Activation of specific interneurons improves V1 feature selectivity and visual perception

Inhibitory interneurons are essential components of the neural circuits underlying various brain functions. In the neocortex, a large diversity of GABA (γ-aminobutyric acid) interneurons has been identified on the basis of their morphology, molecular markers, biophysical properties and innervation pattern. However, how the activity of each subtype of interneurons contributes to sensory processing remains unclear. Here we show that optogenetic activation of parvalbumin-positive (PV+) interneurons in the mouse primary visual cortex (V1) sharpens neuronal feature selectivity and improves perceptual discrimination. Using multichannel recording with silicon probes and channelrhodopsin-2 (ChR2)-mediated optical activation, we found that increased spiking of PV+ interneurons markedly sharpened orientation tuning and enhanced direction selectivity of nearby neurons. These effects were caused by the activation of inhibitory neurons rather than a decreased spiking of excitatory neurons, as archaerhodopsin-3 (Arch)-mediated optical silencing of calcium/calmodulin-dependent protein kinase IIα (CAMKIIα)-positive excitatory neurons caused no significant change in V1 stimulus selectivity. Moreover, the improved selectivity specifically required PV+ neuron activation, as activating somatostatin or vasointestinal peptide interneurons had no significant effect. Notably, PV+ neuron activation in awake mice caused a significant improvement in their orientation discrimination, mirroring the sharpened V1 orientation tuning. Together, these results provide the first demonstration that visual coding and perception can be improved by increased spiking of a specific subtype of cortical inhibitory interneurons.     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Crystal structure of the channelrhodopsin light-gated cation channel

Channelrhodopsins (ChRs) are light-gated cation channels derived from algae that have shown experimental utility in optogenetics; for example, neurons expressing ChRs can be optically controlled with high temporal precision within systems as complex as freely moving mammals. Although ChRs have been broadly applied to neuroscience research, little is known about the molecular mechanisms by which these unusual and powerful proteins operate. Here we present the crystal structure of a ChR (a C1C2 chimaera between ChR1 and ChR2 from Chlamydomonas reinhardtii) at 2.3?? resolution. The structure reveals the essential molecular architecture of ChRs, including the retinal-binding pocket and cation conduction pathway. This integration of structural and electrophysiological analyses provides insight into the molecular basis for the remarkable function of ChRs, and paves the way for the precise and principled design of ChR variants with novel properties.     

Suppression of star formation in early-type galaxies by feedback from supermassive black holes

Detailed high-resolution observations of the innermost regions of nearby galaxies have revealed the presence of supermassive black holes. These black holes may interact with their host galaxies by means of 'feedback' in the form of energy and material jets; this feedback affects the evolution of the host and gives rise to observed relations between the black hole and the host. Here we report observations of the ultraviolet emissions of massive early-type galaxies. We derive an empirical relation for a critical black-hole mass (as a function of velocity dispersion) above which the outflows from these black holes suppress star formation in their hosts by heating and expelling all available cold gas. Supermassive black holes are negligible in mass compared to their hosts but nevertheless seem to play a critical role in the star formation history of galaxies.     

Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I

Segregation of homologous maternal and paternal centromeres to opposite poles during meiosis I depends on post-replicative crossing over between homologous non-sister chromatids, which creates chiasmata and therefore bivalent chromosomes. Destruction of sister chromatid cohesion along chromosome arms due to proteolytic cleavage of cohesin's Rec8 subunit by separase resolves chiasmata and thereby triggers the first meiotic division. This produces univalent chromosomes, the chromatids of which are held together by centromeric cohesin that has been protected from separase by shugoshin (Sgo1/MEI-S332) proteins. Here we show in both fission and budding yeast that Sgo1 recruits to centromeres a specific form of protein phosphatase 2A (PP2A). Its inactivation causes loss of centromeric cohesin at anaphase I and random segregation of sister centromeres at the second meiotic division. Artificial recruitment of PP2A to chromosome arms prevents Rec8 phosphorylation and hinders resolution of chiasmata. Our data are consistent with the notion that efficient cleavage of Rec8 requires phosphorylation of cohesin and that this is blocked by PP2A at meiosis I centromeres.     

Effects of CO2 exposure on distribution of various forms of iron and copper in guinea-pig tissues

Summary The effects on iron and copper distribution and metabolism of exposure to high levels of CO₂ were studied in the guinea-pig. Mature, male animals were placed in an atmosphere of 15% CO₂, 21% O₂ (balance N₂), and sacrificed from 1 h to 1 week thereafter. Total iron and copper concentrations of blood, liver, spleen and bone, as well as concentrations of heme and ferritin iron, were measured together with blood hematocrit, reticulocytes, plasma hemoglobin, plasma ceruloplasmin and copper concentrations. The results show clearly that rapid and sustained red cell damage or hemolysis ensued several h from the start of CO₂ treatment. This resulted in loss of iron and copper from the blood, an influx of both elements into liver, spleen and bone, and a rise in plasma ceruloplasmin. Influx of iron into liver and spleen caused an accumulation of ferritin, the main site for iron storage in cells. Following the effect on red cells, there was an accumulation of heme iron, and a decreased hematocrit, best explained by a depressed activity of the reticuloendothelial and erythropoietic systems. A period of adaptation succeeded these events, in which all blood parameters and most tissue values returned to normal, despite the continuing presence of high CO₂. The only changes not reversed were the elevations in liver, spleen and bone iron stores. These remained high, with a net accumulation of >2 mg iron, or 3–4 times more than originally present. The results indicate that at least in the guinea-pig, high CO₂ exposure results in red cell damage and other events leading to an accumulation of additional iron in the body; also, that iron accumulated as ferritin and hemosiderin in liver and spleen may not be readily available to restore blood hemoglobin concentrations on an acute basis.Acknowledgments. We gratefully acknowledge the technical assistance of Joan R. Moor and Lakshmi Vulimiri with these studies, and the support of Grants No. 17249 and HL22410 from the U.S. Public Health Service.     

农田土壤温室气体释放通量的研究

采用碱石灰吸收法和Hohenheim Chamber法测定了德国南部农田CO2释放规律,并对两种方法进行了比较。供试作物为冬小麦。在实验期间内,各处理的CO2净释放量均为正值,表明在春季土壤－作物系统是碳的源。一天内作物－土壤系统在大部分内表现为CO2净释放,只在中午11：00至13：00且光照充分时才出现净同化。不同轮作方式下农田CO2累计释放量存在差异。不同处理CO2累计释放产为净释放,但处理间存在显著差别。CO2净释放量与气温、土壤温度极显著相关,与PAR相关性不明显。研究结果还表明,碱石灰吸收法吸收时间和吸收剂的数量对试验结果有影响,而吸收时间的影响更为明显。     

Production of the antimalarial drug precursor artemisinic acid in engineered yeast

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.     

Highly variable Northern Hemisphere temperatures reconstructed from low- and high-resolution proxy data

A number of reconstructions of millennial-scale climate variability have been carried out in order to understand patterns of natural climate variability, on decade to century timescales, and the role of anthropogenic forcing. These reconstructions have mainly used tree-ring data and other data sets of annual to decadal resolution. Lake and ocean sediments have a lower time resolution, but provide climate information at multicentennial timescales that may not be captured by tree-ring data. Here we reconstruct Northern Hemisphere temperatures for the past 2,000 years by combining low-resolution proxies with tree-ring data, using a wavelet transform technique to achieve timescale-dependent processing of the data. Our reconstruction shows larger multicentennial variability than most previous multi-proxy reconstructions, but agrees well with temperatures reconstructed from borehole measurements and with temperatures obtained with a general circulation model. According to our reconstruction, high temperatures--similar to those observed in the twentieth century before 1990--occurred around ad 1000 to 1100, and minimum temperatures that are about 0.7 K below the average of 1961-90 occurred around ad 1600. This large natural variability in the past suggests an important role of natural multicentennial variability that is likely to continue.