Genes in the postgenomic era

We outline three very different concepts of the gene - 'instrumental', 'nominal', and 'postgenomic'. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype

CellCognition : time-resolved phenotype annotation in high-throughput live cell imaging

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Methods 7 (2010): 747-754, doi:10.1038/nmeth.1486.Fluorescence time-lapse imaging has become a powerful tool to investigate complex dynamic processes such as cell division or intracellular trafficking. Automated microscopes generate time-resolved imaging data at high throughput, yet tools for quantification of large-scale movie data are largely missing. Here, we present CellCognition, a computational framework to annotate complex cellular dynamics. We developed a machine learning method that combines state-of-the-art classification with hidden Markov modeling for annotation of the progression through morphologically distinct biological states. The incorporation of time information into the annotation scheme was essential to suppress classification noise at state transitions, and confusion between different functional states with similar morphology. We demonstrate generic applicability in a set of different assays and perturbation conditions, including a candidate-based RNAi screen for mitotic exit regulators in human cells. CellCognition is published as open source software, enabling live imaging-based screening with assays that directly score cellular dynamics.Work in the Gerlich laboratory is supported by Swiss National Science Foundation (SNF) research grant 3100A0-114120, SNF ProDoc grant PDFMP3_124904, a European Young Investigator (EURYI) award of the European Science Foundation, an EMBO YIP fellowship, and a MBL Summer Research Fellowship to D.W.G., an ETH TH grant, a grant by the UBS foundation, a Roche Ph.D. fellowship to M.H.A.S, and a Mueller fellowship of the Molecular Life Sciences Ph.D. program Zurich to M.H. M.H. and M.H.A.S are fellows of the Zurich Ph.D. Program in Molecular Life Sciences. B.F. was supported by European Commission’s seventh framework program project Cancer Pathways. Work in the Ellenberg laboratory is supported by a European Commission grant within the Mitocheck consortium (LSHG-CT-2004-503464). Work in the Peter laboratory is supported by the ETHZ, Oncosuisse, SystemsX.ch (LiverX) and the SNF

Orbital effects of a monochromatic plane gravitational wave with ultra-low frequency incident on a gravitationally bound two-body system

We analytically compute the long-term orbital variations of a test particle orbiting a central body acted upon by an incident monochromatic plane gravitational wave. We assume that the characteristic size of the perturbed two-body system is much smaller than the wavelength of the wave. Moreover, we also suppose that the wave's frequency is much smaller than the particle's orbital one. We make neither a priori assumptions about the direction of the wavevector nor on the orbital geometry of the planet. We find that, while the semi-major axis is left unaffected, the eccentricity, the inclination, the longitude of the ascending node, the longitude of pericenter and the mean anomaly undergo non-vanishing long-term changes. They are not secular trends because of the slow modulation introduced by the tidal matrix coefficients and by the orbital elements themselves. They could be useful to indepenedently constrain the ultra-low frequency waves which may have been indirectly detected in the BICEP2 experiment. Our calculation holds, in general, for any gravitationally bound two-body system whose characteristic frequency is much larger than the frequency of the external wave. It is also valid for a generic perturbation of tidal type with constant coefficients over timescales of the order of the orbital period of the perturbed particle.Comment: LaTex2e, 24 pages, no figures, no tables. Changes suggested by the referees include

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Top-down contingent feature-specific orienting with and without awareness of the visual input

In the present article, the role of endogenous feature-specific orienting for conscious and unconscious vision is reviewed. We start with an overview of orienting. We proceed with a review of masking research, and the definition of the criteria of experimental protocols that demonstrate endogenous and exogenous orienting, respectively. Against this background of criteria, we assess studies of unconscious orienting and come to the conclusion that so far studies of unconscious orienting demonstrated endogenous feature-specific orienting. The review closes with a discussion of the role of unconscious orienting in action control

Image based machine learning for identification of macrophage subsets

Macrophages play a crucial rule in orchestrating immune responses against pathogens and foreign materials. Macrophages have remarkable plasticity in response to environmental cues and are able to acquire a spectrum of activation status, best exemplified by pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes at the two ends of the spectrum. Characterisation of M1 and M2 subsets is usually carried out by quantification of multiple cell surface markers, transcription factors and cytokine profiles. These approaches are time consuming, require large numbers of cells and are resource intensive. In this study, we used machine learning algorithms to develop a simple and fast imaging-based approach that enables automated identification of different macrophage functional phenotypes using their cell size and morphology. Fluorescent microscopy was used to assess cell morphology of different cell types which were stained for nucleus and actin distribution using DAPI and phalloidin respectively. By only analysing their morphology we were able to identify M1 and M2 phenotypes effectively and could distinguish them from naïve macrophages and monocytes with an average accuracy of 90%. Thus we suggest high-content and automated image analysis can be used for fast phenotyping of functionally diverse cell populations with reasonable accuracy and without the need for using multiple markers