Altitudinal Movements and Summer Habitat Preferences of Woodland Caribou in the Kluane Ranges, Yukon Territory

The altitudinal movements, preferred topography and plant communities of 150 to 200 woodland caribou (Rangifer tarandus caribou) were recorded for two summers. Nine subalpine or alpine tundra communities constituting their major summer range were quantitatively described. Caribou calved in shrub communities between 1300 and 1450 m, moving upward as the summer progressed. Stags and associated juveniles preferred higher elevations than did other groupings. Caribou disproportionately chose north-facing slopes of less than 20 deg. They fed in birch-sedge meadow and sedge meadow communities nearly twice as much as expected from the areal extent of the communities, and also disproportionately chose other communities with high sedge components. The presence of sedges was the predominant vegetational characteristic chosen regardless of elevations, with only minor differences between caribou sex and age groupings

Shaping innate immune responses: mechanisms that control type I interferon production

Type I interferons (IFN-I) are pleiotropic cytokines that were originally identified for their antiviral properties and are now recognized for playing key roles in the defense against a range of other microorganisms as well as cancer. Their production should be well-controlled to be of benefit to the host, as excessive or chronic IFN-I expression leads to adverse effects such as immunosuppression or the induction of severe immunopathology.The studies presented in this thesis are aimed at uncovering mechanisms that regulate the production of IFN-I. The obtained knowledge on the involved molecular processes, may aid the development of targeted therapies that enhance or intercept IFN-I responses for maximum host protection while minimizing damage.NWO graduate programme (no. 022.006.010)LUMC / Geneeskund

Systematic Review of Multidisciplinary Chronic Pain Treatment Facilities

This study reviewed the published literature evaluating multidisciplinary chronic pain treatment facilities to provide an overview of their availability, caseload, wait times, and facility characteristics. A systematic literature review was conducted using PRISMA guidelines following a search of MEDLINE, PsycINFO, and CINAHL databases. Inclusion criteria stipulated that studies be original research, survey more than one pain treatment facility directly, and describe a range of available treatments. Fourteen articles satisfied inclusion criteria. Results showed little consistency in the research design used to describe pain treatment facilities. Availability of pain treatment facilities was scarce and the reported caseloads and wait times were generally high. A wide range of medical, physical, and psychological pain treatments were available. Most studies reported findings on the percentage of practitioners in different health care professions employed. Future studies should consider using more comprehensive search strategies to survey facilities, improving clarity on what is considered to be a pain treatment facility, and reporting on a consistent set of variables to provide a clear summary of the status of pain treatment facilities. This review highlights important information for policymakers on the scope, demand, and accessibility of pain treatment facilities.Samantha Fashler is supported by an Ontario Graduate Scholarship and a Canadian Institutes of Health Research (CIHR) Vanier Canada Graduate Scholarship. Lindsay Burns is supported by a Frederick Banting and Charles Best CIHR Doctoral Scholarship. Joel Katz is supported by a CIHR Canada Research Chair in Health Psychology. This project was conducted in collaboration with the Canadian Pain Coalition (CPC) as a part of the Report Card on Pain

Having Fun in Learning Formal Specifications

There are many benefits in providing formal specifications for our software. However, teaching students to do this is not always easy as courses on formal methods are often experienced as dry by students. This paper presents a game called FormalZ that teachers can use to introduce some variation in their class. Students can have some fun in playing the game and, while doing so, also learn the basics of writing formal specifications in the form of pre- and post-conditions. Unlike existing software engineering themed education games such as Pex and Code Defenders, FormalZ takes the deep gamification approach where playing gets a more central role in order to generate more engagement. This short paper presents our work in progress: the first implementation of FormalZ along with the result of a preliminary users' evaluation. This implementation is functionally complete and tested, but the polishing of its user interface is still future work

Chemical Tools for Studying TLR Signaling Dynamics

Therapeutic cell differentiatio

An alternative model for type I interferon induction downstream of human TLR2

Surface-exposed Toll-like receptors (TLRs) such as TLR2 and TLR4 survey the extracellular environment for pathogens. TLR activation initiates the production of various cytokines and chemokines including type I interferons (IFN-I). Downstream of TLR4, IFNβ secretion is only vigorously triggered in macrophages when the receptor undergoes endocytosis and switches signaling adaptor; surface TLR4 engagement predominantly induces proinflammatory cytokines via the signaling adaptor MyD88. It is unclear if this dichotomy is generally applicable to other TLRs, cell types, or differentiation states. Here, we report that diverse TLR2 ligands induce an IFN-I response in human monocyte-like cells, but not in differentiated macrophages. This TLR2-dependent IFN-I signaling originates from the cell surface and is dependent on MyD88; it involves combined activation of the transcription factors IRF3 and NF-κB, driven by the kinases TBK1 and TAK1-IKKβ, respectively. TLR2-stimulated monocytes produced modest IFNβ levels that caused productive downstream signaling, reflected by STAT1-phosphorylation and expression of numerous interferon-stimulated genes (ISGs). Our findings reveal that the outcome of TLR2 signaling includes an IFN-I response in human monocytes, which is lost upon macrophage differentiation, and differs mechanistically from IFN-I-induction through TLR4. These findings point to molecular mechanisms tailored to the differentiation state of a cell and the nature of receptors activated to control and limit TLR-triggered IFN-I responses.Bio-organic Synthesi

A Multi-Scale Test of the Forage Maturation Hypothesis in a Partially Migratory Ungulate Population

The forage maturation hypothesis (FMH) proposes that ungulate migration is driven by selection for high forage quality. Because quality declines with plant maturation, but intake declines at low biomass, ungulates are predicted to select for intermediate forage biomass to maximize energy intake by following phenological gradients during the growing season. We tested the FMH in the Canadian Rocky Mountains by comparing forage availability and selection by both migrant and nonmigratory resident elk (Cervus elaphus) during three growing seasons from 2002-2004. First, we confirmed that the expected trade-off between forage quality and quantity occurred across vegetation communities. Next, we modeled forage biomass and phenology during the growing season by combining ground and remote-sensing approaches. The growing season started 2.2 days earlier every 1 km east of the continental divide, was delayed by 50 days for every 1000-m increase in elevation, and occurred 8 days earlier on south aspects. Migrant and resident selection for forage biomass was then compared across three spatial scales (across the study area, within summer home ranges, and along movement paths) using VHF and GPS telemetry locations from 119 female elk. Migrant home ranges occurred closer to the continental divide in areas of higher topographical diversity, resulting in migrants consistently selecting for intermediate biomass at the two largest scales, but not at the. nest scale along movement paths. In contrast, residents selected maximum forage biomass across all spatial scales. To evaluate the consequences of selection, we compared exposure at telemetry locations of migrant and resident elk to expected forage biomass and digestibility. The expected digestibility for migrant elk in summer was 6.5% higher than for residents, which was corroborated with higher fecal nitrogen levels for migrants. The observed differences in digestibility should increase migrant elk body mass, pregnancy rates, and adult and calf survival rates. Whether bottom-up effects of improved forage quality are realized will ultimately depend on trade-offs between forage and predation. Nevertheless, this study provides comprehensive evidence that montane ungulate migration leads to greater access to higher-quality forage relative to nonmigratory congeners, as predicted by the forage maturation hypothesis, resulting primarily from large-scale selection patterns

Submaximal Exercise Testing in Cardiovascular Rehabilitation Settings (BEST Study)

Abstract BACKGROUND: This study compared changes in measured versus predicted peak aerobic power (V̇O2 peak) following cardiovascular rehabilitation (CR). Peak cardiopulmonary exercise testing (CPET) results were compared to four V̇O2 peak estimation methods: the submaximal modified Bruce treadmill, Astrand-Ryhming cycle ergometer, and Chester step tests, and the Duke Activity Status Index (DASI). METHODS: Adults with cardiovascular disease (CVD) who completed a 12-week CR program were assessed at baseline and 12 weeks follow-up. CPET, the DASI and three subsequent submaximal exercise tests were performed in a random order. RESULTS: Of the 50 adults (age: 57 ± 11 years) who participated, 46 completed the 12-week CR program and exercise tests. At baseline 69, 68, and 38% of the treadmill, step and cycle tests were successfully completed, respectively. At follow-up 67, 80, and 46% of the treadmill, step and cycle tests were successfully completed, respectively. No severe adverse events occurred. Significant improvements in V̇O2 peak were observed with CPET (3.6 ± 5.5 mL.kg-1.min-1, p < 0.001) and the DASI (2.3 ± 4.2 mL.kg-1.min-1, p < 0.001). Bland-Altman plots of the change in V̇O2 peak between CPET and the four V̇O2 peak estimation methods revealed the following: a proportional bias and heteroscedastic 95% limits of agreement (95% LoA) for the treadmill test, and for the cycle and step tests and DASI, mean bias' and 95% LoA of 1.0 mL.kg-1.min-1 (21.3, -19.3), 1.4 mL.kg-1.min-1 (15.0, -12.3) and 1.0 mL.kg-1.min-1 (13.8, -11.8), respectively. CONCLUSION: Given the greater number of successful tests, no serious adverse events and acceptable mean bias, the step test appears to be a valid and safe method for assessing group-level mean changes in V̇O2 peak among patients in CR. The DASI also appears to be a valid and practical questionnaire. Wide limits of agreement, however, limit their use to predict individual-level changes. Copyright © 2020 Reed, Cotie, Cole, Harris, Moran, Scott, Terada, Buckley and Pipe. KEYWORDS: cardiovascular diseases; exercise test; physiology; rehabilitation; submaxima

The Epstein-Barr Virus Glycoprotein gp150 Forms an Immune-Evasive Glycan Shield at the Surface of Infected Cells

Cell-mediated immunity plays a key role in host control of viral infection. This is exemplified by life-threatening reactivations of e.g. herpesviruses in individuals with impaired T-cell and/or iNKT cell responses. To allow lifelong persistence and virus production in the face of primed immunity, herpesviruses exploit immune evasion strategies. These include a reduction in viral antigen expression during latency and a number of escape mechanisms that target antigen presentation pathways. Given the plethora of foreign antigens expressed in virus-producing cells, herpesviruses are conceivably most vulnerable to elimination by cell-mediated immunity during the replicative phase of infection. Here, we show that a prototypic herpesvirus, Epstein-Barr virus (EBV), encodes a novel, broadly acting immunoevasin, gp150, that is expressed during the late phase of viral replication. In particular, EBV gp150 inhibits antigen presentation by HLA class I, HLA class II, and the non-classical, lipid-presenting CD1d molecules. The mechanism of gp150-mediated T-cell escape does not depend on degradation of the antigen-presenting molecules nor does it require gp150’s cytoplasmic tail. Through its abundant glycosylation, gp150 creates a shield that impedes surface presentation of antigen. This is an unprecedented immune evasion mechanism for herpesviruses. In view of its likely broader target range, gp150 could additionally have an impact beyond escape of T cell activation. Importantly, B cells infected with a gp150-null mutant EBV displayed rescued levels of surface antigen presentation by HLA class I, HLA class II, and CD1d, supporting an important role for iNKT cells next to classical T cells in fighting EBV infection. At the same time, our results indicate that EBV gp150 prolongs the timespan for producing viral offspring at the most vulnerable stage of the viral life cycle

Conditionally controlling human TLR2 activity via Trans-Cyclooctene Caged Ligands

Toll-like receptors (TLRs) are key pathogen sensors of the immune system. Their activation results in the production of cytokines, chemokines, and costimulatory molecules that are crucial for innate and adaptive immune responses. In recent years, specific (sub)-cellular location and timing of TLR activation have emerged as parameters for defining the signaling outcome and magnitude. To study the subtlety of this signaling, we here report a new molecular tool to control the activation of TLR2 via "click-to-release"-chemistry. We conjugated a bioorthogonal trans-cyclooctene (TCO) protecting group via solid support to a critical position within a synthetic TLR2/6 ligand to render the compound unable to initiate signaling. The TCO-group could then be conditionally removed upon addition of a tetrazine, resulting in restored agonist activity and TLR2 activation. This approach was validated on RAW264.7 macrophages and various murine primary immune cells as well as human cell line systems, demonstrating that TCO-caging constitutes a versatile approach for generating chemically controllable TLR2 agonists.Bio-organic Synthesi