Targeted chemical wedges reveal the role of allosteric DNA modulation in protein-DNA assembly

The cooperative assembly of multiprotein complexes results from allosteric modulations of DNA structure as well as direct intermolecular contacts between proteins. Such cooperative binding plays a critical role in imparting exquisite sequence specificity on the homeobox transcription factor (Hox) family of developmental transcription factors. A well-characterized example includes the interaction of Hox proteins with extradenticle (Exd), a highly conserved DNA binding transcription factor. Although direct interactions are important, the contribution of indirect interactions toward cooperative assembly of Hox and Exd remains unresolved. Here we use minor groove binding polyamides as structural wedges to induce perturbations at specific base steps within the Exd binding site. We find that allosteric modulation of DNA structure contributes nearly 1.5 kcal/mol to the binding of Exd to DNA, even in the absence of direct Hox contacts. In contrast to previous studies, the sequence-targeted chemical wedges reveal the role of DNA geometry in cooperative assembly of Hox-Exd complexes. Programmable polyamides may well serve as general probes to investigate the role of DNA modulation in the cooperative and highly specific assembly of other protein-DNA complexes

Retinoic Acid Promotes the Generation of Pancreatic Endocrine Progenitor Cells and Their Further Differentiation into β-Cells

The identification of secreted factors that can selectively stimulate the generation of insulin producing β-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based β-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of β-cells during normal pancreatic development such putative factors may be identified. In the mouse, β-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of β-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when β-cells are generated. We also provide evidence that RA induces the generation of Ngn3+ endocrine progenitor cells and stimulates their further differentiation into β-cells by activating a program of cell differentiation that recapitulates the normal temporal program of β-cell differentiation

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

Peer reviewe

Measurements of Higgs boson production cross sections and couplings in the diphoton decay channel at root s=13 TeV

Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a sample of proton-proton collisions at root s = 13TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb(-1). Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1.12 +/- 0.09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations.Peer reviewe

Observation of tW production in the single-lepton channel in pp collisions at root s=13 TeV

A measurement of the cross section of the associated production of a single top quark and a W boson in final states with a muon or electron and jets in proton-proton collisions at root s = 13 TeV is presented. The data correspond to an integrated luminosity of 36 fb(-1) collected with the CMS detector at the CERN LHC in 2016. A boosted decision tree is used to separate the tW signal from the dominant t (t) over bar background, whilst the subleading W+jets and multijet backgrounds are constrained using data-based estimates. This result is the first observation of the tW process in final states containing a muon or electron and jets, with a significance exceeding 5 standard deviations. The cross section is determined to be 89 +/- 4 (stat) +/- 12 (syst) pb, consistent with the standard model.Peer reviewe

Measurements of the Electroweak Diboson Production Cross Sections in Proton-Proton Collisions at root s=5.02 TeV Using Leptonic Decays

The first measurements of diboson production cross sections in proton-proton interactions at a center-of-mass energy of 5.02 TeV are reported. They are based on data collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 302 pb(-1). Events with two, three, or four charged light leptons (electrons or muons) in the final state are analyzed. The WW, WZ, and ZZ total cross sections are measured as sigma(WW) = 37:0(-5.2)(+5.5) (stat)(-2.6)(+2.7) (syst) pb, sigma(WZ) = 6.4(-2.1)(+2.5) (stat)(-0.3)(+0.5)(syst) pb, and sigma(ZZ) = 5.3(-2.1)(+2.5)(stat)(-0.4)(+0.5) (syst) pb. All measurements are in good agreement with theoretical calculations at combined next-to-next-to-leading order quantum chromodynamics and next-to-leading order electroweak accuracy

Search for lepton-flavor violating decays of the Higgs boson in the mu tau and e tau final states in proton-proton collisions at root s=13 TeV

A search is presented for lepton-flavor violating decays of the Higgs boson to mu t and et. The dataset corresponds to an integrated luminosity of 137 fb(-1) collected at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV. No significant excess has been found, and the results are interpreted in terms of upper limits on lepton-flavor violating branching fractions of the Higgs boson. The observed (expected) upper limits on the branching fractions are, respectively, B(H -> mu t) e tau) < 0.22(0.16)% at 95% confidence level.Peer reviewe