An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division

RNA interference (RNAi) is an evolutionarily conserved defence mechanism whereby genes are specifically silenced through degradation of messenger RNAs; this process is mediated by homologous double-stranded (ds)RNA molecules. In invertebrates, long dsRNAs have been used for genome-wide screens and have provided insights into gene functions. Because long dsRNA triggers a nonspecific interferon response in many vertebrates, short interfering (si)RNA or short hairpin (sh)RNAs must be used for these organisms to ensure specific gene silencing. Here we report the generation of a genome-scale library of endoribonuclease-prepared short interfering (esi)RNAs from a sequence-verified complementary DNA collection representing 15,497 human genes. We used 5,305 esiRNAs from this library to screen for genes required for cell division in HeLa cells. Using a primary high-throughput cell viability screen followed by a secondary high content videomicroscopy assay, we identified 37 genes required for cell division. These include several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. Thus, our study uncovers new aspects of cell division and establishes esiRNA as a versatile approach for genomic RNAi screens in mammalian cells.     

Clustering criteria for discrete data and latent class models

We show that a well-known clustering criterion for discrete data, the information criterion, is closely related to the classification maximum likelihood criterion for the latent class model. This relation can be derived from the Bryant-Windham construction. Emphasis is placed on binary clustering criteria which are analyzed under the maximum likelihood approach for different multivariate Bernoulli mixtures. This alternative form of criterion reveals non-apparent aspects of clustering techniques. All the criteria discussed can be optimized with the alternating optimization algorithm. Some illustrative applications are included.

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Résumé Nous montrons que le critère de classification de l'information, souvent utilisé pour les données discrètes, est très lié au critère du maximum de vraisemblance classifiante appliqué au modèle des classes latentes. Ce lien peut être analysé sous l'approche de la paramétrisation de Bryant-Windham. L'accent est mis sur le cas des données binaires qui sont analysées sous l'approche du maximum de vraisemblance pour les mélanges de distributions multivariées de Bernoulli. Cette forme de critère permet de mettre en évidence des aspects cachés des méthodes de classification de données binaires. Tous les critères envisagés ici peuvent être optimisés avec l'algorithme d'optimisation alternée. Des exemples concluent cet article.

     

Abductive Reasoning as a Way of Worldmaking

The author deals with the operational core oflogic, i.e. its diverse procedures ofinference, in order to show that logicallyfalse inferences may in fact be right because –in contrast to logical rationality – theyactually enlarge our knowledge of the world.This does not only mean that logically trueinferences say nothing about the world, butalso that all our inferences are inventedhypotheses the adequacy of which cannot beproved within logic but only pragmatically. Inconclusion the author demonstrates, through therelationship between rule-following andrationality, that it is most irrational to wantto exclude the irrational: it may, at times, bemost rational to think and infer irrationally.Focussing on the operational aspects of knowingas inferring does away with the hiatus betweenlogic and life, cognition and the world(reality) – or whatever other dualism one wantsto invoke –: knowing means inferring, inferringmeans rule-governed interpreting, interpretingis a constructive, synthetic act, and aconstruction that proves adequate (viable) inthe ``world of experience', in life, in thepraxis of living, is, to the constructivistmind, knowledge. It is the practice of livingwhich provides the orienting standards forconstructivist thinking and its judgments ofviability. The question of truth is replaced bythe question of viability, and viabilitydepends on the (right) kind of experiential fit.     

Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations

Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug’s chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC₅₀ ≈ 8–10 μM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC₅₀ = 18.7 μM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC₅₀ of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.     

Eight glacial cycles from an Antarctic ice core

The Antarctic Vostok ice core provided compelling evidence of the nature of climate, and of climate feedbacks, over the past 420,000 years. Marine records suggest that the amplitude of climate variability was smaller before that time, but such records are often poorly resolved. Moreover, it is not possible to infer the abundance of greenhouse gases in the atmosphere from marine records. Here we report the recovery of a deep ice core from Dome C, Antarctica, that provides a climate record for the past 740,000 years. For the four most recent glacial cycles, the data agree well with the record from Vostok. The earlier period, between 740,000 and 430,000 years ago, was characterized by less pronounced warmth in interglacial periods in Antarctica, but a higher proportion of each cycle was spent in the warm mode. The transition from glacial to interglacial conditions about 430,000 years ago (Termination V) resembles the transition into the present interglacial period in terms of the magnitude of change in temperatures and greenhouse gases, but there are significant differences in the patterns of change. The interglacial stage following Termination V was exceptionally long--28,000 years compared to, for example, the 12,000 years recorded so far in the present interglacial period. Given the similarities between this earlier warm period and today, our results may imply that without human intervention, a climate similar to the present one would extend well into the future.     

Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype

Tetraodon nigroviridis is a freshwater puffer fish with the smallest known vertebrate genome. Here, we report a draft genome sequence with long-range linkage and substantial anchoring to the 21 Tetraodon chromosomes. Genome analysis provides a greatly improved fish gene catalogue, including identifying key genes previously thought to be absent in fish. Comparison with other vertebrates and a urochordate indicates that fish proteins have diverged markedly faster than their mammalian homologues. Comparison with the human genome suggests approximately 900 previously unannotated human genes. Analysis of the Tetraodon and human genomes shows that whole-genome duplication occurred in the teleost fish lineage, subsequent to its divergence from mammals. The analysis also makes it possible to infer the basic structure of the ancestral bony vertebrate genome, which was composed of 12 chromosomes, and to reconstruct much of the evolutionary history of ancient and recent chromosome rearrangements leading to the modern human karyotype.     

A 'snowball Earth' climate triggered by continental break-up through changes in runoff

Geological and palaeomagnetic studies indicate that ice sheets may have reached the Equator at the end of the Proterozoic eon, 800 to 550 million years ago, leading to the suggestion of a fully ice-covered 'snowball Earth'. Climate model simulations indicate that such a snowball state for the Earth depends on anomalously low atmospheric carbon dioxide concentrations, in addition to the Sun being 6 per cent fainter than it is today. However, the mechanisms producing such low carbon dioxide concentrations remain controversial. Here we assess the effect of the palaeogeographic changes preceding the Sturtian glacial period, 750 million years ago, on the long-term evolution of atmospheric carbon dioxide levels using the coupled climate-geochemical model GEOCLIM. In our simulation, the continental break-up of Rodinia leads to an increase in runoff and hence consumption of carbon dioxide through continental weathering that decreases atmospheric carbon dioxide concentrations by 1,320 p.p.m. This indicates that tectonic changes could have triggered a progressive transition from a 'greenhouse' to an 'icehouse' climate during the Neoproterozoic era. When we combine these results with the concomitant weathering effect of the voluminous basaltic traps erupted throughout the break-up of Rodinia, our simulation results in a snowball glaciation.     

基于AEZ模型的我国主要作物单产潜力的农作制区划分析

本文根据联合国粮农组织(FAO)和国际应用系统分析研究所(IIASA)基于中国1961年以来的统计资料共同开发的AEZ模型,运用GIS平台计算了中国41个农作制亚区6大主要作物(水稻、小麦、玉米、马铃薯、油菜、大豆)的单产潜力.指出以上作物单产最高潜力分布为:水稻在江淮江汉平原,小麦在秦巴山区,玉米在黄淮平原南阳盆地,马铃薯在秦巴山区,油菜在秦巴山区,大豆在鲁西平原鲁中丘陵.研究结果表明:我国以上主要作物的最高单产潜力是目前全国平均单产的1.2-2.9倍.这对指导我国农作物高产育种及栽培具有重要参考意义.