The Traditional Fishery on Deh Cho: An Ethnohistoric and Archaeological Perspective

Dene use of the resources of Deh Cho, the preferred Slavey name for the Mackenzie River, in the late pre-contact and early post-contact periods is not well understood. This paper examines the archaeological record of the Mackenzie Valley in relation to a model of Native use of the river, based upon Alexander Mackenzie's observations on the exploitation of the fishery at the first direct contact between Europeans and the Dene along Deh Cho. Use of archaeological data, ethnographic analogy and later historic sources provokes the conclusion that Dene land and river resource use did not drastically change as a result of European contact and the fur trade.Key words: Slavey, Dogrib, Hare, Dene, Athapaskan, fish, Mackenzie River, traditional harvesting, ethnoarchaeology, ethnohistoryMots clés: Slavey, Dogrib, Hare, Déné, Athapaskan, poisson, fleuve Mackenzie, collecte traditionnelle pour la subsistance, ethnoarchéologie, ethnohistoir

Inner city housing study : interim report

Report : vii, 78, [42] leaves : ill., maps. "August 18, 1978". Study team: Lloyd Axworthy, Project Director; Christine McKee, Project Manager; Jackie DeRoo, Sybil Frenette, Barbara Hanks. "In association with Frank W. Fedoruk"

TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2K923E) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2K923E in vitro. Tyk2K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors

Functional Analysis of the Kinome of the Wheat Scab Fungus Fusarium graminearum

As in other eukaryotes, protein kinases play major regulatory roles in filamentous fungi. Although the genomes of many plant pathogenic fungi have been sequenced, systematic characterization of their kinomes has not been reported. The wheat scab fungus Fusarium graminearum has 116 protein kinases (PK) genes. Although twenty of them appeared to be essential, we generated deletion mutants for the other 96 PK genes, including 12 orthologs of essential genes in yeast. All of the PK mutants were assayed for changes in 17 phenotypes, including growth, conidiation, pathogenesis, stress responses, and sexual reproduction. Overall, deletion of 64 PK genes resulted in at least one of the phenotypes examined, including three mutants blocked in conidiation and five mutants with increased tolerance to hyperosmotic stress. In total, 42 PK mutants were significantly reduced in virulence or non-pathogenic, including mutants deleted of key components of the cAMP signaling and three MAPK pathways. A number of these PK genes, including Fg03146 and Fg04770 that are unique to filamentous fungi, are dispensable for hyphal growth and likely encode novel fungal virulence factors. Ascospores play a critical role in the initiation of wheat scab. Twenty-six PK mutants were blocked in perithecia formation or aborted in ascosporogenesis. Additional 19 mutants were defective in ascospore release or morphology. Interestingly, F. graminearum contains two aurora kinase genes with distinct functions, which has not been reported in fungi. In addition, we used the interlog approach to predict the PK-PK and PK-protein interaction networks of F. graminearum. Several predicted interactions were verified with yeast two-hybrid or co-immunoprecipitation assays. To our knowledge, this is the first functional characterization of the kinome in plant pathogenic fungi. Protein kinase genes important for various aspects of growth, developmental, and infection processes in F. graminearum were identified in this study

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

How critical illness impacts drug pharmacokinetics and pharmacodynamics

Critical illness can affect how drugs work in the body and how the body reacts to drugs. This can have important implications for treatment and the risk of adverse effects

Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals

Although primarily regarded as being intracellular, this study has identified the presence of heat shock protein 60 (Hsp60) in the peripheral circulation of normal individuals. The median Hsp60 concentration was approximately 3.5-fold higher in females than in males and significantly higher levels of anti-human Hsp60 antibodies were also detected in females. There were no differences in the levels of antibodies to mycobacterial Hsp60 between males and females, nor did antibody levels correlate with Hsp60 concentrations. Hsp60 was not released from mitogenically stimulated peripheral blood mononuclear cells. The potential physiological roles for circulating Hsp60 are unknown. Given the emerging evidence that inappropriate reactivity to heat shock proteins is involved in autoimmune disease and that T cells responsive to self Hsp60 appear to be protective, these findings suggest that circulating Hsp60 may be involved in the regulation of tolerance to self and immunity to bacterial forms of these widely expressed and structurally conserved proteins

Early tracking would improve the operative experience of general surgery residents

Objective(S): High surgical complexity and individual career goals has led most general surgery (GS) residents to pursue fellowship training, resulting in a shortage of surgeons who practice broad-based general surgery. We hypothesize that early tracking of residents would improve operative experience of residents planning to be general surgeons, and could foster greater interest and confidence in this career path. Methods: Surgical Operative Log data from GS and fellowship bound residents (FB) applying for the 2008 American Board of Surgery Qualifying Examination (QE) were used to construct a hypothetical training model with 6 months of early specialization (ESP) for FB residents in 4 specialties (cardiac, vascular, colorectal, pediatric); and presumed these cases would be available to GS residents within the same program. Results: A total of 142 training programs had both FB residents (n = 237) and GS residents (n = 402), and represented 70% of all 2008 QE applicants. The mean numbers of operations by FB and GS residents were 1131 and 1091, respectively. There were a mean of 252 cases by FB residents in the chief year, theoretically making 126 cases available for each GS resident. In 9 defined categories, the hypothetical model would result in an increase in the 5-year operative experience of GS residents (mastectomy 6.5%; colectomy 22.8%; gastrectomy 23.4%; antireflux procedures 23.4%; pancreatic resection 37.4%; liver resection 29.3%; endocrine procedures 19.6%; trauma operations 13.3%; GI endoscopy 6.5%). Conclusions: The ESP model improves operative experience of GS residents, particularly for complex gastrointestinal procedures. The expansion of subspecialty ESP should be considered. © 2010 by Lippincott Williams & Wilkins

Associations between vascular health indices and serum total, free and bioavailable 25-hydroxyvitamin D in adolescents.

The role of vitamin D in cardiovascular health remains debated as results have been inconsistent. Previous studies have not considered the bioavailability of 25-hydroxy vitamin D [25(OH)D]. Objectives of our study were to investigate the association between serum concentrations of total, free and bioavailable 25(OH)D and independent predictors of cardiovascular risk such as flow mediated dilatation (FMD) and augmentation index (AIx).This cross-sectional study included 47 post-menarchal, adolescent females [31 African American (AA) and 16 European American (EA)].AIx was standardized to a heart rate of 75 beats/min (AIx75). Free and bioavailable 25(OH)D concentrations were calculated from standard formulas.Mean age of the participants was 15.8 ± 1.4 years and mean body mass index was 23.1 ± 4.0 kg/m2. Serum total 25(OH)D was not associated with FMD, but was positively associated with AIx75 in the adjusted model (rho = 0.4, P = 0.03). AIx75 was positively associated with bioavailable 25(OH)D (rho = 0.4, P = 0.004) and free 25(OH)D (rho = 0.4, P = 0.009) and the associations persisted after adjusting for covariates. In race-specific analyses, total, free and bioavailable 25(OH)D were strongly positively associated with AIx75 in AA (rho = 0.5, 0.4, 0.4, respectively), which persisted even after adjusting for covariates. Whereas in EA there was an inverse association between total 25(OH)D and AIx75 in EA (rho = -0.6), which attenuated after adjusting for covariates.Circulating total, free and bioavailable 25(OH)D were associated with arterial stiffness in adolescent girls, and these associations were race dependent. Notwithstanding, the implications of associations between vascular function indices and 25(OH)D remains unclear