Low-noise 0.8-0.96- and 0.96-1.12-THz superconductor-insulator-superconductor mixers for the Herschel Space Observatory

Heterodyne mixers incorporating Nb SIS junctions and NbTiN-SiO/sub 2/-Al microstrip tuning circuits offer the lowest reported receiver noise temperatures to date in the 0.8-0.96- and 0.96-1.12-THz frequency bands. In particular, improvements in the quality of the NbTiN ground plane of the SIS devices' on-chip microstrip tuning circuits have yielded significant improvements in the sensitivity of the 0.96-1.12-THz mixers relative to previously presented results. Additionally, an optimized RF design incorporating a reduced-height waveguide and suspended stripline RF choke filter offers significantly larger operating bandwidths than were obtained with mixers that incorporated full-height waveguides near 1 THz. Finally, the impact of junction current density and quality on the performance of the 0.8-0.96-THz mixers is discussed and compared with measured mixer sensitivities, as are the relative sensitivities of the 0.8-0.96- and 0.96-1.12-THz mixers

Real bad grammar: realistic grammatical description with grammaticality

Sampson (this issue) argues for a concept of “realistic grammatical description” in which the distinction between grammatical and ungrammatical sentences is irrelevant. In this article I also argue for a concept of “realistic grammatical description” but one in which a binary distinction between grammatical and ungrammatical sentences is maintained. In distinguishing between the grammatical and ungrammatical, this kind of grammar differs from that proposed by Sampson, but it does share the important property that invented sentences have no role to play, either as positive or negative evidence

Stock Selection, Style Rotation, and Risk

Using US data from June 1984 to July 1999, we show that the impact of firm-specific characteristics like size and book-to-price on future excess stock returns varies considerably over time. The impact can be either positive or negative at different times. This time variation is partially predictable. We investigate whether the partial predictability signals security mispricing or risk compensation by formulating alternative modeling strategies. The strategies are compared empirically, In particular, we allow for a state-dependent choice of investment styles rather than a once-and-for-all choice for a particular style, for example based on high book-to-price ratios or small market cap values. Using alternative ways to correct for risk, we find significant and robust excess returns to style rotating investment strategies. Business cycle oriented approaches exhibit the best overall performance. Purely statistical models for style rotation or fixed investment styles reveal less robust behavior

Assessing Plasmodium falciparum transmission in mosquito-feeding assays using quantitative PCR.

BACKGROUND: Evaluating the efficacy of transmission-blocking interventions relies on mosquito-feeding assays, with transmission typically assessed by microscopic identification of oocysts in mosquito midguts; however, microscopy has limited throughput, sensitivity and specificity. Where low prevalence and intensity mosquito infections occur, as observed during controlled human malaria infection studies or natural transmission, a reliable method for detection and quantification of low-level midgut infection is required. Here, a semi-automated, Taqman quantitative PCR (qPCR) assay sufficiently sensitive to detect a single-oocyst midgut infection is described. RESULTS: Extraction of genomic DNA from Anopheles stephensi midguts using a semi-automated extraction process was shown to have equivalent extraction efficiency to manual DNA extraction. An 18S Plasmodium falciparum qPCR assay was adapted for quantitative detection of P. falciparum midgut oocyst infection using synthetic DNA standards. The assay was validated for sensitivity and specificity, and the limit of detection was 0.7 genomes/µL (95% CI 0.4-1.6 genomes/µL). All microscopy-confirmed oocyst infected midgut samples were detected by qPCR, including all single-oocyst positive midguts. The genome number per oocyst was assessed 8-9 days after feeding assay using both qPCR and droplet digital PCR and was 3722 (IQR: 2951-5453) and 3490 (IQR: 2720-4182), respectively. CONCLUSIONS: This semi-automated qPCR method enables accurate detection of low-level P. falciparum oocyst infections in mosquito midguts, and may improve the sensitivity, specificity and throughput of assays used to evaluate candidate transmission-blocking interventions

Persistent detection of Plasmodium falciparum, P. malariae, P. ovale curtisi and P. ovale wallikeri after ACT treatment of asymptomatic Ghanaian school-children.

Two hundred and seventy four asymptomatic Ghanaian school-children aged 5 to 17 years were screened for malaria parasites by examination of blood films. One hundred and fifty five microscopically-positive individuals were treated with dihydroartemisinin-piperaquine and followed for 3 weeks. Retrospective species-specific PCR of all 274 screened samples identified an additional 60 children with sub-patent parasitaemia, and a substantial proportion of co-infections with Plasmodium malariae, Plasmodium ovale curtisi and Plasmodium ovale wallikeri. One hundred individuals harboured at least one non-falciparum parasite species. Using standard double-read microscopy, the 21-day efficacy of treatment against Plasmodium falciparum was 91.4% among the 117 children seen at all 5 visits. Using nested PCR to test 152 visit 5 blood samples, 22 were found to be parasite-positive. Twenty individuals harboured P. falciparum, four harboured P. ovale spp. and two P. malariae, with four of these 22 isolates being mixed species infections. The persistent detection of low density Plasmodium sp. infections following antimalarial treatment suggests these may be a hitherto unrecognised obstacle to malaria elimination

An inter-laboratory comparison of standard membrane-feeding assays for evaluation of malaria transmission-blocking vaccines.

BACKGROUND: An effective malaria transmission-blocking vaccine may play an important role in malaria elimination efforts, and a robust biological assay is essential for its development. The standard membrane-feeding assay (SMFA) for Plasmodium falciparum infection of mosquitoes is considered a "gold standard" assay to measure transmission-blocking activity of test antibodies, and has been utilized widely in both non-clinical and clinical studies. While several studies have discussed the inherent variability of SMFA within a study group, there has been no assessment of inter-laboratory variation. Therefore, there is currently no assurance that SMFA results are comparable between different studies. METHODS: Mouse anti-Pfs25 monoclonal antibody (mAb, 4B7 mAb), rat anti-Pfs48/45 mAb (85RF45.1 mAb) and a human polyclonal antibody (pAb) collected from a malaria-exposed adult were tested at the same concentrations (6-94 μg/mL for 4B7, 1.2-31.3 μg/mL for 85RF45.1 and 23-630 μg/mL for human pAb) in two laboratories following their own standardized SMFA protocols. The mAbs and pAb, previously shown to have strong inhibition activities in the SMFA, were tested at three or four concentrations in two or three independent assays in each laboratory, and percent inhibition in mean oocyst intensity relative to a control in the same feed was determined in each feeding experiment. RESULTS: Both monoclonal and polyclonal antibodies dose-dependently reduced oocyst intensity in all experiments performed at the two test sites. In both laboratories, the inter-assay variability in percent inhibition in oocyst intensity decreased at higher levels of inhibition, regardless of which antibody was tested. At antibody concentrations that led to a >80 % reduction in oocyst numbers, the inter-laboratory variations were in the same range compared with the inter-assay variation observed within a single laboratory, and the differences in best estimates from multiple feeds between the two laboratories were <5 percentage points. CONCLUSIONS: This study confirms previous reports that the precision of the SMFA increases with increasing percent inhibition. Moreover, the variation between the two laboratories is not greater than the variation observed within a laboratory. The findings of this study provide guidance for comparison of SMFA data from different laboratories

Molecular Markers for Sensitive Detection of Plasmodium falciparum Asexual Stage Parasites and their Application in a Malaria Clinical Trial.

Plasmodium falciparum parasite life stages respond differently to antimalarial drugs. Sensitive stage-specific molecular assays may help to examine parasite dynamics at microscopically detectable and submicroscopic parasite densities in epidemiological and clinical studies. In this study, we compared the performance of skeleton-binding protein 1 (SBP1), ring-infected erythrocyte surface antigen, Hyp8, ring-exported protein 1 (REX1), and PHISTb mRNA for detecting ring-stage trophozoite-specific transcripts using quantitative reverse transcriptase polymerase chain reaction. Markers were tested on tightly synchronized in vitro parasites and clinical trial samples alongside established markers of parasite density (18S DNA and rRNA) and gametocyte density (Pfs25 mRNA). SBP1 was the most sensitive marker but showed low-level expression in mature gametocytes. Novel markers REX1 and PHISTb showed lower sensitivity but higher specificity for ring-stage trophozoites. Using in vivo clinical trial samples from gametocyte-negative patients, we observed evidence of persisting trophozoite transcripts for at least 14 days postinitiation of treatment. It is currently not clear if these transcripts represent viable parasites that may have implications for clinical treatment outcome or transmission potential