery as Simulation of Reality: Fear and Beyond—A Tribute to Peter Lang

AbstractThis article pays tribute to the seminal paper by Peter J. Lang (1977; this journal), “Imagery in Therapy: Information Processing Analysis of Fear.” We review research and clinical practice developments in the past five decades with reference to key insights from Lang’s theory and experimental work on emotional mental imagery. First, we summarize and recontextualize Lang’s bio-informational theory of emotional mental imagery (1977, 1979) within contemporary theoretical developments on the function of mental imagery. Second, Lang’s proposal that mental imagery can evoke emotional responses is evaluated by reviewing empirical evidence that mental imagery has a powerful impact on negative as well as positive emotions at neurophysiological and subjective levels. Third, we review contemporary cognitive and behavioral therapeutic practices that use mental imagery, and consider points of extension and departure from Lang’s original investigation of mental imagery in fear-extinction behavior change. Fourth, Lang’s experimental work on emotional imagery is revisited in light of contemporary research on emotional psychopathology-linked individual differences in mental imagery. Finally, key insights from Lang’s experiments on training emotional response during imagery are discussed in relation to how specific techniques may be harnessed to enhance adaptive emotional mental imagery training in future research

Spontaneous cognition in dysphoria: reduced positive bias in imagining the future.

Anomalies in future-oriented cognition are implicated in the maintenance of emotional disturbance within cognitive models of depression. Thinking about the future can involve mental imagery or verbal-linguistic mental representations. Research suggests that future thinking involving imagery representations may disproportionately impact on-going emotional experience in daily life relative to future thinking not involving imagery (verbal-linguistic representation only). However, while higher depression symptoms (dysphoria) are associated with impaired ability to deliberately generate positive relatively to negative imagery representations of the future (when instructed to do so), it is unclear whether dysphoria is associated with impairments in the tendency to do so spontaneously (when not instructed to deliberately generate task unrelated cognition of any kind). The present study investigated dysphoria-linked individual differences in the tendency to experience spontaneous future-oriented cognition as a function of emotional valence and representational format. Individuals varying in dysphoria level reported the occurrence of task unrelated thoughts (TUTs) in real time while completing a sustained attention go/no-go task, during exposure to auditory cues. Results indicate higher levels of dysphoria were associated with lower levels of positive bias in the number of imagery-based future TUTs reported, reflecting higher negative imagery-based future TUT generation (medium to large effect size), and lower positive imagery-based TUT generation (small to medium effect size). Further, this dysphoria-linked bias appeared to be specific in temporal orientation (future, not past) and representational format (imagery, not non-imagery). Reduced tendency to engage in positive relative to negative imagery-based future thinking appears to be implicated in dysphoria

Association between interpretation flexibility and emotional health in an anxious sample: The challenge of measuring flexible adoption of multiple perspectives

Interpreting ambiguous situations in a rigidly negative manner contributes to emotional disorders. Although negative interpretation biases have been well studied in relation to anxiety and depression, the relationship between interpretation flexibility (vs. rigidity) and emotional health remains understudied. The present study is a secondary analysis to test the hypothesis that higher interpretation flexibility is associated with better emotional health, as indicated by lower anxiety and depression levels, and higher quality of life. Here, interpretation flexibility focuses specifically on the ability to recognize multiple possible interpretations within and across ambiguous situations. Using baseline data from N = 939 high trait-anxious community participants who enrolled in an online anxiety intervention, multiple ways of computing interpretation flexibility were applied to help the field learn how different operationalizations can lead to varied conclusions about the connection between interpretation flexibility and emotional health. Using two measures of interpretation style, four approaches (some pre-registered, some exploratory) to computing interpretation flexibility were tested using an internal replication analytic approach. Results varied across type of approach, but in general, contrary to hypotheses, results indicated that higher interpretation flexibility was either unrelated to, or associated with higher, anxiety, and depression, and lower quality of life

Actin–myosin network reorganization breaks symmetry at the cell rear to spontaneously initiate polarized cell motility

We have analyzed the spontaneous symmetry breaking and initiation of actin-based motility in keratocytes (fish epithelial cells). In stationary keratocytes, the actin network flow was inwards and radially symmetric. Immediately before motility initiation, the actin network flow increased at the prospective cell rear and reoriented in the perinuclear region, aligning with the prospective axis of movement. Changes in actin network flow at the cell front were detectable only after cell polarization. Inhibition of myosin II or Rho kinase disrupted actin network organization and flow in the perinuclear region and decreased the motility initiation frequency, whereas increasing myosin II activity with calyculin A increased the motility initiation frequency. Local stimulation of myosin activity in stationary cells by the local application of calyculin A induced directed motility initiation away from the site of stimulation. Together, these results indicate that large-scale actin–myosin network reorganization and contractility at the cell rear initiate spontaneous symmetry breaking and polarized motility of keratocytes

Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice

The mouse mutant mnd2 (motor neuron degeneration 2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age(1,2). Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages'. Here we have identified the mnd2 mutation as the missense mutation Ser276Cys in the protease domain of the nuclear-encoded mitochondrial serine protease Omi (also known as HtrA2 or Prss25). Protease activity of Omi is greatly reduced in tissues of mnd2 mice but is restored in mice rescued by a bacterial artificial chromosome transgene containing the wildtype Omi gene. Deletion of the PDZ domain partially restores protease activity to the inactive recombinant Omi protein carrying the Ser276Cys mutation, suggesting that the mutation impairs substrate access or binding to the active site pocket. Loss of Omi protease activity increases the susceptibility of mitochondria to induction of the permeability transition, and increases the sensitivity of mouse embryonic fibroblasts to stress-induced cell death. The neurodegeneration and juvenile lethality in mnd2 mice result from this defect in mitochondrial Omi protease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62561/1/nature02052.pd

Reversible lysine fatty acylation of an anchoring protein mediates adipocyte adrenergic signaling.

N-myristoylation on glycine is an irreversible modification that has long been recognized to govern protein localization and function. In contrast, the biological roles of lysine myristoylation remain ill-defined. We demonstrate that the cytoplasmic scaffolding protein, gravin-α/A kinase–anchoring protein 12, is myristoylated on two lysine residues embedded in its carboxyl-terminal protein kinase A (PKA) binding domain. Histone deacetylase 11 (HDAC11) docks to an adjacent region of gravin-α and demyristoylates these sites. In brown and white adipocytes, lysine myristoylation of gravin-α is required for signaling via β(2)- and β(3)-adrenergic receptors (β-ARs), which are G protein–coupled receptors (GPCRs). Lysine myristoylation of gravin-α drives β-ARs to lipid raft membrane microdomains, which results in PKA activation and downstream signaling that culminates in protective thermogenic gene expression. These findings define reversible lysine myristoylation as a mechanism for controlling GPCR signaling and highlight the potential of inhibiting HDAC11 to manipulate adipocyte phenotypes for therapeutic purposes

The role of ICT in supporting disruptive innovation: a multi-site qualitative study of nurse practitioners in emergency departments

<p>Abstract</p> <p>Background</p> <p>The disruptive potential of the Nurse Practitioner (NP) is evident in their ability to offer services traditionally provided by primary care practitioners and their provision of a health promotion model of care in response to changing health trends. No study has qualitatively investigated the role of the Emergency NP in Australia, nor the impact of Information and Communication Technology (ICT) on this disruptive workforce innovation. This study aimed to investigate ways in which Nurse Practitioners (NP) have incorporated the use of ICT as a mechanism to support their new clinical role within Emergency Departments.</p> <p>Methods</p> <p>A cross-sectional qualitative study was undertaken in the Emergency Departments (EDs) of two large Australian metropolitan public teaching hospitals. Semi-structured, in-depth interviews were conducted with five nurse practitioners, four senior physicians and five senior nurses. Transcribed interviews were analysed using a grounded theory approach to develop themes in relation to the conceptualisation of the ED nurse practitioner role and the influences of ICT upon the role. Member checking of results was achieved by revisiting the sites to clarify findings with participants and further explore emergent themes.</p> <p>Results</p> <p>The role of the ENP was distinguished from those of Emergency nurses and physicians by two elements: advanced practice and holistic care, respectively. ICT supported the advanced practice dimension of the NP role in two ways: availability and completeness of electronic patient information enhanced timeliness and quality of diagnostic and therapeutic decision-making, expediting patient access to appropriate care. The ubiquity of patient data sourced from a central database supported and improved quality of communication between health professionals within and across sites, with wider diffusion of the Electronic Medical Record holding the potential to further facilitate team-based, holistic care.</p> <p>Conclusions</p> <p>ICT is a facilitator through which the disruptive impact of NPs can be extended. However, integration of ICT into work practices without detracting from provider-patient interaction is crucial to ensure utilisation of such interventions and realisation of potential benefits.</p

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes