Nonpharmacologic approaches to pain management.

This article discusses nonpharmacologic pain management interventions for alternative or concomitant use with nonopioid medications. Potential barriers as well as facilitators to integrating nonpharmacologic interventions are discussed as they relate to nursing practice.

A Holistic Transcendental Leadership Model for Enhancing Innovation, Creativity and Well-Being in Health Care.

Burnout in health care employees and leaders is at an all-time high. Strategies to address burnout can fall short of addressing the broad range of underlying causes, including both organizational culture and personal factors. The National Academies of Medicine has set forth recommendations to address health care burnout from a leadership-based systems level that focuses on the whole employee, body, mind, and spirit.

Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy.

Programmed Cell Death-1 (PD-1) is an inhibitory immune receptor, which plays critical roles in T cell co-inhibition and exhaustion upon binding to its ligands PD-L1 and PD-L2. We report the crystal structure of the human PD-1 ectodomain and the mapping of the PD-1 binding interface. Mutagenesis studies confirmed the crystallographic interface, and resulted in mutant PD-1 receptors with altered affinity and ligand-specificity.

Complementary and Alternative Health Practices in the Rehabilitation Nursing.

This article discusses the connection between the Theory of Integral Nursing and the use of complementary and alternative medicine to rehabilitation nursing. Complementary and alternative health practices refers to methods, practices, and modalities that are outside of the realm of biomedicine. Some of the types of treatments and practices that are considered to be alternative include folk medicine, herbal medicine, homeopathy, faith healing, massage, energy healing, acupuncture and acupressure, supplements, aromatherapy, and music therapy.

Increased Heterologous Protein Expression in Drosophila S2 Cells for Massive Production of Immune Ligands/Receptors and Structural Analysis of Human HVEM.

Many immune ligands and receptors are potential drug targets, which delicately manipulate a wide range of immune responses. We describe here the successful application of an efficient method to dramatically improve the heterologous expression levels in Drosophila Schneider 2 cells, which enables the high-throughput production of several important immune ligands/receptors for raising antibodies, and for the structural and functional analyses. As an example, we purified the protein and characterized the structure of the immune receptor herpesvirus entry mediator (HVEM, TNFRSF14).

Mechanistic basis for functional promiscuity in the TNF and TNF receptor superfamilies: structure of the LIGHT:DcR3 assembly.

LIGHT initiates intracellular signaling via engagement of the two TNF receptors, HVEM and LTβR. In humans, LIGHT is neutralized by DcR3, a unique soluble member of the TNFR superfamily, which tightly binds LIGHT and inhibits its interactions with HVEM and LTβR. DcR3 also neutralizes two other TNF ligands, FasL and TL1A.

Implementing the new CARF wellness standards.

Our objectives in this article are to provide background and practical applications of the implementation of the new wellness standards developed by the Commission on Accreditation of Rehabilitation Facilities (CARF). The focus of rehabilitation in the stroke population ideally extends beyond maximizing functioning and prevention of further debilitation, by addressing wellness and the opportunity to create a healthy lifestyle. This concept has been recognized by CARF, which has included new wellness standards for stroke rehabilitation.

Tissue-expressed B7-H1 critically controls intestinal inflammation.

B7-H1 (PD-L1) on immune cells plays an important role in T cell coinhibition by binding its receptor PD-1. Here, we show that both human and mouse intestinal epithelium express B7-H1 and that B7-H1-deficient mice are highly susceptible to dextran sodium sulfate (DSS)- or trinitrobenzenesulfonic acid (TNBS)-induced gut injury. B7-H1 deficiency during intestinal inflammation leads to high mortality and morbidity, which are associated with severe pathological manifestations in the colon, including loss of epithelial integrity and overgrowth of commensal bacteria.

Structure and T cell inhibition properties of B7 family member, B7-H3.

T cell activity is controlled by a combination of antigen-dependent signaling through the T cell receptor and a set of auxiliary signals delivered through antigen-independent interactions, including the recognition of the B7 family of ligands. B7-H3 is a recently identified B7 family member that is strongly overexpressed in a range of cancers and correlates with poor prognosis. We report the crystal structure of murine B7-H3 at a 3 Å resolution, which provides a model for the organization of the IgV and IgC domains within the ectodomain.

Functional classification of immune regulatory proteins.

The members of the immunoglobulin superfamily (IgSF) control innate and adaptive immunity and are prime targets for the treatment of autoimmune diseases, infectious diseases, and malignancies. We describe a computational method, termed the Brotherhood algorithm, which utilizes intermediate sequence information to classify proteins into functionally related families. This approach identifies functional relationships within the IgSF and predicts additional receptor-ligand interactions.

Structure of Nectin-2 reveals determinants of homophilic and heterophilic interactions that control cell-cell adhesion.

Nectins are members of the Ig superfamily that mediate cell-cell adhesion through homophilic and heterophilic interactions. We have determined the crystal structure of the nectin-2 homodimer at 1.3 Å resolution.

Religiousness, Physical Activity and Obesity among Older Cancer Survivors: Results from the Health and Retirement Study 2000-2010.

The health behaviors of cancer survivors are an important research agenda in light of mounting evidence that aspects of health such as diet and exercise have salutary effects both mentally and physically for cancer survivors, a rapidly growing population in the United States and elsewhere. This paper analyzes data from the Health and Retirement Study 2000-2010 to determine if religious salience impacts the likelihood of obesity, changes in body mass index, and weekly vigorous activity. Two theories propose different hypotheses about the relationship.

Structural and functional characterization of a single-chain peptide-MHC molecule that modulates both naive and activated CD8+ T cells.

Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T-cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8(+) T-cell activation as a result of peptide transfer to cellular MHC molecules.

Decoy strategies: the structure of TL1A:DcR3 complex.

Decoy Receptor 3 (DcR3), a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily, neutralizes three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands engages unique signaling receptors which direct distinct and critical immune responses. We report the crystal structures of the unliganded DcR3 ectodomain and its complex with TL1A, as well as complementary mutagenesis and biochemical studies.

Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis.

The programmed death-1 (PD-1) costimulatory receptor inhibits T and B cell responses and plays a crucial role in peripheral tolerance. PD-1 has recently been shown to inhibit T cell responses during chronic viral infections such as HIV. In this study, we examined the role of PD-1 in infection with Mycobacterium tuberculosis, a common co-infection with HIV.

Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect.

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic beta cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk.

Dynamic equilibrium of B7-1 dimers and monomers differentially affects immunological synapse formation and T cell activation in response to TCR/CD28 stimulation.

Under steady-state conditions, B7-1 is present as a mixed population of noncovalent dimers and monomers on the cell surface. In this study, we examined the physiological significance of this unique dimer-monomer equilibrium state of B7-1. We demonstrate that altering B7-1 to create a uniformly covalent dimeric state results in enhanced CD28-mediated formation of T cell-APC conjugates.

Biochemical and structural characterization of the human TL1A ectodomain.

TNF-like 1A (TL1A) is a newly described member of the TNF superfamily that is directly implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis. We report the crystal structure of the human TL1A extracellular domain at a resolution of 2.5 A, which reveals a jelly-roll fold typical of the TNF superfamily.

Sequence, structure, function, immunity: structural genomics of costimulation.

Costimulatory receptors and ligands trigger the signaling pathways that are responsible for modulating the strength, course, and duration of an immune response. High-resolution structures have provided invaluable mechanistic insights by defining the chemical and physical features underlying costimulatory receptor:ligand specificity, affinity, oligomeric state, and valency. Furthermore, these structures revealed general architectural features that are important for the integration of these interactions and their associated signaling pathways into overall cellular physiology.

1.8 A structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cells.

Glucocorticoid-induced TNF receptor ligand (GITRL), a prominent member of the TNF superfamily, activates its receptor on both effector and regulatory T cells to generate critical costimulatory signals that have been implicated in a wide range of T-cell immune functions. The crystal structures of murine and human orthologs of GITRL recombinantly expressed in Escherichia coli have previously been determined. In contrast to all classical TNF structures, including the human GITRL structure, murine GITRL demonstrated a unique ;strand-exchanged' dimeric organization.

Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2.

Programmed death-1 (PD-1) is a member of the CD28/B7 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. The high-resolution crystal structure of the complex formed by the complete ectodomains of murine PD-1 and PD-L2 revealed a 1:1 receptor:ligand stoichiometry and displayed a binding interface and overall molecular organization distinct from that observed in the CTLA-4/B7 inhibitory complexes. Furthermore, our structure also provides insights into the association between PD-1 and PD-L1 and highlights differences in the interfaces formed by the two PD-1 ligands (PD-Ls) Mutagenesis studies confirmed the details of the proposed PD-1/PD-L binding interfaces and allowed for the design of a mutant PD-1 receptor with enhanced affinity.

The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum.

The PD-1 costimulatory receptor inhibits T cell receptor signaling upon interacting with its ligands PD-L1 and PD-L2. The PD-1/PD-L pathway is critical in maintaining self-tolerance. In this study, we examined the role of PD-1 in a mouse model of acute infection with Histoplasma capsulatum, a major human pathogenic fungus.

Evolution of GITRL immune function: murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily.

Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. In contrast to all previously characterized homotrimeric TNF family members, the mouse GITRL crystal structure reveals a previously unrecognized dimeric assembly that is stabilized via a unique "domain-swapping" interaction. Consistent with its crystal structure, mouse GITRL exists as a stable dimer in solution.

Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function.

Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF family, binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. Structural analysis reveals that the human GITRL (hGITRL) ectodomain self-assembles into an atypical expanded homotrimer with sparse monomer-monomer interfaces. Consistent with the small intersubunit interfaces, hGITRL exhibits a relatively weak tendency to trimerize in solution and displays a monomer-trimer equilibrium not reported for other TNF family members.

Structure of CD84 provides insight into SLAM family function.

The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. These receptors share a common ectodomain organization: a membrane-proximal immunoglobulin constant domain and a membrane-distal immunoglobulin variable domain that is responsible for ligand recognition. CD84 is a homophilic family member that enhances IFN-gamma secretion in activated T cells.