Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2-responding CD4+ T cells.

Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4+ T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4+ T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4+ T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4+ T cells, Nrp1 expression was assessed in vivo and in vitro following AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4+ T cells increases over the course of activation and proliferation in vivo. The actively dividing Nrp1+Foxp3- cells express the classic effector phenotype of CD44hiCD45RBlo, and the increase in Nrp1+Foxp3- cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4+ T cells. The downregulation of Nrp1 on CD4+ T cells was recapitulated in vitro in cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4+Foxp3- cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression both in vitro and in vivo. Collectively, the data demonstrate that Nrp1 is a CD4+ T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4+ T cell responses.

Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2 responding CD4 + T cells.

Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4 + T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4 + T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4 + T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4 + T cells, Nrp1 expression was assessed in vivo and in vitro following AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4 + T cells increases over the course of activation and proliferation in vivo . The actively dividing Nrp1 + Foxp3 - cells express the classic effector phenotype of CD44 hi CD45RB lo , and the increase in Nrp1 + Foxp3 - cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4 + T cells. The downregulation of Nrp1 on CD4 + T cells was recapitulated in vitro in cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4 + Foxp3 - cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression both in vitro and in vivo . Collectively, the data demonstrate that Nrp1 is a CD4 + T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4 + T cell responses.

Use of the knowledge to action model improved physical therapist adherence to a common clinical practice guideline across multiple settings: a multisite case series.

BACKGROUND: When a new guideline is published there is a need to understand how its recommendations can best be implemented in real-world practice. Yet, guidelines are often published with little to no roadmap for organizations to follow to promote adherence to their recommendations. The purpose of this study was to evaluate the impact of using a common process model to implement a single clinical practice guideline across multiple physical therapy clinical settings. METHODS: Five organizationally distinct sites with physical therapy services for patients with peripheral vestibular hypofunction participated. The Knowledge to Action model served as the foundation for implementation of a newly published guideline. Site leaders conducted preliminary gap surveys and face-to-face meetings to guide physical therapist stakeholders' identification of target-behaviors for improved guideline adherence. A 6-month multimodal implementation intervention included local opinion leaders, audit and feedback, fatigue-resistant reminders, and communities of practice. Therapist adherence to target-behaviors for the 6 months before and after the intervention was the primary outcome for behavior change. RESULTS: Therapist participants at all sites indicated readiness for change and commitment to the project. Four sites with more experienced therapists selected similar target behaviors while the fifth, with more inexperienced therapists, identified different goals. Adherence to target behaviors was mixed. Among four sites with similar target behaviors, three had multiple areas of statistically significantly improved adherence and one site had limited improvement. Success was most common with behaviors related to documentation and offering patients low technology resources to support home exercise. A fifth site showed a trend toward improved therapist self-efficacy and therapist behavior change in one provider location. CONCLUSIONS: The Knowledge to Action model provided a common process model for sites with diverse structures and needs to implement a guideline in practice. Multimodal, active interventions, with a focus on auditing adherence to therapist-selected target behaviors, feedback in collaborative monthly meetings, fatigue-resistant reminders, and developing communities of practice was associated with long-term improvement in adherence. Local rather than external opinion leaders, therapist availability for community building meetings, and rate of provider turnover likely impacted success in this model. TRIAL REGISTRATION: This study does not report the results of a health care intervention on human participants.

Constraining movement reveals motor capability in chronic stroke: an initial study.

OBJECTIVE: To determine if persons with chronic stroke and decreased hip and knee flexion during swing can walk with improved swing-phase kinematics when the task demands constrained gait to the sagittal plane. DESIGN: A one-day, within-subject design comparing gait kinematics under two conditions: Unconstrained treadmill walking and a constrained condition in which the treadmill walking space is reduced to limit limb advancement to occur in the sagittal plane. SETTING: Outpatient physical therapy clinic. SUBJECTS: Eight individuals (mean age, 64.1 ±9.3, 2 F) with mild-moderate paresis were enrolled. MAIN MEASURES: Spatiotemporal gait characteristics and swing-phase hip and knee range of motion during unconstrained and constrained treadmill walking were compared using paired t-test and Cohen's d ( d) to determine effect size. RESULTS: There was a significant, moderate-to-large effect of the constraint on hip flexion ( p < 0.001, d = -1.1) during initial swing, and hip ( p < 0.05, d = -0.8) and knee ( p < 0.001, d = -1.1) flexion during midswing. There was a moderate effect of constraint on terminal swing knee flexion ( p = 0.238, d = -0.6). Immediate and significant changes in step width ( p < 0.05, d = 0.9) and paretic step length ( p < 0.05, d = -0.5) were noted in the constrained condition compared with unconstrained. CONCLUSION: Constraining the treadmill walking path altered the gait patterns among the study's participants. The immediate change during constrained walking suggests that patients with chronic stroke may have underlying movement capability that they do not preferentially utilize.

Structural constraints on learning in the neural network.

Recent research suggests the brain can learn almost any brain-computer interface (BCI) configuration; however, contrasting behavioral evidence from structural learning theory argues that previous experience facilitates, or impedes, future learning. A study by Sadtler and colleagues (Nature 512: 423-426, 2014) used BCI to demonstrate that neural network structural characteristics constrain learning, a finding that might also provide insight into how the brain responds to and recovers after injury.