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201.
202.
Sander LE Davis MJ Boekschoten MV Amsen D Dascher CC Ryffel B Swanson JA Müller M Blander JM 《Nature》2011,474(7351):385-389
Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen-associated molecular patterns (PAMPs), which are detected by the immune system, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines. 相似文献
203.
Heart regeneration 总被引:1,自引:0,他引:1
Heart failure plagues industrialized nations, killing more people than any other disease. It usually results from a deficiency of specialized cardiac muscle cells known as cardiomyocytes, and a robust therapy to regenerate lost myocardium could help millions of patients every year. Heart regeneration is well documented in amphibia and fish and in developing mammals. After birth, however, human heart regeneration becomes limited to very slow cardiomyocyte replacement. Several experimental strategies to remuscularize the injured heart using adult stem cells and pluripotent stem cells, cellular reprogramming and tissue engineering are in progress. Although many challenges remain, these interventions may eventually lead to better approaches to treat or prevent heart failure. 相似文献
204.
Dawson MA Prinjha RK Dittmann A Giotopoulos G Bantscheff M Chan WI Robson SC Chung CW Hopf C Savitski MM Huthmacher C Gudgin E Lugo D Beinke S Chapman TD Roberts EJ Soden PE Auger KR Mirguet O Doehner K Delwel R Burnett AK Jeffrey P Drewes G Lee K Huntly BJ Kouzarides T 《Nature》2011,478(7370):529-533
205.
Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic β-cell replication in juvenile mice and humans declines with age, and elucidating the basis for this decay may reveal strategies for inducing β-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent β-cell proliferation in mouse and human pancreatic islets. With age, declining β-cell Pdgfr levels were accompanied by reductions in β-cell enhancer of zeste homologue 2 (Ezh2) levels and β-cell replication. Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration. Targeted human PDGFR-α activation in mouse β-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult β-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated β-cell proliferation. The discovery of a conserved pathway controlling age-dependent β-cell proliferation indicates new strategies for β-cell expansion. 相似文献
206.
Li H Haurigot V Doyon Y Li T Wong SY Bhagwat AS Malani N Anguela XM Sharma R Ivanciu L Murphy SL Finn JD Khazi FR Zhou S Paschon DE Rebar EJ Bushman FD Gregory PD Holmes MC High KA 《Nature》2011,475(7355):217-221
Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease. 相似文献
207.
208.
Cerling TE Wynn JG Andanje SA Bird MI Korir DK Levin NE Mace W Macharia AN Quade J Remien CH 《Nature》2011,476(7358):51-56
The role of African savannahs in the evolution of early hominins has been debated for nearly a century. Resolution of this issue has been hindered by difficulty in quantifying the fraction of woody cover in the fossil record. Here we show that the fraction of woody cover in tropical ecosystems can be quantified using stable carbon isotopes in soils. Furthermore, we use fossil soils from hominin sites in the Awash and Omo-Turkana basins in eastern Africa to reconstruct the fraction of woody cover since the Late Miocene epoch (about 7 million years ago). (13)C/(12)C ratio data from 1,300 palaeosols at or adjacent to hominin sites dating to at least 6 million years ago show that woody cover was predominantly less than ~40% at most sites. These data point to the prevalence of open environments at the majority of hominin fossil sites in eastern Africa over the past 6 million years. 相似文献
209.
Zuber J Shi J Wang E Rappaport AR Herrmann H Sison EA Magoon D Qi J Blatt K Wunderlich M Taylor MJ Johns C Chicas A Mulloy JC Kogan SC Brown P Valent P Bradner JE Lowe SW Vakoc CR 《Nature》2011,478(7370):524-528
Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. 相似文献
210.
Rothberg JM Hinz W Rearick TM Schultz J Mileski W Davey M Leamon JH Johnson K Milgrew MJ Edwards M Hoon J Simons JF Marran D Myers JW Davidson JF Branting A Nobile JR Puc BP Light D Clark TA Huber M Branciforte JT Stoner IB Cawley SE Lyons M Fu Y Homer N Sedova M Miao X Reed B Sabina J Feierstein E Schorn M Alanjary M Dimalanta E Dressman D Kasinskas R Sokolsky T Fidanza JA Namsaraev E McKernan KJ Williams A Roth GT Bustillo J 《Nature》2011,475(7356):348-352
The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome. 相似文献