C8-glycosphingolipids preferentially insert into tumor cell membranes and promote chemotherapeutic drug uptake

AbstractInsufficient drug delivery into tumor cells limits the therapeutic efficacy of chemotherapy. Co-delivery of liposome-encapsulated drug and synthetic short-chain glycosphingolipids (SC-GSLs) significantly improved drug bioavailability by enhancing intracellular drug uptake. Investigating the mechanisms underlying this SC-GSL-mediated drug uptake enhancement is the aim of this study. Fluorescence microscopy was used to visualize the cell membrane lipid transfer intracellular fate of fluorescently labeled C6-NBD-GalCer incorporated in liposomes in tumor and non-tumor cells. Additionally click chemistry was applied to image and quantify native SC-GSLs in tumor and non-tumor cell membranes. SC-GSL-mediated flip-flop was investigated in model membranes to confirm membrane-incorporation of SC-GSL and its effect on membrane remodeling. SC-GSL enriched liposomes containing doxorubicin (Dox) were incubated at 4°C and 37°C and intracellular drug uptake was studied in comparison to standard liposomes and free Dox.SC-GSL transfer to the cell membrane was independent of liposomal uptake and the majority of the transferred lipid remained in the plasma membrane. The transfer of SC-GSL was tumor cell-specific and induced membrane rearrangement as evidenced by a transbilayer flip-flop of pyrene-SM. However, pore formation was measured, as leakage of hydrophilic fluorescent probes was not observed. Moreover, drug uptake appeared to be mediated by SC-GSLs. SC-GSLs enhanced the interaction of doxorubicin (Dox) with the outer leaflet of the plasma membrane of tumor cells at 4°C. Our results demonstrate that SC-GSLs preferentially insert into tumor cell plasma membranes enhancing cell intrinsic capacity to translocate amphiphilic drugs such as Dox across the membrane via a biophysical process

A geometric approach to time evolution operators of Lie quantum systems

Lie systems in Quantum Mechanics are studied from a geometric point of view. In particular, we develop methods to obtain time evolution operators of time-dependent Schrodinger equations of Lie type and we show how these methods explain certain ad hoc methods used in previous papers in order to obtain exact solutions. Finally, several instances of time-dependent quadratic Hamiltonian are solved.Comment: Accepted for publication in the International Journal of Theoretical Physic

Tolerancia a diferentes factores antinutritivos en lechones alimentados con guisantes de invierno (Pisum sativum) y alberjón (Vicia narbonensis) en la fase estárter

Se realizaron dos ensayos para evaluar el efecto de dietas con diferentes niveles de factores antinutritivos: inhibidores de tripsina y quimotripsina (UTI, UQI respectivamente, como unidades) de guisantes de invierno y ¿Glutamyl-S-Ethenyl-Cysteine de alberjón, en el rendimiento de lechones durante el periodo estárter. En cada uno se utilizaron 192 machos castrados, híbridos Duroc x (Large-White x Landrace), con 11,23 y 11,55 kg de peso medio respectivamente, e igual diseño: cuatro tratamientos y ocho réplicas cada una de seis lechones. Los tratamientos del Ensayo 1 fueron: Control: harina de soja 47 y soja extrusionada (0,97 UTI-1,94 UQI/mg de pienso); P-CAR: soja extrusionada y guisante Cartouche (1,62 UTI-3,16 UQI/mg de pienso); P-ICE: soja extrusionada y guisante Iceberg (3,09 UTI-4,95 UQI/mg de pienso); P-LUN: soja extrusionada y guisante Luna (3,19 UTI-5,56 UQI/mg de pienso). Los lechones del tratamiento P-CAR crecieron significativamente más que el resto, con igual consumo y conversión. No hubo diferencias entre Control, P-ICE y P-LUN. El pienso del Ensayo 2 incluía diferentes niveles de alberjón: 0%, 5%, 15% y 25%, y en consecuencia de ¿Glutamyl-S-Ethenyl-Cysteine (1,52% del grano). Los lechones del tratamiento 5% comieron y crecieron más, con igual conversión que los del tratamiento 0%. El rendimiento empeoró con porcentajes del 15% o mayores. Se concluye que lechones de 40 a 61 días de vida mantienen o mejoran el rendimiento con la ingesta de inhibidores de proteasas que exceden 3,28 y 2,86 veces, UTI y UQI respectivamente, los de una dieta de soja, y que la inclusión de 5% de alberjón en el pienso aumenta el consumo y el crecimiento. Two trials were conducted to evaluate the effect of diets with different levels of anti-nutritional factors: trypsin (TIU) and chymotrypsin (CIU) inhibitors units of peas and ¿Glutamyl-S-Ethenyl-Cysteine (GEC) of narbon vetch, in productive performance of pigs from 40 to 61 days of age. 192 barrows were used in each test, Duroc hybrid x (Large White x Landrace), with 11.23 and 11.55 kg body weight respectively, and the same experimental design: four treatments and eight replicates with six piglets in each case. In trial 1 treatments were: Control: soybean meal 47 and soybean extruded (0.97 TIU-1.94 CIU/mg feed); P-CAR: soybean extruded and pea Cartouche (1.62 TIU-3.16 CIU/mg feed); P-ICE: soybean extruded and pea Iceberg (3.09 TIU-4.95 CIU/mg feed); P-LUN: soybean extruded and pea Luna (3.19 TIU-5.56 CIU/mg feed). The piglets of P-CAR treatment grew significantly faster than the others, with the same intake and feed conversion. No significant differences between Control, P-ICE and P-LUN. In trial 2 the feedstuff had different levels of narbon vetch: 0%, 5%, 15% and 25%, and consequently of ¿Glutamyl-S-Ethenyl-Cysteine (1.52% of the grain). The piglets that consumed the treatment of 5% had higher intake and growth, and the same conversion that piglets feeding with the treatment of 0%. The performance worsened significantly with increasing 15%. We conclude that piglets in starter period maintain or improve the performance with intake of proteases inhibitors in feedstuff that exceed 3.28 (TIU) and 2.86 (CIU) times those of a control diet, and that the inclusion of 5% of narbon vetch in feedstuff increases feed intake and growth

Screening, production and biochemical characterization of a new fibrinolytic enzyme produced by Streptomyces sp. (Streptomycetaceae) isolated from Amazonian lichens

Thrombosis is a pathophysiological disorder caused by accumulation of fibrin in the blood. Fibrinolytic proteases with potent thrombolytic activity have been produced by diverse microbial sources. Considering the microbial biodiversity of the Amazon region, this study aimed at the screening, production and biochemical characterization of a fibrinolytic enzyme produced by Streptomyces sp. isolated from Amazonian lichens. The strain Streptomyces DPUA1576 showed the highest fibrinolytic activity, which was 283 mm2. Three variables at two levels were used to assess their effects on the fibrinolytic production. The parameters studied were agitation (0.28 - 1.12 g), temperature (28 - 36 ºC) and pH (6.0 - 8.0); all of them had significant effects on the fibrinolytic production. The maximum fibrinolytic activity (304 mm2) was observed at 1.12 g, 28 ºC, and pH of 8.0. The crude extract of the fermentation broth was used to assess the biochemical properties of the enzyme. Protease and fibrinolytic activities were stable during 6 h, at a pH ranging from 6.8 to 8.4 and 5.8 to 9.2, respectively. Optimum temperature for protease activity ranged between 35 and 55 °C, while the highest fibrinolytic activity was observed at 45 ºC. Proteolytic activity was inhibited by Cu2+ and Co2+ ions, phenylmethylsulfonyl fluoride (PMSF) and pepstatin A, which suggests that the enzyme is a serine protease. Enzymatic extract cleaved fibrinogen at the subunits A-chain, A-chain, and -chain. The results indicated that Streptomyces sp. DPUA 1576 produces enzymes with fibrinolytic and fibrinogenolytic activity, enzymes with an important application in the pharmaceutical industry.The authors grateful acknowledge the financial support of Fundação de Amparo a Pesquisa do Estado de Pernambuco (FACEPE, Pernambuco, Brazil, N. 0158-2.12/11), CNPq/ RENORBIO (National Counsel of Technological and Scientific Development, N.55146/2010-3) and National Council for the Improvement of Higher Education (CAPES, Brazil) for the scholarship. The author thanks editor and reviewers for their review and comments.info:eu-repo/semantics/publishedVersio

Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}=2.76 TeV

The elliptic, $v_2$, triangular, $v_3$, and quadrangular, $v_4$, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions and (anti-)protons in Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range $|\eta|<0.8$ at different collision centralities and as a function of transverse momentum, $p_{\rm T}$, out to $p_{\rm T}=20$ GeV/$c$. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for $p_{\rm T}>8$ GeV/$c$. The small $p_{\rm T}$ dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to $p_{\rm T}=8$ GeV/$c$. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least $p_{\rm T}=8$ GeV/$c$ indicating that the particle type dependence persists out to high $p_{\rm T}$.Comment: 16 pages, 5 captioned figures, authors from page 11, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/186

Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm{NN}}} = 2.76 TeV

The inclusive transverse momentum ($p_{\rm T}$) distributions of primary charged particles are measured in the pseudo-rapidity range $|\eta|<0.8$ as a function of event centrality in Pb-Pb collisions at $\sqrt{s_{\rm{NN}}}=2.76$ TeV with ALICE at the LHC. The data are presented in the $p_{\rm T}$ range $0.15<p_{\rm T}<50$ GeV/$c$ for nine centrality intervals from 70-80% to 0-5%. The Pb-Pb spectra are presented in terms of the nuclear modification factor $R_{\rm{AA}}$ using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-$p_{\rm T}$ particles strongly depends on event centrality. In central collisions (0-5%) the yield is most suppressed with $R_{\rm{AA}}\approx0.13$ at $p_{\rm T}=6$-7 GeV/$c$. Above $p_{\rm T}=7$ GeV/$c$, there is a significant rise in the nuclear modification factor, which reaches $R_{\rm{AA}} \approx0.4$ for $p_{\rm T}>30$ GeV/$c$. In peripheral collisions (70-80%), the suppression is weaker with $R_{\rm{AA}} \approx 0.7$ almost independently of $p_{\rm T}$. The measured nuclear modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/284

Measurement of charm production at central rapidity in proton-proton collisions at s=2.76\sqrt{s} = 2.76 TeV

The $p_{\rm T}$-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D$^0$, D$^+$, and D$^{*+}$ in the rapidity range $|y|<0.5$, and for transverse momentum $1< p_{\rm T} <12$ GeV/$c$, were measured in proton-proton collisions at $\sqrt{s} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D$^0 \rightarrow$K$\pi$, D$^+ \rightarrow$K$\pi\pi$, D$^{*+} \rightarrow$D$^0\pi$, and their charge conjugates, and was performed on a $L_{\rm int} = 1.1$ nb$^{-1}$ event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at $\sqrt{s} = 2.76$ TeV and at 7 TeV was evaluated by extrapolating to the full phase space the $p_{\rm T}$-differential production cross sections at $\sqrt{s} = 2.76$ TeV and our previous measurements at $\sqrt{s} = 7$ TeV. The results were compared to existing measurements and to perturbative-QCD calculations. The fraction of cdbar D mesons produced in a vector state was also determined.Comment: 20 pages, 5 captioned figures, 4 tables, authors from page 15, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/307

Particle-yield modification in jet-like azimuthal di-hadron correlations in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The yield of charged particles associated with high-$p_{\rm T}$ trigger particles ($8 < p_{\rm T} < 15$ GeV/$c$) is measured with the ALICE detector in Pb-Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV relative to proton-proton collisions at the same energy. The conditional per-trigger yields are extracted from the narrow jet-like correlation peaks in azimuthal di-hadron correlations. In the 5% most central collisions, we observe that the yield of associated charged particles with transverse momenta $p_{\rm T}> 3$ GeV/$c$ on the away-side drops to about 60% of that observed in pp collisions, while on the near-side a moderate enhancement of 20-30% is found.Comment: 15 pages, 2 captioned figures, 1 table, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/350

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter