Arctic introgression and chromatin regulation facilitated rapid Qinghai-Tibet Plateau colonization by an avian predator

The Qinghai-Tibet Plateau (QTP), possesses a climate as cold as that of the Arctic, and also presents uniquely low oxygen concentrations and intense ultraviolet (UV) radiation. QTP animals have adapted to these extreme conditions, but whether they obtained genetic variations from the Arctic during cold adaptation, and how genomic mutations in non-coding regions regulate gene expression under hypoxia and intense UV environment, remain largely unknown. Here, we assemble a high-quality saker falcon genome and resequence populations across Eurasia. We identify female-biased hybridization with Arctic gyrfalcons in the last glacial maximum, that endowed eastern sakers with alleles conveying larger body size and changes in fat metabolism, predisposing their QTP cold adaptation. We discover that QTP hypoxia and UV adaptations mainly involve independent changes in non-coding genomic variants. Our study highlights key roles of gene flow from Arctic relatives during QTP hypothermia adaptation, and cis-regulatory elements during hypoxic response and UV protection

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

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

A proposal to sequence the genome of the platypus, ornithorhynchus anatinus

© 2004 National Human Genome Research InstitutePeter D.Temple-Smith, Jennifer A. Marshall Graves, Frank Grützner, Janine Deakin, Marilyn B. Renfree, Katherine Belov, Robert Miller, Randy Jirtle, Kerstin Lindblad-Toh, Eric S. Lander and Richard K. Wilso

Towards complete and error-free genome assemblies of all vertebrate species.

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species1-4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences

Pain, Analgesic Use, and Patient Satisfaction With Spinal Versus General Anesthesia for Hip Fracture Surgery : A Randomized Clinical Trial.

BACKGROUND: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported. OBJECTIVE: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia. DESIGN: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505). SETTING: 46 U.S. and Canadian hospitals. PARTICIPANTS: Patients aged 50 years or older undergoing hip fracture surgery. INTERVENTION: Spinal or general anesthesia. MEASUREMENTS: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care. RESULTS: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups. LIMITATION: Missing outcome data and multiple outcomes assessed. CONCLUSION: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institut