Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications

Mammalian members of the proton-coupled oligopeptide transporter family (SLC15) are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs. The driving force for uphill electrogenic symport is the chemical gradient and membrane potential which favors proton uptake into the cell along with the peptide/mimetic substrate. The peptide transporters are responsible for the absorption and conservation of dietary protein digestion products in the intestine and kidney, respectively, and in maintaining homeostasis of neuropeptides in the brain. They are also responsible for the absorption and disposition of a number of pharmacologically important compounds including some aminocephalosporins, angiotensin-converting enzyme inhibitors, antiviral prodrugs, and others. In this review, we provide updated information on the structure-function of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4) and PhT2 (SLC15A3), and their expression and localization in key tissues. Moreover, mammalian peptide transporters are discussed in regard to pharmacogenomic and regulatory implications on host pharmacology and disease, and as potential targets for drug delivery. Significant emphasis is placed on the evolving role of these peptide transporters as elucidated by studies using genetically modified animals. Whenever possible, the relevance of drug-drug interactions and regulatory mechanisms are evaluated using in vivo studies.

Proton diffusion tensor spectroscopy of metabolites in human muscle in vivo

PURPOSE To study the apparent diffusivity and its directionality for metabolites of skeletal muscle in humans in vivo by (1) H magnetic resonance spectroscopy. METHODS The diffusion tensors were determined on a 3 Tesla MR system using optimized acquisition and processing methods including an adapted STEAM sequence with orientation-dependent diffusion weighting, pulse-triggering with individually adapted delays, eddy-current correction schemes, median filtering, and simultaneous prior-knowledge fitting of all related spectra. RESULTS The average apparent diffusivities, as well as the fractional anisotropies of taurine (ADCav  = 0.74 × 10(-3) s/mm(2) , FA = 0.46), creatine (ADCav  = 0.41 × 10(-3)  s/mm(2) , FA = 0.33), trimethylammonium compounds (ADCav  = 0.48 × 10(-3)  s/mm(2) , FA = 0.34), carnosine (ADCav  = 0.46 × 10(-3)  s/mm(2) , FA = 0.47), and water (ADCav  = 1.5 × 10(-3)  s/mm(2) , FA = 0.36) were estimated. The diffusivities of most metabolites and water were significantly different from each other. Diffusion was found to be anisotropic and the diffusion tensors showed tensor correlation coefficients close to 1 and were hence found to be essentially coaligned. The magnitudes of apparent metabolite diffusivities were largely ordered according to molecular weight, with taurine as the smallest molecule diffusing fastest, both along and across the fiber direction. CONCLUSION Diffusivities, directional dependence of diffusion and fractional anisotropies of (1) H MRS-visible muscle metabolites were presented. It was shown that metabolites share diffusion directionality with water and have similar fractional anisotropies, hinting at similar diffusion barriers. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.

Proton entry into the near-lunar plasma wake for magnetic field aligned flow

We report the first observation of protons in the near-lunar (100-200 km from the surface) and deeper (near anti-subsolar point) plasma wake when the interplanetary magnetic field (IMF) and solar wind velocity (vsw) are parallel (aligned flow; angle between IMF and vsw≤10°). More than 98% of the observations during aligned flow condition showed the presence of protons in the wake. These observations are obtained by the Solar Wind Monitor sensor of the Sub-keV Atom Reflecting Analyser experiment on Chandrayaan-1. The observation cannot be explained by the conventional fluid models for aligned flow. Back tracing of the observed protons suggests that their source is the solar wind. The larger gyroradii of the wake protons compared to that of solar wind suggest that they were part of the tail of the solar wind velocity distribution function. Such protons could enter the wake due to their large gyroradii even when the flow is aligned to IMF. However, the wake boundary electric field may also play a role in the entry of the protons into the wake.

Measurements of Production Properties of K0S mesons and Lambda hyperons in Proton-Carbon Interactions at 31 GeV/c

Spectra of K0S mesons and Λ hyperons were measured in p+C interactions at 31 GeV/c with the large acceptance NA61/SHINE spectrometer at the CERN SPS. The data were collected with an isotropic graphite target with a thickness of 4% of a nuclear interaction length. Interaction cross sections, charged pion spectra, and charged kaon spectra were previously measured using the same data set. Results on K0S and Λ production in p+C interactions serve as reference for the understanding of the enhancement of strangeness production in nucleus-nucleus collisions. Moreover, they provide important input for the improvement of neutrino flux predictions for the T2K long baseline neutrino oscillation experiment in Japan. Inclusive production cross sections for K0S and Λ are presented as a function of laboratory momentum in intervals of the laboratory polar angle covering the range from 0 up to 240 mrad. The results are compared with predictions of several hadron production models. The K0S mean multiplicity in production processes and the inclusive cross section for K0S production were measured and amount to 0.127 ± 0.005 (stat) ± 0.022 (sys) and 29.0 ± 1.6 (stat) ± 5.0 (sys) mb, respectively.

Feasibility of post mortem cardiac proton density weighted fast field echo imaging in two cases of sudden death

OBJECTIVE The aim of this work is to investigate and compare cardiac proton density (PD) weighted fast field echo (FFE) post-mortem magnetic resonance (PMMR) imaging with standard cardiac PMMR imaging (T1-weighted and T2-weighted turbo spin-echo (TSE)), postmortem CT (PMCT) as well as autopsy. MATERIALS AND METHODS Two human cadavers sequentially underwent cardiac PMCT and PMMR imaging (PD-weighted FFE, T1-weighted and T2-weighted TSE) and autopsy. The cardiac PMMR images were compared to each other as well as to PMCT and autopsy findings. RESULTS For the first case, cardiac PMMR exhibited a focal region of low signal in PD-weighted FFE and T2-weighted TSE images, surrounded by a signal intense rim in the T2-weighted images. T1-weighted TSE and PMCT did not appear to identify any focal abnormality. Macroscopic inspection identified a blood clot; histology confirmed this to be a thrombus with an adhering myocardial infarction. In the second case, a myocardial rupture with heart tamponade was identified in all PMMR images, located at the anterior wall of the left ventricle; PMCT excluded additional ruptures. In PD-weighted FFE and T2-weighted TSE images, it occurred hypo-intense, while resulting in small clustered hyper-intense spots in T1-weighted TSE. Autopsy confirmed the PMMR and PMCT findings. CONCLUSIONS Presented initial results have shown PD-weighted FFE to be a valuable imaging sequence in addition to traditional T2-weighted TSE imaging for blood clots and myocardial haemorrhage with clearer contrast between affected and healthy myocardium.

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

The jet energy scale (JES) 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 sqrt(s) = 7 TeV corresponding to an integrated luminosity of 38 inverse pb. 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 eta<4.5. The JES systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams. The JES uncertainty is less than 2.5% in the central calorimeter region (eta<0.8) for jets with 60 < pt < 800 GeV, and is maximally 14% for pt < 30 GeV in the most forward region 3.2 50 GeV after a dedicated correction for this effect. The JES 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, providing an improved jet energy resolution and a reduced flavour dependence of the jet response. The JES systematic uncertainty determined from a combination of in situ techniques are 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.

Measurement of the differential cross-section of B⁺ meson production in pp collisions at sqrts = 7 TeV at ATLAS

The production cross-section of B+ mesons is measured as a function of transverse momentum p T and rapidity y in proton-proton collisions at centre-of-mass energy root s = 7 TeV, using 2.4 fb(-1) of data recorded with the ATLAS detector at the Large Hadron Collider. The differential production cross-sections, determined in the range 9 GeV < p(T) < 120 GeV and vertical bar y vertical bar < 2.25, are compared to next-to-leading-order theoretical predictions.

A search for prompt lepton-jets in pp collisions at sqrts=7 TeV with the ATLAS detector

We present a search for a light (mass < 2 GeV) boson predicted by Hidden Valley supersymmetric models that decays into a final state consisting of collimated muons or electrons, denoted "lepton-jets". The analysis uses 5 fb(-1) of root s = 7 TeV proton-proton collision data recorded by the ATLAS detector at the Large Hadron Collider to search for the following signatures: single lepton-jets with at least four muons; pairs of lepton-jets, each with two or more muons; and pairs of lepton-jets with two or more electrons. This study finds no statistically significant deviation from the Standard Model prediction and places 95% confidence-level exclusion limits on the production cross section times branching ratio of light bosons for several parameter sets of a Hidden Valley model.

Search for charged Higgs bosons through the violation of lepton universality in t art events using collision data at sqrts=7 TeV with the AT experiment

In several extensions of the Standard Model, the top quark can decay into a bottom quark and a light charged Higgs boson H+, t -> bH(+), in addition to the Standard Model decay t -> bW. Since W bosons decay to the three lepton generations equally, while H+ may predominantly decay into tau nu, charged Higgs bosons can be searched for using the violation of lepton universality in top quark decays. The analysis in this paper is based on 4.6 fb(-1) of proton-proton collision data at root s = 7 TeV collected by the ATLAS experiment at the Large Hadron Collider. Signatures containing leptons (e or mu) and/or a hadronically decaying tau (tau(had)) are used. Event yield ratios between e+ tau(had) and e + mu, as well as between mu + tau(had) and mu + e, final states are measured in the data and compared to predictions from simulations. This ratio-based method reduces the impact of systematic uncertainties in the analysis. No significant deviation from the Standard Model predictions is observed. With the assumption that the branching fraction B(H+ -> tau nu) is 100%, upper limits in the range 3.2%-4.4% can be placed on the branching fraction B(t -> bH(+)) for charged Higgs boson masses m(H+) in the range 90-140GeV. After combination with results from a search for charged Higgs bosons in t (t) over bar decays using the tau(had) + jets final state, upper limits on B(t -> bH(+)) can be set in the range 0.8%-3.4%, for m(H+) in the range 90-160GeV.

Search for the neutral Higgs bosons of the Minimal Supersymmetric Standard Model in pp collisions at sqrts=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7 TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb(-1) to 4.8 fb(-1). Higgs boson decays into oppositely-charged in muon or tau lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, phi, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters m(A) and tan beta in the m(h)(max) scenario for m(A) in the range of 90 GeV to 500 GeV.

Measurement of ℤℤ production in pp collisions at sqrts=7 TeV and limits on anomalous ℤℤℤ ℤℤgamma couplings with the ATLAS detector

A measurement of the ZZ production cross section in proton-proton collisions at root s = 7 TeV using data recorded by the ATLAS experiment at the Large Hadron Collider is presented. In a data sample corresponding to an integrated luminosity of 4.6 fb(-1) collected in 2011, events are selected that are consistent either with two Z bosons decaying to electrons or muons or with one Z boson decaying to electrons or muons and a second Z boson decaying to neutrinos. The ZZ((*)) -> l(+)l(-)l'(+)l'(-) and ZZ -> l(+)l(-) nu(nu) over bar cross sections are measured in restricted phase-space regions. These results are then used to derive the total cross section for ZZ events produced with both Z bosons in the mass range 66 to 116 GeV, sigma(tot)(ZZ) = 6.7 +/- 0.7 (stat.) (+0.4)(-0.3) (syst.) +/- 0.3 (lumi.) pb, which is consistent with the Standard Model prediction of 5.89(-0.18)(+0.22) pb calculated at next-to-leading order in QCD. The normalized differential cross sections in bins of various kinematic variables are presented. Finally, the differential event yield as a function of the transverse momentum of the leading Z boson is used to set limits on anomalous neutral triple gauge boson couplings in ZZ production.

Search for resonances decaying into top-quark pairs using fully hadronic decays in pp collisions with ATLAS at sqrts=7 TeV

A search for resonances produced in 7 TeV proton-proton collisions and decaying into top-quark pairs is described. In this Letter events where the top-quark decay produces two massive jets with large transverse momenta recorded with the ATLAS detector at the Large Hadron Collider are considered. Two techniques that rely on jet substructure are used to separate top-quark jets from those arising from light quarks and gluons. In addition, each massive jet is required to have evidence of an associated bottom-quark decay. The data are consistent with the Standard Model, and limits can be set on the production cross section times branching fraction of a Z' boson and a Kaluza-Klein gluon resonance. These limits exclude, at the 95% credibility level, Z' bosons with masses 0.70-1.00 TeV as well as 1.28-1.32 TeV and Kaluza-Klein gluons with masses 0.70-1.62 TeV.

Search for supersymmetry in events with photons, bottom quarks, and missing transverse momentum in proton-proton collisions at a centre-of-mass energy of 7 TeV with the ATLAS detector

A search has been performed for the experimental signature of an isolated photon with high transverse momentum, at least one jet identified as originating from a bottom quark, and high missing transverse momentum. Such a final state may originate from supersymmetric models with gauge-mediated supersymmetry breaking in events in which one of a pair of higgsino-like neutralinos decays into a photon and a gravitino while the other decays into a Higgs boson and a gravitino. The search is performed using the full dataset of 7 TeV proton-proton collisions recorded with the ATLAS detector at the LHC in 2011, corresponding to an integrated luminosity of 4.7 fb(-1). A total of 7 candidate events are observed while 7.5 +/- 2.2 events are expected from the Standard Model background. The results of the search are interpreted in the context of general gauge mediation to exclude certain regions of a benchmark plane for higgsino-like neutralino production.

Search for displaced muonic lepton jets from light Higgs boson decay in proton-proton collisions at sqrts TeV with the ATLAS detector

A search is performed for collimated muon pairs displaced from the primary vertex produced in the decay of long-lived neutral particles in proton-proton collisions at root s = 7 TeV centre-of-mass energy, with the ATLAS detector at the LHC. In a 1.9 fb(-1) event sample collected during 2011, the observed data are consistent with the Standard Model background expectations. Limits on the product of the production cross section and the branching ratio of a Higgs boson decaying to hidden-sector neutral long-lived particles are derived as a function of the particles' mean lifetime.