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.     

Warming experiments underpredict plant phenological responses to climate change

Warming experiments are increasingly relied on to estimate plant responses to global climate change. For experiments to provide meaningful predictions of future responses, they should reflect the empirical record of responses to temperature variability and recent warming, including advances in the timing of flowering and leafing. We compared phenology (the timing of recurring life history events) in observational studies and warming experiments spanning four continents and 1,634 plant species using a common measure of temperature sensitivity (change in days per degree Celsius). We show that warming experiments underpredict advances in the timing of flowering and leafing by 8.5-fold and 4.0-fold, respectively, compared with long-term observations. For species that were common to both study types, the experimental results did not match the observational data in sign or magnitude. The observational data also showed that species that flower earliest in the spring have the highest temperature sensitivities, but this trend was not reflected in the experimental data. These significant mismatches seem to be unrelated to the study length or to the degree of manipulated warming in experiments. The discrepancy between experiments and observations, however, could arise from complex interactions among multiple drivers in the observational data, or it could arise from remediable artefacts in the experiments that result in lower irradiance and drier soils, thus dampening the phenological responses to manipulated warming. Our results introduce uncertainty into ecosystem models that are informed solely by experiments and suggest that responses to climate change that are predicted using such models should be re-evaluated.     

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.     

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ～ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.     

First documentation of Salmincola californiensis in Lake Tahoe, CA–NV, USA

Salmincola californiensis is a parasitic copepod in the Lernaeopodidae family that commonly parasitizes salmonid fishes ( Oncorhynchus spp.) by attaching near the fins and on gill filaments. Historically their distribution was limited to streams that emptied into the Pacific Ocean. During the summer of 2006, several rainbow trout ( Oncorhynchus mykiss ) captured in Lake Tahoe were infested with S. californiensis . This is the first known record of S. californiensis in Lake Tahoe.     

形状记忆材料的热力学设计

以新一代溶液模型考察了合金元素对Fe-Mn-Si基合金层错能的影响，并预测了Fe-Mn-Si合金面心立方(fcc)→密排六方(hcp)马氏体的相变温度．应用规则溶液模型计算了含Ce和Y的ZrO2基陶瓷四方(t)→单斜(m)马氏体相变的自由能，结合测得ZrO2基陶瓷的强度，预测了马氏体相变的开始温度．对Ni-Mn-Ga磁驱动记忆合金的磁性转变温度Tc、体心立方至体心正方(bcc→bct)马氏体相变温度Tmart和饱和磁化强度Ms与成分的关系进行了优化，提出了具有较佳综合性能的成分范围．应用热力学方法对Fe-Mn-Si基合金、ZrO2基陶瓷和Ni-Mn-Ga铁磁合金等形状记忆材料作出的成分设计均与实验结果符合较好．     

工业石膏在自来水厂污泥调解和脱水中的作用

自来水厂污泥的处理和利用是一个至今没有得到完全解决的问题,通常的做法是将其直接排放或脱水后填埋.在实验研究的基础上,论述了采用工业石膏(CaSO4·2H2O)和有机聚合物对自来水厂污泥进行双重调解进而脱水的方法.实验结果表明,用11(工业石膏和有机聚合物的重量比)的投量对自来水厂污泥进行双重调解可明显改善污泥的过滤性能.脱水实验证明双重调解后的污泥经机械脱水,其泥饼含水率可比单纯有机聚合物调解后脱水的泥饼含水率低大约7个百分点.此项研究的意义在于探索自来水厂污泥脱水后农用及作为人工湿地填料的可能性,同时也为自来水厂污泥脱水后的最终处置探索新思路.     

Pleistocene dates for the human occupation of New Ireland, northern Melanesia

Pleistocene dates from three cave sites indicate the human capacity to colonise across two oceanic straits to the east of a former Tasmania-Australia-New Guinea continent by 33 kyr BP. The sites demonstrate exploitation of costal marine and lowland tropical forest resources. They extend Pleistocene occupation into island Melanesia and demonstrate that the large islands of northern Melanesia have an antiquity of human occupation of the same order as the adjacent Greater Australian continent.