The effects of an L-methionine combination supplement on symptoms of upper respiratory tract infections and performance in ultramarathon runners before, during and after ultra-endurance exercise

Objective. To evaluate whether supplementation with an L-methionine combination would reduce the incidence of upper respiratory tract symptoms (URTS) and improve performance in ultramarathon runners. Design. A double-blind placebo-controlled study. Setting. Twenty-one ultramarathon runners (17 males, 4 females) preparing for participation in an 87.3 km ultramarathon. Interventions. L-methionine combination supplement (L-methionine, vitamin B6, vitamin B12, folic acid and magnesium) or placebo containing potato starch. Main outcome measures. Incidence of URTS was recorded during the runner's preparation for an ultramarathon race (75 days) and recovery from the same (75 days). CD4+, CD8+ cell counts and ratios were measured pre race, immediately post race and 75 days post race. VO2max and endurance fitness (percentage VO2max at 4 mmol-1 lactate concentration) were measured during the preparation for the race. Results. During the preparation period the incidence of URTS was 36% in the supplement group and 80% in the placebo group (p = 0.08). The incidence of URTS during the 3 weeks post race was 27% in the supplement group and 40% in the placebo group (p = 0.65). The CD4+/CD8+ cell ratios were not significantly different between groups. Endurance fitness prior to the race and race times were not significantly different. Conclusions. Although the findings of the current study show that an L-methionine combination supplement did not reduce the incidence of URTS or improve performance in ultramarathon runners, benefits may be found with a more detailed investigation using larger sample sizes and immunosuppressed athletes. South African Journal of Sports Medicine Vol.16(1) 2004: 10-1

Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N–Terminal Peptide Binding

Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N–terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl–terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N–terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR–cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required

VLDL Hydrolysis by Hepatic Lipase Regulates PPARδ Transcriptional Responses

PPARs (α,γ,δ) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Using PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL≫LDL, IDL) to activate PPARδ preferentially over PPARα or PPARγ, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPARδ in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPARδ target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPARδ activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPARδ activation and ADRP gene regulation in vitro.These data define a novel pathway involving HL hydrolysis of VLDL that activates PPARδ through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription

Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity <it>in vitro</it>. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.</p> <p>Methods</p> <p>To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition <it>in vitro </it>using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m²/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).</p> <p>Results</p> <p>Doxycyline <it>in vitro </it>completely abolished MMP-9 activity at 500 μg/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.</p> <p>Conclusion</p> <p>Doxycycline can block MMP-2 and MMP-9 activities from glioma cells <it>in vitro</it>. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.</p

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

A seesaw model for intermolecular gating in the kinesin motor protein

Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine. Kinesin-1, similar to many kinesin family members, assembles to form homodimers that use alternating ATPase cycles of the catalytic motor domains, or “heads”, to proceed unidirectionally along its partner filament (the microtubule) via a hand-over-hand mechanism. Cryo-electron microscopy has now revealed 8-Å resolution, 3D reconstructions of kinesin-1•microtubule complexes for all three of this motor’s principal nucleotide-state intermediates (ADP-bound, no-nucleotide, and ATP analog), the first time filament co-complexes of any cytoskeletal motor have been visualized at this level of detail. These reconstructions comprehensively describe nucleotide-dependent changes in a monomeric head domain at the secondary structure level, and this information has been combined with atomic-resolution crystallography data to synthesize an atomic-level "seesaw" mechanism describing how microtubules activate kinesin’s ATP-sensing machinery. The new structural information revises or replaces key details of earlier models of kinesin’s ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin–microtubule complex is essential for understanding the structural basis of the cycle. I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT