A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, ratelimiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12)United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208)American Society for Radiation Oncology (Resident Seed Grant RA-2011-1)European Molecular Biology Organization (Long-Term Fellowship)National Institutes of Health (U.S.) (R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389)United States. Department of Defense (W81XWH-14-PRCRP-IA)Alexander and Margaret Stewart Trus

Bidirectional intraflagellar transport is restricted to two sets of microtubule doublets in the trypanosome flagellum

Intraflagellar transport (IFT) is the rapid bidirectional movement of large protein complexes driven by kinesin and dynein motors along microtubule doublets of cilia and flagella. In this study, we used a combination of high-resolution electron and light microscopy to investigate how and where these IFT trains move within the flagellum of the protist Trypanosoma brucei. Focused ion beam scanning electron microscopy (FIB-SEM) analysis of trypanosomes showed that trains are found almost exclusively along two sets of doublets (3–4 and 7–8) and distribute in two categories according to their length. High-resolution live imaging of cells expressing mNeonGreen::IFT81 or GFP::IFT52 revealed for the first time IFT trafficking on two parallel lines within the flagellum. Anterograde and retrograde IFT occurs on each of these lines. At the distal end, a large individual anterograde IFT train is converted in several smaller retrograde trains in the space of 3–4 s while remaining on the same side of the axoneme

Heat as a tracer for understanding transport processes in fractured media: Theory and field assessment from multiscale thermal push-pull tracer tests

International audienceThe characterization and modeling of heat transfer in fractured media is particularly challenging as the existence of fractures at multiple scales induces highly localized flow patterns. From a theoretical and numerical analysis of heat transfer in simple conceptual models of fractured media, we show that flow channeling has a significant effect on the scaling of heat recovery in both space and time. The late time tailing of heat recovery under channeled flow is shown to diverge from the TðtÞ / t 21:5 behavior expected for the classical parallel plate model and follow the scaling TðtÞ / 1=tðlog tÞ 2 for a simple channel modeled as a tube. This scaling, which differs significantly from known scalings in mobile-immobile systems, is of purely geometrical origin: late time heat transfer from the matrix to a channel corresponds dimensionally to a radial diffusion process, while heat transfer from the matrix to a plate may be considered as a one-dimensional process. This phenomenon is also manifested on the spatial scaling of heat recovery as flow channeling affects the decay of the thermal breakthrough peak amplitude and the increase of the peak time with scale. These findings are supported by the results of a field experimental campaign performed on the fractured rock site of Ploemeur. The scaling of heat recovery in time and space, measured from thermal breakthrough curves measured through a series of push-pull tests at different scales, shows a clear signature of flow channeling. The whole data set can thus be successfully represented by a multichannel model parametrized by the mean channel density and aperture. These findings, which bring new insights on the effect of flow channeling on heat transfer in fractured rocks, show how heat recovery in geothermal tests may be controlled by fracture geometry. In addition, this highlights the interest of thermal push-pull tests as a complement to solute tracers tests to infer fracture aperture and geometry

Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model

The alignment in flavour space of the Yukawa matrices of a general two-Higgs-doublet model results in the absence of tree-level flavour-changing neutral currents. In addition to the usual fermion masses and mixings, the aligned Yukawa structure only contains three complex parameters, which are potential new sources of CP violation. For particular values of these three parameters all known specific implementations of the model based on discrete Z_2 symmetries are recovered. One of the most distinctive features of the two-Higgs-doublet model is the presence of a charged scalar. In this work, we discuss its main phenomenological consequences in flavour-changing processes at low energies and derive the corresponding constraints on the parameters of the aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP. References added. Discussion slightly extended. Conclusions unchange

Search for Higgs bosons decaying to tautau pairs in ppbar collisions at sqrt(s) = 1.96 TeV

We present a search for the production of neutral Higgs bosons decaying into tautau pairs in ppbar collisions at a center-of-mass energy of 1.96 TeV. The data, corresponding to an integrated luminosity of 5.4 fb-1, were collected by the D0 experiment at the Fermilab Tevatron Collider. We set upper limits at the 95% C.L. on the product of production cross section and branching ratio for a scalar resonance decaying into tautau pairs, and we then interpret these limits as limits on the production of Higgs bosons in the minimal supersymmetric standard model (MSSM) and as constraints in the MSSM parameter space.Comment: 7 pages, 5 figures, submitted to PL

Measurement of three-jet differential cross sections d sigma-3jet / d M-3jet in p anti-p collisions at sqrt(s)=1.96 TeV

We present the first measurement of the inclusive three-jet differential cross section as a function of the invariant mass of the three jets with the largest transverse momenta in an event in p anti-p collisions at sqrt(s) = 1.96 TeV. The measurement is made in different rapidity regions and for different jet transverse momentum requirements and is based on a data set corresponding to an integrated luminosity of 0.7 fb^{-1} collected with the D0 detector at the Fermilab Tevatron Collider. The results are used to test the three-jet matrix elements in perturbative QCD calculations at next-to-leading order in the strong coupling constant. The data allow discrimination between parametrizations of the parton distribution functions of the proton.Comment: 10 pages, 4 figures, 2 tables, submitted to Phys. Lett. B, corrected chi2 values for NNPD

Precise measurement of the top quark mass in the dilepton channel at D0

We measure the top quark mass (mt) in ppbar collisions at a center of mass energy of 1.96 TeV using dilepton ttbar->W+bW-bbar->l+nubl-nubarbbar events, where l denotes an electron, a muon, or a tau that decays leptonically. The data correspond to an integrated luminosity of 5.4 fb-1 collected with the D0 detector at the Fermilab Tevatron Collider. We obtain mt = 174.0 +- 1.8(stat) +- 2.4(syst) GeV, which is in agreement with the current world average mt = 173.3 +- 1.1 GeV. This is currently the most precise measurement of mt in the dilepton channel.Comment: 7 pages, 4 figure

Search for pair production of the scalar top quark in muon+tau final states

We present a search for the pair production of scalar top quarks ($\tilde{t}_{1}$), the lightest supersymmetric partners of the top quarks, in $p\bar{p}$ collisions at a center-of-mass energy of 1.96 TeV, using data corresponding to an integrated luminosity of {7.3 $fb^{-1}$} collected with the \dzero experiment at the Fermilab Tevatron Collider. Each scalar top quark is assumed to decay into a $b$ quark, a charged lepton, and a scalar neutrino ($\tilde{\nu}$). We investigate final states arising from $\tilde{t}_{1} \bar{\tilde{t}_{1}} \rightarrow b\bar{b}\mu\tau \tilde{\nu} \tilde{\nu}$ and $\tilde{t}_{1} \bar{\tilde{t}_{1}} \rightarrow b\bar{b}\tau\tau \tilde{\nu} \tilde{\nu}$. With no significant excess of events observed above the background expected from the standard model, we set exclusion limits on this production process in the ($m_{\tilde{t}_{1}}$,$m_{\tilde{\nu}}$) plane.Comment: Submitted to Phys. Lett.

Measurements of inclusive W+jets production rates as a function of jet transverse momentum in ppbar collisions at sqrt{s}=1.96 TeV

This Letter describes measurements of inclusive W (--> e nu) + n jet cross sections (n = 1-4), presented as total inclusive cross sections and differentially in the nth jet transverse momentum. The measurements are made using data corresponding to an integrated luminosity of 4.2 fb-1 collected by the D0 detector at the Fermilab Tevatron Collider, and achieve considerably smaller uncertainties on W +jets production cross sections than previous measurements. The measurements are compared to next-to-leading order perturbative QCD (pQCD) calculations in the n =1-3 jet multiplicity bins and to leading order pQCD calculations in the 4-jet bin. The measurements are generally in agreement with pQCD predictions, although certain regions of phase space are identified where the calculations could be improved

A search for charged massive long-lived particles

We report on a search for charged massive long-lived particles (CMLLPs), based on 5.2 fb$^{-1}$ of integrated luminosity collected with the D0 detector at the Fermilab Tevatron $p\bar{p}$ collider. We search for events in which one or more particles are reconstructed as muons but have speed and ionization energy loss $(dE/dx)$ inconsistent with muons produced in beam collisions. CMLLPs are predicted in several theories of physics beyond the standard model. We exclude pair-produced long-lived gaugino-like charginos below 267 GeV and higgsino-like charginos below 217 GeV at 95% C.L., as well as long-lived scalar top quarks with mass below 285 GeV.Comment: submitted to Phys. Rev. Letter