Changes in hypothalamic-pituitary-adrenal axis function, immunity, and glucose during acute Plasmodium relictum infection in house sparrows (Passer domesticus).

Hosts of the same species vary in physiological responses to the same parasite, and some groups of individuals can disproportionately affect disease dynamics; however, the underlying pathophysiology of host-parasite interactions is poorly understood in wildlife. We tested the hypothesis that the hypothalamic-pituitary-adrenal (HPA) axis mediates host resistance and tolerance to avian malaria during the acute phase of infection by evaluating whether individual variation in circulating glucocorticoids predicted resistance to avian malaria in a songbird. We experimentally inoculated wild-caught house sparrows (Passer domesticus) with naturally sourced Plasmodium relictum and quantified baseline and restraint-induced circulating corticosterone, negative feedback ability, cellular and humoral immune function, and baseline and restraint-induced glycemia, prior to and during acute malaria infection. During peak parasitemia, we also evaluated the expression of several liver cytokines that are established pathological hallmarks of malaria in mammals: two pro-inflammatory (IFN-γ and TNF-α) and two anti-inflammatory (IL-10 and TGF-ß). Although most of the host metrics we evaluated were not correlated with host resistance or tolerance to avian malaria, this experiment revealed novel relationships between malarial parasites and the avian immune system that further our understanding of the pathology of malaria infection in birds. Specifically, we found that: (1) TNF-α liver expression was positively correlated with parasitemia; (2) sparrows exhibited an anti-inflammatory profile during malaria infection; and (3) IFN-γ and circulating glucose were associated with several immune parameters, but only in infected sparrows. We also found that, during the acute phase of infection, sparrows increased the strength of corticosterone negative feedback at the level of the pituitary. In the context of our results, we discuss future methodological considerations and aspects of host physiology that may confer resistance to avian malaria, which can help inform conservation and rehabilitation strategies for avifauna at risk.

Concordance of the Adaptive Behavior Assessment System, second and third editions.

BACKGROUND: Adaptive functioning is an important area of assessment with implications for differential diagnosis, educational placement, service eligibility and criminal sentencing. While periodic normative and content updates of adaptive functioning measures are necessary to keep measures relevant, knowledge of equivalence between versions is also required if adaptive measures are to be used to track the stability of adaptive functioning skills over time. METHOD: This paper presents two studies that used between-group and within-group comparison designs to examine the equivalence of the second and third editions of the Adaptive Behavior Assessment System (ABAS) in a mixed clinical sample. In study 1, ABAS-2 scores for children assessed between 2014 and 2015 (n = 1036; mean age = 10.24, SD = 3.44) were compared with ABAS-3 scores for children assessed between 2015 and 2016 (n = 1291; mean age = 10.51, SD = 3.70). Study 2 examined a separate sample of clinically referred children (n = 572) for whom parent ratings had been obtained on both the ABAS-2 (mean age = 9.65, SD = 2.80) and ABAS-3 (mean age = 13.33, SD = 2.95) in the course of repeated assessment. RESULTS: For Study 1, while no intelligence quotient score differences were observed between the ABAS-2 group (mean Verbal Comprehension Index = 93.67, SD = 16.95) and the ABAS-3 group (mean Verbal Comprehension Index = 93.08, SD = 17.42), ABAS-2 scores were lower than ABAS-3 scores on the Conceptual, Practical, and General Adaptive Composite scales. In study 2, a similar pattern was observed (ABAS-2 < ABAS-3 on the Conceptual, Practical, and General Adaptive Composite scales), and concordance correlation coefficients ranged from 0.54 [0.49, 0.58] (Practical composite) to 0.68 [0.64, 0.72] (Conceptual composite). The Practical composite had the lowest concordance correlation coefficient value and the largest mean score difference between ABAS versions. CONCLUSIONS: The ABAS-3 scores may be higher than ABAS-2 scores in clinical populations. Knowledge of these potential discrepancies will be critical when interpreting standard score changes across ABAS versions in the course of clinical, educational and forensic assessments.

A novel approach for selecting extreme climate change scenarios for climate change impact studies.

One of the main challenges in climate change impact assessment studies is selecting climate change scenarios. By focusing on selecting projected extremes in a high dimensional space, one is confronted with the shrinkage of ensemble size while preserving the projection spread. This study proposes a novel integrated computational geometry algorithm to select extreme climate change scenarios in a high dimensional space. A set of 12 prominent climate extremes indices were used (as input to the algorithm) out of the 27 core indices recommended by the World Meteorological Organization's Expert Team on Climate Change Detection and Indices (ETCCDI). The ETCCDI indices were projected by Coupled Model Intercomparison Project Phase 5 (CMIP5) for the period of 2081-2100 relative to the baseline period 1986-2005. The approach enables the user to shrink the initial selected ensemble into smaller sub-ensembles while still capturing a wide range of simulated changes for selected climatological variables. The conservation of the projection spread was evaluated using a robust validation method when the spread error was calculated for each simulation run. The developed algorithm was applied to three different regions where the geographical domain was narrowed-down from sub-continental (western North America) to its regional (Alberta, Canada), and local (Athabasca River basin, Alberta, Canada) subdomains. Results revealed that selected extreme scenarios can vary from one region to another within the same geographical domain in response to the spatial variation in climatic regime.

A long-term, temporally consistent, gridded daily meteorological dataset for northwestern North America.

We describe a spatially contiguous, temporally consistent high-resolution gridded daily meteorological dataset for northwestern North America. This >4 million km2 region has high topographic relief, seasonal snowpack, permafrost and glaciers, crosses multiple jurisdictional boundaries and contains the entire Yukon, Mackenzie, Saskatchewan, Fraser and Columbia drainages. We interpolate daily station data to 1/16° spatial resolution using a high-resolution monthly 1971-2000 climatology as a predictor in a thin-plate spline interpolating algorithm. Only temporally consistent climate stations with at least 40 years of record are included. Our approach is designed to produce a dataset well suited for driving hydrological models and training statistical downscaling schemes. We compare our results to two commonly used datasets and show improved performance for climate means, extremes and variability. When used to drive a hydrologic model, our dataset also outperforms these datasets for runoff ratios and streamflow trends in several, high elevation, sub-basins of the Fraser River.

Attribution of the Influence of Human-Induced Climate Change on an Extreme Fire Season.

A record 1.2 million ha burned in British Columbia, Canada's extreme wildfire season of 2017. Key factors in this unprecedented event were the extreme warm and dry conditions that prevailed at the time, which are also reflected in extreme fire weather and behavior metrics. Using an event attribution method and a large ensemble of regional climate model simulations, we show that the risk factors affecting the event, and the area burned itself, were made substantially greater by anthropogenic climate change. We show over 95% of the probability for the observed maximum temperature anomalies is due to anthropogenic factors, that the event's high fire weather/behavior metrics were made 2-4 times more likely, and that anthropogenic climate change increased the area burned by a factor of 7-11. This profound influence of climate change on forest fire extremes in British Columbia, which is likely reflected in other regions and expected to intensify in the future, will require increasing attention in forest management, public health, and infrastructure.

Desoxycorticosterone Pivalate Duration of Action and Individualized Dosing Intervals in Dogs with Primary Hypoadrenocorticism.

BACKGROUND: Clinicians alter dosing for desoxycorticosterone pivalate (DOCP) to mitigate costs, but this practice has not been critically evaluated in a prospective clinical trial. HYPOTHESIS/OBJECTIVES: The duration of action of DOCP is longer than 30 days in dogs with primary hypoadrenocorticism (PH). ANIMALS: A total of 53 client-owned dogs with PH. Twenty-four dogs with newly diagnosed PH (Group 1) and 29 dogs with treated PH (Group 2). METHODS: Prospective, multicenter, clinical trial. For phase I, DOCP was administered and plasma sodium and potassium concentrations were measured until the dog developed hyponatremia or hyperkalemia at a planned evaluation, or displayed clinical signs with plasma electrolyte concentrations outside of the reference interval independent of a planned evaluation, thus defining DOCP duration of action. Plasma electrolyte concentrations then were assessed at the end of the individualized dosing interval (IDI; i.e., DOCP duration of action minus 7 days, phase II and at least 3 months after concluding phase II, phase III). RESULTS: The duration of action of DOCP in dogs in phase I with naïve PH (n = 24) ranged from 32 to 94 days (median, 62 days; 95% confidence interval [CI], 57, 65) and previously treated PH (n = 29) from 41 to 124 days (median, 67 days; CI, 56, 72). Overall, the final DOCP dosing interval for all dogs that completed phase II (n = 36) ranged from 38 days to 90 days (median, 58 days; CI, 53, 61). No dog that completed phase III (n = 15) required reduction in the IDI. The DOCP duration of action, independent of group, was not significantly associated with several baseline variables. The median drug cost reduction using IDI was approximately 57.5% per year. CONCLUSION AND CLINICAL IMPORTANCE: The duration of action of DOCP in dogs with PH is >30 days, and plasma sodium and potassium concentrations can be maintained with an IDI >30 days long term.

Efficacy and safety of liraglutide, a once-daily human glucagon-like peptide-1 receptor agonist, in African-American people with Type 2 diabetes: a meta-analysis of sub-population data from seven phase III trials.

AIM: To evaluate the efficacy and safety of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide in African-American people with Type 2 diabetes. METHODS: Analyses were performed on patient-level data from individuals self-defined as African-American or non-African-American in seven phase III studies. Endpoints included change in HbA1c level, fasting plasma glucose level and body weight from baseline, proportion of patients reaching HbA1c target [< 53 mmol/mol (< 7.0%)], and incidence of hypoglycaemia and nausea. Analyses used data obtained after 26 weeks. Within-population comparisons of liraglutide were performed vs placebo for African-American and non-African-American patient groups. In addition, between-population comparisons with non-African-American patients were performed for each treatment. RESULTS: In African-American patients (n = 225), HbA1c was significantly reduced at 26 weeks with liraglutide 1.2 and 1.8 mg (-11 and -14 mmol/mol, respectively compared with placebo; P < 0.0001). There were also significant reductions in fasting plasma glucose (-2.4 and -3.1 mmol/l, respectively, compared with placebo; P < 0.0001). Statistically significant reductions in body weight were observed with 1.8 mg liraglutide (-2.1 kg compared with placebo; P = 0.0056), but not with 1.2 mg liraglutide (-0.26 kg; P = 0.7307). The P value for interaction between treatment and race was significant for body weight (P = 0.0355). The incidence of non-severe hypoglycaemia with liraglutide was low (11-15% of patients), and < 25% of patients receiving liraglutide experienced nausea. CONCLUSIONS: This meta-analysis suggests that liraglutide is well tolerated and efficacious for treatment of Type 2 diabetes in African-American patients, with an efficacy that was shown not to differ from that observed in non-African-American patients over 26 weeks.

Recurrent activating mutations of CD28 in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T-cell neoplasms with a poor prognosis. Recently, mutations in TET2 and other epigenetic modifiers as well as RHOA have been identified in these diseases, particularly in angioimmunoblastic T-cell lymphoma (AITL). CD28 is the major co-stimulatory receptor in T cells which, upon binding ligand, induces sustained T-cell proliferation and cytokine production when combined with T-cell receptor stimulation. We have identified recurrent mutations in CD28 in PTCLs. Two residues-D124 and T195-were recurrently mutated in 11.3% of cases of AITL and in one case of PTCL, not otherwise specified (PTCL-NOS). Surface plasmon resonance analysis of mutations at these residues with predicted differential partner interactions showed increased affinity for ligand CD86 (residue D124) and increased affinity for intracellular adaptor proteins GRB2 and GADS/GRAP2 (residue T195). Molecular modeling studies on each of these mutations suggested how these mutants result in increased affinities. We found increased transcription of the CD28-responsive genes CD226 and TNFA in cells expressing the T195P mutant in response to CD3 and CD86 co-stimulation and increased downstream activation of NF-κB by both D124V and T195P mutants, suggesting a potential therapeutic target in CD28-mutated PTCLs.

Efficacy and safety of liraglutide 3.0 mg for weight management are similar across races: subgroup analysis across the SCALE and phase II randomized trials.

The efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to diet and exercise, was evaluated in racial subgroups. This post hoc analysis of pooled data from five double-blind randomized, placebo-controlled trials was conducted in 5325 adults with either a body mass index (BMI) ≥27 kg/m(2) plus ≥1 comorbidity or a BMI ≥30 kg/m(2). Statistical interaction tests evaluated possible treatment effect differences between racial subgroups: white (4496, 84.4%), black/African-American (550, 10.3%), Asian (168, 3.2%) and other (111, 2.1%). Effects of liraglutide 3.0 mg on weight loss, associated metabolic effects and safety profile were generally consistent across racial subgroups. All achieved statistically significant mean weight loss at end-of-treatment with liraglutide 3.0 mg versus placebo: white 7.7% versus 2.3%, black/African-American 6.3% versus 1.4%, Asian 6.3% versus 2.5%, other 7.3% versus 0.49%. Treatment effects on weight and cardiovascular risk markers generally showed no dependence on race (interaction test p > 0.05). Adverse events were similar across racial subgroups.

Examining the connectivity between different cellular processes in the Barrett tissue microenvironment.

In Barrett associated tumorigenesis, oxidative phosphorylation and glycolysis are reprogrammed early in the disease sequence and act mutually to promote disease progression. However, the link between energy metabolism and its connection with other central cellular processes within the Barrett microenvironment is unknown. The aim of this study was to examine the relationship between metabolism (ATP5B/GAPDH), hypoxia (HIF1α), inflammation (IL1ß/SERPINA3), p53 and obesity status using in-vivo and ex-vivo models of Barrett oesophagus. At the protein level, ATP5B (r = 0.71, P < 0.0001) and p53 (r = 0.455, P = 0.015) were found to be strongly associated with hypoxia. In addition, levels of ATP5B (r = 0.53, P = 0.0031) and GAPDH (r = -0.39, P = 0.0357) were positively associated with p53 expression. Moreover, we demonstrate that ATP5B (r = 0.8, P < 0.0001) and GAPDH (r = 0.43, P = 0.022) were positively associated with IL1ß expression. Interestingly, obesity was negatively associated with oxidative phosphorylation (r = -0.6016, P = 0.0177) but positively associated with glycolysis (r = 0.743, P = 0.0015). Comparable correlations were exhibited in the ex-vivo explant tissue between metabolism, p53, hypoxia, inflammation and angiogenesis (P < 0.05). We have shown that metabolism is closely linked with many cellular processes in the Barrett tissue microenvironment.

Structure and function of CrACA1, the major PM-type Ca2+-ATPase, expressed at the peak of the gravity-directed trans-cell calcium current in spores of the fern Ceratopteris richardii.

Spores of the fern Ceratopteris richardii have proven to be a valuable single-cell system for studying gravity responses. The earliest cellular change directed by gravity in these cells is a trans-cell calcium current, which peaks near 10 h after the spores are induced to germinate. This current is needed for gravity-directed axis alignment, and its peak is coincident with the time period when gravity polarises the direction of subsequent nuclear migration and rhizoid growth. Transcriptomic analysis of genes expressed at the 10-h time point revealed several that encode proteins likely to be key components that either drive the current or regulate it. Notable among these is a plasma membrane (PM)-type Ca(2+) ATPase, CrACA1, whose activity pumping Ca(2+) out of cells is regulated by gravity. This report provides an initial characterisation of the structure and expression of this protein, and demonstrates its heterologous function complementing the K616 mutant of yeast, which is deficient in PM-type Ca(2+) pump activity. Gravity-induced changes in the trans-cell Ca(2+) current occur within seconds, a result consistent with the hypothesis that the force of gravity can rapidly alter the post-translational state of the channels and pumps that drive this current across spore cells. This report identifies a transporter likely to be a key driver of the current, CrACA1, and characterises the role of this protein in early germination and gravity-driven polarity fixation through analysis of expression levels, functional complementation and pharmacological treatments. These data, along with newly available transcriptomic data obtained at the 10-h time point, indicate that CrACA1 is present, functional and likely a major contributing component of the trans-cell Ca(2+) efflux. CrACA1 is not necessary for polar axis alignment, but pharmacological perturbations of it disrupt rhizoid development. These data support and help refine the post-translational modification model for gravity responses.

The lumbar supraspinous ligament demonstrates increased material stiffness and strength on its ventral aspect.

The present work represents the first reported quantified anisotropic, inhomogeneous material constitutive data for the human supraspinous ligament (SSL). Multi-axial material data from 30 human cadaveric SSL samples was collected from distinct locations (dorsal, midsection, and ventral). A structurally motivated strain-energy based continuum model was employed to characterize anisotropic constitutive parameters for each sample. The anisotropic constitutive response correlated well with the reported experimental data (R2>0.97). Results show that in the lumbar spine both the material stiffness and stress at failure were significantly higher in the ventral region of the SSL as compared with the dorsal region (p<0.05). In the along fiber direction a higher stiffness and stress at failure were observed when compared to the transverse direction. These results indicate that modeling spinal ligaments using the hyperelastic line elements that have typically been used may be insufficient to capture their complex material response.

Detection of pulsed gamma rays above 100 GeV from the Crab pulsar.

We report the detection of pulsed gamma rays from the Crab pulsar at energies above 100 giga-electron volts (GeV) with the Very Energetic Radiation Imaging Telescope Array System (VERITAS) array of atmospheric Cherenkov telescopes. The detection cannot be explained on the basis of current pulsar models. The photon spectrum of pulsed emission between 100 mega-electron volts and 400 GeV is described by a broken power law that is statistically preferred over a power law with an exponential cutoff. It is unlikely that the observation can be explained by invoking curvature radiation as the origin of the observed gamma rays above 100 GeV. Our findings require that these gamma rays be produced more than 10 stellar radii from the neutron star.

Gamma-ray flares from the Crab Nebula.

A young and energetic pulsar powers the well-known Crab Nebula. Here, we describe two separate gamma-ray (photon energy greater than 100 mega-electron volts) flares from this source detected by the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. The first flare occurred in February 2009 and lasted approximately 16 days. The second flare was detected in September 2010 and lasted approximately 4 days. During these outbursts, the gamma-ray flux from the nebula increased by factors of four and six, respectively. The brevity of the flares implies that the gamma rays were emitted via synchrotron radiation from peta-electron-volt (10(15) electron volts) electrons in a region smaller than 1.4 × 10(-2) parsecs. These are the highest-energy particles that can be associated with a discrete astronomical source, and they pose challenges to particle acceleration theory.

Radio imaging of the very-high-energy gamma-ray emission region in the central engine of a radio galaxy.

The accretion of matter onto a massive black hole is believed to feed the relativistic plasma jets found in many active galactic nuclei (AGN). Although some AGN accelerate particles to energies exceeding 10(12) electron volts and are bright sources of very-high-energy (VHE) gamma-ray emission, it is not yet known where the VHE emission originates. Here we report on radio and VHE observations of the radio galaxy Messier 87, revealing a period of extremely strong VHE gamma-ray flares accompanied by a strong increase of the radio flux from its nucleus. These results imply that charged particles are accelerated to very high energies in the immediate vicinity of the black hole.

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5.

OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.

Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes.

OBJECTIVE: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. METHODS: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. RESULTS: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. CONCLUSION: PGRN mutations are not a common cause of ALS phenotypes.

Effect of salinity on osmoregulatory patch epithelia in gills of the blue crab Callinectes sapidus.

In euryhaline crabs, ion-transporting cells are clustered into osmoregulatory patches on the lamellae of the posterior gills. To examine changes in the branchial osmoregulatory patch in the blue crab Callinectes sapidus in response to change in salinity and to correlate these changes with other osmoregulatory responses, crabs were acclimated to a range of salinities between 10 and 35 ppt. When crabs that had been acclimated to 35 ppt were subsequently transferred to 10 ppt, both the size of the osmoregulatory patch on individual gill lamellae and the specific activity of Na+, K+-ATPase in whole-gill homogenates increased only after the first 24 h of exposure to dilute seawater. Enzyme activity and size of patch area increased gradually and reached their maxima (increasing by 200% and 60%, respectively) 6 days following transfer to 10 ppt seawater and then remained at these levels. Patch size at acclimation varied inversely with the salinity for seawater dilutions below 26 ppt (the isosmotic point of the crab), although it did not vary in salinities at or above 26 ppt. Thus, the size of the patch clearly is modulated with acclimation salinity, but it increases only in those salinities in which the crab hyperosmoregulates. An increase in the total RNA/DNA ratio in gill homogenates, the lack of mitotic figures in the lamellae, and the lack of incorporation of bromodeoxyuridine into nuclei of lamellar epithelial cells during acclimation to dilute seawater were interpreted as evidence that no cell proliferation had occurred and that increases in the size of the osmoregulatory patch occurred through differentiation of existing gas exchange cells or of undifferentiated epithelial cells into ion-transporting cells.

Hydrophilicity of 3-D biomaterials: the Washburn equation.

Characterisation and quantification of the surface energy of biomaterials used as tissue engineering scaffolds is important, but many of the techniques available to examine these properties are only applicable to smooth flat samples, not porous materials. This paper describes the application of the Washburn equation to measure the surface energy of a range of porous polyether polyurethane scaffolds with three test liquids; n-Hexane was used to measure a material constant, whilst ethanol and xylene were used to measure contact angles. The results show that the Washburn equation is not applicable in its current form, reasons for this could be that the voids in the materials are too wide for effective capillarity; absorption of the solvents into the polymer matrix may further complicate the measured imbibition profile. Another possible reason is the differences between the sizes of the interconnecting pores in scaffolds with varying void sizes; this could affect the capillary effect of the test liquids through the material. The repeatability of the results and the similar patterns observed with the different liquids suggest that if these issues could be quantified and incorporated into the Washburn equation, it may be possible to generate useful results for similar materials.