Proceedings of the National Academy of Sciences of the United States of America
-
Proc. Natl. Acad. Sci. U.S.A. · Nov 2015
Biography Historical ArticleBill Paul: The heart of immunology.
-
Proc. Natl. Acad. Sci. U.S.A. · Nov 2015
CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice.
Here, we show CRISPR/Cas9-based targeted somatic multiplex-mutagenesis and its application for high-throughput analysis of gene function in mice. Using hepatic single guide RNA (sgRNA) delivery, we targeted large gene sets to induce hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We observed Darwinian selection of target genes, which suppress tumorigenesis in the respective cellular/tissue context, such as Pten or Cdkn2a, and conversely found low frequency of Brca1/2 alterations, explaining mutational spectra in human ICC/HCC. ⋯ The analysis of CRISPR/Cas9-induced tumors provided support for a major role of chromatin modifiers in hepatobiliary tumorigenesis, including that of ARID family proteins, which have recently been reported to be mutated in ICC/HCC. We have also comprehensively characterized the frequency and size of chromosomal alterations induced by combinatorial sgRNA delivery and describe related limitations of CRISPR/Cas9 multiplexing, as well as opportunities for chromosome engineering in the context of hepatobiliary tumorigenesis. Our study describes novel approaches to model and study cancer in a high-throughput multiplexed format that will facilitate the functional annotation of cancer genomes.
-
Proc. Natl. Acad. Sci. U.S.A. · Oct 2015
Randomized Controlled Trial Multicenter StudyPlacebo analgesia and its opioidergic regulation suggest that empathy for pain is grounded in self pain.
Empathy for pain activates brain areas partially overlapping with those underpinning the first-hand experience of pain. It remains unclear, however, whether such shared activations imply that pain empathy engages similar neural functions as first-hand pain experiences. To overcome the limitations of previous neuroimaging research, we pursued a conceptually novel approach: we used the phenomenon of placebo analgesia to experimentally reduce the first-hand experience of pain, and assessed whether this results in a concomitant reduction of empathy for pain. ⋯ In a second step, we used a psychopharmacological manipulation (n = 50) to determine whether these effects can be blocked via an opioid antagonist. The administration of the opioid antagonist naltrexone blocked placebo analgesia and also resulted in a corresponding "normalization" of empathy for pain. Taken together, these findings suggest that pain empathy may be associated with neural responses and neurotransmitter activity engaged during first-hand pain, and thus might indeed be grounded in our own pain experiences.
-
Proc. Natl. Acad. Sci. U.S.A. · Oct 2015
National Institutes of Health addresses the science of diversity.
The US biomedical research workforce does not currently mirror the nation's population demographically, despite numerous attempts to increase diversity. This imbalance is limiting the promise of our biomedical enterprise for building knowledge and improving the nation's health. ⋯ Herein, we identify four cross-cutting diversity challenges ripe for scientific exploration and opportunity: research evidence for diversity's impact on the quality and outputs of science; evidence-based approaches to recruitment and training; individual and institutional barriers to workforce diversity; and a national strategy for eliminating barriers to career transition, with scientifically based approaches for scaling and dissemination. Evidence-based data for each of these challenges should provide an integrated, stepwise approach to programs that enhance diversity rapidly within the biomedical research workforce.