Isotopic evolution of the terminal Neoproterozoic and early Cambrian carbon cycle on the northern Yangtze Platform, South China

Profound geotectonic, climatic and biological changes occur during the terminal Neoproterozoic and its transition into the early Cambrian. These are reflected in temporal variations of the chemical and isotopic composition of seawater. We are studying a sequence of sedimentary rocks at the Shatan section, northern Yangtze Platform, Sichuan Province of China. This succession comprises, in ascending stratigraphic order, predominantly calcareous sediments of the Sinian upper Dengying Formation and black shales of the lower Cambrian Guojiaba Formation (time equivalent of Niutitang Fm.). Paleoenvironmental setting represents shallow-water shelf deposits. The objective of our study is to provide temporal records for the isotopic compositions of organic and carbonate carbon throughout this time interval. Organic carbon isotope values display a range between -35.8‰ and -30.1‰ with clear stratigraphic variations. Carbonate carbon isotope data vary between -3.5‰ and +0.5‰. These secular variations are interpreted to reflect perturbations of the global carbon cycle, specifically changes in the fractional burial of organic carbon. However, local conditions have further affected the isotopic signals.     

Multicategory Purchase Incidence Models for Partitions of Product Categories

We analyze multicategory purchases of households by means of heterogeneous multivariate probit models that relate to partitions formed from a total of 25 product categories. We investigate both prior and post hoc partitions. We search model structures by a stochastic algorithm and estimate models by Markov chain Monte Carlo simulation. The best model in terms of cross‐validated log‐likelihood refers to a post hoc partition with two groups; the second‐best model considers all categories as one group. Among prior partitions with at least two category groups a five‐group model performs best. Effects on average basket value differ for the model with five prior category groups from those for the best‐performing model in 40% and 24% of the investigated categories for features and displays, respectively. In addition, the model with five prior category groups also underestimates total sales revenue across all categories by about 28%. Copyright © 2016 John Wiley & Sons, Ltd.     

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

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.     

Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology

Neurotransmission effected by GABA (gamma-aminobutyric acid) is predominantly mediated by a gated chloride channel intrinsic to the GABAA receptor. This heterooligomeric receptor exists in most inhibitory synapses in the vertebrate central nervous system (CNS) and can be regulated by clinically important compounds such as benzodiazepines and barbiturates. The primary structures of GABAA receptor alpha- and beta-subunits have been deduced from cloned complementary DNAs. Co-expression of these subunits in heterologous systems generates receptors which display much of the pharmacology of their neural counterparts, including potentiation by barbiturates. Conspicuously, however, they lack binding sites for, and consistent electrophysiological responses to, benzodiazepines. We now report the isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed gamma 2, which shares approximately 40% sequence identity with alpha- and beta-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS. Importantly, coexpression of the gamma 2 subunit with alpha 1 and beta 1 subunits produces GABAA receptors displaying high-affinity binding for central benzodiazepine receptor ligands.     

The knockout mouse project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.     

Observation of Hanbury Brown-Twiss anticorrelations for free electrons

Fluctuations in the counting rate of photons originating from uncorrelated point sources become, within the coherently illuminated area, slightly enhanced compared to a random sequence of classical particles. This phenomenon, known in astronomy as the Hanbury Brown-Twiss effect, is a consequence of quantum interference between two indistinguishable photons and Bose Einstein statistics. The latter require that the composite bosonic wavefunction is a symmetric superposition of the two possible paths. For fermions, the corresponding two-particle wavefunction is antisymmetric: this excludes overlapping wave trains, which are forbidden by the Pauli exclusion principle. Here we use an electron field emitter to coherently illuminate two detectors, and find anticorrelations in the arrival times of the free electrons. The particle beam has low degeneracy (about 10(-4) electrons per cell in phase space); as such, our experiment represents the fermionic twin of the Hanbury Brown-Twiss effect for photons.     

High-throughput retroviral tagging to identify components of specific signaling pathways in cancer

Genetic screens carried out in lower organisms such as yeast, Drosophila melanogaster and Caenorhabditis elegans have revealed many signaling pathways. For example, components of the RAS signaling cascade were identified using a mutant eye phenotype in D. melanogaster as a readout. Screening is usually based on enhancing or suppressing a phenotype by way of a known mutation in a particular signaling pathway. Such in vivo screens have been difficult to carry out in mammals, however, owing to their relatively long generation times and the limited number of animals that can be screened. Here we describe an in vivo mammalian genetic screen used to identify components of pathways contributing to oncogenic transformation. We applied retroviral insertional mutagenesis in Myc transgenic (E mu Myc) mice lacking expression of Pim1 and Pim2 to search for genes that can substitute for Pim1 and Pim2 in lymphomagenesis. We determined the chromosomal positions of 477 retroviral insertion sites (RISs) derived from 38 tumors from E mu Myc Pim1(-/-) Pim2(-/-) mice and 27 tumors from E mu Myc control mice using the Ensembl and Celera annotated mouse genome databases. There were 52 sites occupied by proviruses in more than one tumor. These common insertion sites (CISs) are likely to contain genes contributing to tumorigenesis. Comparison of the RISs in tumors of Pim-null mice with the RISs in tumors of E mu Myc control mice indicated that 10 of the 52 CISs belong to the Pim complementation group. In addition, we found that Pim3 is selectively activated in Pim-null tumor cells, which supports the validity of our approach.