Gun Control: State Versus Federal Regulation of Firearms

William Harwood addresses the complex question of whether gun control should be regulated by the federal or state government, or by some combination of both. In a thorough look at the history of federal and Maine state gun control—and at the various ways the issue of gun violence can be framed—Harwood concludes that neither level of government has a clear mandate to regulate exclusively. Rather, he argues for a more cooperative federal-state approach that allows the federal government to apply uniform regulations when appropriate and the states to experiment with further regulations if so desired

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology

Abstracts

Abstracts of papers about Giuseppe Verdi and his works, presented at joint meetings of the AIVS and Greater NY Chapter of the American Musicological Society, 1979-81 (Hepokoski, Lawton, Chusid, Hornick, Nádas, Tomlinson, Garrison, Powers), at the 1982 national meeting of the American Musicological Society (Harwood), and at an NEH-sponsored summer seminar at NYU in 1980 (Beams, Cole, Cordell, Davis, Fry, King, Mason, McCauley, Town)

Speed breeding is a powerful tool to accelerate crop research and breeding

The growing human population and a changing environment have raised significant concern for global food security, with the current improvement rate of several important crops inadequate to meet future demand1. This slow improvement rate is attributed partly to the long generation times of crop plants. Here, we present a method called ‘speed breeding’, which greatly shortens generation time and accelerates breeding and research programmes. Speed breeding can be used to achieve up to 6 generations per year for spring wheat (Triticum aestivum), durum wheat (T. durum), barley (Hordeum vulgare), chickpea (Cicer arietinum) and pea (Pisum sativum), and 4 generations for canola (Brassica napus), instead of 2–3 under normal glasshouse conditions. We demonstrate that speed breeding in fully enclosed, controlled-environment growth chambers can accelerate plant development for research purposes, including phenotyping of adult plant traits, mutant studies and transformation. The use of supplemental lighting in a glasshouse environment allows rapid generation cycling through single seed descent (SSD) and potential for adaptation to larger-scale crop improvement programs. Cost saving through light-emitting diode (LED) supplemental lighting is also outlined. We envisage great potential for integrating speed breeding with other modern crop breeding technologies, including high-throughput genotyping, genome editing and genomic selection, accelerating the rate of crop improvement

Co-directional replication-transcription conflicts lead to replication restart

August 24, 2011Head-on encounters between the replication and transcription machineries on the lagging DNA strand can lead to replication fork arrest and genomic instability1, 2. To avoid head-on encounters, most genes, especially essential and highly transcribed genes, are encoded on the leading strand such that transcription and replication are co-directional. Virtually all bacteria have the highly expressed ribosomal RNA genes co-directional with replication3. In bacteria, co-directional encounters seem inevitable because the rate of replication is about 10–20-fold greater than the rate of transcription. However, these encounters are generally thought to be benign2, 4, 5, 6, 7, 8, 9. Biochemical analyses indicate that head-on encounters10 are more deleterious than co-directional encounters8 and that in both situations, replication resumes without the need for any auxiliary restart proteins, at least in vitro. Here we show that in vivo, co-directional transcription can disrupt replication, leading to the involvement of replication restart proteins. We found that highly transcribed rRNA genes are hotspots for co-directional conflicts between replication and transcription in rapidly growing Bacillus subtilis cells. We observed a transcription-dependent increase in association of the replicative helicase and replication restart proteins where head-on and co-directional conflicts occur. Our results indicate that there are co-directional conflicts between replication and transcription in vivo. Furthermore, in contrast to the findings in vitro, the replication restart machinery is involved in vivo in resolving potentially deleterious encounters due to head-on and co-directional conflicts. These conflicts probably occur in many organisms and at many chromosomal locations and help to explain the presence of important auxiliary proteins involved in replication restart and in helping to clear a path along the DNA for the replisome.Biotechnology and Biological Sciences Research Council (Great Britain) (Grant BB/E006450/1)Wellcome Trust (London, England) (Grant 091968/Z/10/Z)National Institutes of Health (U.S.) (Grant GM41934)National Institutes of Health (U.S.) (Postdoctoral Fellowship GM093408)Biotechnology and Biological Sciences Research Council (Great Britain) (Sabbatical Visit

Solar Occultation Satellite Data and Derived Meteorological Products: Sampling Issues and Comparisons with Aura MLS

Derived Meteorological Products (DMPs, including potential temperature (theta), potential vorticity, equivalent latitude (EqL), horizontal winds and tropopause locations) have been produced for the locations and times of measurements by several solar occultation (SO) instruments and the Aura Microwave Limb Sounder (MLS). DMPs are calculated from several meteorological analyses for the Atmospheric Chemistry Experiment-Fourier Transform Spectrometer, Stratospheric Aerosol and Gas Experiment II and III, Halogen Occultation Experiment, and Polar Ozone and Aerosol Measurement II and III SO instruments and MLS. Time-series comparisons of MLS version 1.5 and SO data using DMPs show good qualitative agreement in time evolution of O3, N2O, H20, CO, HNO3, HCl and temperature; quantitative agreement is good in most cases. EqL-coordinate comparisons of MLS version 2.2 and SO data show good quantitative agreement throughout the stratosphere for most of these species, with significant biases for a few species in localized regions. Comparisons in EqL coordinates of MLS and SO data, and of SO data with geographically coincident MLS data provide insight into where and how sampling effects are important in interpretation of the sparse SO data, thus assisting in fully utilizing the SO data in scientific studies and comparisons with other sparse datasets. The DMPs are valuable for scientific studies and to facilitate validation of non-coincident measurements

The emergence of modern statistics in agricultural science : Analysis of variance, experimental design and the reshaping of research at Rothamsted Experimental Station, 1919–1933

During the twentieth century statistical methods have transformed research in the experimental and social sciences. Qualitative evidence has largely been replaced by quantitative results and the tools of statistical inference have helped foster a new ideal of objectivity in scientific knowledge. The paper will investigate this transformation by considering the genesis of analysis of variance and experimental design, statistical methods nowadays taught in every elementary course of statistics for the experimental and social sciences. These methods were developed by the mathematician and geneticist R. A. Fisher during the 1920s, while he was working at Rothamsted Experimental Station, where agricultural research was in turn reshaped by Fisher’s methods. Analysis of variance and experimental design required new practices and instruments in field and laboratory research, and imposed a redistribution of expertise among statisticians, experimental scientists and the farm staff. On the other hand the use of statistical methods in agricultural science called for a systematization of information management and made computing an activity integral to the experimental research done at Rothamsted, permanently integrating the statisticians’ tools and expertise into the station research programme. Fisher’s statistical methods did not remain confined within agricultural research and by the end of the 1950s they had come to stay in psychology, sociology, education, chemistry, medicine, engineering, economics, quality control, just to mention a few of the disciplines which adopted them

Roadmap on photonic metasurfaces

Funding: C.R. and U.L. acknowledge support through the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy via the Excellence Cluster 3D Matter Made to Order (EXC-2082/1, Grant No. 390761711). A.B.E. acknowledges support through the Cluster of Excellence PhoenixD (EXC 2122, Project ID No. 390833453). I.F.-C. and C.R. acknowledge support through the CRC Waves: Analysis and Numerics (SFB 1173, Grant No. 258734477. K.A. acknowledges funding from the Swiss National Science Foundation (Project No. PZ00P2_193221).Here we present a roadmap on Photonic metasurfaces. This document consists of a number of perspective articles on different applications, challenge areas or technologies underlying photonic metasurfaces. Each perspective will introduce the topic, present a state of the art as well as give an insight into the future direction of the subfield.Peer reviewe

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies