Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma

The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT(2) and/or AT(1) mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy

Isothermal Microcalorimetry, a New Tool to Monitor Drug Action against Trypanosoma brucei and Plasmodium falciparum

Isothermal microcalorimetry is an established tool to measure heat flow of physical, chemical or biological processes. The metabolism of viable cells produces heat, and if sufficient cells are present, their heat production can be assessed by this method. In this study, we investigated the heat flow of two medically important protozoans, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Heat flow signals obtained for these pathogens allowed us to monitor parasite growth on a real-time basis as the signals correlated with the number of viable cells. To showcase the potential of microcalorimetry for measuring drug action on pathogenic organisms, we tested the method with three antitrypanosomal drugs, melarsoprol, suramin and pentamidine and three antiplasmodial drugs, chloroquine, artemether and dihydroartemisinin, each at two concentrations on the respective parasite. With the real time measurement, inhibition was observed immediately by a reduced heat flow compared to that in untreated control samples. The onset of drug action, the degree of inhibition and the time to death of the parasite culture could conveniently be monitored over several days. Microcalorimetry is a valuable element to be added to the toolbox for drug discovery for protozoal diseases such as human African trypanosomiasis and malaria. The method could probably be adapted to other protozoan parasites, especially those growing extracellularly

Measurement of the ratio of branching fractions BR(B0 -> K*0 gamma)/BR(Bs0 -> phi gamma)

The ratio of branching fractions of the radiative B decays B0 -> K*0 gamma and Bs0 -> phi gamma has been measured using 0.37 fb-1 of pp collisions at a centre of mass energy of sqrt(s) = 7 TeV, collected by the LHCb experiment. The value obtained is BR(B0 -> K*0 gamma)/BR(Bs0 -> phi gamma) = 1.12 +/- 0.08 ^{+0.06}_{-0.04} ^{+0.09}_{-0.08}, where the first uncertainty is statistical, the second systematic and the third is associated to the ratio of fragmentation fractions fs/fd. Using the world average for BR(B0 -> K*0 gamma) = (4.33 +/- 0.15) x 10^{-5}, the branching fraction BR(Bs0 -> phi gamma) is measured to be (3.9 +/- 0.5) x 10^{-5}, which is the most precise measurement to date.Comment: 15 pages, 1 figure, 2 table

Precise measurements of the properties of the B-1(5721)(0,+) and B-2*(5747)(0,+) states and observation of B-+,B-0 pi(-,+) mass structures

Invariant mass distributions of B+π− and B0π+ combinations are investigated in order to study excited B mesons. The analysis is based on a data sample corresponding to 3.0 fb−1 of pp collision data, recorded by the LHCb detector at centre-of-mass energies of 7 and 8 TeV. Precise measurements of the masses and widths of the B1(5721)0,+ and B2(5747)0,+ states are reported. Clear enhancements, particularly prominent at high pion transverse momentum, are seen over background in the mass range 5850-6000 MeV in both B+π− and B0π+ combinations. The structures are consistent with the presence of four excited B mesons, labelled BJ (5840)0,+ and BJ (5960)0,+, whose masses and widths are obtained under different hypotheses for their quantum numbers

Contribution of the clathrin adaptor AP-1 subunit µ1 to acidic cluster protein sorting.

Acidic clusters act as sorting signals for packaging cargo into clathrin-coated vesicles (CCVs), and also facilitate down-regulation of MHC-I by HIV-1 Nef. To find acidic cluster sorting machinery, we performed a gene-trap screen and identified the medium subunit (µ1) of the clathrin adaptor AP-1 as a top hit. In µ1 knockout cells, intracellular CCVs still form, but acidic cluster proteins are depleted, although several other CCV components were either unaffected or increased, indicating that cells can compensate for long-term loss of AP-1. In vitro experiments showed that the basic patch on µ1 that interacts with the Nef acidic cluster also contributes to the binding of endogenous acidic cluster proteins. Surprisingly, µ1 mutant proteins lacking the basic patch and/or the tyrosine-based motif binding pocket could rescue the µ1 knockout phenotype completely. In contrast, these mutants failed to rescue Nef-induced down-regulation of MHC class I, suggesting a possible mechanism for attacking the virus while sparing the host cell

Holocene carbon dynamics at the forest – steppe ecotone of southern Siberia

The forest–steppe ecotone in southern Siberia is highly sensitive to climate change; global warming is expected to push the ecotone northwards, at the same time resulting in degradation of the underlying permafrost. To gain a deeper understanding of long-term forest–steppe carbon dynamics, we use a highly resolved, multiproxy, palaeolimnological approach, based on sediment records from Lake Baikal. We reconstruct proxies that are relevant to understanding carbon dynamics including carbon mass accumulation rates (CMAR; g C m−2 yr−1) and isotope composition of organic matter (δ13CTOC). Forest–steppe dynamics were reconstructed using pollen, and diatom records provided measures of primary production from near- and off-shore communities. We used a generalized additive model (GAM) to identify significant change points in temporal series, and by applying generalized linear least-squares regression modelling to components of the multiproxy data, we address (1) What factors influence carbon dynamics during early Holocene warming and late Holocene cooling? (2) How did carbon dynamics respond to abrupt sub-Milankovitch scale events? and (3) What is the Holocene carbon storage budget for Lake Baikal. CMAR values range between 2.8 and 12.5 g C m−2 yr−1. Peak burial rates (and greatest variability) occurred during the early Holocene, associated with melting permafrost and retreating glaciers, while lowest burial rates occurred during the neoglacial. Significant shifts in carbon dynamics at 10.3, 4.1 and 2.8 kyr bp provide compelling evidence for the sensitivity of the region to sub-Milankovitch drivers of climate change. We estimate that 1.03 Pg C was buried in Lake Baikal sediments during the Holocene, almost one-quarter of which was buried during the early Holocene alone. Combined, our results highlight the importance of understanding the close linkages between carbon cycling and hydrological processes, not just temperatures, in southern Siberian environments

Differential branching fractions and isospin asymmetries of B -> K ((*)) μ(+) μ(-) decays

The isospin asymmetries of B -> K μ(+) μ(-) and B -> K (*) μ(+) μ(-) decays and the partial branching fractions of the B (0) -> K (0) μ(+) μ(-), B (+) -> K (+) μ(+) μ(-) and B (+) -> K (*+) μ(+) μ(-) decays are measured as functions of the dimuon mass squared, q (2). The data used correspond to an integrated luminosity of 3 fb(-1) from proton-proton collisions collected with the LHCb detector at centre-of-mass energies of 7 TeV and 8 TeV in 2011 and 2012, respectively. The isospin asymmetries are both consistent with the Standard Model expectations. The three measured branching fractions favour lower values than their respective theoretical predictions, however they are all individually consistent with the Standard Model

Searches for Majorana neutrinos in B- decays

Searches for heavy Majorana neutrinos in B- decays in final states containing hadrons plus a \mu- \mu- pair have been performed using 0.41/fb of data collected with the LHCb detector in proton-proton collisions at a center-of-mass energy of 7 TeV. The D+ \mu- \mu- and D*+ \mu- \mu- final states can arise from the presence of virtual Majorana neutrinos of any mass. Other final states containing \pi+, Ds+, or D0\pi+ can be mediated by an on-shell Majorana neutrino. No signals are found and upper limits are set on Majorana neutrino production as a function of mass, and also on the B- decay branching fractions.Comment: 18 pages, 15 figure

Study of the kinematic dependences of Λ0b production in pp collisions and a measurement of the Λ0 b → Λ+c π− branching fraction

The kinematic dependences of the relative production rates, fΛ0 b /fd, of Λ0 b baryons and B0 mesons are measured using Λ0 b → Λ + c π − and B 0 → D+π − decays. The measurements use proton-proton collision data, corresponding to an integrated luminosity of 1 fb−1 at a centre-of-mass energy of 7 TeV, recorded in the forward region with the LHCb experiment. The relative production rates are observed to depend on the transverse momentum, pT, and pseudorapidity, η, of the beauty hadron, in the studied kinematic region 1.5 < pT < 40 GeV/c and 2 < η < 5. Using a previous LHCb measurement of fΛ0 b /fd in semileptonic decays, the branching fraction B Λ 0 b → Λ + c π − = 4.30±0.03 +0.12 −0.11±0.26± 0.21 ×10−3 is obtained, where the first uncertainty is statistical, the second is systematic, the third is from the previous LHCb measurement of fΛ0 b /fd and the fourth is due to the B 0 → D+π − branching fraction. This is the most precise measurement of a Λ0 b branching fraction to date

Measurement of the CP-violating phase ϕs in B¯s0→Ds+Ds− decays

We present a measurement of the CP-violating weak mixing phase ϕs using the decay B¯0s→D+sD−s in a data sample corresponding to 3.0 fb−1 of integrated luminosity collected with the LHCb detector in pp collisions at center-of-mass energies of 7 and 8 TeV. An analysis of the time evolution of the system, which does not use the constraint |λ|=1 to allow for the presence of CP violation in decay, yields ϕs=0.02±0.17(stat)±0.02(syst)  rad, |λ|=0.91+0.18−0.15(stat)±0.02(syst). This result is consistent with the standard model expectation