Precautionary Regulation in Europe and the United States: A Quantitative Comparison

Much attention has been addressed to the question of whether Europe or the United States adopts a more precautionary stance to the regulation of potential environmental, health, and safety risks. Some commentators suggest that Europe is more risk-averse and precautionary, whereas the US is seen as more risk-taking and optimistic about the prospects for new technology. Others suggest that the US is more precautionary because its regulatory process is more legalistic and adversarial, while Europe is more lax and corporatist in its regulations. The flip-flop hypothesis claims that the US was more precautionary than Europe in the 1970s and early 1980s, and that Europe has become more precautionary since then. We examine the levels and trends in regulation of environmental, health, and safety risks since 1970. Unlike previous research, which has studied only a small set of prominent cases selected non-randomly, we develop a comprehensive list of almost 3,000 risks and code the relative stringency of regulation in Europe and the US for each of 100 risks randomly selected from that list for each year from 1970 through 2004. Our results suggest that: (a) averaging over risks, there is no significant difference in relative precaution over the period, (b) weakly consistent with the flip-flop hypothesis, there is some evidence of a modest shift toward greater relative precaution of European regulation since about 1990, although (c) there is a diversity of trends across risks, of which the most common is no change in relative precaution (including cases where Europe and the US are equally precautionary and where Europe or the US has been consistently more precautionary). The overall finding is of a mixed and diverse pattern of relative transatlantic precaution over the period

Anchoring Bias in Online Voting

Voting online with explicit ratings could largely reflect people's preferences and objects' qualities, but ratings are always irrational, because they may be affected by many unpredictable factors like mood, weather, as well as other people's votes. By analyzing two real systems, this paper reveals a systematic bias embedding in the individual decision-making processes, namely people tend to give a low rating after a low rating, as well as a high rating following a high rating. This so-called \emph{anchoring bias} is validated via extensive comparisons with null models, and numerically speaking, the extent of bias decays with interval voting number in a logarithmic form. Our findings could be applied in the design of recommender systems and considered as important complementary materials to previous knowledge about anchoring effects on financial trades, performance judgements, auctions, and so on.Comment: 5 pages, 4 tables, 5 figure

Feasibility of free space quantum key distribution with coherent polarization states

We demonstrate for the first time the feasibility of free space quantum key distribution with continuous variables under real atmospheric conditions. More specifically, we transmit coherent polarization states over a 100m free space channel on the roof of our institute's building. In our scheme, signal and local oscillator are combined in a single spatial mode which auto-compensates atmospheric fluctuations and results in an excellent interference. Furthermore, the local oscillator acts as spatial and spectral filter thus allowing unrestrained daylight operation.Comment: 12 pages, 8 figures, extensions in sections 2, 3.1, 3.2 and 4. This is an author-created, un-copyedited version of an article accepted for publication in New Journal of Physics (Special Issue on Quantum Cryptography: Theory and Practice). IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from i

Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents

Generation of an equine biobank to be used for Functional Annotation of Animal Genomes project

The Functional Annotation of Animal Genomes (FAANG) project aims to identify genomic regulatory elements in both sexes across multiple stages of development in domesticated animals. This study represents the first stage of the FAANG project for the horse, Equus caballus. A biobank of 80 tissue samples, two cell lines and six body fluids was created from two adult Thoroughbred mares. Ante-mortem assessments included full physical examinations, lameness, ophthalmologic and neurologic evaluations. Complete blood counts and serum biochemistries were also performed. At necropsy, in addition to tissue samples, aliquots of serum, ethylenediaminetetraacetic acid (EDTA) plasma, heparinized plasma, cerebrospinal fluid, synovial fluid, urine and microbiome samples from all regions of the gastrointestinal and urogenital tracts were collected. Epidermal keratinocytes and dermal fibroblasts were cultured from skin samples. All tissues were grossly and histologically evaluated by a board-certified veterinary pathologist. The results of the clinical and pathological evaluations identified subclinical eosinophilic and lymphocytic infiltration throughout the length of the gastrointestinal tract as well as a mild clinical lameness in both animals. Each sample was cryo-preserved in multiple ways, and nuclei were extracted from selected tissues. These samples represent the first published systemically healthy equine-specific biobank with extensive clinical phenotyping ante- and post-mortem. The tissues in the biobank are intended for community-wide use in the functional annotation of the equine genome. The use of the biobank will improve the quality of the reference annotation and allow all equine researchers to elucidate unknown genomic and epigenomic causes of disease

Regulation of membrane ruffling by polarized STIM1 and ORAI1in cortactin-rich domains

La movilidad celular y la migración requieren la reorganización del citoesqueleto cortical en el borde principal de las células y la entrada de Ca2 + extracelular es esencial para esta reorganización. Sin embargo, la naturaleza molecular de los reguladores de esta vía es desconocida. Este trabajo contribuye a comprender el papel de STIM1 y ORAI1 en la promoción de la ondulación de la membrana al mostrar que la fosfo-STIM1 se localiza en el borde principal de las células, y que tanto phospho-STIM1 como ORAI1 se localizan conjuntamente con la cortactina (CTTN), un regulador del citoesqueleto en las zonas de rizo de la membrana. Las líneas celulares STIM1-KO y ORAI1-KO se generaron mediante la edición del genoma CRISPR / Cas9 en células U2OS. En ambos casos, las células KO presentaron una reducción notable de la entrada de Ca2 + operada por el almacén (SOCE) que se rescató mediante la expresión de STIM1-mCherry y ORAI1-mCherry. Estos resultados demostraron que SOCE regula la deformación de la membrana en el borde anterior de las células. Por otra parte, ORAI1 endógeno y ORAI1-GFP sobreexpresado coinmuno precipitado con CTTN endógeno. Este último resultado, además del fenotipo de las células KO, la preservación de la co-localización de ORAI1-CTTN durante el fruncido, y la inhibición de la rizo de la membrana por parte del inhibidor del canal de Ca2 + SKF96365, apoya aún más un vínculo funcional entre el SOCE y el fruncido de la membrana.Cell motility and migration requires the reorganization of the cortical cytoskeleton at the leading edge of cells and extracellular Ca2+ entry is essential for this reorganization. However the molecular nature of the regulators of this pathway is unknown. This work contributes to understanding the role of STIM1 and ORAI1 in the promotion of membrane ruffling by showing that phospho-STIM1 localizes at the leading edge of cells, and that both phospho-STIM1 and ORAI1 co-localize with cortactin (CTTN), a regulator of the cytoskeleton at membrane ruffling areas. STIM1-KO and ORAI1-KO cell lines were generated by CRISPR/Cas9 genome editing in U2OS cells. In both cases, KO cells presented a notable reduction of store-operated Ca2+ entry (SOCE) that was rescued by expression of STIM1-mCherry and ORAI1-mCherry. These results demonstrated that SOCE regulates membrane ruffling at the leading edge of cells. Moreover, endogenous ORAI1 and overexpressed ORAI1-GFP co-immuno precipitated with endogenous CTTN. This latter result, in addition to the KO cells’ phenotype, the preservation of ORAI1-CTTN co-localization during ruffling, and the inhibition of membrane ruffling g by the Ca2+- channel inhibitor SKF96365, further supports a functional link between SOCE and membrane ruffling.• Ministerio de Economía y Competitividad y Fondo Social Europeo. Becas BFU2011-22798 y BFU2014-52401-P, para Francisco Javier Martín Romero • Consejo de Investigación Médica. Beca MC_UU_12016 / 2, para Darío R. Alessi • Ministerio de Economía y Competitividad. Beca BES-2012-052061, para Aida María López Guerrero • Gobierno de Extremadura. Ayuda PD10081, para Patricia Tomás Martín • Ministerio de Educación, Cultura y Deporte. Beca FPU13 / 03430, para Carlos Pascual Caro • Consejo de Investigación Médica. Ayuda MR / K015869 / 1, para Graeme Ball • EMBO. Beca ASTF-311-2014, para Eulalia Pozo Guisado • Ministerio de Educación, Cultura Española y Deporte. Beca PRX14 / 00176, para Francisco Javier Martín RomeropeerReviewe

Local Ca2+ Entry Via Orai1 Regulates Plasma Membrane Recruitment of TRPC1 and Controls Cytosolic Ca2+ Signals Required for Specific Cell Functions

Store-operated Ca2+ entry (SOCE) has been associated with two types of channels: CRAC channels that require Orai1 and STIM1 and SOC channels that involve TRPC1, Orai1, and STIM1. While TRPC1 significantly contributes to SOCE and SOC channel activity, abrogation of Orai1 function eliminates SOCE and activation of TRPC1. The critical role of Orai1 in activation of TRPC1-SOC channels following Ca2+ store depletion has not yet been established. Herein we report that TRPC1 and Orai1 are components of distinct channels. We show that TRPC1/Orai1/STIM1-dependent ISOC, activated in response to Ca2+ store depletion, is composed of TRPC1/STIM1-mediated non-selective cation current and Orai1/STIM1-mediated ICRAC; the latter is detected when TRPC1 function is suppressed by expression of shTRPC1 or a STIM1 mutant that lacks TRPC1 gating, STIM1(684EE685). In addition to gating TRPC1 and Orai1, STIM1 mediates the recruitment and association of the channels within ER/PM junctional domains, a critical step in TRPC1 activation. Importantly, we show that Ca2+ entry via Orai1 triggers plasma membrane insertion of TRPC1, which is prevented by blocking SOCE with 1 µM Gd3+, removal of extracellular Ca2+, knockdown of Orai1, or expression of dominant negative mutant Orai1 lacking a functional pore, Orai1-E106Q. In cells expressing another pore mutant of Orai1, Orai1-E106D, TRPC1 trafficking is supported in Ca2+-containing, but not Ca2+-free, medium. Consistent with this, ICRAC is activated in cells pretreated with thapsigargin in Ca2+-free medium while ISOC is activated in cells pretreated in Ca2+-containing medium. Significantly, TRPC1 function is required for sustained KCa activity and contributes to NFκB activation while Orai1 is sufficient for NFAT activation. Together, these findings reveal an as-yet unidentified function for Orai1 that explains the critical requirement of the channel in the activation of TRPC1 following Ca2+ store depletion. We suggest that coordinated regulation of the surface expression of TRPC1 by Orai1 and gating by STIM1 provides a mechanism for rapidly modulating and maintaining SOCE-generated Ca2+ signals. By recruiting ion channels and other signaling pathways, Orai1 and STIM1 concertedly impact a variety of critical cell functions that are initiated by SOCE

Lazarus1, a DUF300 Protein, Contributes to Programmed Cell Death Associated with Arabidopsis acd11 and the Hypersensitive Response

Programmed cell death (PCD) is a necessary part of the life of multi-cellular organisms. A type of plant PCD is the defensive hypersensitive response (HR) elicited via recognition of a pathogen by host resistance (R) proteins. The lethal, recessive accelerated cell death 11 (acd11) mutant exhibits HR-like accelerated cell death, and cell death execution in acd11 shares genetic requirements for HR execution triggered by one subclass of R proteins

Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease

Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease

Confounding conventional wisdom: political not principled differences in the transatlantic regulatory relationship

The transatlantic complaints over hormone-treated beef and genetically modified organisms before the World Trade Organisation (WTO) seem to confirm two separate but related conventional wisdoms about the transatlantic economic relationship: that it is highly conflictual and that many of the conflicts are rooted in profoundly different approaches to regulation. This article argues that neither of the two conventional wisdoms is accurate. Rather, it contends that they are products of two, compounding analytical shortcomings: one methodological, one empirical. The methodological shortcoming takes the form of an implicit selection bias. While WTO complaints are high profile they are rare and extreme examples; it is, therefore, unsound to generalise from them to the regulatory relationship as a whole. The empirical shortcoming has to do with neither the beef hormones nor the GMO dispute demonstrating what it is purported to. The article thus serves as a cautionary tale about the dangers of relying on obvious cases and the need to question whether evidence really does support a prevailing popular narrative