Human iPS derived progenitors bioengineered into liver organoids using an inverted colloidal crystal poly (ethylene glycol) scaffold.

Generation of human organoids from induced pluripotent stem cells (iPSCs) offers exciting possibilities for developmental biology, disease modelling and cell therapy. Significant advances towards those goals have been hampered by dependence on animal derived matrices (e.g. Matrigel), immortalized cell lines and resultant structures that are difficult to control or scale. To address these challenges, we aimed to develop a fully defined liver organoid platform using inverted colloid crystal (ICC) whose 3-dimensional mechanical properties could be engineered to recapitulate the extracellular niche sensed by hepatic progenitors during human development. iPSC derived hepatic progenitors (IH) formed organoids most optimally in ICC scaffolds constructed with 140 μm diameter pores coated with type I collagen in a two-step process mimicking liver bud formation. The resultant organoids were closer to adult tissue, compared to 2D and 3D controls, with respect to morphology, gene expression, protein secretion, drug metabolism and viral infection and could integrate, vascularise and function following implantation into livers of immune-deficient mice. Preliminary interrogation of the underpinning mechanisms highlighted the importance of TGFβ and hedgehog signalling pathways. The combination of functional relevance with tuneable mechanical properties leads us to propose this bioengineered platform to be ideally suited for a range of future mechanistic and clinical organoid related applications

The structural basis for Z α1-antitrypsin polymerization in the liver

The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α1-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α1-antitrypsin as “polymer” chains in liver tissue. No detailed structural analysis has been performed of this material. Moreover, there is little information on the relevance of well-studied artificially induced polymers to these disease-associated molecules. We have isolated polymers from the liver tissue of Z α1-antitrypsin homozygotes (E342K) who have undergone transplantation, labeled them using a Fab fragment, and performed single-particle analysis of negative-stain electron micrographs. The data show structural equivalence between heat-induced and ex vivo polymers and that the intersubunit linkage is best explained by a carboxyl-terminal domain swap between molecules of α1-antitrypsin

Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications.

Use of hepatocytes derived from induced pluripotent stem cells (i-Heps) is limited by their functional differences in comparison with primary cells. Extracellular niche factors likely play a critical role in bridging this gap. Using image-based characterization (high content analysis; HCA) of freshly isolated hepatocytes from 17 human donors, we devised and validated an algorithm (Hepatocyte Likeness Index; HLI) for comparing the hepatic properties of cells against a physiological gold standard. The HLI was then applied in a targeted screen of extracellular niche factors to identify substrates driving i-Heps closer to the standard. Laminin 411, the top hit, was validated in two additional induced pluripotent stem cell (iPSC) lines, primary tissue, and an in vitro model of α1-antitrypsin deficiency. Cumulatively, these data provide a reference method to control and screen for i-Hep differentiation, identify Laminin 411 as a key niche protein, and underscore the importance of combining substrates, soluble factors, and HCA when developing iPSC applications

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 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

Circulating polymers in α1-antitrypsin deficiency.

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Search for flavour-changing neutral-current couplings between the top quark and the photon with the ATLAS detector at s=13 TeV

This letter documents a search for flavour-changing neutral currents (FCNCs), which are strongly suppressed in the Standard Model, in events with a photon and a top quark with the ATLAS detector. The analysis uses data collected in pp collisions at s=13 TeV during Run 2 of the LHC, corresponding to an integrated luminosity of 139 fb−1. Both FCNC top-quark production and decay are considered. The final state consists of a charged lepton, missing transverse momentum, a b-tagged jet, one high-momentum photon and possibly additional jets. A multiclass deep neural network is used to classify events either as signal in one of the two categories, FCNC production or decay, or as background. No significant excess of events over the background prediction is observed and 95% CL upper limits are placed on the strength of left- and right-handed FCNC interactions. The 95% CL bounds on the branching fractions for the FCNC top-quark decays, estimated (expected) from both top-quark production and decay, are B(t→uγ)<0.85(0.88−0.25+0.37)×10−5 and B(t→cγ)<4.2(3.40−0.95+1.35)×10−5 for a left-handed tqγ coupling, and B(t→uγ)<1.2(1.20−0.33+0.50)×10−5 and B(t→cγ)<4.5(3.70−1.03+1.47)×10−5 for a right-handed coupling

Measurement of muon pairs produced via γγ scattering in nonultraperipheral Pb + Pb collisions at √sNN = 5.02 TeV with the ATLAS detector

Results of a measurement of dimuon photoproduction in nonultraperipheral Pb + Pb collisions at √sNN = 5.02 TeV are presented. Themeasurement uses ATLAS data from the 2015 and 2018 Pb + Pb data-taking periods at the LHC with an integrated luminosity of 1.94 nb.1. The γγ → μ+ μ- pairs are identified via selections on pair momentum asymmetry and acoplanarity. Differential cross sections for dimuon production are measured in different centrality, average muon momentum, and pair rapidity intervals as functions of acoplanarity and k⊥, the transverse momentum kick of one muon relative to the other. Measurements are also made as a function of the rapidity separation of the muons and the angle of the muon pair relative to the second-order event plane to test whether magnetic fields generated in the quark-gluon plasma affect the measured muons. A prior observation of a centrality-dependent broadening of the acoplanarity distribution is confirmed. Furthermore, the improved precision of the measurement reveals a depletion in the number of pairs having small acoplanarity or k⊥ values in more central collisions. The acoplanarity distributions in a given centrality interval are observed to vary with the mean pT of the muons in the pair, but the k⊥ distributions do not. Comparisons with recent theoretical predictions are made. The predicted trends associated with effects of magnetic fields on the dimuons are not observed