Inference of Evolutionary Jumps in Large Phylogenies using Lévy Processes.

Although it is now widely accepted that the rate of phenotypic evolution may not necessarily be constant across large phylogenies, the frequency and phylogenetic position of periods of rapid evolution remain unclear. In his highly influential view of evolution, G. G. Simpson supposed that such evolutionary jumps occur when organisms transition into so-called new adaptive zones, for instance after dispersal into a new geographic area, after rapid climatic changes, or following the appearance of an evolutionary novelty. Only recently, large, accurate and well calibrated phylogenies have become available that allow testing this hypothesis directly, yet inferring evolutionary jumps remains computationally very challenging. Here, we develop a computationally highly efficient algorithm to accurately infer the rate and strength of evolutionary jumps as well as their phylogenetic location. Following previous work we model evolutionary jumps as a compound process, but introduce a novel approach to sample jump configurations that does not require matrix inversions and thus naturally scales to large trees. We then make use of this development to infer evolutionary jumps in Anolis lizards and Loriinii parrots where we find strong signal for such jumps at the basis of clades that transitioned into new adaptive zones, just as postulated by Simpson's hypothesis. [evolutionary jump; Lévy process; phenotypic evolution; punctuated equilibrium; quantitative traits.

Predictive control of intersegmental tarsal movements in an insect.

In many animals intersegmental reflexes are important for postural and movement control but are still poorly undesrtood. Mathematical methods can be used to model the responses to stimulation, and thus go beyond a simple description of responses to specific inputs. Here we analyse an intersegmental reflex of the foot (tarsus) of the locust hind leg, which raises the tarsus when the tibia is flexed and depresses it when the tibia is extended. A novel method is described to measure and quantify the intersegmental responses of the tarsus to a stimulus to the femoro-tibial chordotonal organ. An Artificial Neural Network, the Time Delay Neural Network, was applied to understand the properties and dynamics of the reflex responses. The aim of this study was twofold: first to develop an accurate method to record and analyse the movement of an appendage and second, to apply methods to model the responses using Artificial Neural Networks. The results show that Artificial Neural Networks provide accurate predictions of tarsal movement when trained with an average reflex response to Gaussian White Noise stimulation compared to linear models. Furthermore, the Artificial Neural Network model can predict the individual responses of each animal and responses to others inputs such as a sinusoid. A detailed understanding of such a reflex response could be included in the design of orthoses or functional electrical stimulation treatments to improve walking in patients with neurological disorders as well as the bio/inspired design of robots.

Comparison of mechanical properties and host tissue response to OviTex™ and Strattice™ surgical meshes.

PURPOSE: This study compared the in vitro/benchtop and in vivo mechanical properties and host biologic response to ovine rumen-derived/polymer mesh hybrid OviTex™ with porcine-derived acellular dermal matrix Strattice™ Firm. METHODS: OviTex 2S Resorbable (OviTex 2S-R) and Strattice morphology were examined in vitro using histology and scanning electron microscopy; mechanical properties were assessed via tensile test; in vivo host biologic response and explant mechanics were evaluated in a rodent subcutaneous model. Separately, OviTex 1S Permanent (OviTex 1S-P) and Strattice were evaluated in a primate abdominal wall repair model. RESULTS: OviTex 2S-R demonstrated layer separation, whereas Strattice retained its structural integrity and demonstrated higher maximum load than OviTex 2S-R out-of-package (124.8 ± 11.1 N/cm vs 37.9 ± 5.5 N/cm, p < 0.001), 24 h (55.7 ± 7.4 N/cm vs 5.6 ± 3.8 N/cm, p < 0.001), 48 h (45.3 ± 14.8 N/cm vs 2.8 ± 2.6 N/cm, p = 0.003), and 72 h (29.2 ± 10.5 N/cm vs 3.2 ± 3.1 N/cm, p = 0.006) following collagenase digestion. In rodents, inflammatory cell infiltration was observed between OviTex 2S-R layers, while Strattice induced a minimal inflammatory response. Strattice retained higher maximum load at 3 (46.3 ± 27.4 N/cm vs 9.5 ± 3.2 N/cm, p = 0.041) and 6 weeks (28.6 ± 14.1 N/cm vs 7.0 ± 3.0 N/cm, p = 0.029). In primates, OviTex 1S-P exhibited loss of composite mesh integrity whereas Strattice integrated into host tissue with minimal inflammation and retained higher maximum load at 1 month than OviTex 1S-P (66.8 ± 43.4 N/cm vs 9.6 ± 4.4 N/cm; p = 0.151). CONCLUSIONS: Strattice retained greater mechanical strength as shown by lower susceptibility to collagenase degradation than OviTex 2S-R in vitro, as well as higher maximum load and improved host biologic response than OviTex 2S-R in rodents and OviTex 1S-P in primates.

Budget impact of the Oncotype DX® test compared to other gene expression tests in patients with early breast cancer in Germany.

PURPOSE: Gene expression tests can inform decisions on whether to recommend chemotherapy for patients with HR+, HER2- early breast cancer. The goal of this analysis was to compare treatment costs by an expanded budget impact model of reimbursed gene expression tests in Germany. METHODS: A cost comparison was constructed as an expanded budget impact model to calculate average total costs per patient covered by public health insurance. Based on the strong clinical evidence from the prospective randomized controlled trial TAILORx including more than 10,000 patients with HR+ and node negative breast cancer, the assumption was made that the Oncotype DX® test accurately predicts chemotherapy benefit and clinical outcomes. For the further reimbursed tests (EndoPredict®, MammaPrint®, Prosigna®), results from comparative studies - aligned with prognosis studies - as analyzed in IQWiG Rapid Report D19-01 were applied. RESULTS: The use of the Oncotype DX test led to estimated average savings per patient of 2,500 € vs. EndoPredict, 1,936 € vs. MammaPrint, and 649 € vs. Prosigna. Savings were achieved by reduction of unnecessary chemotherapy use, a consequence of false-positive test results (EndoPredict 73%, MammaPrint 42%, Prosigna 20%). False-negative test results (EndoPredict 5%, MammaPrint 22%, Prosigna 49%) reduced necessary chemotherapies, which initially results in cost savings, but may lead to increased long-term costs associated with management of progressive disease. CONCLUSION: The results from this model suggest that the use of the Oncotype DX test reduces the cost of health care in Germany making it the most cost effective test compared to the further tests.

CD4+ murine T cell clones that express high levels of immunoglobulin binding belong to the interleukin 4-producing T helper cell type 2 subset.

A panel of 20 murine CD4+ clones was examined for the presence of surface membrane receptors for IgA, IgM, IgD, IgE, and IgG. High level expression of multiple Fc receptors (FcRs) was found on all Th2 clones. FcR expression was low or undetected on the Th1 clones. The preferential expression of FcR on activated Th2 cells suggests potential mechanisms for immunoregulatory interactions with B cells.

Impact of inflammation-mediated response on pan-coronary plaque vulnerability, myocardial viability and ventricular remodeling in the postinfarction period - the VIABILITY study: Protocol for a non-randomized prospective clinical study.

INTRODUCTION: While the role of inflammation in acute coronary events is well established, the impact of inflammatory-mediated vulnerability of coronary plaques from the entire coronary tree, on the extension of ventricular remodeling and scaring, has not been clarified yet. MATERIALS AND METHODS: The present manuscript describes the procedures of the VIABILITY trial, a descriptive prospective single-center cohort study. The main purpose of this trial is to assess the link between systemic inflammation, pan-coronary plaque vulnerability (referring to the plaque vulnerability within the entire coronary tree), myocardial viability and ventricular remodeling in patients who had suffered a recent ST-segment elevation acute myocardial infarction (STEMI). One hundred patients with STEMI who underwent successful revascularization of the culprit lesion in the first 12 hours after the onset of symptoms will be enrolled in the study. The level of systemic inflammation will be evaluated based on the serum biomarker levels (hs-CRP, matrix metalloproteinases, interleukin-6) in the acute phase of the myocardial infarction (MI) and at 1 month. Pan-coronary plaque vulnerability will be assessed based on serum biomarkers known to be associated with increased plaque vulnerability (V-CAM or I-CAM) and at 1 month after infarction, based on computed tomographic angiography analysis of vulnerability features of all coronary plaques. Myocardial viability and remodeling will be assessed based on 3D speckle tracking echocardiography associated with dobutamine infusion and LGE-CMR associated with post-processing imaging methods. The study population will be categorized in 2 subgroups: subgroup 1 - subjects with STEMI and increased inflammatory response at 7 days after the acute event (hs-CRP ≥ 3 mg/dl), and subgroup 2 - subjects with STEMI and no increased inflammatory response at 7 days (hs-CRP < 3 mg/dl). Study outcomes will consist in the rate of post-infarction heart failure development and the major adverse events (MACE) rate. CONCLUSION: VIABILITY is the first prospective study designed to evaluate the influence of infarct-related inflammatory response on several major determinants of post-infarction outcomes, such as coronary plaque vulnerability, myocardial viability, and ventricular remodeling.

Exploring the effects of walking the labyrinth.

PURPOSE: This pilot study examines the effects of walking a labyrinth. METHOD: A convenience sample of 25 community members participated in a four-group, repeated measures study to gather information about vital signs and affect before and after labyrinth walks. Because of the small sample size, results were inspected for effect size (ES) differences in pre-to postcomparisons. Mean postwalk scores were also compared to control group scores. FINDINGS: Systolic and diastolic blood pressures showed essentially no ES differences pre to postwalk. The remaining ES comparisons showed .14 ES for pulse differences, .37 ES for respirations, and .22 and .56 ES differences for positive and negative affect measures, respectively. CONCLUSIONS: Comparisons of postwalk scores for walkers to nonwalkers showed mixed results in significance of differences. IMPLICATIONS: This pilot study shows the feasibility of the procedures for assessing the effects of labyrinth walking on basic parameters of health.

Spirituality and clinical care: exploring developmental changes in nursing and medical students.

OBJECTIVE: This study identifies and assesses changes in spiritual experiences and the perceived importance of spiritual issues in nursing and medical students participating in a Spirituality and Clinical Care course. Students participated in the study by completing two survey instruments: the Spiritual Experience Index-Revised (SEI-R) and the Spiritual Importance (SI) scales. Differences from pretest to posttest by sex and by discipline (medicine vs nursing) and changes in spiritual maturity are assessed and analyzed. RESULTS: Data analyses explored discipline differences, sex differences, and changes in levels of spiritual maturity one year after the two-week course. Students (N = 416) participating in the course reflected a significant increase in perceived importance of spirituality in practice, with females of both disciplines showing greater increases than males, and students in nursing showing greater increases than students in medicine. Female students were more trusting than male students in spiritual measures for support. An interesting finding revealed that both male and female students evidenced reduced dogmatic perceptions over time, with medical students declining more sharply than nursing students. Finally, changes in the levels of spiritual maturity of the students were measured. Students in contrasting developmental groups (n = 127) regressed over time to more dogmatic and underdeveloped levels of spiritual maturity. CONCLUSIONS: Maintenance or advancement of spiritual development was the expected outcome as students began to develop the art of their practice. It was unexpected that students would regress to a more dogmatic or underdeveloped spiritual level. Several explanations for these findings are explored.

A modified two-stage Markov clustering algorithm for large and sparse networks.

BACKGROUND: Graph-based hierarchical clustering algorithms become prohibitively costly in both execution time and storage space, as the number of nodes approaches the order of millions. OBJECTIVE: A fast and highly memory efficient Markov clustering algorithm is proposed to perform the classification of huge sparse networks using an ordinary personal computer. METHODS: Improvements compared to previous versions are achieved through adequately chosen data structures that facilitate the efficient handling of symmetric sparse matrices. Clustering is performed in two stages: the initial connected network is processed in a sparse matrix until it breaks into isolated, small, and relatively dense subgraphs, which are then processed separately until convergence is obtained. An intelligent stopping criterion is also proposed to quit further processing of a subgraph that tends toward completeness with equal edge weights. The main advantage of this algorithm is that the necessary number of iterations is separately decided for each graph node. RESULTS: The proposed algorithm was tested using the SCOP95 and large synthetic protein sequence data sets. The validation process revealed that the proposed method can reduce 3-6 times the processing time of huge sequence networks compared to previous Markov clustering solutions, without losing anything from the partition quality. CONCLUSIONS: A one-million-node and one-billion-edge protein sequence network defined by a BLAST similarity matrix can be processed with an upper-class personal computer in 100 minutes. Further improvement in speed is possible via parallel data processing, while the extension toward several million nodes needs intermediary data storage, for example on solid state drives.

A Proactive Innovation for Health Care Transformation: Health and Wellness Nurse Coaching.

A cohort of holistic nurses, recognizing opportunities inherent in health care transformation, organized and worked together from 2009 to 2012. The goal was to hold space for holistic nursing by developing a health and wellness coaching role and certification program for holistic nurses. The intent was to ensure that holistic nurses could work to the fullest of their ability within the evolving health care system, and others could discover the merit of holistic nursing as they explored the possibilities of nurse coaching. Challenges emerged that required the cohort plan strategies that would hold the space for nursing while also moving toward the intended goal. As they worked, this cohort demonstrated leadership skills, knowledge, values, and attitudes of holistic nursing that provide an example for others who follow in the wake of health care transformation. The American Holistic Credentialing Corporation's perspective of the events that unfolded and of the related decisions made by the coalition provides a record of the evolution of holistic nursing.

Improved system identification using artificial neural networks and analysis of individual differences in responses of an identified neuron.

Mathematical modelling is used routinely to understand the coding properties and dynamics of responses of neurons and neural networks. Here we analyse the effectiveness of Artificial Neural Networks (ANNs) as a modelling tool for motor neuron responses. We used ANNs to model the synaptic responses of an identified motor neuron, the fast extensor motor neuron, of the desert locust in response to displacement of a sensory organ, the femoral chordotonal organ, which monitors movements of the tibia relative to the femur of the leg. The aim of the study was threefold: first to determine the potential value of ANNs as tools to model and investigate neural networks, second to understand the generalisation properties of ANNs across individuals and to different input signals and third, to understand individual differences in responses of an identified neuron. A metaheuristic algorithm was developed to design the ANN architectures. The performance of the models generated by the ANNs was compared with those generated through previous mathematical models of the same neuron. The results suggest that ANNs are significantly better than LNL and Wiener models in predicting specific neural responses to Gaussian White Noise, but not significantly different when tested with sinusoidal inputs. They are also able to predict responses of the same neuron in different individuals irrespective of which animal was used to develop the model, although notable differences between some individuals were evident.

The influence of tissue transglutaminase on the function of Fc receptors.

In contrast to FcRII the soluble Fc receptor (FcRI) of human peripheral mononuclear blood cells (PMBC) is shed from PMBC following a 4-37 degrees C temperature shift and inhibits rosette formation of nonshed PMBC with antibody-coated erythrocytes (EA). Purified FcR, could be polymerized by tissue transglutaminase as was revealed by SDS-polyacrylamide gel electrophoresis. Comparing the Sephadex G-150 elution profile of the EA rosette inhibitory capacity of FcRI vs FcRI incubated in the presence of transglutaminase, the latter was found in a higher mol. wt region and could inhibit rosette formation by both FcRI and FcRII. Furthermore, the shedding of FcRI could be prevented by the addition of transglutaminase or Ca2+-ionophore A23187 (which leads to the activation of PMBC transglutaminase) to the cell suspension. The function of FcRII was not affected by either the addition of transglutaminase or Ca2+-ionophore to the cells. The results point to the involvement of transglutaminase in the determination of the functional state of the Fc receptor on the cell surface.

Changes in the lateral ordering of the macrophage plasma membrane during Fc receptor mediated phagocytosis.

The macrophage plasma membrane was labelled with an intercalated 5-doxyl stearic acid spin probe, and structural changes induced by IgG-coated erythrocytes (EA) were followed with particular emphasis on the possible role of lipid reordering in the sequential events of phagocytosis. We present three lines of experimental evidence to show that these structural changes were induced by the lateral aggregation of cell surface Fc receptors. Cytochalasin B, an inhibitor of microfilament function, blocked this membrane reordering; if it was added after EA binding induced membrane reordering had already been detected for 15 min, a rapid reversal process was observed resulting in a reversible restoration of the initial order parameter value. We suggest that these structural changes indicate lipid-lipid lateral phase separation, in line with morphological findings.

The binding of IgG1 containing immune complexes to the FcR of allogenically activated T cells induces changes in the membrane potential and the cell surface charge.

The effect on membrane potential and cell surface charge of binding immune complexes containing IgG1 and IgG2a monoclonal antibodies to Fc receptors was studied in resting and allogenically activated murine T cells. IgG1 complexed by antigen or heat aggregation induced electrophysiological changes on activated T cells. A biphasic alteration of membrane potential was detected by measurement of the intra- and extracellular distribution of the fluorescent dye, DiOC6. A short-lived hyperpolarization, detectable for 4-6 min after adding the respective ligand, was followed by a longer lasting depolarization. The cell surface charge, measured by cell electrophoresis, was also changed. This alteration was detected 2-4 hr after addition of immune complexes and disappeared by the 8th hr of incubation. Monoclonal antibody 2.4.G2, reactive with mouse FcR, induced a similar membrane potential response on activated T cells, but did not affect the cell surface charge. Monomeric IgGs and complexes of IgG2a did not modify these parameters. FcR ligands had no effect on the studied characteristics of resting T cells.

Immunoglobulin (Fc) receptors on murine T- and B-lymphocytes: investigations using tumor models.

Lymphoid tumors are productive experimental models for the study of lymphocyte immunoglobulin receptors. Investigations with Fc receptor expressing lymphoid tumor cells have generated much useful information about: (a) the developmental expression of the different classes of Fc receptors on lymphoid cells of the T- and B-lineages; (b) the biochemical steps involved in the regulation of Fc receptor expression on lymphoid cells; (c) the structures of lymphoid cell Fc receptors and their genes; (d) the signals that induce alterations in the expression of Fc receptors on lymphoid cells; and (e) the molecular specificity of the binding of immunoglobulin to lymphoid cells Fc receptors. In addition, tumors that secrete immunoglobulins are providing useful models for analysis of the mechanisms by which B-cells influence Fc receptor expression and function on T-cells. An interesting, bi-directional immunoregulatory circuit involving Fc epsilon R+ host T-cells and IgE-secreting hybridoma cells has been identified that could prove useful in the analysis of the regulation of epsilon heavy chain expression. The studies discussed in this article and elsewhere in this volume serve to emphasize that, in addition to being clonal sources of key molecules such as Fc receptors and their messenger RNAs, lymphoid tumor cells that express Fc receptors are powerful and unique experimental models for investigating the developmental biology, regulation and function of lymphocyte Fc receptors.

The Fc epsilon RII/CD23 gene is actively transcribed during all stages of murine B-lymphocyte development.

It is generally accepted that the expression of Fc epsilon RII/CD23 on the surface of the B-lineage cells is restricted to the stage of the resting, mature (sIgM+/sIgD+) B-lymphocyte. However, it is unknown whether activation of the Fc epsilon RII/CD23 gene is also restricted to the stage of the mature B-lymphocyte. To address this question we investigated a panel of B-lineage cell lines for the presence of transcripts encoding Fc epsilon RII/CD23. We detected transcripts in 16 of 26 B-lineage cell lines representing the entire spectrum of B-cell development. In most cases (13 of 16) active transcription of the murine Fc epsilon RII/CD23 gene was not coupled with the expression of cell surface Fc epsilon RII/CD23 expression did not hold for all murine B-cell lines. One post-switch B-cell line (sIgM-/sIgG+) expressed Fc epsilon RII/CD23 on the cell surface and another could be induced with IL-4 and LPS to express surface Fc epsilon RII/CD23. Transcription of the murine CD23 gene in the absence of cell surface expression of Fc epsilon RII/CD23 does not appear to simply be an aberrant feature of transformed B-cells since we found transcripts, but not surface expression, in some normal splenic and peritoneal B-lymphocytes. Our findings suggest that the potential for expression of Fc epsilon RII/CD23 may occur over a much broader development window of the B-lineage than previously suspected. Transcription of the Fc epsilon RII/CD23 gene, in the absence of detectable cell surface protein expression in B-lineage cell lines, and in sort-purified B-lymphocyte subpopulations, implies that in addition to regulatory mechanisms already known, murine CD23 is also regulated through post-transcriptional mechanisms that have not yet been characterized.

Inhibition of antigen-specific T cell trafficking into the central nervous system via blocking PECAM1/CD31 molecule.

Trafficking of antigen-specific T cells into the central nervous system (CNS) is an important initiating step in inflammation in the brain. In spite of the extensive knowledge about the role of adhesion molecules in T cell migration across peripheral vessels, the mechanism of the entry of antigen-specific T cells into the CNS is not known. This work was designed to study the regulatory roles of adhesion molecules in antigen-specific T cell migration into the CNS. Antigen-specific T cells were tracked in an in vivo migration assay using T cell receptor (TCR) transgenic mice having 95% of T cells specific for a defined antigen. pigeon cytochrome c (PCC). TCR transgenic mice were cannulated intraventricularly (IVT) for PCC antigen infusion and cerebrospinal fluid (CSF) sampling. Upon PCC infusion into the CNS, the number of alpha/beta TCR+ Vbeta3+ Mac1- cells in the CSF was characterized in the presence or absence of anti-adhesion molecule reagents. We found that antibodies against VCAM-1 (CD106), VLA-4 (CD49d/CD29), ICAM-1 (CD54), and LFA-1 (CD11a/CD18) did not influence the increased number of antigen-specific T cells in the CSF However, upon intravenous (i.v.) injection, anti-PECAM-1 (CD31) antibody or PECAM-Ig chimeric molecule inhibited the trafficking of alpha/beta TCR+ Vbeta3+ Mac1- cells into the CNS. The expression of PECAM-1 (CD31) was also up-regulated on antigen-specific T cells in a time-dependent manner in vitro upon antigenic stimulation. The antigen-induced activation of T cells in vivo was measured by CD44 and LFA-1 expression and found to be comparable between mPECAMIg-treated mice and wild-type serum control-treated groups. This indicates that CD31 inhibition of antigen-specific T cell accumulation in the CNS is probably not due to a functional inhibition of these cells. Finally, adoptive transfer of CFSE-labeled AND transgenic cells into naïve animals resulted in the accumulation of these cells in the CNS upon PCC IVT immunization that was also inhibited by mPECAMIg treatment. Hence, PECAM-1 (CD31) might play an important role in regulating antigen-specific T cells trafficking in CNS inflammatory diseases.

Expression of IgA and IgM Fc receptors on murine T lymphocytes.

Fc receptors are induced on T cells following activation via the TCR. T cells that express Fc receptors transiently have the ability to use two different cognate systems: the TCR and immunoglobulins bound to the Fc receptors. The studies discussed in this article are focused on the Fc alpha and Fc mu receptors that can be induced on certain subsets of murine T lymphocytes. The article emphasizes the role of the T cell receptor for antigen in the expression of Fc alpha and Fc mu receptors on murine T cells and reviews experimental observations that suggest significant molecular heterogeneity of these Fc receptors. The finding that regulation of expression of Fc alpha receptors and Fc mu receptors on T lymphocytes is linked to cellular activation via the CD3/TCR complex implies that these Fc receptors might mediate important functions in the biology and pathology of T cells.