“Dial Up and Lock In”: Asymmetric organo-Brønsted acid catalysis incorporating stable isotopes

An operationally simple organo-Brønsted-acid-catalyzed asymmetric and regioselective “dial up and lock in” of one or more stable isotopes into organic compounds is unknown. Here, we describe a newly designed, chemically versatile protocol mediating single- or multiple-isotope incorporation into aziridines via a one-pot, three-component, two-step process. By exploiting easy-to-generate isotope-derived starting materials, it allows complete control of isotope positioning, affords >95 atom % isotope incorporation, and generates cis-aziridines with excellent optical activities and regioselectivities. Demonstrating a “low entry point,” and thus easy access to a broad range of researchers, it requires no specialist laboratory equipment and employs readily attainable reaction conditions. Demonstrating their utility, the aziridines are easily transformed into sought-after chiral non-racemic α-amino acids appended with one to three (or more) identical or different isotopes. The widespread use of these compounds ensures that our methodology will be of interest to biological, medicinal, pharmaceutical, agrochemical, biotechnology, materials, and process chemists alike

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Is There a Positive Synergistic Effect of Biochar and Compost Soil Amendments on Plant Growth and Physiological Performance?

The combination of biochar (BC) with compost has been suggested to be a promising strategy to promote plant growth and performance, but although “synergistic” effects have been stated to occur, full-factorial experiments are few, and explicit tests for synergism are lacking. We tested the hypothesis that a combination of BC and spent mushroom substrate (SMS) has a positive synergistic effect on plant growth and physiological performance in a nutrient-limited growing media. A greenhouse experiment with a full factorial design was conducted using mixed-wood BC (3.0 kg·m−2) and SMS (1.5 kg·m−2) (the combination was not co-composted) as organic soil amendments for the annual Abutilon theophrasti and the perennial Salix purpurea. Several measurements related to plant growth and physiological performance were taken throughout the experiment. Contrary to the hypothesis, we found that the combination of BC + SMS had neutral or antagonistic interactive effects on many plant growth traits. Antagonistic effects were found on maximum leaf area, above- and belowground biomass, reproductive allocation, maximum plant height, chlorophyll fluorescence, and stomatal conductance of A. theophrasti. The effect on S. purpurea was mostly neutral. We conclude that the generalization that BC and compost have synergistic effects on plant performance is not supported

Is There a Positive Synergistic Effect of Biochar and Compost Soil Amendments on Plant Growth and Physiological Performance?

The combination of biochar (BC) with compost has been suggested to be a promising strategy to promote plant growth and performance, but although “synergistic” effects have been stated to occur, full-factorial experiments are few, and explicit tests for synergism are lacking. We tested the hypothesis that a combination of BC and spent mushroom substrate (SMS) has a positive synergistic effect on plant growth and physiological performance in a nutrient-limited growing media. A greenhouse experiment with a full factorial design was conducted using mixed-wood BC (3.0 kg·m−2) and SMS (1.5 kg·m−2) (the combination was not co-composted) as organic soil amendments for the annual Abutilon theophrasti and the perennial Salix purpurea. Several measurements related to plant growth and physiological performance were taken throughout the experiment. Contrary to the hypothesis, we found that the combination of BC + SMS had neutral or antagonistic interactive effects on many plant growth traits. Antagonistic effects were found on maximum leaf area, above- and belowground biomass, reproductive allocation, maximum plant height, chlorophyll fluorescence, and stomatal conductance of A. theophrasti. The effect on S. purpurea was mostly neutral. We conclude that the generalization that BC and compost have synergistic effects on plant performance is not supported

Calix[4]arene-based metal-organic frameworks: Towards hierarchically porous materials

An upper rim-functionalised calix[4]arene dicarboxylic acid (H caldc) has been used to prepare four metal-organic frameworks, three of which have been structurally characterised and shown to form two- or three-dimensional network structures. Simulations suggest that such networks are likely to display interesting selectivity to guest molecules