Variability of the Ross Gyre, Southern Ocean: Drivers and responses revealed by satellite altimetry

Year-round variability in the Ross Gyre (RG), Antarctica, during 2011–2015, is derived using radar altimetry. The RG is characterized by a bounded recirculating component and a westward throughflow to the south. Two modes of variability of the sea surface height and ocean surface stress curl are revealed. The first represents a large-scale sea surface height change forced by the Antarctic Oscillation. The second represents semiannual variability in gyre area and strength, driven by fluctuations in sea level pressure associated with the Amundsen Sea Low. Variability in the throughflow is also linked to the Amundsen Sea Low. An adequate description of the oceanic circulation is achieved only when sea ice drag is accounted for in the ocean surface stress. The drivers of RG variability elucidated here have significant implications for our understanding of the oceanic forcing of Antarctic Ice Sheet melting and for the downstream propagation of its ocean freshening footprint

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

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

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Sustained monitoring of the Southern Ocean at Drake Passage: past achievements and future priorities

Drake Passage is the narrowest constriction of the Antarctic Circumpolar Current (ACC) in the Southern Ocean, with implications for global ocean circulation and climate. We review the long-term sustained monitoring programmes that have been conducted at Drake Passage, dating back to the early part of the twentieth century. Attention is drawn to numerous breakthroughs that have been made from these programmes, including (a) the first determinations of the complex ACC structure and early quantifications of its transport; (b) realization that the ACC transport is remarkably steady over interannual and longer periods, and a growing understanding of the processes responsible for this; (c) recognition of the role of coupled climate modes in dictating the horizontal transport, and the role of anthropogenic processes in this; (d) understanding of mechanisms driving changes in both the upper and lower limbs of the Southern Ocean overturning circulation, and their impacts. It is argued that monitoring of this passage remains a high priority for oceanographic and climate research, but that strategic improvements could be made concerning how this is conducted. In particular, long-term programmes should concentrate on delivering quantifications of key variables of direct relevance to large-scale environmental issues: in this context, the time-varying overturning circulation is, if anything, even more compelling a target than the ACC flow. Further, there is a need for better international resource-sharing, and improved spatio-temporal coordination of the measurements. If achieved, the improvements in understanding of important climatic issues deriving from Drake Passage monitoring can be sustained into the future

Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 x 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 x 10(-7)) and 13% for RAB38/CTSC (P = 5.8 x 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria