The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers

Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.     

基于ASCP-CS算法的桥式吊车滑模控制器设计

针对桥式吊车滑模控制器参数设置繁琐以及布谷鸟搜索算法(Cuckoo Search,CS)全局搜索能力不足问题,提出了自适应选取交叉操作算子的布谷鸟搜索算法(Cuckoo Search Algorithm with Adaptively Selecting Crossover Points,ASCP-CS),并将该算法用于桥式吊车滑模控制器参数整定.该算法在CS算法的基础上改进自适应搜索步长,并在交叉操作过程中引入自适应选取染色体交叉点.通过对4种典型寻优函数进行测试的结果表明:ASCP-CS算法具有较好的寻优精度和搜索能力.对桥式吊车滑模控制器采用不同优化算法进行参数整定,仿真实验表明,基于该算法的控制器能更快地实现吊车负载定位,更有效抑制负载摆角,并具有较好的鲁棒性.     

Continental warming preceding the Palaeocene-Eocene thermal maximum

Marine and continental records show an abrupt negative shift in carbon isotope values at ～55.8?Myr ago. This carbon isotope excursion (CIE) is consistent with the release of a massive amount of isotopically light carbon into the atmosphere and was associated with a dramatic rise in global temperatures termed the Palaeocene-Eocene thermal maximum (PETM). Greenhouse gases released during the CIE, probably including methane, have often been considered the main cause of PETM warming. However, some evidence from the marine record suggests that warming directly preceded the CIE, raising the possibility that the CIE and PETM may have been linked to earlier warming with different origins. Yet pre-CIE warming is still uncertain. Disentangling the sequence of events before and during the CIE and PETM is important for understanding the causes of, and Earth system responses to, abrupt climate change. Here we show that continental warming of about 5?°C preceded the CIE in the Bighorn Basin, Wyoming. Our evidence, based on oxygen isotopes in mammal teeth (which reflect temperature-sensitive fractionation processes) and other proxies, reveals a marked temperature increase directly below the CIE, and again in the CIE. Pre-CIE warming is also supported by a negative amplification of δ(13)C values in soil carbonates below the CIE. Our results suggest that at least two sources of warming-the earlier of which is unlikely to have been methane-contributed to the PETM.     

Genomic and functional adaptation in surface ocean planktonic prokaryotes

The understanding of marine microbial ecology and metabolism has been hampered by the paucity of sequenced reference genomes. To this end, we report the sequencing of 137 diverse marine isolates collected from around the world. We analysed these sequences, along with previously published marine prokaryotic genomes, in the context of marine metagenomic data, to gain insights into the ecology of the surface ocean prokaryotic picoplankton (0.1-3.0?μm size range). The results suggest that the sequenced genomes define two microbial groups: one composed of only a few taxa that are nearly always abundant in picoplanktonic communities, and the other consisting of many microbial taxa that are rarely abundant. The genomic content of the second group suggests that these microbes are capable of slow growth and survival in energy-limited environments, and rapid growth in energy-rich environments. By contrast, the abundant and cosmopolitan picoplanktonic prokaryotes for which there is genomic representation have smaller genomes, are probably capable of only slow growth and seem to be relatively unable to sense or rapidly acclimate to energy-rich conditions. Their genomic features also lead us to propose that one method used to avoid predation by viruses and/or bacterivores is by means of slow growth and the maintenance of low biomass.     

Endoderm contributes to endocardial composition during cardiogenesis

Heart formation commences from a single heart tube, which fuses from bilateral primordial heart fields. The developing heart tube is composed of outerlayer myocardial cells and innerlayer endocardial cells. Several distinct populations of precardiac cells contribute to cardiac morphogenesis. However, it still remains not very clear about the lineage of endocardium at gastrulation stage. Thereby, this study focused on ascertaining the correlation between the hypoblast in gastrulation and endocardium during cardiogenesis. Firstly, the fusing heart tube morphologically is closed to endoderm-derived pharynx floor, implying the possibility that pharynx floor might be wrapped into the formation of endoderm. Secondly, HNK1 is expressed in hypoblast strongly at gastrula stage and subsequently appeared in endocardium of cardiogenesis. Moreover, fate map data displayed that DiI labeled hypoblast was also present in endocardium later on. One more evidence is chickquail chimera of hypoblast transplantation, in which quailhypoblast derivative could be identified in endocardium of cardiogenesis by QCPN antibody. In sum, our current data suggests that endoderrn in gastrula contribute at least partly to the formation of endocardium of cardiogenesis.     

Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U)

During infection, enterohaemorrhagic Escherichia coli (EHEC) takes over the actin cytoskeleton of eukaryotic cells by injecting the EspF(U) protein into the host cytoplasm. EspF(U) controls actin by activating members of the Wiskott-Aldrich syndrome protein (WASP) family. Here we show that EspF(U) binds to the autoinhibitory GTPase binding domain (GBD) in WASP proteins and displaces it from the activity-bearing VCA domain (for verprolin homology, central hydrophobic and acidic regions). This interaction potently activates WASP and neural (N)-WASP in vitro and induces localized actin assembly in cells. In the solution structure of the GBD-EspF(U) complex, EspF(U) forms an amphipathic helix that binds the GBD, mimicking interactions of the VCA domain in autoinhibited WASP. Thus, EspF(U) activates WASP by competing directly for the VCA binding site on the GBD. This mechanism is distinct from that used by the eukaryotic activators Cdc42 and SH2 domains, which globally destabilize the GBD fold to release the VCA. Such diversity of mechanism in WASP proteins is distinct from other multimodular systems, and may result from the intrinsically unstructured nature of the isolated GBD and VCA elements. The structural incompatibility of the GBD complexes with EspF(U) and Cdc42/SH2, plus high-affinity EspF(U) binding, enable EHEC to hijack the eukaryotic cytoskeletal machinery effectively.