Suppressing Glucose Transporter Gene Expression in Schistosomes Impairs Parasite Feeding and Decreases Survival in the Mammalian Host

Adult schistosomes live in the host's bloodstream where they import nutrients such as glucose across their body surface (the tegument). The parasite tegument is an unusual structure since it is enclosed not by the typical one but by two closely apposed lipid bilayers. Within the tegument two glucose importing proteins have been identified; these are schistosome glucose transporter (SGTP) 1 and 4. SGTP4 is present in the host interactive, apical tegumental membranes, while SGTP1 is found in the tegumental basal membrane (as well as in internal tissues). The SGTPs act by facilitated diffusion. To examine the importance of these proteins for the parasites, RNAi was employed to knock down expression of both SGTP genes in the schistosomula and adult worm life stages. Both qRT-PCR and western blotting analysis confirmed successful gene suppression. It was found that SGTP1 or SGTP4-suppressed parasites exhibit an impaired ability to import glucose compared to control worms. In addition, parasites with both SGTP1 and SGTP4 simultaneously suppressed showed a further reduction in capacity to import glucose compared to parasites with a single suppressed SGTP gene. Despite this debility, all suppressed parasites exhibited no phenotypic distinction compared to controls when cultured in rich medium. Following prolonged incubation in glucose-depleted medium however, significantly fewer SGTP-suppressed parasites survived. Finally, SGTP-suppressed parasites showed decreased viability in vivo following infection of experimental animals. These findings provide direct evidence for the importance of SGTP1 and SGTP4 for schistosomes in importing exogenous glucose and show that these proteins are important for normal parasite development in the mammalian host

The Tegument of the Human Parasitic Worm Schistosoma mansoni as an Excretory Organ: The Surface Aquaporin SmAQP Is a Lactate Transporter

Adult schistosomes are intravascular parasites that metabolize imported glucose largely via glycolysis. How the parasites get rid of the large amounts of lactic acid this generates is unknown at the molecular level. Here, we report that worms whose aquaporin gene (SmAQP) has been suppressed using RNAi fail to rapidly acidify their culture medium and excrete less lactate compared to controls. Functional expression of SmAQP in Xenopus oocytes demonstrates that this protein can transport lactate following Michaelis-Menten kinetics with low apparent affinity (Km = 41±5. 8 mM) and with a low energy of activation (Ea = 7.18±0.7 kcal/mol). Phloretin, a known inhibitor of lactate release from schistosomes, also inhibits lactate movement in SmAQP-expressing oocytes. In keeping with the substrate promiscuity of other aquaporins, SmAQP is shown here to be also capable of transporting water, mannitol, fructose and alanine but not glucose. Using immunofluorescent and immuno-EM, we confirm that SmAQP is localized in the tegument of adult worms. These findings extend the proposed functions of the schistosome tegument beyond its known capacity as an organ of nutrient uptake to include a role in metabolic waste excretion

Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

Genetic association studies, including a large meta-analysis, report association of Regulator of G Protein Signaling 4 (RGS4) with schizophrenia in the context of heterogeneity. The central role of RGS4 in regulating signaling via Gi/o coupled neurotransmitter receptors led us to hypothesize that there may be RGS4 genotypes predictive of specific disease phenotypes and antipsychotic treatment responses

Characterization of Schistosome Tegumental Alkaline Phosphatase (SmAP)

Schistosomes are parasitic platyhelminths that currently infect over 200 million people globally. The parasites can live for years in a putatively hostile environment - the blood of vertebrates. We have hypothesized that the unusual schistosome tegument (outer-covering) plays a role in protecting parasites in the blood; by impeding host immunological signaling pathways we suggest that tegumental molecules help create an immunologically privileged environment for schistosomes. In this work, we clone and characterize a schistosome alkaline phosphatase (SmAP), a predicted ∼60 kDa glycoprotein that has high sequence conservation with members of the alkaline phosphatase protein family. The SmAP gene is most highly expressed in intravascular parasite life stages. Using immunofluorescence and immuno-electron microscopy, we confirm that SmAP is expressed at the host/parasite interface and in internal tissues. The ability of living parasites to cleave exogenous adenosine monophosphate (AMP) and generate adenosine is very largely abolished when SmAP gene expression is suppressed following RNAi treatment targeting the gene. These results lend support to the hypothesis that schistosome surface enzymes such as SmAP could dampen host immune responses against the parasites by generating immunosuppressants such as adenosine to promote their survival. This notion does not rule out other potential functions for the adenosine generated e.g. in parasite nutrition

Moiapu 3: Settlement on Moiapu Hill at the very end of Lapita, Caution Bay hinterland

The Caution Bay archaeological project on the south coast of mainland Papua New Guinea has excavated 122 sites over a 9 km² area. Lapita ceramics appear at a number of sites at c. 2900 cal. BP. Here we present the results of excavations at Moiapu 3, a site that helps define the end of the dentate-stamped Lapita phase of this region. It is suggested that the decline and ultimate cessation of dentate stamping related to a loss of symbolism during a period of major socioeconomic readjustment and innovation

Ruisasi 1 and the earliest evidence of mass-produced ceramics in Caution Bay (Port Moresby region), Papua New Guinea

The history of pottery use along the south coast of Papua New Guinea spans from Lapita times, here dated to 2900–2600 cal BP, through to mass production of pottery associated with a number of ethnographically-known interaction (and exchange) networks. Understanding the antecedents and developmental histories of these interaction networks is of considerable importance to archaeological research from local to western Pacific geographical scales. The archaeological site of Ruisasi 1 located at Caution Bay near Port Moresby provides new insights into scales of pottery production before the development of the regional Motu hiri exchange system within the past 500 years. Here faunal remains indicate occupation by marine specialists who exploited a diverse range of local marine environments. Nearly 20,000 ceramic sherds are present in Square A, mostly from a 26 cm thick ‘pottery midden’. A minimum of 45 red slip/plainware vessels based on conjoined sets of sherds plus two vessels with incised decoration are present; the maximum number of clay vessels based on Fabric Types is 155. The globular red slip/plainware pots have highly standardized shapes and sizes, consistent with mass pottery production. The concentration of sherds from these pots within the pottery midden reflects short-duration depositional events within the period of village life c. 1630–1220 cal BP. Whether or not the pots were made locally or imported is the subject of ongoing research. Whatever the case, Ruisasi 1 raises the possibility of mass pottery production possibly linked to a regional interaction network pre-dating the hiri

Study of DJ meson decays to D+π−, D0π+ and D∗+π− final states in pp collisions

A study of D+π−, D0π+ and D∗+π− final states is performed using pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV with the LHCb detector. The D1(2420)0 resonance is observed in the D∗+π− final state and the D∗2(2460) resonance is observed in the D+π−, D0π+ and D∗+π− final states. For both resonances, their properties and spin-parity assignments are obtained. In addition, two natural parity and two unnatural parity resonances are observed in the mass region between 2500 and 2800 MeV. Further structures in the region around 3000 MeV are observed in all the D∗+π−, D+π− and D0π+ final states

Measurement of the relative rate of prompt χc0, χc1 and χc2 production at √s=7TeV

Prompt production of charmonium χc0, χc1 and χc2 mesons is studied using proton-proton collisions at the LHC at a centre-of-mass energy of √s=7TeV. The χc mesons are identified through their decay to J/ψγ, with J/ψ→μ+mu− using photons that converted in the detector. A data sample, corresponding to an integrated luminosity of 1.0fb−1 collected by the LHCb detector, is used to measure the relative prompt production rate of χc1 and χc2 in the rapidity range 2.0<y<4.5 as a function of the J/ψ transverse momentum from 3 to 20 GeV/c. First evidence for χc0 meson production at a hadron collider is also presented

Measurement of the CKM angle γ from a combination of B±→Dh± analyses

A combination of three LHCb measurements of the CKM angle γ is presented. The decays B±→D K± and B±→Dπ± are used, where D denotes an admixture of D0 and D0 mesons, decaying into K+K−, π+π−, K±π∓, K±π∓π±π∓, K0Sπ+π−, or K0S K+K− final states. All measurements use a dataset corresponding to 1.0 fb−1 of integrated luminosity. Combining results from B±→D K± decays alone a best-fit value of γ =72.0◦ is found, and confidence intervals are set γ ∈ [56.4,86.7]◦ at 68% CL, γ ∈ [42.6,99.6]◦ at 95% CL. The best-fit value of γ found from a combination of results from B±→Dπ± decays alone, is γ =18.9◦, and the confidence intervals γ ∈ [7.4,99.2]◦ ∪ [167.9,176.4]◦ at 68% CL are set, without constraint at 95% CL. The combination of results from B± → D K± and B± → Dπ± decays gives a best-fit value of γ =72.6◦ and the confidence intervals γ ∈ [55.4,82.3]◦ at 68% CL, γ ∈ [40.2,92.7]◦ at 95% CL are set. All values are expressed modulo 180◦, and are obtained taking into account the effect of D0–D0 mixing

Searches for B0(s)→J/ψppˉ and B+→J/ψppˉπ+ decays

The results of searches for B0(s)→J/ψ pp¯ and B + → J/ψ p p¯ π+ decays are reported. The analysis is based on a data sample, corresponding to an integrated luminosity of 1.0 fb−1 of pp collisions, collected with the LHCb detector. An excess with 2.8 σ significance is seen for the decay B0s→J/ψ pp¯ and an upper limit on the branching fraction is set at the 90 % confidence level: B(B0s→J/ψ pp¯) < 4.8 × 10−6, which is the first such limit. No significant signals are seen for B0 → J/ψ pp¯ and B+ → J/ψ pp¯ π + decays, for which the corresponding limits are set: B(B0→J/ψ pp¯) < 5.2 × 10−7, which significantly improves the existing limit; and B(B+→J/ψ pp¯π+) < 5.0 × 10−7, which is the first limit on this branching fraction