Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders

Mitochondrial myopathies and defects in oxidative phosphorylation have been described in some patients with peroxisomal disorders. Although peroxisomes and mitochondria play a role in the β-oxidation of fatty acids, the metabolic interactions between the two are not well defined. Defects in peroxisomal β-oxidation are associated with extracellular accumulation of very long-chain fatty acids and may be accompanied by alterations in the intracellular pool of fatty acyl-CoAs, which are known to alter mitochondrial function. This study was initiated to examine alterations in the intracellular pool of acyl-CoAs and mitochondrial function in two children with generalized disorders of peroxisomal function and clinical lactic/pyruvic acidaemia. Fibroblasts were cultured from skin biopsies obtained from one child with neonatal adrenoleukodystrophy (NALD) and another with rhizomelic chondrodysplasia punctata (RCDP). Fibroblast lactate oxidation was significantly inhibited in NALD by 76% and RCDP by 92% compared to control values of 1.9±0.1 nmol/min per mg protein. Pyruvate dehydrogenase (PDH) (mean±SEM; activity nmol/min per mg protein) was: NALD 0.55±0.02 ( p <0.01), RCDP 0.44±0.02 ( p <0.01), and controls 0.83±0.02. The acid-insoluble (long-chain and very long-chain) acyl-CoA levels (mean±SEM; pmol/mg protein) were: NALD 129±69 ( p <0.01), RCDP 65±15 ( p <0.05), and control 45±7. These two patients with generalized peroxisomal disorders exhibited an increase in intracellular acyl-CoA species accompanied by decreased PDH activity and clinical lactic/pyruvic acidaemia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42496/1/10545_2004_Article_BF00710284.pd

Integrated Expression Profiling and Genome-Wide Analysis of ChREBP Targets Reveals the Dual Role for ChREBP in Glucose-Regulated Gene Expression

The carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper transcription factor, plays a critical role in the control of lipogenesis in the liver. To identify the direct targets of ChREBP on a genome-wide scale and provide more insight into the mechanism by which ChREBP regulates glucose-responsive gene expression, we performed chromatin immunoprecipitation-sequencing and gene expression analysis. We identified 1153 ChREBP binding sites and 783 target genes using the chromatin from HepG2, a human hepatocellular carcinoma cell line. A motif search revealed a refined consensus sequence (CABGTG-nnCnG-nGnSTG) to better represent critical elements of a functional ChREBP binding sequence. Gene ontology analysis shows that ChREBP target genes are particularly associated with lipid, fatty acid and steroid metabolism. In addition, other functional gene clusters related to transport, development and cell motility are significantly enriched. Gene set enrichment analysis reveals that ChREBP target genes are highly correlated with genes regulated by high glucose, providing a functional relevance to the genome-wide binding study. Furthermore, we have demonstrated that ChREBP may function as a transcriptional repressor as well as an activator

Combined searches for the production of supersymmetric top quark partners in proton–proton collisions at √s=13Te

A combination of searches for top squark pair production using proton–proton collision data at a center-of-mass energy of 13TeV at the CERN LHC, corresponding to an integrated luminosity of 137fb$^{-1}$ 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 the model, the combined result excludes a top squark mass up to 1325GeV for a massless neutralino, and a neutralino mass up to 700GeV for a top squark mass of 1150GeV. Top squarks with masses from 145 to 295GeV, for neutralino masses from 0 to 100GeV, with a mass difference between the top squark and the neutralino in a window of 30GeV 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 420GeV

Search for a vector-like quark T′ → tH via the diphoton decay mode of the Higgs boson in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for the electroweak production of a vector-like quark T′, decaying to a top quark and a Higgs boson is presented. The search is based on a sample of proton-proton collision events recorded at the LHC at = 13 TeV, corresponding to an integrated luminosity of 138 fb−1. This is the first T′ search that exploits the Higgs boson decay to a pair of photons. For narrow isospin singlet T′ states with masses up to 1.1 TeV, the excellent diphoton invariant mass resolution of 1–2% results in an increased sensitivity compared to previous searches based on the same production mechanism. The electroweak production of a T′ quark with mass up to 960 GeV is excluded at 95% confidence level, assuming a coupling strength κT = 0.25 and a relative decay width Γ/MT′ < 5%

Precision luminosity measurement in proton–proton collisions at √s=13TeV in 2015 and 2016 at CMS

The measurement of the luminosity recorded by the CMS detector installed at LHC interaction point 5, using proton–proton collisions at √s=13TeV in 2015 and 2016, is reported. The absolute luminosity scale is measured for individual bunch crossings using beam-separation scans (the van der Meer method), with a relative precision of 1.3 and 1.0% in 2015 and 2016, respectively. The dominant sources of uncertainty are related to residual differences between the measured beam positions and the ones provided by the operational settings of the LHC magnets, the factorizability of the proton bunch spatial density functions in the coordinates transverse to the beam direction, and the modeling of the effect of electromagnetic interactions among protons in the colliding bunches. When applying the van der Meer calibration to the entire run periods, the integrated luminosities when CMS was fully operational are 2.27 and 36.3 fb$^{-1}$ in 2015 and 2016, with a relative precision of 1.6 and 1.2%, respectively. These are among the most precise luminosity measurements at bunched-beam hadron colliders

Proton reconstruction with the CMS-TOTEM Precision Proton Spectrometer

The Precision Proton Spectrometer (PPS) of the CMS and TOTEM experiments collected 107.7 fb-1 in proton-proton (pp) collisions at the LHC at 13 TeV (Run 2). This paper describes the key features of the PPS alignment and optics calibrations, the proton reconstruction procedure, as well as the detector efficiency and the performance of the PPS simulation. The reconstruction and simulation are validated using a sample of (semi)exclusive dilepton events. The performance of PPS has proven the feasibility of continuously operating a near-beam proton spectrometer at a high luminosity hadron collider

Search for high-mass resonances decaying to a jet and a Lorentz-boosted resonance in proton-proton collisions at √s = 13 TeV

A search is reported for high-mass hadronic resonances that decay to a parton and a Lorentz-boosted resonance, which in turn decays into a pair of partons. The search is based on data collected with the CMS detector at the LHC in proton-proton collisions at , corresponding to an integrated luminosity of 138. The boosted resonance is reconstructed as a single wide jet with substructure consistent with a two-body decay. The high-mass resonance is thus considered as a dijet system. The jet substructure information and the kinematic properties of cascade resonance decays are exploited to disentangle the signal from the large quantum chromodynamics multijet background. The dijet mass spectrum is analyzed for the presence of new high-mass resonances, and is found to be consistent with the standard model background predictions. Results are interpreted in a warped extra dimension model where the high-mass resonance is a Kaluza–Klein gluon, the boosted resonance is a radion, and the final state partons are all gluons. Limits on the production cross section are set as a function of the Kaluza–Klein gluon and radion masses. These limits exclude at 95% confidence level models with Kaluza–Klein gluon masses in the range 2.0 to 4.3 TeV and radion masses in the range 0.20 to 0.74 TeV. By exploring a novel experimental signature, the observed limits on the Kaluza–Klein gluon mass are extended by up to about 1 TeV compared to previous searches