Микробиом кишечника и метаболизм лекарственных соединений

The human physiology textbooks traditionally consider the intestine as a metabolically active organ, with its activity primarily associated with the production of numerous digestive enzymes. The development of molecular analysis technologies has significantly detailized this picture, primarily by decoding the metabolic potential of the intestinal microbiota. Data from numerous metagenomic studies indicate that the number of eukaryotic and bacterial cells in the human body is comparable - about 3.0×1013, while the number of genes in the intestinal metagenome is one hundred times greater than in the human genome. Obviously, the gut microbiota exhibits both direct and indirect effects on the metabolism of drugs and xenobiotics, that can affect their effectiveness and toxicity. Orally administrated xenobiotics have been found to be metabolized by intestinal microbial enzymes before being absorbed from the gastrointestinal tract into the blood flow. The metabolic reactions performed by the gut microbiota greatly differ from the metabolic reactions of the liver, providing modification of drugs by acetylation, deacetylation, decarboxylation, dehydroxylation, demethylation, dehalogenation, etc. Despite the metabolism of xenobiotics by microbial enzymes of the intestine is rather known, information about the specific microflora mediating each metabolic reaction is still limited, mainly by the lack of an adequate model of the intestinal microbial community to allow the accumulation of experimental data for the creation of computational models. Currently, studies of drug metabolism use microfluidic chips, reproducing functions of various organs and tissues, such as the liver, kidney, lungs and intestine, as in vitro models in the form of 2D and 3D cell cultures. Supplementation of such systems with the microbial community will allow to get as close as possible to in vitro modeling of complicated biological processes in the interests of pharmacological research and the accumulation of data for constructing computational models.В курсе физиологии человека кишечник традиционно рассматривают как метаболически активный орган, деятельность которого связывают в первую очередь с продукцией многочисленных пищеварительных ферментов. Развитие технологий молекулярного анализа позволило существенно детализировать эту картину, в первую очередь за счет расшифровки метаболического потенциала кишечной микробиоты. Данные многочисленных метагеномных исследований свидетельствуют, что количество эукариотических и бактериальных клеток в организме человека сопоставимо – около 3.0х1013, при этом количество генов в метагеноме кишечника в сто раз больше, чем в геноме человека. Очевидно, что микробиота кишечника оказывает как прямое, так и опосредованное влияние на метаболизм лекарственных препаратов и ксенобиотиков, что может сказаться на их эффективности и токсичности. Обнаружено, что ксенобиотики, вводимые перорально, могут метаболизироваться кишечными микробными ферментами еще до всасывания из желудочно-кишечного тракта в кровь. Метаболические реакции, выполняемые микробиотой кишечника, значительно отличаются от метаболических реакций печени, обеспечивая модификацию лекарственных препаратов путем ацетилирования, деацетилирования, декарбоксилирования, дегидроксилирования, деметилирования, дегалогенирования и др. Несмотря на то, что метаболизм ксенобиотиков микробными ферментами кишечника до некоторой степени известен, информация о конкретной микрофлоре, опосредующей каждую метаболическую реакцию, всё ещё ограничена, в первую очередь, отсутствием адекватной модели микробного сообщества кишечника, позволяющей накапливать экспериментальные данные для построения вычислительных моделей. Сегодня в исследовании метаболизма лекарственных средств применяют микрофлюидные чипы, на которых функции различных органов и тканей, таких как печень, почки, легкие и кишечник, воспроизводятся в виде in vitro моделей в форме 2D и 3D клеточных культур. Дополнение таких систем микробным сообществом позволит максимально приблизиться к моделированию in vitro сложных биологических процессов в интересах фармакологических исследований и накопления данных для построения вычислительных моделей

Which blazars are neutrino loud?

Protons accelerated in the cores of active galactic nuclei can effectively produce neutrinos only if the soft radiation background in the core is sufficiently high. We find restrictions on the spectral properties and luminosity of blazars under which they can be strong neutrino sources. We analyze the possibility that neutrino flux is highly beamed along the rotation axis of the central black hole. The enhancement of neutrino flux compared to GeV gamma-ray flux from a given source makes the detection of neutrino point sources more probable. At the same time the smaller open angle reduces the number of possible neutrino-loud blazars compared to the number of gamma-ray loud ones. We present the table of 15 blazars which are the most likely candidates for the detection by future neutrino telescopes.Comment: 9 pages, 5 figures, version to be published in PR

New hadrons as ultra-high energy cosmic rays

Ultra-high energy cosmic ray (UHECR) protons produced by uniformly distributed astrophysical sources contradict the energy spectrum measured by both the AGASA and HiRes experiments, assuming the small scale clustering of UHECR observed by AGASA is caused by point-like sources. In that case, the small number of sources leads to a sharp exponential cutoff at the energy E<10^{20} eV in the UHECR spectrum. New hadrons with mass 1.5-3 GeV can solve this cutoff problem. For the first time we discuss the production of such hadrons in proton collisions with infrared/optical photons in astrophysical sources. This production mechanism, in contrast to proton-proton collisions, requires the acceleration of protons only to energies E<10^{21} eV. The diffuse gamma-ray and neutrino fluxes in this model obey all existing experimental limits. We predict large UHE neutrino fluxes well above the sensitivity of the next generation of high-energy neutrino experiments. As an example we study hadrons containing a light bottom squark. These models can be tested by accelerator experiments, UHECR observatories and neutrino telescopes.Comment: 17 pages, revtex style; v2: shortened, as to appear in PR

Ultra-High Energy Neutrino Fluxes and Their Constraints

Applying our recently developed propagation code we review extragalactic neutrino fluxes above 10^{14} eV in various scenarios and how they are constrained by current data. We specifically identify scenarios in which the cosmogenic neutrino flux, produced by pion production of ultra high energy cosmic rays outside their sources, is considerably higher than the "Waxman-Bahcall bound". This is easy to achieve for sources with hard injection spectra and luminosities that were higher in the past. Such fluxes would significantly increase the chances to detect ultra-high energy neutrinos with experiments currently under construction or in the proposal stage.Comment: 11 pages, 15 figures, version published in Phys.Rev.

Associated Charm Production in Neutrino-Nucleus Interactions

In this paper a search for associated charm production both in neutral and charged current $\nu$-nucleus interactions is presented. The improvement of automatic scanning systems in the {CHORUS} experiment allows an efficient search to be performed in emulsion for short-lived particles. Hence a search for rare processes, like the associated charm production, becomes possible through the observation of the double charm-decay topology with a very low background. About 130,000 $\nu$ interactions located in the emulsion target have been analysed. Three events with two charm decays have been observed in the neutral-current sample with an estimated background of 0.18$\pm$0.05. The relative rate of the associated charm cross-section in deep inelastic $\nu$ interactions, $\sigma(c\bar{c}\nu)/\sigma_\mathrm{NC}^\mathrm{DIS}= (3.62^{+2.95}_{-2.42}({stat})\pm 0.54({syst}))\times 10^{-3}$ has been measured. One event with two charm decays has been observed in charged-current $\nu_\mu$ interactions with an estimated background of 0.18$\pm$0.06 and the upper limit on associated charm production in charged-current interactions at 90% C.L. has been found to be $\sigma (c\bar{c} \mu^-)/\sigma_\mathrm{CC} < 9.69 \times 10^{-4}$.Comment: 10 pages, 4 figure

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 isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters