Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery

Analysis of isoflavones and flavonoids in human urine by UHPLC

A rapid, ultra high-performance liquid chromatographic (UHPLC) method has been developed and validated for simultaneous identification and analysis of the isoflavones genistein, daidzein, glycitin, puerarin, and biochanin A, and the flavonoids (±)-catechin, (−)-epicatechin, rutin, hesperidin, neohesperidin, quercitrin, and hesperetin in human urine. Urine samples were incubated with β-glucuronidase/sulfatase. UHPLC was performed with a Hypersil Gold (50 × 2.1 mm, 1.9 μm) analytical column. Elution was with a gradient prepared from aqueous trifluoroacetic acid (0.05%) and acetonitrile. UV detection was performed at 254 and 280 nm. The calibration curves were indicative of good linearity (r2 ≥ 0.9992) in the range of interest for each analyte. LODs ranged between 15.4 and 107.0 ng mL−1 and 3.9 and 20.4 ng mL−1 for flavonoids and isoflavones, respectively. Intra-day and inter-day precision (C.V., %) was less than 3.9% and 3.8%, respectively, and accuracy was between 0.03% and 5.0%. Recovery was 70.35–96.58%. The method is very rapid, simple, and reliable, and suitable for pharmacokinetic analysis. It can be routinely used for simultaneous determination of these five isoflavones and seven flavonoids in human urine. The method can also be applied to studies after administration of pharmaceutical preparations containing isoflavones and flavonoids to humans

Protection Induced by Plasmodium falciparum MSP142 Is Strain-Specific, Antigen and Adjuvant Dependent, and Correlates with Antibody Responses

Vaccination with Plasmodium falciparum MSP142/complete Freund's adjuvant (FA) followed by MSP142/incomplete FA is the only known regimen that protects Aotus nancymaae monkeys against infection by erythrocytic stage malaria parasites. The role of adjuvant is not defined; however complete FA cannot be used in humans. In rodent models, immunity is strain-specific. We vaccinated Aotus monkeys with the FVO or 3D7 alleles of MSP142 expressed in Escherichia coli or with the FVO allele expressed in baculovirus (bv) combined with complete and incomplete FA, Montanide ISA-720 (ISA-720) or AS02A. Challenge with FVO strain P. falciparum showed that suppression of cumulative day 11 parasitemia was strain-specific and could be induced by E. coli expressed MSP142 in combination with FA or ISA-720 but not with AS02A. The coli42-FVO antigen induced a stronger protective effect than the bv42-FVO antigen, and FA induced a stronger protective effect than ISA-720. ELISA antibody (Ab) responses at day of challenge (DOC) were strain-specific and correlated inversely with c-day 11 parasitemia (r = −0.843). ELISA Ab levels at DOC meeting a titer of at least 115,000 ELISA Ab units identified the vaccinees not requiring treatment (noTx) with a true positive rate of 83.3% and false positive rate of 14.3 %. Correlation between functional growth inhibitory Ab levels (GIA) and cumulative day 11 parasitemia was weaker (r = −0.511), and was not as predictive for a response of noTx. The lowest false positive rate for GIA was 30% when requiring a true positive rate of 83.3%. These inhibition results along with those showing that antigen/FA combinations induced a stronger protective immunity than antigen/ISA-720 or antigen/AS02 combinations are consistent with protection as ascribed to MSP1-specific cytophilic antibodies. Development of an effective MSP142 vaccine against erythrocytic stage P. falciparum infection will depend not only on antigen quality, but also upon the selection of an optimal adjuvant component

A bioavailable strontium (⁸⁷Sr/⁸⁶Sr) isoscape for Aotearoa New Zealand: Implications for food forensics and biosecurity

As people, animals and materials are transported across increasingly large distances in a globalized world, threats to our biosecurity and food security are rising. Aotearoa New Zealand is an island nation with many endemic species, a strong local agricultural industry, and a need to protect these from pest threats, as well as the economy from fraudulent commodities. Mitigation of such threats is much more effective if their origins and pathways for entry are understood. We propose that this may be addressed in Aotearoa using strontium isotope analysis of both pests and products. Bioavailable radiogenic isotopes of strontium are ubiquitous markers of provenance that are increasingly used to trace the origin of animals and plants as well as products, but currently a baseline map across Aotearoa is lacking, preventing use of this technique. Here, we have improved an existing methodology to develop a regional bioavailable strontium isoscape using the best available geospatial datasets for Aotearoa. The isoscape explains 53% of the variation (R² = 0.53 and RMSE = 0.00098) across the region, for which the primary drivers are the underlying geology, soil pH, and aerosol deposition (dust and sea salt). We tested the potential of this model to determine the origin of cow milk produced across Aotearoa. Predictions for cow milk (n = 33) highlighted all potential origin locations that share similar ⁸⁷Sr/⁸⁶Sr values, with the closest predictions averaging 7.05 km away from their true place of origin. These results demonstrate that this bioavailable strontium isoscape is effective for tracing locally produced agricultural products in Aotearoa. Accordingly, it could be used to certify the origin of Aotearoa’s products, while also helping to determine if new pest detections were of locally breeding populations or not, or to raise awareness of imported illegal agricultural products

Strong interface-induced spin-orbit coupling in graphene on WS2

Interfacial interactions allow the electronic properties of graphene to be modified, as recently demonstrated by the appearance of satellite Dirac cones in the band structure of graphene on hexagonal boron nitride (hBN) substrates. Ongoing research strives to explore interfacial interactions in a broader class of materials in order to engineer targeted electronic properties. Here we show that at an interface with a tungsten disulfide (WS2) substrate, the strength of the spin-orbit interaction (SOI) in graphene is very strongly enhanced. The induced SOI leads to a pronounced low-temperature weak anti-localization (WAL) effect, from which we determine the spin-relaxation time. We find that spin-relaxation time in graphene is two-to-three orders of magnitude smaller on WS2 than on SiO2 or hBN, and that it is comparable to the intervalley scattering time. To interpret our findings we have performed first-principle electronic structure calculations, which both confirm that carriers in graphene-on-WS2 experience a strong SOI and allow us to extract a spin-dependent low-energy effective Hamiltonian. Our analysis further shows that the use of WS2 substrates opens a possible new route to access topological states of matter in graphene-based systems.Comment: Originally submitted version in compliance with editorial guidelines. Final version with expanded discussion of the relation between theory and experiments to be published in Nature Communication

The Formation and Evolution of the First Massive Black Holes

The first massive astrophysical black holes likely formed at high redshifts (z>10) at the centers of low mass (~10^6 Msun) dark matter concentrations. These black holes grow by mergers and gas accretion, evolve into the population of bright quasars observed at lower redshifts, and eventually leave the supermassive black hole remnants that are ubiquitous at the centers of galaxies in the nearby universe. The astrophysical processes responsible for the formation of the earliest seed black holes are poorly understood. The purpose of this review is threefold: (1) to describe theoretical expectations for the formation and growth of the earliest black holes within the general paradigm of hierarchical cold dark matter cosmologies, (2) to summarize several relevant recent observations that have implications for the formation of the earliest black holes, and (3) to look into the future and assess the power of forthcoming observations to probe the physics of the first active galactic nuclei.Comment: 39 pages, review for "Supermassive Black Holes in the Distant Universe", Ed. A. J. Barger, Kluwer Academic Publisher

Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus

Incidence of human breast cancer (HBC) varies geographically, but to date no environmental factor has explained this variation. Previously, we reported a 44% reduction in the incidence of breast cancer in women fully immunosuppressed following organ transplantation (Stewart et al (1995) Lancet346: 796–798). In mice infected with the mouse mammary tumour virus (MMTV), immunosuppression also reduces the incidence of mammary tumours. DNA with 95% identity to MMTV is detected in 40% of human breast tumours (Wang et al (1995) Cancer Res55: 5173–5179). These findings led us to ask whether the incidence of HBC could be correlated with the natural ranges of different species of wild mice. We found that the highest incidence of HBC worldwide occurs in lands where Mus domesticus is thse resident native or introduced species of house mouse. Given the similar responses of humans and mice to immunosuppression, the near identity between human and mouse MTV DNA sequences, and the close association between HBC incidence and mouse ranges, we propose that humans acquire MMTV from mice. This zoonotic theory for a mouse-viral cause of HBC allows testable predictions and has potential importance in prevention. © 2000 Cancer Research Campaig

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay

Marked variation in MSP-119 antibody responses to malaria in western Kenyan highlands

<p>Abstract</p> <p>Background</p> <p>Assessment of malaria endemicity at different altitudes and transmission intensities, in the era of dwindling vector densities in the highlands, will provide valuable information for malaria control and surveillance. Measurement of serum anti-malarial antibodies is a useful marker of malaria exposure that indicates long-term transmission potential. We studied the serologic evidence of malaria endemicity at two highland sites along a transmission intensity cline. An improved understanding of the micro-geographic variation in malaria exposure in the highland ecosystems will be relevant in planning effective malaria control.</p> <p>Methods</p> <p>Total IgG levels to <it>Plasmodium falciparum </it>MSP-1₁₉were measured in an age-stratified cohort (< 5, 5-14 and ≥ 15 years) in 795 participants from an uphill and valley bottom residents during low and high malaria transmission seasons. Antibody prevalence and level was compared between different localities. Regression analysis was performed to examine the association between antibody prevalence and parasite prevalence. Age-specific MSP-1₁₉seroprevalence data was fitted to a simple reversible catalytic model to investigate the relationship between parasite exposure and age.</p> <p>Results</p> <p>Higher MSP-1₁₉seroprevalence and density were observed in the valley residents than in the uphill dwellers. Adults (> 15 years) recorded high and stable immune response in spite of changing seasons. Lower responses were observed in children (≤ 15 years), which, fluctuated with changing seasons particularly in the valley residents. In the uphill population, annual seroconversion rate (SCR) was 8.3% and reversion rate was 3.0%, with seroprevalence reaching a plateau of 73.3% by age of 20. Contrary, in the valley bottom population, the annual SCR was 35.8% and the annual seroreversion rate was 3.5%, and seroprevalence in the population had reached 91.2% by age 10.</p> <p>Conclusion</p> <p>The study reveals the micro-geographic variation in malaria endemicity in the highland eco-system; this validates the usefulness of sero-epidemiological tools in assessing malaria endemicity in the era of decreasing sensitivity of conventional tools.</p

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

The jet energy scale 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 √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. 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 {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy 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, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is 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. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration