A necroptosis-independent function of RIPK3 promotes immune dysfunction and prevents control of chronic LCMV infection

Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damageand impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic andpersistent viral infections and within individual organ systems. The role of necroptotic signalling is further complicated becauseproteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like(MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by individually defining therole of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributesto the death of LCMV-specific CD8+ T cells or virally infected target cells during infection. We provide evidence showing thatnecroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docilestrain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads arenot altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, weidentified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. Thiswas not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function ofRIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to animpaired antiviral immune response and abrogated clearance of chronic LCMV infectio

Greenland and Canadian Arctic ice temperature profiles database

Here, we present a compilation of 95 ice temperature profiles from 85 boreholes from the Greenland ice sheet and peripheral ice caps, as well as local ice caps in the Canadian Arctic. Profiles from only 31 boreholes (36 %) were previously available in open-access data repositories. The remaining 54 borehole profiles (64 %) are being made digitally available here for the first time. These newly available profiles, which are associated with pre-2010 boreholes, have been submitted by community members or digitized from published graphics and/or data tables. All 95 profiles are now made available in both absolute (meters) and normalized (0 to 1 ice thickness) depth scales and are accompanied by extensive metadata. These metadata include a transparent description of data provenance. The ice temperature profiles span 70 years, with the earliest profile being from 1950 at Camp VI, West Greenland. To highlight the value of this database in evaluating ice flow simulations, we compare the ice temperature profiles from the Greenland ice sheet with an ice flow simulation by the Parallel Ice Sheet Model (PISM). We find a cold bias in modeled near-surface ice temperatures within the ablation area, a warm bias in modeled basal ice temperatures at inland cold-bedded sites, and an apparent underestimation of deformational heating in high-strain settings. These biases provide process level insight on simulated ice temperatures

Endothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria

Caspase-8 transduces signals from death receptor ligands, such as tumor necrosis factor, to drive potent responses including inflammation, cell proliferation or cell death. This is a developmentally essential function because in utero deletion of endothelial Caspase-8 causes systemic circulatory collapse during embryogenesis. Whether endothelial Caspase-8 is also required for cardiovascular patency during adulthood was unknown. To address this question, we used an inducible Cre recombinase system to delete endothelial Casp8 in 6-week-old conditionally gene-targeted mice. Extensive whole body vascular gene targeting was confirmed, yet the dominant phenotype was fatal hemorrhagic lesions exclusively within the small intestine. The emergence of these intestinal lesions was not a maladaptive immune response to endothelial Caspase-8-deficiency, but instead relied upon aberrant Toll-like receptor sensing of microbial commensals and tumor necrosis factor receptor signaling. This lethal phenotype was prevented in compound mutant mice that lacked the necroptotic cell death effector, MLKL. Thus, distinct from its systemic role during embryogenesis, our data show that dysregulated microbial- and death receptor-signaling uniquely culminate in the adult mouse small intestine to unleash MLKL-dependent necroptotic hemorrhage after loss of endothelial Caspase-8. These data support a critical role for Caspase-8 in preserving gut vascular integrity in the face of microbial commensals.<br/

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic&nbsp;leukaemia treated with ibrutinib from 3 clinical trials.

Patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1-12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow-up of 28&nbsp;months, overall response rate was 85% and estimated 30-month progression-free and overall survival rates were 57% [95% confidence interval (CI) 50-64] and 69% (95% CI 61-75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression-free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult-to-treat CLL/SLL populations

Greenland and Canadian Arctic ice temperature profiles

Here, we present a compilation of 85 ice temperature profiles from 79 boreholes from the Greenland Ice Sheet and peripheral ice caps, as well as local ice caps in the Canadian Arctic. Only 25 profiles (32 %) were previously available in open-access data repositories. The remaining 54 profiles (68 %) are being made digitally available here for the first time. These newly available profiles, which are associated with pre-2010 boreholes, have been submitted by community members or digitized from published graphics and/or data tables. All 85 profiles are now made available in both absolute (meters) and normalized (0 to 1 ice thickness) depth scales, and are accompanied by extensive metadata. This metadata includes a transparent description of data provenance. The ice temperature profiles span 70 years, with the earliest profile being from 1950 at Camp VI, West Greenland. To highlight the value of this database in evaluating ice flow simulations, we compare the ice temperature profiles from the Greenland Ice Sheet with an ice flow simulation by the Parallel Ice Sheet Model (PISM). We find a cold bias in modeled near-surface ice temperatures within the ablation area, a warm bias in modeled basal ice temperatures at inland cold-bedded sites, and an apparent underestimation of deformational heating in high-strain settings. These biases provide process-level insight on simulated ice temperatures.ISSN:1994-0432ISSN:1994-044

Greenland and Canadian Arctic ice temperature profiles database

Here, we present a compilation of 95 ice temperature profiles from 85 boreholes from the Greenland ice sheet and peripheral ice caps, as well as local ice caps in the Canadian Arctic. Profiles from only 31 boreholes (36 %) were previously available in open-access data repositories. The remaining 54 borehole profiles (64 %) are being made digitally available here for the first time. These newly available profiles, which are associated with pre-2010 boreholes, have been submitted by community members or digitized from published graphics and/or data tables. All 95 profiles are now made available in both absolute (meters) and normalized (0 to 1 ice thickness) depth scales and are accompanied by extensive metadata. These metadata include a transparent description of data provenance. The ice temperature profiles span 70 years, with the earliest profile being from 1950 at Camp VI, West Greenland. To highlight the value of this database in evaluating ice flow simulations, we compare the ice temperature profiles from the Greenland ice sheet with an ice flow simulation by the Parallel Ice Sheet Model (PISM). We find a cold bias in modeled near-surface ice temperatures within the ablation area, a warm bias in modeled basal ice temperatures at inland cold-bedded sites, and an apparent underestimation of deformational heating in high-strain settings. These biases provide process level insight on simulated ice temperatures.ISSN:1994-0416ISSN:1994-042

Greenland and Canadian Arctic ice temperature profiles database

Here, we present a compilation of 95 ice temperature profiles from 85 boreholes from the Greenland ice sheet and peripheral ice caps, as well as local ice caps in the Canadian Arctic. Profiles from only 31 boreholes (36 %) were previously available in open-Access data repositories. The remaining 54 borehole profiles (64 %) are being made digitally available here for the first time. These newly available profiles, which are associated with pre-2010 boreholes, have been submitted by community members or digitized from published graphics and/or data tables. All 95 profiles are now made available in both absolute (meters) and normalized (0 to 1 ice thickness) depth scales and are accompanied by extensive metadata. These metadata include a transparent description of data provenance. The ice temperature profiles span 70 years, with the earliest profile being from 1950 at Camp VI, West Greenland. To highlight the value of this database in evaluating ice flow simulations, we compare the ice temperature profiles from the Greenland ice sheet with an ice flow simulation by the Parallel Ice Sheet Model (PISM). We find a cold bias in modeled near-surface ice temperatures within the ablation area, a warm bias in modeled basal ice temperatures at inland cold-bedded sites, and an apparent underestimation of deformational heating in high-strain settings. These biases provide process level insight on simulated ice temperatures.</p

Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls

CONTEXT: A substantial body of research on the pathophysiology of chronic fatigue syndrome (CFS) has focused on hypothalamic-pituitary-adrenal axis dysregulation. The cortisol awakening response has received particular attention as a marker of hypothalamic-pituitary-adrenal axis dysregulation. OBJECTIVE: The objective of the current study was to evaluate morning salivary cortisol profiles in persons with CFS and well controls identified from the general population. DESIGN AND SETTING: We conducted a case-control study at an outpatient research clinic. CASES AND OTHER PARTICIPANTS: We screened a sample of 19,381 residents of Georgia and identified those with CFS and a matched sample of well controls. Seventy-five medication-free CFS cases and 110 medication-free well controls provided complete sets of saliva samples. MAIN OUTCOME MEASURES: We assessed free cortisol concentrations in saliva collected on a regular workday immediately upon awakening and 30 and 60 min after awakening. RESULTS: There was a significant interaction effect, indicating different profiles of cortisol concentrations over time between groups, with the CFS group showing an attenuated morning cortisol profile. Notably, we observed a sex difference in this effect. Women with CFS exhibited significantly attenuated morning cortisol profiles compared with well women. In contrast, cortisol profiles were similar in men with CFS and male controls. CONCLUSIONS: CFS was associated with an attenuated morning cortisol response, but the effect was limited to women. Our results suggest that a sex difference in hypocortisolism may contribute to increased risk of CFS in women