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Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at s√=0.9, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with pT≥0.5 GeV/c in |η|≤0.8. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity (Nch) is reported for events with different pT scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low Nch, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean pT with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.
The production of K∗(892)0 and ϕ(1020) in pp collisions at s√=7 TeV was measured by the ALICE experiment at the LHC. The yields and the transverse momentum spectra d2N/dydpT at midrapidity |y|<0.5 in the range 0<pT<6 GeV/c for K∗(892)0 and 0.4<pT<6 GeV/c for ϕ(1020) are reported and compared to model predictions. Using the yield of pions, kaons, and Omega baryons measured previously by ALICE at s√=7 TeV, the ratios K∗/K−, ϕ/K∗, ϕ/K−, ϕ/π−, and (Ω + Ω¯¯¯¯)/ϕ are presented. The values of the K∗/K−, ϕ/K∗ and ϕ/K− ratios are similar to those found at lower centre-of-mass energies. In contrast, the ϕ/π− ratio, which has been observed to increase with energy, seems to saturate above 200 GeV. The (Ω + Ω¯¯¯¯)/ϕ ratio in the pT range 1-5 GeV/c is found to be in good agreement with the prediction of the HIJING/BB v2.0 model with a strong colour field.
Measurement of electrons from semileptonic heavy-flavor hadron decays in pp collisions at √s = 7 TeV
(2012)
The differential production cross section of electrons from semileptonic heavy-flavour hadron decays has been measured at mid-rapidity (|y|<0.5) in proton-proton collisions at s√=7 TeV with ALICE at the LHC. Electrons were measured in the transverse momentum range 0.5 <pT< 8 GeV/c. Predictions from a fixed order perturbative QCD calculation with next-to-leading-log resummation agree with the data within the theoretical and experimental uncertainties.
The ALICE experiment at the LHC has studied J/psi production at mid-rapidity in pp collisions at sqrt{s}=7 TeV through its electron pair decay on a data sample corresponding to an integrated luminosity L_int = 5.6nb-1. The fraction of J/psi from the decay of long-lived beauty hadrons was determined for J/psi candidates with transverse momentum p_t>1.3 GeV/c and rapidity |y|<0.9. The cross section for prompt J/psi mesons, i.e. directly produced J/psi and prompt decays of heavier charmonium states such as the Psi(2S) and Csi_c resonances, is sigma_prompt-J/psi(pt > 1.3 GeV/c, |y| < 0.9) = 8.3 +- 0.8(stat.) +- 1.1(syst.) + 1.5 - 1.4(syst. pol.) micro barn. The cross section for the production of b-hadrons decaying to J/psi with p_t>1.3 GeV/c and |y|<0.9 is sigma_{J/psi<-h_B} = 1.46 +- 0.38(stat.) + 0.26 -0.32(syst.) micro barn. The results are compared to QCD model predictions. The shape of the p_t and y distributions of b-quarks predicted by perturbative QCD model calculations are used to extrapolate the measured cross section to derive the b-bbar pair total cross section and dsigma/dy at mid-rapidity.
The forward muon spectrometer of ALICE (A Large Ion Collider Experiment) is equipped with a trigger system made of four planes of Resistive Plate Chambers (RPC), arranged in two stations with two planes each, for a total area of about 140 m2. The system provides single and di-muon triggers with suitable transverse momentum selection, optimised for the physics of quarkonia and open heavy flavour. In the first two years of data-taking at the Large Hadron Collider (2010 and 2011) the 72 RPCs were operated in highly saturated avalanche mode in both pp and Pb-Pb collisions. The integrated charge was about 1.3 mC/cm2 on average and 3.5 mC/cm2 for the most exposed detectors. This paper describes two main results. The first result is the determination of the RPC performance, with particular focus on the stability of the main detector parameters such as efficiency, dark current, and dark rate. The second result is the measurement of the muon trigger performance in Pb-Pb collisions at √sNN = 2.76 TeV, in terms of the reliability and stability of the trigger decision logic.
The first measurement of neutron emission in electromagnetic dissociation of 208Pb nuclei at the LHC is presented. The measurement is performed using the neutron Zero Degree Calorimeters of the ALICE experiment, which detect neutral particles close to beam rapidity. The measured cross sections of single and mutual electromagnetic dissociation of Pb nuclei at sNN−−−√ = 2.76 TeV with neutron emission are σsingle EMD=187.4±0.2 (stat.) +13.2−11.2 (syst.) b and σmutual EMD=5.7±0.1 (stat.) ±0.4 (syst.) b, respectively. The experimental results are compared to the predictions from a relativistic electromagnetic dissociation model.
Suppression of high transverse momentum D mesons in central Pb-Pb collisions at √sNN = 2.76 TeV
(2012)
The production of the prompt charm mesons D0, D+, D∗+, and their antiparticles, was measured with the ALICE detector in Pb-Pb collisions at the LHC, at a centre-of-mass energy sNN−−−−√=2.76 TeV per nucleon--nucleon collision. The pT-differential production yields in the range 2<pT<16 GeV/c at central rapidity, |y|<0.5, were used to calculate the nuclear modification factor RAA with respect to a proton-proton reference obtained from the cross section measured at s√=7 TeV and scaled to s√=2.76 TeV. For the three meson species, RAA shows a suppression by a factor 3-4, for transverse momenta larger than 5 GeV/c in the 20% most central collisions. The suppression is reduced for peripheral collisions.
The ALICE experiment has measured the inclusive J/ψ production in Pb-Pb collisions at sNN−−−√=2.76 TeV down to zero transverse momentum in the rapidity range 2.5<y<4. A suppression of the inclusive J/ψ yield in Pb-Pb is observed with respect to the one measured in pp collisions scaled by the number of binary nucleon-nucleon collisions. The nuclear modification factor, integrated over the 0-80% most central collisions, is 0.545±0.032(stat.)±0.083(syst.) and does not exhibit a significant dependence on the collision centrality. These features appear significantly different from measurements at lower collision energies. Models including J/ψ production from charm quarks in a deconfined partonic phase can describe our data.
Measurement of charm production at central rapidity in proton-proton collisions at √s = 2.76 TeV
(2012)
The pT-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D0, D+, and D∗+ in the rapidity range |y|<0.5, and for transverse momentum 1<pT<12 GeV/c, were measured in proton-proton collisions at s√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D0→Kπ, D+→Kππ, D∗+→D0π, and their charge conjugates, and was performed on a Lint=1.1 nb−1 event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at s√=2.76 TeV and at 7 TeV was evaluated by extrapolating to the full phase space the pT-differential production cross sections at s√=2.76 TeV and our previous measurements at 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.
Inhibitor of apoptosis (IAPs) proteins are characterized by the presence of evolutionarily conserved baculoviral inhibitor of apoptosis repeat (BIR) domains, predominantly known for their role in inhibiting caspases and, thereby, apoptosis. We have shown previously that multi-BIR domain-containing IAPs, cellular IAPs, and X-linked IAP can control tumor cell migration by directly regulating the protein stability of C-RAF kinase. Here, we extend our observations to a single BIR domain containing IAP family member melanoma-IAP (ML-IAP). We show that ML-IAP can directly bind to C-RAF and that ML-IAP depletion leads to an increase in C-RAF protein levels, MAPK activation, and cell migration in melanoma cells. Thus, our results unveil a thus far unknown role for ML-IAP in controlling C-RAF stability and cell migration.
ADAM15 protein amplifies focal adhesion kinase phosphorylation under genotoxic stress conditions
(2012)
ADAM15, a disintegrin and metalloproteinase, is capable of counteracting genotoxic stress-induced apoptosis by the suppression of caspase-3 activation. A cell line expressing the membrane-bound ADAM15 without its cytoplasmic tail, however, lost this anti-apoptotic property, suggesting a crucial role of the intracellular domain as a scaffold for recruitment of survival signal-transducing kinases. Accordingly, an enhanced phosphorylation of FAK at Tyr-397, Tyr-576, and Tyr-861 was detected upon genotoxic stress by camptothecin in ADAM15-transfected T/C28a4 cells, but not in transfectants expressing an ADAM15 mutant without the cytoplasmic tail. Accordingly, a specific binding of the cytoplasmic ADAM15 domain to the C terminus of FAK could be shown by mammalian two-hybrid, pulldown, and far Western studies. In cells expressing full-length ADAM15, a concomitant activation of Src at Tyr-416 was detected upon camptothecin exposure. Cells transfected with a chimeric construct consisting of the extracellular IL-2 receptor α-chain and the cytoplasmic ADAM15 domain were IL-2-stimulated to prove that the ADAM15 tail can transduce a percepted extracellular signal to enhance FAK and Src phosphorylation. Our studies further demonstrate Src binding to FAK but not a direct Src interaction with ADAM15, suggesting FAK as a critical intracellular adaptor for ADAM15-dependent enhancement of FAK/Src activation. Moreover, the apoptosis induction elicited by specific inhibitors (PP2, FAK 14 inhibitor) of FAK/Src signaling was significantly reduced by ADAM15 expression. The newly uncovered counter-regulatory response to genotoxic stress in a chondrocytic survival pathway is potentially also relevant to apoptosis resistance in neoplastic growth.
The social amoeba Dictyostelium discoideum is a widely used model organism for studying basic functions of protozoan and metazoan cells, such as osmoregulation and cell motility. There is evidence from other species that cellular water channels, aquaporins (AQP), are central to both processes. Yet, data on D. discoideum AQPs is almost absent. Despite cloning of two putative D. discoideum AQPs, WacA, and AqpA, water permeability has not been shown. Further, WacA and AqpA are expressed at the late multicellular stage and in spores but not in amoebae. We cloned a novel AQP, AqpB, from amoeboidal D. discoideum cells. Wild-type AqpB was impermeable to water, glycerol, and urea when expressed in Xenopus laevis oocytes. Neither stepwise truncation of the N terminus nor selected point mutations activated the water channel. However, mutational truncation by 12 amino acids of an extraordinary long intracellular loop induced water permeability of AqpB, hinting at a novel gating mechanism. This AqpB mutant was inhibited by mercuric chloride, confirming the presence of a cysteine residue in the selectivity filter as predicted by our structure model. We detected AqpB by Western blot analysis in a glycosylated and a non-glycosylated form throughout all developmental stages. When expressed in D. discoideum amoebae, AqpB-GFP fusion constructs localized to vacuolar structures, to the plasma membrane, and to lamellipodia-like membrane protrusions. We conclude that the localization pattern in conjunction with channel gating may be indicative of AqpB functions in osmoregulation as well as cell motility of D. discoideum.
Mitochondria and chloroplasts are of endosymbiotic origin. Their integration into cells entailed the development of protein translocons, partially by recycling bacterial proteins. We demonstrate the evolutionary conservation of the translocon component Tic22 between cyanobacteria and chloroplasts. Tic22 in Anabaena sp. PCC 7120 is essential. The protein is localized in the thylakoids and in the periplasm and can be functionally replaced by a plant orthologue. Tic22 physically interacts with the outer envelope biogenesis factor Omp85 in vitro and in vivo, the latter exemplified by immunoprecipitation after chemical cross-linking. The physical interaction together with the phenotype of a tic22 mutant comparable with the one of the omp85 mutant indicates a concerted function of both proteins. The three-dimensional structure allows the definition of conserved hydrophobic pockets comparable with those of ClpS or BamB. The results presented suggest a function of Tic22 in outer membrane biogenesis.
Background: Although Tic22 is involved in protein import into chloroplasts, the function in cyanobacteria is unknown.
Results: Cyanobacterial Tic22 is required for OM biogenesis, shares structural features with chaperones, and can be substituted by plant Tic22.
Conclusion: Tic22, involved in outer membrane biogenesis, is functionally conserved in cyanobacteria and plants.
Significance: The findings are important for the understanding of periplasmic protein transport.
Background: Radiofrequency ablation is a minimal invasive therapy in the treatment of bone metastases. In this study we present a new ablation system enabling an ablation in multiple directions and with an adaptable size and shape.
Material and methods: VX-2 tumor was used for the induction of experimental bone metastases in the femur of six New Zealand white rabbits. X-ray imaging as well as CT and MRI scans before and after treatment was carried out. After detecting bone tumor, radiofrequency ablation was performed. The ablation instrument contained a 10 g bipolar, articulated extendable electrode and a proprietary generator with an impedance controlled algorithm. All bones and the soft tissue were examined histologically.
Results: All animals developed local bone tumor. Mean duration until first osteolytic lesions on CT-scans was 48±14 days. The mean lesion area was 26 mm(2). No systemic tumor spread was seen. 6 radiofrequency procedures were carried out with a mean application time of 6 min±2:30 and an average temperature in the region of effect of 55 °C±4. MRI imaging demonstrated an ablation zone of 23±6 mm around the electrode. Histopathology showed an extensive heat necrosis with no remaining tumor cells in the ablation area.
Conclusion: Radiofrequency ablation is a quickly developing treatment option on the field of minimal invasive bone tumor therapy. The electrode enables an ablation adapted to size and shape of the metastases. Further clinical studies are necessary to test and enhance this radiofrequency system.
Lantibiotics are peptide-derived antibiotics that inhibit the growth of Gram-positive bacteria via interactions with lipid II and lipid II-dependent pore formation in the bacterial membrane. Due to their general mode of action the Gram-positive producer strains need to express immunity proteins (LanI proteins) for protection against their own lantibiotics. Little is known about the immunity mechanism protecting the producer strain against its own lantibiotic on the molecular level. So far, no structures have been reported for any LanI protein. We solved the structure of SpaI, a LanI protein from the subtilin producing strain Bacillus subtilis ATCC 6633. SpaI is a 16.8-kDa lipoprotein that is attached to the outside of the cytoplasmic membrane via a covalent diacylglycerol anchor. SpaI together with the ABC transporter SpaFEG protects the B. subtilis membrane from subtilin insertion. The solution-NMR structure of a 15-kDa biologically active C-terminal fragment reveals a novel fold. We also demonstrate that the first 20 N-terminal amino acids not present in this C-terminal fragment are unstructured in solution and are required for interactions with lipid membranes. Additionally, growth tests reveal that these 20 N-terminal residues are important for the immunity mediated by SpaI but most likely are not part of a possible subtilin binding site. Our findings are the first step on the way of understanding the immunity mechanism of B. subtilis in particular and of other lantibiotic producing strains in general.
Escherichia coli nitrate reductase A (NarGHI) is a membrane-bound enzyme that couples quinol oxidation at a periplasmically oriented Q-site (Q(D)) to proton release into the periplasm during anaerobic respiration. To elucidate the molecular mechanism underlying such a coupling, endogenous menasemiquinone-8 intermediates stabilized at the Q(D) site (MSQ(D)) of NarGHI have been studied by high-resolution pulsed EPR methods in combination with (1)H2O/2H2O exchange experiments. One of the two non-exchangeable proton hyperfine couplings resolved in hyperfine sublevel correlation (HYSCORE) spectra of the radical displays characteristics typical from quinone methyl protons. However, its unusually small isotropic value reflects a singularly low spin density on the quinone carbon α carrying the methyl group, which is ascribed to a strong asymmetry of the MSQ(D) binding mode and consistent with single-sided hydrogen bonding to the quinone oxygen O1. Furthermore, a single exchangeable proton hyperfine coupling is resolved, both by comparing the HYSCORE spectra of the radical in 1H2O and 2H2O samples and by selective detection of the exchanged deuterons using Q-band 2H Mims electron nuclear double resonance (ENDOR) spectroscopy. Spectral analysis reveals its peculiar characteristics, i.e. a large anisotropic hyperfine coupling together with an almost zero isotropic contribution. It is assigned to a proton involved in a short ∼1.6 Å in-plane hydrogen bond between the quinone O1 oxygen and the Nδ of the His-66 residue, an axial ligand of the distal heme b(D). Structural and mechanistic implications of these results for the electron-coupled proton translocation mechanism at the Q(D) site are discussed, in light of the unusually high thermodynamic stability of MSQ(D).
We proposed previously that closure of voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane after ethanol exposure leads to suppression of mitochondrial metabolite exchange. Because ureagenesis requires extensive mitochondrial metabolite exchange, we characterized the effect of ethanol and its metabolite, acetaldehyde (AcAld), on total and ureagenic respiration in cultured rat hepatocytes. Ureagenic substrates increased cellular respiration from 15.8 ± 0.9 nmol O(2)/min/10(6) cells (base line) to 29.4 ± 1.7 nmol O(2)/min/10(6) cells in about 30 min. Ethanol (0-200 mM) suppressed extra respiration after ureagenic substrates (ureagenic respiration) by up to 51% but not base line respiration. Urea formation also declined proportionately. Inhibition of alcohol dehydrogenase, cytochrome P450 2E1, and catalase with 4-methylpyrazole, trans-1,2-dichloroethylene, and 3-amino-1,2,3-triazole restored ethanol-suppressed ureagenic respiration by 46, 37, and 66%, respectively. By contrast, inhibition of aldehyde dehydrogenase with phenethyl isothiocyanate increased the inhibitory effect of ethanol on ureagenic respiration by an additional 60%. AcAld, an intermediate product of ethanol oxidation, suppressed ureagenic respiration with an apparent IC(50) of 125 μM. AcAld also inhibited entry of 3-kDa rhodamine-conjugated dextran in the mitochondrial intermembrane space of digitonin-permeabilized hepatocytes, indicative of VDAC closure. In conclusion, AcAld, derived from ethanol metabolism, suppresses ureagenesis in hepatocytes mediated by closure of VDAC.
DNA translocators of natural transformation systems are complex systems critical for the uptake of free DNA and provide a powerful mechanism for adaptation to changing environmental conditions. In natural transformation machineries, outer membrane secretins are suggested to form a multimeric pore for the uptake of external DNA. Recently, we reported on a novel structure of the DNA translocator secretin complex, PilQ, in Thermus thermophilus HB27 comprising a stable cone and cup structure and six ring structures with a large central channel. Here, we report on structural and functional analyses of a set of N-terminal PilQ deletion derivatives in T. thermophilus HB27. We identified 136 N-terminal residues exhibiting an unusual ααβαββα fold as a ring-building domain. Deletion of this domain had a dramatic effect on twitching motility, adhesion, and piliation but did not abolish natural transformation. These findings provide clear evidence that the pilus structures of T. thermophilus are not essential for natural transformation. The truncated complex was not affected in inner and outer membrane association, indicating that the 136 N-terminal residues are not essential for membrane targeting. Analyses of complex formation of the truncated PilQ monomers revealed that the region downstream of residue 136 is required for multimerization, and the region downstream of residue 207 is essential for monomer stability. Possible implications of our findings for the mechanism of DNA uptake are discussed.
Searching for new strategies to trigger apoptosis in rhabdomyosarcoma (RMS), we investigated the effect of two novel classes of apoptosis-targeting agents, i.e. monoclonal antibodies against TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (mapatumumab) and TRAIL receptor 2 (lexatumumab) and small-molecule inhibitors of inhibitor of apoptosis (IAP) proteins. Here, we report that IAP inhibitors synergized with lexatumumab, but not with mapatumumab, to reduce cell viability and to induce apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1). Cotreatment-induced apoptosis was accompanied by enhanced activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and caspase-dependent apoptosis. In addition, IAP inhibitor and lexatumumab cooperated to stimulate the assembly of a cytosolic complex containing RIP1, FADD, and caspase-8. Importantly, knockdown of RIP1 by RNA interference prevented the formation of the RIP1·FADD·caspase-8 complex and inhibited subsequent activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and apoptosis upon treatment with IAP inhibitor and lexatumumab. In addition, RIP1 silencing rescued clonogenic survival of cells treated with the combination of lexatumumab and IAP inhibitor, thus underscoring the critical role of RIP1 in cotreatment-induced apoptosis. By comparison, the TNFα-blocking antibody Enbrel had no effect on IAP inhibitor/lexatumumab-induced apoptosis, indicating that an autocrine TNFα loop is dispensable. By demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent but TNFα-independent manner in RMS cells, our findings substantially advance our understanding of IAP inhibitor-mediated regulation of TRAIL-induced cell death.
A simple and fast method of lipid analysis of isolated intact mitochondria by means of MALDI-TOF mass spectrometry is described. Mitochondria isolated from bovine heart and yeast have been employed to set up and validate the new method of lipid analysis. The mitochondrial suspension is directly applied over the target and, after drying, covered by a thin layer of the 9-aminoacridine matrix solution. The lipid profiles acquired with this procedure contain all peaks previously obtained by analyzing the lipid extracts of isolated mitochondria by TLC and/or mass spectrometry. The novel procedure allows the quick, simple, precise, and accurate analysis of membrane lipids, utilizing only a tiny amount of isolated organelle; it has also been tested with intact membranes of the bacterium Paracoccus denitrificans for its evolutionary link to present-day mitochondria. The method is of general validity for the lipid analysis of other cell fractions and isolated organelles.