Optimal Capital Structure in Centralized Agricultural Cooperatives

Agribusiness,

Patent Landscape of Influenza A Virus Prophylactic Vaccines and Related Technologies

Executive Summary: This report focuses on patent landscape analysis of technologies related to prophylactic vaccines targeting pandemic strains of influenza. These technologies include methods of formulating vaccine, methods of producing of viruses or viral subunits, the composition of complete vaccines, and other technologies that have the potential to aid in a global response to this pathogen. The purpose of this patent landscape study was to search, identify, and categorize patent documents that are relevant to the development of vaccines that can efficiently promote the development of protective immunity against pandemic influenza virus strains. The search strategy used keywords which the team felt would be general enough to capture (or “recall”) the majority of patent documents which were directed toward vaccines against influenza A virus. After extensive searching of patent literature databases, approximately 33,500 publications were identified and collapsed to about 3,800 INPADOC families. Relevant documents, almost half of the total, were then identified and sorted into the major categories of vaccine compositions (about 570 families), technologies which support the development of vaccines (about 750 families), and general platform technologies that could be useful but are not specific to the problems presented by pandemic influenza strains (about 560 families). The first two categories, vaccines and supporting technologies, were further divided into particular subcategories to allow an interested reader to rapidly select documents relevant to the particular technology in which he or she is focused. This sorting process increased the precision of the result set. The two major categories (vaccines and supporting technologies) were subjected to a range of analytics in order to extract as much information as possible from the dataset. First, patent landscape maps were generated to assess the accuracy of the sorting procedure and to reveal the relationships between the various technologies that are involved in creating an effective vaccine. Then, filings trends are analyzed for the datasets. The country of origin for the technologies was determined, and the range of distribution to other jurisdictions was assessed. Filings were also analyzed by year, by assignee, and by inventor. Finally, the various patent classification systems were mapped to find which particular classes tend to hold influenza vaccine-related technologies. Besides the keywords developed during the searches and the landscape map generation, the classifications represent an alternate way for further researchers to identify emerging influenza technologies. The analysis included creation of a map of keywords, as shown above, describing the relationship of the various technologies involved in the development of prophylactic influenza A vaccines. The map has regions corresponding to live attenuated virus vaccines, subunit vaccines composed of split viruses or isolated viral polypeptides, and plasmids used in DNA vaccines. Important technologies listed on the map include the use of reverse genetics to create reassortant viruses, the growth of viruses in modified cell lines as opposed to the traditional methods using eggs, the production of recombinant viral antigens in various host cells, and the use of genetically-modified plants to produce virus-like particles. Another major finding was that the number of patent documents related to influenza being published has been steadily increasing in the last decade, as shown in the figure below. Until the mid-1990s, there were only a few influenza patent documents being published each year. The number of publications increased noticeably when TRIPS took effect, resulting in publication of patent applications. However, since 2006 the number of vaccine publications has exploded. In each of 2011 and 2012, about 100 references disclosing influenza vaccine technologies were published. Thus, interest in developing new and more efficacious influenza vaccines has been growing in recent years. This interest is probably being driven by recent influenza outbreaks, such as the H5N1 (bird flu) epidemic that began in the late 1990s and the 2009 H1N1 (swine flu) pandemic. The origins of the vaccine-related inventions were also analyzed. The team determined the country in which the priority application was filed, which was taken as an indication of the country where the invention was made or where the inventors intended to practice the invention. By far, most of the relevant families originated with patent applications filed in the United States. Other prominent priority countries were the China and United Kingdom, followed by Japan, Russia, and South Korea. France was a significant priority country only for supporting technologies, not for vaccines. Top assignees for these families were mostly large pharmaceutical companies, with the majority of patent families coming from Novartis, followed by GlaxoSmithKline, Pfizer, U.S. Merck (Merck, Sharpe, & Dohme), Sanofi, and AstraZeneca. Governmental and nonprofit institutes in China, Japan, Russia, South Korea and the United States also are contributing heavily to influenza vaccine research. Lastly, the jurisdictions were inventors have sought protection for their vaccine technologies were determined, and the number of patent families filing in a given country is plotted on the world map shown on page seven. The United States, Canada, Australia, Japan, South Korea and China have the highest level of filings, followed by Germany, Brazil, India, Mexico and New Zealand. However, although there are a significant number of filings in Brazil, the remainder of Central and South America has only sparse filings. Of concern, with the exception of South Africa, few other African nations have a significant number of filings. In summary, the goal of this report is to provide a knowledge resource for making informed policy decisions and for creating strategic plans concerning the assembly of efficacious vaccines against a rapidly-spreading, highly virulent influenza strain. The team has defined the current state of the art of technologies involved in the manufacture of influenza vaccines, and the important assignees, inventors, and countries have been identified. This document should reveal both the strengths and weaknesses of the current level of preparedness for responding to an emerging pandemic influenza strain. The effects of H5N1 and H1N1 epidemics have been felt across the globe in the last decade, and future epidemics are very probable in the near future, so preparations are necessary to meet this global health threat

Experimental Validation of a Four-Way Outphasing Combiner for Microwave Power Amplification

This letter presents a 2.14 GHz, four-way power combining and outphasing system for high-power amplifiers such as those in radio basestations (RBS). The combiner is ideally lossless, and enables power control through load modulation of the power amplifiers (PAs). A discrete-component power combiner is designed and characterized, and combined with inverse Class-F PAs using GaN HEMT devices to develop a complete PA system. We demonstrate the effectiveness of the system over a range of outphasing control angles. This first-ever microwave implementation of the outphasing system has a peak CW drain efficiency of 68.9%, with efficiency greater than 55% over a 5.5 dB power range. It provides an average modulated efficiency of 57% for a W-CDMA signal with 3.47 dB peak to average power ratio (PAPR) at 42 dBm output power.Massachusetts Institute of Technology. Center for Integrated Circuits and System

Protein-DNA charge transport: Redox activation of a DNA repair protein by guanine radical

DNA charge transport (CT) chemistry provides a route to carry out oxidative DNA damage from a distance in a reaction that is sensitive to DNA mismatches and lesions. Here, DNA-mediated CT also leads to oxidation of a DNA-bound base excision repair enzyme, MutY. DNA-bound Ru(III), generated through a flash/quench technique, is found to promote oxidation of the [4Fe-4S](2+) cluster of MutY to [4Fe-4S](3+) and its decomposition product [3Fe-4S](1+). Flash/quench experiments monitored by EPR spectroscopy reveal spectra with g = 2.08, 2.06, and 2.02, characteristic of the oxidized clusters. Transient absorption spectra of poly(dGC) and [Ru(phen)(2)dppz](3+) (dppz = dipyridophenazine), generated in situ, show an absorption characteristic of the guanine radical that is depleted in the presence of MutY with formation instead of a long-lived species with an absorption at 405 nm; we attribute this absorption also to formation of the oxidized [4Fe-4S](3+) and [3Fe4S](1+) clusters. In ruthenium-tethered DNA assemblies, oxidative damage to the 5'-G of a 5'-GG-3' doublet is generated from a distance but this irreversible damage is inhibited by MutY and instead EPR experiments reveal cluster oxidation. With ruthenium-tethered assemblies containing duplex versus single-stranded regions, MutY oxidation is found to be mediated by the DNA duplex, with guanine radical as an intermediate oxidant; guanine radical formation facilitates MutY oxidation. A model is proposed for the redox activation of DNA repair proteins through DNA CT, with guanine radicals, the first product under oxidative stress, in oxidizing the DNA-bound repair proteins, providing the signal to stimulate DNA repair

Computational Efficiency of Frequency-- and Time--Domain Calculations of Extreme Mass--Ratio Binaries: Equatorial Orbits

Gravitational waveforms and fluxes from extreme mass--ratio inspirals can be computed using time--domain methods with accuracy that is fast approaching that of frequency--domain methods. We study in detail the computational efficiency of these methods for equatorial orbits of fast spinning Kerr black holes, and find the number of modes needed in either method --as functions of the orbital parameters-- in order to achieve a desired accuracy level. We then estimate the total computation time and argue that for high eccentricity orbits the time--domain approach is more efficient computationally. We suggest that in practice low--$m$ modes are computed using the frequency--domain approach, and high--$m$ modes are computed using the time--domain approach, where $m$ is the azimuthal mode number.Comment: 19 figures, 6 table

Mesospheric Density Climatologies Determined at Midlatitudes Using Rayleigh Lidar

The original Rayleigh-scatter lidar that operated at the Atmospheric Lidar Observatory (ALO; 41.7°N, 111.8°W) in the Center for Atmospheric and Space Sciences (CASS) on the campus of Utah State University (USU), collected 11 years of data between 1993 and 2004. From Rayleigh lidar photon-count returns, relative densities throughout the mesosphere, from 45 to 90 km, were determined. Using these relative densities, three climatologies are derived, each using a different density normalization method at 45 km: the first method normalized the relative densities to a constant; the second normalized them to the NRLMSISe00 empirical model; and the third normalized them to the CPC analyses, a first principles, assimilative, meteorological model. From there, the average density profile for each night of the composite year is found by averaging the nighttime density profiles in a multi-year, 31-day window centered on that particular night. From these three density climatologies, some different and many common features in the mesospheric densities are evident. In the future, with improvements to the lidar, it will be possible to provide an absolute normalization for the density profiles

The pharmacy care plan service: Service evaluation and estimate of cost-effectiveness

Background: The UK Community Pharmacy Future group developed the Pharmacy Care Plan (PCP) service with a focus on patient activation, goal setting and therapy management.  Objective: To estimate the effectiveness and cost-effectiveness of the PCP service from a health services perspective.  Methods: Patients over 50 years of age prescribed one or more medicines including at least one for cardiovascular disease or diabetes were eligible. Medication review and person-centred consultation resulted in agreed health goals and actions towards achieving them. Clinical, process and cost-effectiveness data were collected at baseline and 12-months between February 2015 and June 2016. Mean differences are reported for clinical and process measures. Costs (NHS) and quality-adjusted life year scores were estimated and compared for 12 months pre- and post-baseline.  Results: Seven hundred patients attended the initial consultation and 54% had a complete set of data obtained. There was a significant improvement in patient activation score (mean difference 5.39; 95% CI 3.9 – 6.9; p<0.001), systolic (mean difference -2.90 mmHg ; 95% CI -4.7 - -1; p=0.002) and diastolic blood pressure (mean difference -1.81 mmHg; 95% CI -2.8 - -0.8; p<0.001), adherence (mean difference 0.26; 95% CI 0.1 – 0.4; p<0.001) and quality of life (mean difference 0.029; 95% CI 0.015 – 0.044; p<0.001). HDL cholesterol reduced significantly and QRisk2 scores increased significantly over the course of the 12 months. The mean incremental cost associated with the intervention was estimated to be £202.91 (95% CI 58.26 to £346.41) and the incremental QALY gain was 0.024 (95% CI 0.014 to 0.034), giving an incremental cost per QALY of £8,495.  Conclusions: Enrolment in the PCP service was generally associated with an improvement over 12 months in key clinical and process metrics. Results also suggest that the service would be cost-effective to the health system even when using worst case assumptions

Heterotic String Field Theory

We construct the Neveu-Schwarz sector of heterotic string field theory using the large Hilbert space of the superghosts and the multi-string products of bosonic closed string field theory. No picture-changing operators are required as in Wess-Zumino-Witten-like open superstring field theory. The action exhibits a novel kind of nonpolynomiality: in addition to terms necessary to cover missing regions of moduli spaces, new terms arise from the boundary of the missing regions and its subspaces. We determine the action up to quintic order and a subset of terms to all orders.Comment: 15 pages, no figures, LaTeX2e; v2: minor cosmetic change

Cloning and functional characterization of the fatty acid elongase 1 (FAE1) gene from high erucic Crambe abyssinica cv. Prophet.

A genomic fatty acid elongation 1 (FAE1) clone was isolated from Crambe abyssinica. The genomic clone corresponds to a 1521-bp open reading frame, which encodes a protein of 507 amino acids. In yeast cells expression of CrFAE led to production of new very long chain monounsaturated fatty acids such as eicosenoic (20:1(delta11)) and erucic (22:1(delta13)) acids. Seed-specific expression in Arabidopsis thaliana resulted in up to a 12-fold increase in the proportion of erucic acid. On the other hand, in transgenic high-erucic Brassica carinata plants, the proportion of erucic acid was as high as 51.9% in the best transgenic line, a net increase of 40% compared to wild type. These results indicate that the CrFAE gene encodes a condensing enzyme involved in the biosynthesis of very long-chain fatty acids utilizing monounsaturated and saturated acyl substrates, with a strong capability for improving the erucic acid content

Gaining insight into the role of serine 282 in B. napus FAE1 condensing enzyme

AbstractTo gain some insight whether there is an absolute requirement for the serine 282 to yield a functional fatty acid elongase 1 condensing enzyme we have introduced point mutations in the FAE1 coding sequence which led to the substitution of serine 282 with several aliphatic or aromatic amino acids. The mutated FAE1 polypeptides were expressed in yeast. Gas chromatography analyses of the fatty acid methyl esters from yeast lysates and fatty acid elongase activity assays demonstrated that there is not an absolute requirement for serine at position 282 to yield a functional FAE1 condensing enzyme