Development of Typhax, a Salmonella Typhi Vi polysaccharide protein capsular matrix vaccine

Matrivax Research & Development Corporation is researching and developing a novel technology termed Protein Capsular Matrix Vaccine (PCMV) as an alternative to polysaccharide-protein conjugate vaccines. In a PCMV, polysaccharide antigens are entrapped in a cross-linked protein ‘carrier’ matrix. This process is simpler than conjugate vaccines and should yield polysaccharide vaccines that elicit TH-cell ‘memory’, are highly efficacious, and less expensive to manufacture. Typhoid fever, caused by Salmonella enterica serovar Typhi, is a disease that afflicts ~16 million people worldwide, resulting in 600,000 deaths, annually. Although typhoid fever vaccines are commercially available, there are significant limitations. Ty21a is an oral vaccine that requires a multi-dose regimen; whereas Typherix® and TyphimVi® are parenteral and associated with local reactogenicity. The existing typhoid vaccines confer variable, ~70%, protective efficacy, do not protect young children (\u3c2 years old), and are not used for routine immunization. Please click Additional Files below to see the full abstract

Fixed versus Flexible: Lessons from EMS Order Flow

This paper addresses the puzzle of regime-dependent volatility in foreign exchange. We extend the literature in two ways. First, our microstructural model provides a qualitatively new explanation for the puzzle. Second, we test implications of our model using Europe's recent shift to rigidly fixed rates (EMS to EMU). In the model, shocks to order flow induce volatility under flexible rates because they have portfolio-balance effects on price, whereas under fixed rates the same shocks do not have portfolio-balance effects. These effects arise in one regime and not the other because the elasticity of speculative demand for foreign exchange is (endogenously) regime-dependent: low elasticity under flexible rates magnifies portfolio-balance effects; under credibly fixed rates, elasticity of speculative demand is infinite, eliminating portfolio-balance effects. New data on FF/DM transactions show that order flow had persistent effects on the exchange rate before EMU parities were announced. After announcement, determination of the FF/DM rate was decoupled from order flow, as predicted by the model.

An examination of the molecular mechanisms controlling the tissue accumulation of conjugated linoleic acid (CLA) in cattle

End of project reportLong chain n-3 polyunsaturated fatty acids (n-3 PUFA) and conjugated linoleic acid (CLA) have demonstrable and potential human health benefits in terms of preventing cancer, diabetes, chronic inflammation, obesity and coronary heart disease. Supplementation of cattle diets with a blend of oils rich in n-3 PUFA and linoleic acid have a synergistic effect on the accumulation of ruminal and tissue concentrations of trans vaccenic acid (TVA), the main substrate for ?-9 desaturase which is responsible for de novo tissue synthesis of the cis 9, trans 11 isomer of CLA. This dietary strategy translates into increases in milk concentrations of CLA in dairy cows; however, concentrations in the muscle of beef animals have not always been increased. There is an apparent paradox in that n-3 PUFA supplementation enhances ruminal synthesis of trans-vaccenic acid (TVA), but then inhibits its conversion to CLA possibly through altering the activity of ?-9 desaturase. Recently, the promoter regions of the bovine ?- 9 desaturase gene has been isolated and analysed and has been shown to contain a conserved PUFA response region

Global gene expression in endometrium of high and low fertility heifers during the mid-luteal phase of the estrous cycle

peer-reviewedBackground In both beef and dairy cattle, the majority of early embryo loss occurs within the first 14 days following insemination. During this time-period, embryos are completely dependent on their maternal uterine environment for development, growth and ultimately survival, therefore an optimum uterine environment is critical to their survival. The objective of this study was to investigate whether differences in endometrial gene expression during the mid-luteal phase of the estrous cycle exist between crossbred beef heifers ranked as either high (HF) or low fertility (LF) (following four rounds of artificial insemination (AI)) using the Affymetrix® 23 K Bovine Gene Chip. Results Conception rates for each of the four rounds of AI were within a normal range: 70–73.3%. Microarray analysis of endometrial tissue collected on day 7 of the estrous cycle detected 419 differentially expressed genes (DEG) between HF (n = 6) and LF (n = 6) animals. The main gene pathways affected were, cellular growth and proliferation, angiogenesis, lipid metabolism, cellular and tissue morphology and development, inflammation and metabolic exchange. DEG included, FST, SLC45A2, MMP19, FADS1 and GALNT6. Conclusions This study highlights, some of the molecular mechanisms potentially controlling uterine endometrial function during the mid-luteal phase of the estrous cycle, which may contribute to uterine endometrial mediated impaired fertility in cattle. Differentially expressed genes are potential candidate genes for the identification of genetic variation influencing cow fertility, which may be incorporated into future breeding programmes.Teagasc Walsh Fellowship Programm

Heat shock proteins of vegetative and fruiting Myxococcus xanthus cells

The heat shock response of Myxococcus xanthus was investigated and characterized. When shifted from 28 to 40°C, log-phase cells rapidly ceased growth, exhibited a 50% reduction in CFU, and initiated the synthesis of heat shock proteins (HTPs). Heat-shocked log-phase M. xanthus cells labeled with [35S]methionine were found to produce 18 major HTPs. The HTPs, analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography, were characterized with regard to molecular mass, subcellular location (periplasm, membrane, or cytoplasm), and temperature required for expression. Most HTPs were expressed at 36°C, the optimum growth temperature of M. xanthus. Cells preincubated at 36°C for 1 h before being shifted to 40°C demonstrated increased thermotolerance compared with cells shifted directly from 28 to 40°C. The HTPs produced by heat-shocked starvation-induced fruiting cells and glycerol-induced sporulating cells were also analyzed and characterized. Thirteen HTPs were detected in fruiting cells shifted from 28 to 40°C. Six of these HTPs were not seen in vegetative M. xanthus cells. Log-phase cells induced to sporulate by the addition of glycerol produced 17 HTPs after being shifted to 40°C. These HTPs were found to be a mixture of HTPs detected in heat-shocked log-phase cells and heat-shocked fruiting cells

Vorticity and divergence in the high‐latitude upper thermosphere

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95126/1/grl5327.pd

DEVELOPMENT OF PROTEIN CAPSULAR MATRIX VACCINE (PCMV) TECHNOLOGY

Matrivax R&D Corp. is a start-up biotechnology company with R&D operations located in Boston, USA and a vaccine pilot facility in Haikou, China. We are developing a proprietary vaccine process that entraps polysaccharides in a cross-linked protein ‘carrier’ or matrix, termed Protein Capsular Matrix Vaccine (PCMV), as an alternative to conjugate vaccine technology. Despite highly efficacious pneumococcal vaccines such as Prevnar®, S. pneumoniae causes \u3e 1 million deaths worldwide annually. Likewise, typhoid fever afflicts ~16 million people, resulting in 600,000 deaths despite effective vaccines such as Typhim Vi® and Ty21a. The premise is that inexpensive,efficacious polysaccharide vaccines that elicit TH-cell ‘memory’ will actively displace their unconjugated and conjugated vaccine counterparts. Towards this end, Matrivax is actively research and developing pneumococcal, enteric fever, and meningococcal PCMV candidates. In preliminary studies, a pneumococcal capsular polysaccharide (PPS) 14 ‘whole reaction’ PCMV employing ‘unoptimized chemistry’ elicited an anti-PPS14 reciprocal IgG antibody titer of ~7,000. Functional antibodies were elicited as evidenced by anti-sera facilitated opsonization and passively transferred antibodies conferring protection against lethal pneumococcal challenge. Recently Matrivax devised ‘optimized’ PCMV chemical reaction conditions improving polysaccharide incorporation into protein matrices as well as separated ‘whole reaction’ PCMV by size-exclusion chromatography yielding ‘size-fractionated’ PCMV particles. Size fractionated PPS14 PCMVs and Prevnar® were used to immunize mice in a three dose, bi-weekly regimen. Particle sized PCMV containing 0.12 and 0.03 ug PPS14 elicited anti-PPS14 reciprocal antibody GMT of 617,077 and 501,103,respectively, compared to Prevnar® (2 ug PPS14) which elicited a titer of 776,047. Thus, optimized PCMVs containing 1.5% or 6% the amount of PPS14 contained in Prevnar® elicited a comparable anti-PPS14 antibody response. Matrivax next evaluated PCMV’s applicability to Vi antigen. SDS-PAGE data demonstrated that Vi was captured in a DNI matrix and capture ELISA further indicated that Vi antigen was localized at the surface of PCMV particles. Size fractionated Vi-DNI PMCV was compared to Typhim Vi® following a three dose, bi-weekly vaccine regimen in a murine immunogenicity study. Ten (10) ug Typhim Vi elicited an anti-Vi reciprocal antibody GMT of 200 whereas size-fractionated PCMVs containing ~2 ug Vi elicited an anti-Vi antibody GMT of \u3e600. A Vi PCMV Phase 1 clinical trial is scheduled for 2Q11

Preventing childhood malaria in Africa by protecting adults from mosquitoes with insecticide-treated nets

Malaria prevention in Africa merits particular attention as the world strives toward a better life for the poorest. Insecticide-treated nets (ITNs) represent a practical means to prevent malaria in Africa, so scaling up coverage to at least 80% of young children and pregnant women by 2010 is integral to the Millennium Development Goals (MDG). Targeting individual protection to vulnerable groups is an accepted priority, but community-level impacts of broader population coverage are largely ignored even though they may be just as important. We therefore estimated coverage thresholds for entire populations at which individual- and community-level protection are equivalent, representing rational targets for ITN coverage beyond vulnerable groups

The acquisition of information and learning technology skills by FE teachers

The core of this thesis is to investigate the perceptions of teachers in Further Education (FE) when dealing with the continuous change caused by the expansion of information and learning technology (ILT). This thesis also identifies the potential links between the increase in the range and availability of learning technology and the development of self- directed and student-centred learning. It explores the perceptions of practicing teachers with reference to their personal development and if such development indicates compliance with adult learning theory. It also analysis the external pressures placed on FE colleges and their teaching staff due to the development of ILT and the related governmental policy. The thesis regards teachers in the FE sector as a unique group of adult learners with a wide range of experience, qualifications and entry routes into the profession. It investigates a sample of teachers using questionnaires and focus groups analysing their perceptions of ILT, preferred learning styles, identified needs and self evaluation techniques and analysis any correlation between these factors and the biographical parameters obtained from the questionnaire responses. An aspect of the investigation was to analyse how teachers became proficient in the use of ILT, routes staff use to obtain the skills and knowledge required and if the aspects of adult learning theory are being applied. A related aspect of this research is the investigation of whether the perceptions of teacher of their personal development experiences related to ILT indicate if an FE college is or can become a “learning organisation” and if such a concept is valid for the FE sector

An improved mosquito electrocuting trap that safely reproduces epidemiologically relevant metrics of mosquito human-feeding behaviours as determined by human landing catch

Background: Reliable quantification of mosquito host—seeking behaviours is required to determine the efficacy of vector control methods. For malaria, the gold standard approach remains the risky human landing catch (HLC). Here compare the performance of an improved prototype of the mosquito electrocuting grid trap (MET) as a safer alternative with HLC for measuring malaria vector behaviour in Dar es Salaam, Tanzania. Methods: Mosquito trapping was conducted at three sites within Dar es Salaam representing a range of urbanicity over a 7-month period (December 2012–July 2013, 168 sampling nights). At each site, sampling was conducted in a block of four houses, with two houses being allocated to HLC and the other to MET on each night of study. Sampling was conducted both indoors and outdoors (from 19:00 to 06:00 each night) at all houses, with trapping method (HLC and MET) being exchanged between pairs of houses at each site using a crossover design. Results: The MET caught significantly more Anopheles gambiae sensu lato than the HLC, both indoors (RR [95 % confidence interval (CI)]) = 1.47 [1.23–1.76], P < 0.0001 and outdoors = 1.38 [1.14–1.67], P < 0.0001). The sensitivity of MET compared with HLC did not detectably change over the course of night for either An. gambiae s.l. (OR [CI]) = 1.01 [0.94–1.02], P = 0.27) or Culex spp. (OR [CI]) = 0.99 [0.99–1.0], P = 0.17) indoors and declined only slightly outdoors: An. gambiae s.l. (OR [CI]) = 0.92 [0.86–0.99], P = 0.04), and Culex spp. (OR [CI]) = 0.99 [0.98–0.99], P = 0.03). MET-based estimates of the proportions of mosquitoes caught indoors (P i ) or during sleeping hours (P fl ), as well as the proportion of human exposure to bites that would otherwise occurs indoors (π i ), were statistically indistinguishable from those based on HLC for An. gambiae s.l. (P = 0.43, 0.07 and 0.48, respectively) and Culex spp. (P = 0.76, 0.24 and 0.55, respectively). Conclusions: This improved MET prototype is highly sensitive tool that accurately quantifies epidemiologically-relevant metrics of mosquito biting densities, behaviours and human exposure distribution