Yeast strains and a method of expression in yeast of the monooxygenase activity of heterologous cytochromes P450 are disclosed. Within the genome of the yeast strain, genes for NADPH-cytochrome P450 reductase and cytochrome b5 are stably integrated and coexpressed. The genome is transformed with a plasmid carrying a cassette for the expression of a heterologous P450 gene.

The cytochromes P450 (hereinafter abbreviated to P450) constitute a superfamily of membrane enzymes having very varied monooxygenase type activities. Their activities are capable of being used in a wide range of fields of application. There may be mentioned, by way of non-limiting examples:
the bioconversion of a virtually unlimited number of lipophilic molecules by means of reactions of insertion of an oxygen atom, followed or otherwise by rearrangements in carbon--carbon or carbon-hydrogen bonds, and by means of the addition of oxygen to a variety of hetero atoms (sulfur, nitrogen, phosphorus). P450 utilizes aerial oxygen as oxidizing agent. PA1 in vitro diagnosis of the formation of toxic or mutagenic metabolites by human hepatic metabolism of natural or artificial xenobiotic molecules (pollutants, medicinal products, additives). Such prediction is of primary importance, especially in the case of the development of new molecules of pharmaceutical importance. PA1 The identification and destruction of molecules which are toxic or pollute the environment. PA1 too low a reductase/heterologous P450 mole ratio leads to a low specific activity as a result of the lack of reductase. PA1 too high a reductase/heterologous P450 mole ratio leads to the destruction of a considerable fraction of the P450 as a result of the large increase in the number of abortive catalytic cycles and of the production by the excess of reductase of oxygen-containing radicals which are dangerous to the cell. The outcome is a loss of viability of the cells, or even a drop in activity due to the destruction of cytochromes P450. PA1 too low a cytochrome b5/P450 mole ratio leads to a reduced activity of class B P450. Moreover, the presence of a high level of cytochrome b5 appears to exert a protective effect against the toxic effects linked to excessive reductase levels; PA1 too high a cytochrome b5/P450 mole ratio leads to the inhibition of class A P450 activity, and can potentially reduce the amount of unbound intracellular heme and thus be toxic to the cell. PA1 by the construction of fusion proteins artificially combining an NADPH-cytochrome P450 reductase (homologous or heterologous) and the cytochrome P450 itself on the same polypeptide chain. PA1 by the use of a vector carrying both an expression unit for the P450 reductase and an expression unit for a heterologous P450 on the same plasmid. PA1 the first is that it does not permit an adjustment of the ratio of the amount of reductase to that of the P450. Since the reductase has a priori a much faster catalytic cycle than the cytochrome, the optimum ratio for the activity is not necessarily 1:1, and can vary from one P450 to another, or even from one substrate to another for the same P450. PA1 the second stems from the poor yield of synthesis (or from poor stability) of the fusion protein; this manifests itself in most cases in a large reduction in the level of expression of the fusion protein relative to that of the P450 expressed alone. This decrease causes most, if not all, of the gain in specific activity resulting from the fusion to be lost in terms of yield. PA1 the third defect is the impossibility, if not technical, then at least practical, of generalizing this approach to the fusion of more than two proteins. PA1 (a) inactivation by mutation of one of the heterologous genes. Such an event is generally selected spontaneously as a result of the toxicity to the cell of the heterologous genes or at least of the associated activities. PA1 (b) deletion by recombination of the heterologous gene on duplication of the wild-type gene (conversion) within a heterozygous locus (see Diagram 1). The selective advantage is twofold, since it has both an identical effect to (a) and an effect which leads to a wild-type homozygous context. PA1 (c) elimination of one of the heterologous genes, or evolution of important characteristics of the strain (linked to the rearrangement of unknown endogenous heterozygous genes which are not directly linked to the heterologous genes but have significant functions for the activities of interest) by a meiotic recombination which might occur at the heterozygous loci and which would be followed by sporulations and then by spontaneous crosses. PA1 the strains of this set are completely isogenic with one another, with the exception of the specifically modified loci, in particular the mating-type locus; PA1 an NADPH-cytochrome P450 reductase and a cytochrome b5 are produced in each cell, at a homogeneous level independent of the level and nature of the heterologous cytochrome P450 possibly expressed; PA1 the total level of reductase and of b5 is adjustable by modification of the composition of the culture medium, independently of the level of heterologous P450 possibly expressed; PA1 the maximum total level of expression of the reductase and of b5 can be at least equal (in molar terms and at maximum induction) to that of the heterologous P450 produced; PA1 the minimum levels of the reductase and of heterologous b5 which can be produced (under non-induction conditions) are at least 10-fold lower than the maximum level of the reductase and of b5 defined above; PA1 the reductase may be overproduced independently of the cytochrome b5; PA1 these strains carry the selectable markers needed for the use of common plasmids, and are, independently of the above properties, "good hosts" for the expression of heterologous cytochromes P450. PA1 the elements PES1-1 and PES1-2 are not in themselves novel, since they are, respectively, the haploid mating type a and alpha forms of S. cerevisiae yeast strain W303.1B.
In view of this broad field of application, the expression of heterologous forms of P450 and of their activities in microorganisms which lack them clearly merits attention. Two problems then became apparent: first, the membrane nature of the P450 of eukaryotes makes it desirable to use a host microorganism of the eukaryotic type, leading to the choice of yeasts; second, these enzymes are functional only in the presence of "associated enzymes" which play the part of specific electron transporters. Whereas the diversity of cytochromes P450 is extreme, the "associated REDOX enzymes" are few in number and comprise cytochrome b5, NADH-cytochrome b5 reductase and, most especially, NADPH-cytochrome P450 reductase. Moreover, certain enzymes, termed phase II, such as, for example, microsomal epoxide hydrolase, may be needed for the metabolic coupling between different P450's, or for the destruction of highly reactive chemical intermediates formed during certain reactions, such as, for example, the metabolism of polycyclic hydrocarbons.
The high level in vivo expression of heterologous cytochromes P450 in yeast leads to high levels of activity only if these "associated redox enzymes", which are essential to the functioning of P450, can be coexpressed in the yeast, in suitable stoichiometries relative to one another and to the P450. Recent data show that,
In order to solve these problems, there was constructed according to the invention, by genomic integration of synthetic genes, a set of yeast strains expressing, stably and in a manner which can be modulated (by the composition of the culture medium), an enzymatic environment which can be optimized for expression of the activity of any heterologous P450.
Many publications have described the expression of heterologous cytochromes P450 in yeast. Nevertheless, the problem of optimization of the cellular environment to permit high activity in vivo has seldom been tackled, the proteins produced often being used for analytical purposes or purposes of in vitro research.
The problem of optimization of the activities has been tackled hitherto in two ways:
Both of these systems, namely the construction of fusion proteins (P450--P450 reductase) or of plasmid coexpression vectors, possess serious drawbacks:
1--the construction of fusion proteins (P450-reductase) is a lengthy operation which is difficult to optimize (except empirically by a trial-and-error approach), in the present state of knowledge, in respect of the molecular design of the fusion. This is not a priori a genuine defect when attention is focused on a single activity and when lengthy research can be devoted to it; it is, however, a serious weakness during a process of development where several types of activity have to be tested in a reasonable time in order to adjust the tool to the problem. Apart from this fact, this system possesses three major defects which are inherent in it: PA0 2--The coexpression of several heterologous proteins from a single plasmid appears at first sight to be a good approach. Nevertheless, such large plasmids are potentially unstable genetically, most especially (and this is most often the case) when the same promoter elements are used for the different genes. This instability is a definite problem for an industrial application. PA0 . . XXX . . . YYYY . . . ZZZ.fwdarw. . . . XXX . . . YYYY . . . ZZZ . . . PA0 . . XXX . . . hhhhh . . . ZZZ .fwdarw. . . . XXX . . . YYYY . . . ZZZ . . . PA0 XXX and ZZZ : wild-type intergenetic sequences PA0 hhhhhh : heterologous gene PA0 YYYYY : wild-type gene which is the target of the integration PA0 1--the yeast strain is a diploid strain in which the alleles are isogenic, with the exception of the loci which carry the heterologous genes and of the mating-type locus, which are heterozygous, PA0 2--the heterozygous loci lack an allele carrying a wild-type gene, and PA0 3--the heterologous genes are placed under the control of an inducible and regulable promoter. PA0 1--the genomic sequences of PES1-2 yeast lying between the first Kpn1 site located upstream of the endogenous coding frame of NADPH-cytochrome P450 reductase and the first codon of this same coding frame are removed. PA0 2--the sequences removed are replaced, starting from the Kpn1 (half-site) and in the following order, by: the gene encoding orotidine-5-phosphate decarboxylase (of S. cerevisiae), a fragment of the GAL10 gene of S. cerevisiae), a fragment of the CYC1 gene of S. cerevisiae comprising the transcription initiation sequences of this gene and a few nucleotides of synthetic sequence. PA0 1--the genomic sequences lying between the Kpn1 half-site immediately preceding the functional URA3 gene of PES1-3 and the first BspMI site encountered on the 5' side (relative to the orientation of the coding frame of the reductase gene) of this position (formerly in the promoter portion of the wild-type NADPH-cytochrome P450 reductase gene) are removed. PA0 2--the whole of the NADPH-450 reductase coding frame (starting from the BamHI site) together with its flanking portion on the 3' side as far as the first BspMI site encountered on the 3' side (same convention as above) is removed. PA0 3--The portion removed is partially replaced, in the following order and starting from the end where the BspMI site encountered on the 3' side was located and in the following order: the gene encoding orotidine-5-phosphate decarboxylase (of S. cerevisiae), a fragment of the GAL10 gene of S. cerevisiae, a fragment of the CYC1 gene of S. cerevisiae comprising the transcription initiation sequences of this gene followed by a few nucleotides of synthetic sequence, and by the complete coding frame of the human cytochrome b5 gene, followed by a short synthetic sequence, followed by a fragment of the phosphoglycerate kinass gene of yeast and comprising the 3'-flanking sequences of this gene. PA0 4--The mating-type sign of the strain is changed from alpha to a. PA0 The strain PSE1-34 consists of the diploid of the haploid strains PSE1-3 and PSE1-4. PA0 The strain PSE1-31 consists of the diploid of the haploid strains PSE1-3 and PSE1-1. PA0 The strain PSE1-42 consists of the diploid of the haploid strains PSE1-4 and PSE1-2. PA0 The strain PES1-12 consists of the diploid of the haploid strains PSE1-1 and PSE1-2.
Moreover, the multicopy plasmids used, as a result of the random distribution of the number of copies in each cell, lead to cell populations which are very heterogeneous as regards the level of expression of each of these two enzymes (reductase and P450). The mono-oxygenase activity obtained (which is in practice the useful value) is then the mean of a square-law distribution; this value is bound, for obvious reasons, to be lower than the activity value which would be achieved if the P450 (even on a multicopy plasmid) were expressed in a cellular context having a homogeneous and high level of reductase.

Yeast strains with stable integration of heterologous genes

Centre National De La Recherche Scientifique


The invention is an electronic circuit for testing a receiver. In detail, the circuit includes a RF signal generator providing an RF signal to a first mixer. A first oscillator providing a first signal to the first mixer. The first mixer receives the RF signal and the first signal and provides a first output signal comprising the RF signal plus the first signal and the RF signal minus the first signal. A first filter is coupled to the first mixer for receiving the first output signal and providing a second output signal wherein the RF signal plus the first output signal is removed. A second mixer is coupled to the first filter and is adapted to receive the second output signal and a second input signal from a second oscillator; and provides a third output signal to a second filter. A fourth output signal from the second filter provides a fifth output signal for testing the receiver that is amplitude and temperature insensitive.

1. Field of the Invention
The invention relates to the field of electronic test equipment and electronic systems and, in particular, to a circuit design that provides an amplitude and temperature-insensitive signal-to-noise ratio for determining the performance of equipment such as radio receivers and the like.
2. Description of Related Art
Microwave thermal noise has long been employed for built-in test (BIT) of receivers and radiometers. Such systems are discussed in Microwave Journal article "Using Noise For RF Receivers Built In Test Applications" by Patrick Robbins, dated February, 2004. A common application using noise is to test the RF spectral gain/loss response of the front-end transmission line and microwave control components from the antenna through the RF receiver. The receiver then detects the noise signal, which, in theory, is flat over the frequency band. If the detector is swept over frequency, the system will have the spectral data of its front end.
If the noise source is used in conjunction with a received RF signal (either an over-the-air signal or an injected signal, wherein injected implies the signal is directly applied, for example, via a coaxial cable (or similar connection) or otherwise provided by the receiver itself) to create a known signal-to-noise ratio then it becomes important to closely control not only the level of the noise but also the level of the received signal. This becomes difficult as received signal levels fluctuate and the operating temperature of the system changes. A known signal-to-noise ratio produces a known performance level in the receiver.
Thus, it is a primary object of the invention to provide a circuit for generating a test signal to determine if an electronic communication system is working properly.
It is another primary object of the invention to provide a circuit for generating a test signal to determine if an electronic device is working properly by generating a controlled signal-to-noise ratio test signal.
It is a further object of the invention to provide a circuit for generating a test signal to determine if an electronic device is working properly by generating a controlled signal-to-noise ratio test signal that is independent of both the received signal amplitude and operating temperature.
It is a further object of the invention to provide a circuit for generating a test signal to determine if an electronic device is working properly by generating a controlled signal-to-noise ratio test signal that is independent of both the received signal amplitude and operating temperature wherein both the signal and noise are derived from the signal.

Controlled signal-to-noise ratio generator circuit


New process for the preparation of acetylenic macrocyclic ketones, which compounds represent useful intermediates for the synthesis of valuable perfuming ingredients, viz. muscone and EXALTONE.RTM. (cyclopentadecanone).

Among the most appreciated musky ingredients known in the art of perfumery, muscone (or 3-methyl-cyclopentadecanone) and EXALTONE.RTM. (or cyclopentadecanone) have acquired a special renown. In an attempt to develop a large scale preparation of these derivatives, hitherto numerous synthetic approaches have been devised [see e.g. Cosmetics and Perfumery, 88, 67(1973)]. In spite of this undertaking no economical synthetic process has been satisfactorily applied so far to their industrial preparation.
Among the variety of processes known, one may cite the following: ##STR3##
By making the preparation of certain critical intermediates easier, the novel process of the present invention provides an original solution to the problem of economically synthetizing macrocyclic ketones.

Process for the preparation of macrocyclic ketones


The disclosure discloses a reformer of a system for preparing hydrogen with an aqueous solution of methanol, a system for preparing hydrogen with an aqueous solution of methanol and a hydrogen production method. An end of a reformer of a system for preparing hydrogen with an aqueous solution of methanol has an initiation device, the initiation device includes a holder, the holder has a material input tube, a heating vaporization tube, an ignition device and a temperature detection device; the material input tube and the heating vaporization tube are communicated, the material enters the heating vaporization tube through the material input tube and is exported from an end of the heating vaporization tube; a position of the ignition device is corresponding to the end of the heating vaporization tube, the ignition device is applied to ignite the material exported from the heating vaporization tube.

Hydrogen is one of the most ideal energy sources in 21st century, hydrogen generates the most amount of energy under the circumstance of burning the same weight of coal, gasoline and hydrogen, and the product of combustion is water without ashes or emissions, which will not harm the environment; products of combustion after burning coal and petroleum are primarily CO2 and SO2, which cause the greenhouse effect and the acid rain respectively. Reserves of coal and petroleum are restricted, hydrogen is primarily reserved in water, and water is the only product of combustion, which can generate hydrogen continuously without limitation. Hydrogen is spread widely, water is the warehouse of hydrogen, with 11% hydrogen included. The soil contains 1.5% hydrogen; hydrogen can be found in petroleum, coal, natural gas, animals and plants. Hydrogen primarily exists in a form of water, and water covers 70% surface of the earth, which is considerable, therefore, hydrogen is a limitless resource. Hydrogen will be an inexpensive energy source if it can be produced by a proper method.
At present, an annual yield of hydrogen worldwide is around 36 thousand tons, hydrogen is primarily prepared by two methods: one is prepared by petroleum, coal and natural gas, which will consume limited mineral materials, and most hydrogen is generated by the manner; the other is prepared by the method of electrolysis of water, which consumes a great deal of electric energy and is not economic, around 4% hydrogen is produced by the method. The technology that prepares hydrogen with an aqueous solution of methanol is improved with the development of technique, which can reduce energy consumption and costs in chemical production, hopefully substituting the process of electrolysis of water generating hydrogen that requires a large amount of electric energy. Hybrid gases of H2 and CO2 are obtained by advanced reforming technology of producing hydrogen with an aqueous solution of methanol, H2 and CO2 can be separated by a palladium membrane separator.
Referring to Chinese patent application No. 201310340475.0 (applicant: SHANGHAI HEJI DEDONG HYDROGEN MACHINE CO LTD), an aqueous solution of methanol vapor undergo methanol decomposition and a reaction of carbon monoxide in a temperature of 350-409° C. and a pressure of 1-5 MPa with assistance of a catalyst, producing hydrogen and carbon oxide, which is a multi-componential, multi-reactional catalytic system with gases and solids. Reaction equations are as follows:CH3OH→CO+2H2  (1)H2O+CO→CO2+H2  (2)CH3OH+H2O→CO2+3H2  (3)
H2 and CO2 generated by the reforming reaction are separated by the palladium membrane separator of a separation chamber, highly purified hydrogen can be achieved.
The catalytic reaction of an aqueous solution of methanol occurs in the reformer of the device producing hydrogen with an aqueous solution of methanol, the reformer includes a reforming housing and a combustion chamber and a reforming chamber in the reforming housing, as well as an initiation device, generally, a temperature in the reforming chamber is 350-409° C., a temperature in the combustion chamber is 405-570° C., which make the reformer to run properly. Initiation of the reformer is triggered by the initiation device, in a conventional technique, it takes long to cold start, generally more than 5 hours, and warm start consumes a great deal of energy, keeping devices such as the reforming chamber in a high temperature.
Accordingly, the inventor applied a patent No. 201310578086.1 on Nov. 18, 2013 (applicant: SHANGHAI HEJI DEDONG HYDROGEN MACHINE CO LTD), the patent disclosed a system for preparing hydrogen with an aqueous solution of methanol that can be started rapidly and a method of preparing hydrogen thereof, the system for preparing hydrogen with an aqueous solution of methanol includes an initiation device, the initiation device includes a first initiation device and a second initiation device, the first initiation device includes a housing, a first heater, a first vaporization tube, the first vaporization tube twists the first heater tightly; the first heater can be an electric heating rod, powered by an alternating current, a rechargeable battery or a battery, the first heater heats the first vaporization tube to output vaporized methanol from the first vaporization tube; the second initiation device includes a second vaporization tube, vaporized methanol exported from the first vaporization tube is burned to heat the second vaporization tube, in order to vaporize methanol in the second vaporization tube, so that the second vaporization tube heats the reforming chamber for initiating the system of producing hydrogen.
However, the system for preparing hydrogen with an aqueous solution of methanol still has following shortcomings: vaporization of methanol in the first vaporization tube of the first initiation device needs to be heated by the first heater, and the heater is an electric heating rod, powered by an alternating current, a rechargeable battery or a battery, it takes shorter time to initiate the reformer by electric heating in a conventional technique, but not short enough, for vaporization or burning of an aqueous solution of methanol, the first vaporization tube generally needs to be heated up to more than 200° C. Moreover, it might be unsafe to be powered by the alternating current, a power bank such as a rechargeable battery or a battery is consumed rapidly, charging and replacing of which bring extra trouble. Moreover, the first vaporization tube twists the heater, which prevents all the heat generated by the heater being applied on the first vaporization tube, the first initiation device and the device preparing hydrogen (reformer) need to be disposed separately, which reduce heating efficiency of the first initiation device heating the second initiation device in the device preparing hydrogen (reformer).

Reformer of system preparing hydrogen with an aqueous solution of methanol, system preparing hydrogen with an aqueous solution of methanol, method of preparing hydrogen

GUANGDONG HYDROGEN ENERGY SCIENCE & TECHNOLOGY CO.


The invention relates to a process and to a unit for chemical looping oxidation-reduction combustion of a hydrocarbon feed, wherein heat exchanges are controlled through a level variation of a dense fluidized bed of active mass particles in an external heat exchanger (E1, E2), positioned on a transport line carrying particles circulating between a reduction zone (210) and an oxidation zone (200) for the particles in the chemical loop. The bed level variation is allowed through controlled application of a pressure drop on a fluidization gas outlet in the heat exchanger, said pressure drop being compensated by the level variation of an active mass particle bed in a reservoir zone provided on the particle circuit in the chemical loop.

In the text hereafter, what is referred to as chemical looping oxidation-reduction combustion (CLC) is an oxidation-reduction or redox looping process on an active mass. It can be noted that, in general, the terms oxidation and reduction are used in connection with the respectively oxidized or reduced state of the active mass. The oxidation reactor is the reactor where the redox mass is oxidized and the reduction reactor is the reactor where the redox mass is reduced. The reactors operate under fluidized bed conditions and the active mass circulates between the oxidation reactor and the reduction reactor. The circulating fluidized bed technology is used to enable continuous change of the active mass from the oxidized state thereof in the oxidation reactor to the reduced state thereof in the reduction reactor.
In a context of increasing world energy demand, capture of carbon dioxide (CO2) for sequestration thereof has become an imperative necessity in order to limit greenhouse gas emissions harmful to the environment. The CLC process allows to produce energy from hydrocarbon-containing fuels while facilitating capture of the CO2 emitted during the combustion.
The CLC process consists in using redox reactions of an active mass, typically a metal oxide, for splitting the combustion reaction into two successive reactions. A first oxidation reaction of the active mass, with air or an oxidizing gas, allows the active mass to be oxidized.
A second reduction reaction of the active mass thus oxidized, using a reducing gas, then allows to obtain a reusable active mass and a gas mixture essentially comprising CO2 and water, or even syngas containing hydrogen and carbon monoxide. This technique thus enables to isolate the CO2 or the syngas in a gas mixture practically free of oxygen and nitrogen.
Chemical looping combustion enables to produce energy from this process, in form of vapour or electricity for example. The feed combustion heat is similar to the heat encountered in conventional combustion. It corresponds to the sum of the reduction and oxidation heats in the chemical loop. The heat is generally extracted through exchangers arranged within or on the wall of, or inserted in the combustion and/or oxidation enclosures, on the fumes lines, or on the metal oxide transfer lines.
In addition to the advantage of recovering the combustion heat to produce energy, it is important to be able to control the temperature in a CLC process. Indeed, the temperature of the reactions in the oxidation and reduction zones needs to be controlled for safety reasons and in order to guarantee good performances of the process. This heat recovery for controlling the process heat is preferably achieved by heat exchange with the active mass circulating in the loop.
This heat recovery can be achieved at the walls of the redox reactors in a CLC process. However, this configuration may not be optimal, notably because the thermal exchanges are limited due to an exchange surface limited to the walls, and because only part of the particles is in contact with this exchange surface, but also because it is not always possible to modify the flow rate of the oxygen-carrying solid in these reactions zones for the sole purpose of heat exchange control. Indeed, the oxygen-carrying solid flow is directly related to the amount of oxygen used for combustion, and any change in the flow rate of the oxygen-carrying solid has an impact on the progress of the reactions, which may for example cause fuel management and/or reaction stoichiometry problems, and eventually affect the process yield.
Using heat exchangers outside the combustion and/or oxidation enclosures may be considered.
In general terms, such fluidized bed heat exchange devices are known in some fields such as circulating fluidized bed thermal power plants, and they are identified as fluidized bed heat exchangers (FBHE) or external heat exchangers (EHE). They generally come in form of a vessel comprising an inlet for a solid in form of particles, a fluidization device using a gas, a gas outlet and a solid outlet (Q. Wang et al., Chemical Engineering and Processing 42 (2003), 327-335).
To achieve heat exchange, tube bundles are conventionally provided in the fluidized bed so as to generate an exchange surface between the fluidized bed and a heat-carrying fluid circulating in the tubes. Conventionally, in the field of energy, in particular in thermal power plants, the heat-carrying fluid is pressurized boiler water that is either heated or at least partly vaporized, or overheated in the tube bundles of the heat exchanger. These exchangers generally operate with an overflow mechanism for discharge of the solid, as illustrated for example in patent U.S. Pat. No. 4,716,856 or by Wang et al. (Chemical Engineering and Processing 42, 2003, pp. 327-335). Using an overflow pipe implies that the volume of the fluidized bed is constant and therefore that the exchange surface with the fluidized bed is constant. This makes it impossible to modulate the heat recovery through a variation of this surface and requires modulating the operating parameters such as, for example, the flow of solid passing through the exchange zone.
A solid flow control device such as a mechanical valve, as described in patent EP-0,090,641 A2, can then be used. One drawback of this option is the use of a mechanical device for controlling the flow of solid. This type of device is particularly limitative in processes operating at high temperatures, such as a CLC process, and it can lead to reliability problems inherent in the implementation of a mechanical device comprising mobile parts in a bed of fluidized particles abrasive at high temperatures.
In order to regulate the flow of solids, it is possible to use nonmechanical valves such as the pneumatic valves described in patent application WO-2011/007,055, used to control the circulation of the solid active mass particles in a CLC process. This type of pneumatic valve allows to tackle the problem of temperature and abrasion. However, the smooth operation of these pneumatic valves is limited to the use of certain particle classes, namely the particles of group B in Geldart's classification.
FIG. 1 (extracted from K. Shakourzadeh, Techniques de fluidisation, réf. J3390, Techniques de l'Ingénieur, p. 10) illustrates a particular system allowing to modify the flow of solid passing through an external fluidized bed heat exchanger operating with an overflow pipe, optionally with a valve on the solid stream entering the exchanger. This system is installed in a conventional circulating bed coal (air) combustion unit comprising a combustion reactor 10 from which a gas mixture containing the combustion gases and solid particles is sent to a cyclone 20. An external heat exchanger 50 equipped with an overflow pipe is arranged between cyclone 20 and reactor 10. According to this system, only part of the solid stream recovered in the bottom of cyclone 20 is sent through a pipe 40 to heat exchanger 50 prior to returning to reactor 10, the other part of the solid stream being sent back through the agency of a siphon/return leg assembly 30 to reactor 10. A valve is generally provided on pipe 40. Heat exchange is thus controlled by modifying the solid flow passing through exchanger 50. This configuration, consisting in a solid flow by-pass, complexifies the architecture of the unit and the process in which it is implemented, all the more so as it involves using a valve on the circuit of the solid so as to orient it towards the by-pass.
Generally, solutions consisting in modulating the flow of solid by means of a valve in order to modify the heat flux can affect the proper operation of the process and/or limit the operation thereof. For example, if it is desired to limit or even to cancel the exchange between the solid and the heat-carrying fluid, either the flow of solid needs to be limited or stopped, which can lead to the slowdown or standstill of the unit, or the circulation of the heat carrier has to be limited or stopped, which may damage the tube bundles of the heat exchanger.
There is thus a need for an improved CLC process wherein heat exchanges with the circulating oxygen carrier can occur within an external exchanger without using a valve on the solid flow for modifying the amount of exchanged heat. This need is all the more markedly felt as the temperature of the circulating fluidized bed of a CLC process can be substantially higher than with a conventional circulating fluidized bed (CFB) combustion process, depending on the nature of the oxygen carrier and on the feed treated, which makes it difficult to install a mechanical valve.

Process and apparatus for chemical looping redox combustion with control of the heat exchanges


A method to prevent movable structures within a MEMS device, and more specifically, in recesses having one or more dimension in the micrometer range or smaller (i.e., smaller than about 10 microns) from being inadvertently bonded to non-moving structures during a bonding process. The method includes surface preparation of silicon both structurally and chemically to aid in preventing moving structures from bonding to adjacent surfaces during bonding, including during high force, high temperature fusion bonding.

This invention relates in general to valves and to semiconductor electromechanical devices, and in particular, to micromachined components formed from wafers of a semiconductor material, such as silicon, bonded together.
MEMS (micro electro mechanical systems) are a class of systems that are physically small, having features or clearances with sizes in the micrometer range or smaller (i.e., smaller than about 10 microns; as is well known, "micron" is another term for micrometer, a unit of length equal to 0.001 millimeter). These systems have both electrical and mechanical components. The term "micro machining" is commonly understood to mean the production of three-dimensional structures and moving parts of MEMS devices. MEMS originally used modified integrated circuit (e.g., computer chip) fabrication techniques (such as chemical etching) and materials (such as silicon semiconductor material) to micro machine these very small mechanical devices. Today there are many more micro machining techniques and materials available. The term "MEMS device" as may be used in this application means a device that includes a micro machined component having features or clearances with sizes in the micrometer range, or smaller (i.e., smaller than about 10 microns). It should be noted that if components other than the micro machined component are included in the MEMS device, these other components may be micro machined components or standard sized (i.e., larger) components. Similarly, the term "microvalve" as may be used in this application means a valve having features or clearances with sizes in the micrometer range, or smaller (i.e., smaller than about 10 microns) and thus by definition is at least partially formed by micro machining. The term "microvalve device" as may be used in this application means a device that includes a microvalve, and that may include other components. It should be noted that if components other than a microvalve are included in the microvalve device, these other components may be micro machined components or standard sized (i.e., larger) components.
Many MEMS devices may be made of multiple wafers (or plates) of material, which may be micromachined to form components of the MEMS device prior to assembly of the multiple wafers into a completed MEMS device. For example, such a MEMS device may be manufactured using suitable MEMS fabrication techniques, such as the fabrication techniques disclosed in U.S. Pat. No. 6,761,420, the disclosures of which are incorporated herein by reference; U.S. Pat. No. 7,367,359, the disclosures of which are incorporated herein by reference; Klassen, E. H. et al. (1995), "Silicon Fusion Bonding and Deep Reactive Ion Etching: A New Technology for Miscrostructures," Proc. Transducers 95 Stockholm Sweden pp. 556-559, the disclosures of which are incorporated herein by reference; and Petersen, K. E. et al. (June 1991), "Surface Micromachined Structures Fabricated with Silicon Fusion Bonding," Proc. Transducers 91 pp. 397-399, the disclosures of which are incorporated herein by reference.

Process and structure for high temperature selective fusion bonding


This invention relates to improvements in so-called "virtual reality" computer systems. The display system described enables the effective integration of computer generated images and real, naturally occurring images in the visual display units which provide the user with his entire visual stimulation. Areas of the user's notional field of view where computer-generated imagery is required (for example the cockpit canopy in an aircraft flight simulator) are coloured with a predetermined colour or intensity. Two video cameras are provided, each of which is mounted so that its field of view corresponds to a respective one of the notional fields of view of the user's eyes. The signals from the video cameras are analysed to determine the presence of the predetermined colour or intensity, thereby giving an indication that a computer generated image is required for that part of the video camera's field of view. If the predetermined colour or intensity is not present, the signal from the video camera is relayed directly to the appropriate one of the visual display units.

Recent developments in computer technology have enabled so-called "virtual reality" computer systems to be produced. These systems provide complete visual stimulation for the user usually by means of a helmet mounted display apparatus comprising a pair of miniature Visual Display Units (VDUs) arranged to project their images into respective ones of the user's eyes such that the image displayed is perceived stereoscopically thereby creating the illusion that the image is three-dimensional. These systems allow the user to interact with the displayed image by providing a means of monitoring movement of the user's head and, in some examples, movement of his eyes and other parts of his body. The information obtained by monitoring these movements allows the system to generate and present different images to the respective eyes of the user corresponding to changes in his line of sight. An example of such a system is given in British patent no. 2201069.
Current virtual reality systems present the user with a graphics display which is entirely computer generated. The computer graphics system generates the complete visual image for each of the VDUs in the helmet mounted display. In many applications highly complex images need to be generated which, combined with the necessity to have them produced in real time, makes very heavy demands on computing power in terms of memory size and speed of access. One particularly notable problem is that of realistically representing the user's hands, legs and feet whenever the user's current line of sight would include those parts of his body. The result is that the systems are extremely expensive or they provide simpler images than are desirable for optimum realism.
Attempts have been made to overcome the need for high computing power by laying the computer generated image over the real image of a scene by using an optical combiner to combine the two images. Although these systems are less demanding in terms of what is required of the computer generated images because the images may then occupy a smaller area, the system now must determine which part of the scene viewed by the user the computer generated image should occupy as his line of sight changes as a result of eye and head movements. Current head position sensors are limited in terms of positional accuracy, and, when used with such visually coupled systems, any errors in the calculation of head position cause the computer generated image to move relatively and unrealistically within the real scene. Under certain circumstances this image motion can be extremely objectionable and may even cause nausea.

Integrated real and virtual environment display system


A printer providing time coded heating energy applications to printhead resistors to provide variable volmetric densities. Variable densities can also be provided through integrating dithering with the varying of volumetric densities. The printer can provide either one of two kinds of printing technologies by selection.

The present invention relates to computer controlled printers and, more particularly, to such printers printing colored materials on the recording sheets to provide a color image.
The use of personal computers and, correspondingly, desk top printers controlled in part by such computers has increased very rapidly over the last several years. Many different printing technologies have been developed for these devices beyond that used in the impact printers initially performing in this role, including ink jet, thermal wax transfer and thermal diffusion, or dye sublimation, printing technologies.
These last technologies have been especially important in the growth of color printers, those having the capability of providing a colored image on a recording medium. The order of listing of these printing technologies above is typically the order of the quality of the results obtained in using them with ink jet technology generally providing the poorest quality of these technologies, and thermal diffusion giving the best. Unfortunately, the order of listing is also the order of cost with ink jet printers generally being cheapest and thermal diffusion printers being the costliest.
The desire for high quality in images recorded by such printers has led to those printers having often provided therein substantial computing capabilities in their own right to permit close control of electrical currents through the resistors in the thermal printhead which, in each supplying heat to the coloring material source to direct material therefrom onto the recording sheet, leads to each effectively providing a corresponding a color constituent of a pixel, on that sheet. In addition, extensive mechanical systems with expensive components such as high speed and high precision stepper motors, are usually used in such printers.
One possibility for reducing the cost of such printers is to have a significant fraction of the computing done by a computer controlling such a printer, as the capabilities of such computers have also grown substantially to permit such processing of printing data without too severely retarding the performance of the controlling computer in accomplishing its other purposes. However, the results of such computations in the controlling computer must be transmitted to the printer over the connecting cable which can take a relatively long time if the computer must be capable of transmitting for each printhead resistor any of all the possible intensities to be followed by that resistor, or any of all the possible patterns of intensities to be followed by groups of those resistors.
Another possibility to reduce cost is to always use the cheapest printing technology which will provide the needed quality in the resulting printed images. However, if quality needs differ from one printing task to another, purchase of sufficient different printers to provide the different printing technologies necessary will be expensive. Thus, there is a desire for less expensive color printers which do not lead to inordinately slow printing, or yield too poor a quality printing result, because of measures taken to reduce costs.


The invention refers to a method for the reduction of the sag and/or of the different stress profile of a flattened tubular film web produced by a blown film process and made of thermo-plastic synthetic resin, transversely to its longitudinal direction. For the solution of the problem to provide a method according to which the sag and/or the different states of tension transversely to the tubular film web can be easily reduced or eliminated to a maximum degree, the tubular film web is heated along its width and then cooled and/or stretched. Furthermore, the invention refers to an apparatus for carrying out the method.

1. Field of the Invention
This invention refers to a method for the reduction of the sag and/or of the varying stress profile of a flattened tubular film web produced by a blown film process and made of thermo-plastic synthetic resin, transversely to its longitudinal direction.
2. Description of Prior Art
During their production, after the inflation to form a tubular film bubble, tubular films are drawn thereoff by a pair of pinch rolls which are preceded by flattening plates extending wedge-shaped to each other, which converge in direction towards the roll gap of the pair of pinch rolls. A result of this kind of flattening of the tubular film web drawn off from the tubular film bubble is that the laterally folded edge sections of the tubular film web directly pass into the roll gap of the pair of pinch rolls, whereas the web portions lying between the folded edge sections of the web slide over the inner sides of the flattening plates with an unavoidable friction and, starting from opposite sleeve lines of the film web, are progressively pressed in a flat form in which then the wall parts of the web, lying flat on top of each other, pass through the draw-off roll gap. The result of this kind of flattening of the tubular film web drawn off the tubular film bubble is that in the flat state the center parts of the web portions lying one on top of the other have been stretched in a longitudinal direction to a larger degree than the folded edge sections which without a previous sliding on the flattening plates have directly passed into the roll gap of the pair of draw-off rolls. By said different stretching of the web portions of the tubular film web, lying on top of each other, with respect to the edge section the web has a certain sag in its center section, which becomes visible when the flattened web is observed which is loosely supported in a horizontal plane. The sag can also be observed when the flattened tubular film web is separated along its width into longitudinal strips of identical width, and weights of identical size are hanged onto the individual longitudinal strips. Due to the different lengths of the web sections, the weights then show the form of a curved line.
Due to this different stretching of the tubular film web along its cross-section during its production, different tensions in the web are obtained transversely to its longitudinal direction.
If such a tubular film web were e.g. to be cut along its center line, the two half tubular webs would be deflected to the outside, since the tension at the outside is larger than the one in the center section, due to which the half tubular webs would show a curved form. Such curvings of webs, however, are undesirable with a view to the further processing. If such webs were to be printed in printing machines, decisive difficulties would arise, since the register and the corner mark (format lengths) could not be exactly met.

Method and apparatus for the reduction of the sag and/or of the varying stress profile of a flattened tubular film web produced by a blown film process


A composite comprising at least one diamond/polymer brush and a method of making the composite comprising covalently bonding at least one polymer to said diamond surface.

Polymer brush composites comprising polymers bonded to solid substrates are known in the prior art as evidenced by the disclosures in U.S. Pat. Nos. 6,833,276; 6,780,492 and 6,423,465.
Interest in developing carbon nanostructures appropriately surface-derivatized for diverse applications remains high. Considerable progress has been made in controlling the dispersibility and wettability properties of single-walled (SWNTs) or multi-walled (MWNTs) carbon nanotubes through either covalent or non-covalent surface derivatization. [Sinani et al, J. Am. Chern. Soc. 2005, 127, 3463; Zhao et al, J. Am. Chern. Soc. 2005, 127, 8197; Niyogi et al, Ace. Chern. Res. 2002, 35, 1105].
Most recently, radical initiator functional groups appropriate for effecting in situ atom-transfer-radical-polymerization (ATRP) have been grafted to surface sites on SWNTs or MWNTs to form SWNT/poly(n-butyl methacrylate), SWNT/poly(acrylic acid), SWNT/poly(methyl methacrylate), SWNT/poly(tert-butyl acrylate), SWNT/poly(acrylic acid), MWNT/poly(methyl methacrylate), and MWNT/poly(methyl methacrylate)x(hydroxyethyl methacrylate)y as polymer brushes having either hydrophobic or hydrophilic surfaces [Qin et al, J. Am. Chern. Soc. 2004, 126, 170; Qin et al, Macromolecules 2004, 37, 752; Kong et al, J. Am. Chem. Soc. 2004, 126, 412; Yao et al, J. Am. Chem. Soc. 2003, 125, 16015].
ATRP methods have also been used to extend polymer chains within carbon nanotube/polymer brushes [Baskaran et al, Angew. Chem., Int. Ed. Engl. 2004, 43, 2138; Kong et al, J. Mater. Chem. 2004, 14, 1401].
Graphitic carbon nanofibers (GCNFs) represent a class of nanostructured carbon fibers having atomic structures uniquely different from that of carbon nanotubes [Rodriguez et al, Langmuir 1995, 11, 3862; Mowles, E. D. Surface Functionalization of VGCNFs with Pendant Amino Groups, M. S. thesis, Vanderbilt University 2001]. Herringbone GCNFs possess canted graphene sheets (also described as geodesic-like conical graphene sheets) stacked in a nested fashion along the long fiber axis. GCNFs of this type can be prepared having average diameters from 25 nm-200 nm and lengths on the micron scale. The graphitic atomic structure of herringbone GCNFs gives a carbon nanofiber long-axis surface comprised of C(sp2) edge sites, usually passivated by hydrogen atoms.
The surface-functionalization of herringbone GCNFs with reactive linker molecules using surface oxidation and carboxyl group coupling chemistry occurs without degradation of the structural integrity of the GCNF backbone and affords surface-derivatized GCNFs having a high surface density of functional groups [Zhong et al, Polym. Compos. 2005, 26, 128]. Covalent binding of such linker molecules to either polymer resins or ceramic condensation oligomers gives GCNF/polymer or GCNF/ceramer hybrid materials [Zhong et al, Polym. Compos. 2005, 26, 128; Li et al, Compos. Interfaces 2004, 11,525; Xu et al, J. Compos. Mater. 2004, 38, 1563].
Novel graphitic carbon nanofiber (GCNF)/polymer brushes and a novel method for their synthesis are disclosed in provisional application U.S. Ser. No. 60/861,252.
It is an object of the invention to provide novel diamond/polymer hybrid composites or brushes as well as methods for their synthesis.


A rotary article storage and outfeed apparatus stores a plurality of groups of generally flat articles in a facewise stacked condition and delivers a supply of these articles to an infeed for a device wherein the articles are to be utilized. The apparatus comprises an upper rotary carousel rotatable about an upper axis and a lower rotary carousel located below the upper carousel and rotatable about a lower axis parallel to and offset from the upper axis. Each of the carousels has a plurality of circumferentially spaced vertically oriented pockets, each pocket being dimensioned for receiving a group of articles in a facewise stacked condition. A frame mounts the upper and lower carousels so that an upper end of the pockets of the lower carousel is spaced below a lower end of the pockets of the upper carousel, and so that the lower and upper axes are offset in such a way that one of the pockets of the lower carousel coaxially aligns with one of the pockets of the upper carousel at one position in the respective rotations thereof to define an article transfer position. An article transfer device is provided for transferring a group of articles between the pockets of the respective carousels which are aligned and located in the transfer position.

This invention relates generally to article storage and feeding apparatus for providing a supply of articles to article utilization equipment, and more particularly to a novel and improved rotary article storage and outfeed apparatus for storing a supply of articles such as collapsed or folded cartons or carton blanks and feeding the articles on demand to utilization equipment.
Modern consumer products processing and filling equipment operates at relatively high rates of speed to attain economical production costs in the filling process. In order to maintain these relatively high speeds, the filling equipment must be provided with a reliable and continuous supply of cartons or packages to be filled. Specialized equipment sometimes called feeding or infeeding equipment has been devised to meet this need.
One particularly successful type of infeed device is a so-called carousel-type feeder, such as those described and claimed for use with can ends in U.S. Pat. Nos. 3,722,741 and 4,000,709. A similar carousel-type feeder for carton blanks is also described in U.S. Pat. No. 4,592,462. All of the above-noted U.S. Patents are commonly owned herewith.
Similar requirements and problems are encountered in processing relatively flat, thin articles such as collapsed or folded cartons or carton blanks or so-called out-serts, which are generally folded printed materials such as instructions, coupons, advertising materials or the like which are packaged with products, often on the exterior of the packaging, to be held by shrink wrap or the like. Hence, the name out-serts, rather than the more familiar inserts which would be physically inserted within the package or other container. The equipment of the above-referenced patents, as well as the present invention, can also be adapted to handle a wide variety of stackable products or parts, such as metal, plastic or paperboard lids, tubs, stampings or box flats.
The use of such carousel feed units with carton blanks or out-serts require somewhat more careful handling than in the case of metal parts such as can ends. For example, it is important to avoid damage, bending or fraying of the edges of these paper or cardboard products. The handling often involves transfer from an outfeed or supply pocket or chamber of the carousel feeding apparatus to a receiving pocket or chamber or other intake device of a supply means for subsequent processing equipment.
In U.S. Pat. No. 5,096,371, which is commonly owned herewith, there is described a device for delivering stacked carton blanks or the like from an outfeed or supply pocket of a carousel feeding device to an elevated intake of a product filling lane. In this regard, the intake or infeed apparatus of the product filling line is located at a higher vertical level than the carousel feeding device.
While the use of the carousel feeding device and transfer for carton feeding apparatus of the above-mentioned '371 patent has proven highly successful in operation, some generally lower volume or lower speed applications exist which do not require the high capacity of operation and overall size of this equipment. In this regard, a typical carousel feeding apparatus of this type (i.e., as in U.S. Pat. No. 4,592,462) may employ twenty or more supply pockets to be filled with articles such as can ends or carton blanks. In some applications, this amount of accumulation and the attendant expense of a machine of this size are not necessary.
Accordingly, the present invention provides a smaller capacity and overall smaller size of carton feeding and transfer apparatus for storing a supply of articles such as carton blanks at a level easily accessible by an operator from floor level and for feeding these carton blanks upwardly to a vertical level above the supply and outfeeding the cartons from this higher level to an infeed or input for utilization equipment. With the smaller size of the present invention an operator can both operate the equipment and continue to supply the carton blanks or other articles to a storage portion of the device from a single operator station. Moreover, two or more apparatuses in accordance with the invention may be placed in relatively close proximity, such that a single operator can monitor the operation and provide an ongoing supply of articles to these two or more units. It should be recognized that the much larger overall size of the rotary feeder device as described for example in the above-referenced '741, '709 and '462 patents, is such that an operator is generally only able to operate and resupply articles to a single one of devices of this type. Thus, with the apparatus of the invention, only one operator may in fact be required to supply several packaging lines with carton blanks, out-serts or similar articles.

Rotary article storage and outfeed apparatus


The invention relates to a solar concentrator comprising a solid body consisting of a transparent material that has a light coupling surface and a light decoupling surface, the solid body having a light guide part that tapers towards the light decoupling surface, being located between the light coupling surface and the light decoupling surface and being delimited by a light guide surface between the light coupling surface and the light decoupling surface, the light guide surface merging into the light decoupling surface with a constant first derivation. The invention also relates to a method for the production of a solar concentrator, wherein the transparent material is precision-molded between the molds.

FIG. 1 shows a known solar concentrator 101 which is depicted in FIG. 2 by way of a cross-sectional representation. The solar concentrator 101 comprises a light entry face 102 and a ground light exit face 103 as well as a light guide portion 104 arranged between the light entry face 102 and the light exit face 103 and tapering in the direction of the light exit face 103. Reference numeral 105 denotes a light guide portion surface which restricts the light guide portion 104 between the light entry face 102 and the light exit face 103.
Document EP 1 396 035 B1 discloses a solar concentrator module comprising, on its frontal side, a front lens and, on its rear side, a receiver cell, and, between the front lens and the receiver cell, a reflector which has inclined side walls along two opposing sides of the receiver cell, and, in the center of the module, a flat vertical reflector.
It is an object of the invention to reduce the costs for manufacturing solar concentrators. It is a further object of the invention to produce solar concentrators of a particularly high quality within a restricted budget.

Solar concentrator and production method thereof


A method for identifying T-cell epitopes which can be used to elicit T cells targeting cells capable of regenerating cancers is disclosed. The method identifies T-cell epitopes with a high curative potential, high potency and high probability of T cell recognition (HP). The method includes: (i) identifying high curative potential tumor protein target i.e., identifying HP-TP; (ii) identifying peptide sequences within the protein sequence of an HP-TP that have a high probability of eliciting T cell killing; and (iii) qualifying the sequence specificity based on the fold difference between the specific target and non-targets. The identified T-cell epitopes include a core sequence of 9 amino acids homologous to a sequence expressed within a qualified HP-TP. The T-cell epitopes can be used in a method for reprogramming T cells to selectively attack tumor cells capable of perpetuating a tumor and treating patients, for example, cancer patients.

Targeted antibody technologies have advanced the treatment of cancer. For example, cancer immunotherapies involving antibody-drug targets have improved targeted cancer cell killing. Cancer vaccines used to engender a targeted T cell response have met with more limited success. In all cases, the therapies are rarely curative. At least some of the modest efficacy can be attributed to lack of highly effective targets.
Adoptive Cell Transfer (ACT) is one of the most potent approaches to cancer immunotherapy due to its direct enhancement of T cell killing. Recently, the curative potential of ACT has been demonstrated clinically in leukemia and melanoma. Tumor infiltrating lymphocytes (TIL) (a source of tumor-reactive T cells) have been harvested for ACT, expanded and transferred back to patients to increase the number of tumor-reactive T cells. The antigens TIL recognize are unidentified, but presumed to be tumor related. This approach has achieved durable regression in some patients (about 20% of patients on average), but not in the majority of those treated. The TIL repertoire can be refined by selectively expanding a T cell population using one or more antigens to stimulate specific sub-populations of T cells before transfer.
Ideally, a cancer therapy should eliminate a cancer's regeneration-capable cells (C-RC) to achieve the best possibility for durable regression. The use of ACT is severely limited for most solid cancers because of the inability to direct enhanced T cell killing to biologically-relevant tumor markers, i.e., proteins essential to the recurrence of the cancer. These proteins enable the cancer cells to survive and regenerate the cancer. ACT that targets a tumor's C-RC is particularly needed in cancers of vital organs, where complete ablation of a normal, functionally critical cell type is not feasible. ACT is also one of the most promising options for the treatment of late-stage metastatic cancers but most likely only if high probability, high potency, high specificity T-cell antigens can be identified within proteins essential to regenerative capacity. While the use if TIL increases the opportunity for relevant tumor reactivity, its ultimate effectiveness is limited by lack of peptide antigens (Ag) with high curative potential, high potency and high probability (collectively denoted as "HP") of T cell recognition (HP-Ag).
Tumor-reactive TIL may be used to discover antigenic tumor protein targets. However, this is laborious and the TIL approach to target discovery has several drawbacks that limit the discovery of HP-Ag. Methods that rely on a patients' immune response to identify T cell epitopes can be highly individualized and can miss many potentially valuable antigens. In many patients the immune system has gone through countless refinements and insults leading to a skewed, less than optimal and often ineffective response. Inherent selection of antigen by an individual's immune system is a major drawback to the development of HP ACT (HP-ACT) because of its bias towards certain antigens that may be naturally dominant but not useful for killing the C-RC.
The presence of reactive TILs in patients that have advanced cancer indicates that mere T cell recognition within the tumor is not enough. Aside from supporting the immune response with T cell checkpoint blockade or the use of interleukins, there must be an adequate number of T cells within the tumor or in the circulation. While this is something that ACT can achieve, for it to be an HP-ACT therapy, at least some of these T cells must respond to at least one peptide antigen that is pivotal to the C-RC phenotype.
The fact that targeting a pivotal protein essential for perpetuation of the cancer is the way to achieve a reliable, durable response in solid tumors has gone unrecognized. The lead author of a recent detailed genomic analysis on the "non-Darwinian evolution" of a tumor's mutational landscape concluded that a cancer should be nearly impossible to eliminate with a single target due to extremely high genetic diversity (Ling et al., Proc Nat Acad Sci USA., 112(47):E6496 (2015)). However what has gone unappreciated is that, while this is true for most mutations, it will not be true for proteins essential to regeneration of the cancer, i.e., those pivotal to the C-RC. Irrespective of the complex and differing mutational landscape in each individual, there are proteins pivotal to perpetuation and the C-RC that are likely to be shared by genetic subtypes of cancer. If one can target those pivotal proteins involved in key pathways that are needed for the type of cancer to persist and use it an effective modality like ACT, then it creates the opportunity to eliminate the cancer using a single or a minimal number of targets. There are additional practical advantages to targeting a protein responsible for a key oncogenic pathway: it means that expression of the protein is more likely to be one that persists as the tumor progresses and metastasizes. This is evidenced in the expression of at least two HP-TP proteins (AKAP4 and TMPRSS2-ERG) described herein, In addition, if the C-RC driver is lost due to mutation, the likelihood is that those cancer cells will have evolved into something less lethal, if they survive at all. Using ACT as the modality targeted to the C-RC will eliminate the cancer before it has an opportunity to develop resistant/alternative clones as seen in response to targeted drugs or immune therapies that leave the C-RC behind. Therefore the combination of a C-RC target and the modality deliver the therapy's high curative potential. Methods used to discover epitopes as presented in antigen presenting cells (APC), such as dendritic cells, fail to fully consider the connective steps required to move an immune response from APC and antigen digest to presentation and activation of effector T cells. In many patients these steps are flooded with irregularities from previous treatments and immune regulators leading to a lower probability of epitope effectiveness. These methods do not evaluate the value of the protein associated with the target up front leading to a large amount of work for data that may be of low curative value. Solely genomic methodologies do not necessarily capture the exome and may be limited by pre- and post-transcriptional regulation, making epitope evaluation of little translatable value without substantial further investigation. Strictly screening stem cell exomes, either genomic or proteomic, limits targets to normal developmental or proliferative antigens and may miss mutation-, translocation-derived or novel expressed antigens, Moreover, most proliferative or metabolic antigens are likely conserved and in use in normal tissue turnover.
Genomic screens with limited additional expression patterning analysis can lead to simple overexpression candidates. This is exemplified by the studies of Ochsenreither, et al. (Ochsenreither, et al. Blood 119(23):5492-5501 (2012)) where, after a large effort, Cyclin-A1 presented as a viable target, yet, the normal expression pattern of Cyclin-A1 makes it a poor target, highly susceptible to off-target responses or possibly normal immune regulatory diminution of the response. Multiplatform analyses based on primarily genomic (Hoadley, et al. Cell 158(4):929-944 (2014)) data have been performed with relatively predictable results uncovering genetic mutations and amplifications clustered in well-known pathways such as p53 and PI3kinase within the subtypes these categorize. There remains a need for methods for identifying T cell epitopes that target cells capable of regenerating cancers, and hence have curative potential.
It is therefore an object of the present invention to provide a method for identifying T-cell epitopes which target cells capable of regenerating cancers.
It is also an object of the present invention to provide epitopes with a high curative potential, high potency and high probability of T cell recognition.
It is still an object of the present invention to provide methods and systems for programming T cells to selectively attack important tumor cells involved in proliferation, or invasion in an individual.

Identification, selection and use of high curative potential T cell epitopes


The present invention relates to a connector lock for locking a first electrical connector to a second electrical connector. The connector lock comprises a first mounting bracket adapted to mount to the first electrical connector and a second mounting bracket adapted to mount to the second electrical connector. The second mounting bracket is pivotally displaceable with respect to the first mounting bracket such that the second mounting bracket can be pivoted relative to the first mounting bracket to align mating portions of the first and second electrical connectors.

Mechanical fastening devices are needed to ensure positive connection between mating connectors to avoid accidental decoupling and loss of electrical connection. Several mechanical devices have been developed for locking connectors together. In one common example, threaded fasteners such as screws are provided on both ends of a free plug. These fasteners are adapted to be received by threaded apertures provided in the mating connector, typically a chassis mounted receptacle. Although simple in design and generally effective in locking the two connectors together, auxiliary locking means are necessary when the plug comprises an end fed connector. The reason for this is because the cable to which the end fed connector is attached occupies the space in which a threaded fastener would be used to secure the cable end of the connector to the chassis mounted receptacle. Accordingly, when locking an end fed connector to such a receptacle, the free end of the connector normally is secured to the receptacle with a threaded fastener while the cable end of the connector normally is secured in place with a cable tie. Although such an arrangement is effective once in place, the locking process can be difficult. In particular, the tightly packed arrangement in which such end fed connectors are used makes it difficult for the operator to secure the cable tie in place. Moreover, often times additional mounting hardware is needed if such cable ties are to be used. Another disadvantage is that, once the connector plug is locked in place with the threaded fastener and the cable tie, the plug can only be removed by severing the cable tie. Hence, a new cable tie must be used if the connector plug is to be again locked to the chassis mounted receptacle.
In other designs, plugs are secured to mating chassis mounted receptacles with bailing clips. Such bailing clips typically take the form of metal wires that are adapted to wrap around a boss or mating bailing clip provided on the chassis mounted receptacle. Although effective, these bailing clips normally occupy precious chassis space that could be better utilized. In addition, since the bailing clips provided on the plug often are designed to mate with a specific type of boss or other bailing clip, it frequently is necessary for the user to purchase both the plug and receptacle from the same manufacturer, thereby limiting purchase options.
In yet another design, the plug and the chassis mounted receptacle each is provided with specially designed locking tabs. Due to cost and spatial constraints, these locking tabs tend to be slight in design and therefore not capable of providing secure locking between the plug and the chassis mounted receptacle. In addition, like some of the bailing clip systems currently available, both the plug and the chassis mounted receptacle usually must be purchased from the same manufacturer if such locking tabs are used.
From the above, it can be appreciated that it would be desirable to have a connector lock that is simple in both design and operation that securely locks two connectors of any manufacturer such as a plug and a chassis mounted receptacle together.


The invention comprises a rocker switch which includes a rocker member having an actuating surface, a bottom surface, and a pivot member. A circuit board has a dome switch mounted thereon. A bracket is secured to the circuit board having a pivot guide to receive the pivot member. A elastomeric member is received between the bottom surface of the rocker member and the dome switch. Actuation of the rocker member presses the bottom surface of the rocker member against the elastomeric member which presses against the dome switch thereby activating the switch.

Membrane switches are well known as a method to activate switches in consumer products. These switches are typically either of the electromechanical type of switch or the elastomeric membrane switch. U.S. Pat. No. 5,147,990 shows the use of a slide switch to activate the elastomeric membrane switch. A slide switch activates a cantilevered beam which is pressed onto an elastomeric keypad. A conductive pad on the elastomeric keypad is then pushed into contact with traces on the keypad.
U.S. Pat. No. 4,401,864 shows a rocker switch that is used to activate electromechanical switches mounted on a substrate. The switch has a return member which returns the switch to a neutral position so that it is ready for the next switching operation.
When a rocker switch is used on a piece of outdoor equipment, such as a snowmobile, it is necessary to build a rocker switch that provides greater tactile feel. When the equipment is in operation, it is necessary to provide a switch in which the operator can feel that he has activated the switch. This feel must be detectable through equipment vibration and also through layers of clothing. It is also necessary to protect the underlying switches from damage due to excess force and from damage due to ice build up.


A computer-implemented method of performing image reconstruction with sequential cycle-spinning includes a computer system acquiring an input signal comprising k-space data using a magnetic resonance imaging (MRI) device and initializing an estimate of a sparse signal associated with the input signal. The computer system selects one or more orthogonal wavelet transforms corresponding to a wavelet family and performs an iterative reconstruction process to update the estimate of the sparse signal over a plurality of iterations. During each iteration, one or more orthogonal wavelet transforms are applied to the estimate of the sparse signal to yield one or more orthogonal domain signals, the estimate of the sparse signal is updated by applying a non-convex shrinkage function to the one or more orthogonal domain signals, and a shift to the orthogonal wavelet transforms. Following the iterative reconstruction process, the computer system generates an image based on the estimate of the sparse signal.

Imaging inverse problems such as reconstruction, deblurring, super-resolution, inpainting, or denoising can be solved by assuming the target image is sparse in the wavelet domain. Orthogonal wavelet transforms are not shift-invariant; image features are processed differently depending on their position with respect to the wavelet grid, and this can result in blocking artifacts.
An early way to reduce blocking artifacts in image denoising was the use of parallel cycle spinning: process the image separately with a wavelet transform offset by multiple different shifts in all dimensions, then average the results. However this simple averaging is not justified mathematically and makes the method difficult to extend to other inverse problems. As a result additional techniques have been developed such as the utilization of undecimated redundant wavelet transforms in conjunction with a nested inner algorithm inside the main solver (e.g. Chambolle-Pock or Dykstra inside FISTA) to solve the proximal operation performed during reconstruction.
These conventional methods require the application of multiple shifted wavelet transforms at each iteration, which incurs an extra computational cost of at least a factor of 2 per image dimension. Additionally, exact undecimated wavelet methods also require storing the wavelet coefficients of the image, which again are larger than the image by a factor of 2 in every dimension. This becomes too large with large-dimension use-cases such as dynamic volumetric reconstruction (3D+T), motion-compensated imaging, multi-contrast imaging including flow or diffusion, etc. Accordingly, it is desired to produce a reconstruction technique which minimizes blocking artifacts while also being efficient from a memory and computational standpoint.

Fast and memory efficient redundant wavelet regularization with sequential cycle spinning


The present invention is a system and method for providing conflict resolution for broadcast slot assignments. Method may include receiving a message from at least two nodes. Method may determine from received messages that at least two other nodes in a network have elected to transmit in a single broadcast slot. Method may determine individual node identifier information for each of a second and third node. Method may arrange a second and third node in an order based on individual node identifier information determination. Prior to the completion of a bootstrap cycle, method may select which of a second or third node may utilize the desired broadcast slot based on the arranged order for each of the second and third node. Method may broadcast a node selection to all nodes in a network.

Mobile networks are utilized in a variety of tactical military and commercial applications. These applications often require a mobile network to be self-organizing, wireless networks that can operate in dynamic environments and provide peer-to-peer, multi-hop, multi-media communications. As a result, mobile networks are known for their rapid and convenient deployment, self-organization, mobility, and survivability. To accomplish these goals, mobile networks generally include a neighborhood defined by nodes that may be within line of sight of a transmitting node. Such line of sight nodes are generally termed to be within one "hop" of the transmitting node. In these types of networks, a transmission from one node may be broadcast to all nodes in its "neighborhood". Typically, in order for data transmitted from a node to propagate multiple hops, the data must be relayed by one or more node neighbors. The data may be relayed in this manner until it has arrived at all intended destination nodes.
One important aspect of data transmission via a nodal network is the ability of neighboring nodes to transmit without interference. However, in a multiple access broadcast network, all network nodes may share a single shared communication channel, which may increase the possibility that two or more transmissions may collide. This may be especially true when two or more nodes transmit at overlapping times. Because there may be limitations on the number of simultaneous transmissions that a receiver can successfully process, collisions are typically avoided by the assignment of time slots in which individual nodes can transmit. To accomplish this, a node may select a time slot and channel that may not cause a collision at the intended receiver. However, during scheduling, a situation may occur where two or more nodes propose to utilize a particular slot. This is especially problematic when 2 or more nodes that are 2 or more hops apart, and therefore cannot hear each other, attempt to use the same fixed slot on the same channel. The result may be interference at the node connecting the 2 or more nodes.
Typically, this interference may be resolved by a bootstrap slot at the receiving node identifying that a conflict or contention exists. Conflict identification by a bootstrap slot generally results in all contending nodes backing off and selecting alternative broadcast slots for transmission. However, because the bootstrap slot for the resolving node may have already passed, conflict resolution generally requires the completion of an entire bootstrap cycle, which may consist of a number of frames, prior to resolution. Disadvantageously, this latency in conflict resolution often results in unreliable broadcast transmissions at the node receiving multiple transmissions.
Consequently, it would be advantageous if a system and method existed which quickly resolved broadcast slot assignment conflicts.

System and method for broadcast conflict resolution


An SOI integrated circuit contains Al implanted below the channel areas of NFETs and has a positive substrate bias, the magnitude of the substrate bias and the implant dose being set such that the bias suppresses backside leakage in the PFETs and the implant dose suppresses leakage in the NFEts in spite of the bias.

In SOI MOSFETs, electrical leakage between source and drain diffusions can occur in the SOI silicon layer at the interface with the back oxide layer. This leakage results from weak inversion at the back interface due to charge at the interface or in the back oxide. This charge may result from contamination introduced during processing, from trap generation at the interface or in the bulk of the back oxide during processing, from the operating environment (i.e. ionizing radiation), or due to the electrical operating conditions (giving rise to impact ionization).
In the past, with relatively thick SOI layers (>200 nm) it was possible to tailor the vertical doping profile in the SOI MOSFET channels such that the doping concentration at the backside is greater than at the frontside of the SOI layer. An ion implantation having a peak near the back interface between the device layer and the insulating layer is used to achieve the desired doping profile (boron for the NFETs, phosphorus or arsenic for PFETs). This produced the effect of increasing the backside threshold voltage without increasing the frontside threshold voltage V.sub.t. Thus, it was possible to suppress backside leakage without seriously affecting the performance of the device.
With the thin SOI layers employed today (<100 nm) attempts to increase the doping at the backside of the SOI significantly increase the doping at the frontside. This degrades the characteristics of the MOSFETs.
U.S. Pat. No. 5,231,045 illustrates a method of forming NMOS SOI integrated circuits, including the step of implanting aluminum ions into a substrate wafer prior to a bonding step in which two wafers are bonded together to form the SOI wafer. This method produces a uniform dopant concentration of Al across the entire wafer. If applied to CMOS processing, this method would leave implanted charge underneath both the NFETs and the PFETs. Although backside leakage in the NFETs is suppressed, this approach would have the unfortunate effect that the magnitude of the threshold for the PFETs will be lowered by the implanted ions and the PFET leakage current would be increased. This prior art work teaches away from implantation of Al through the device layer because of damage to the crystal structure of the device layer.

Method of fabricating low leakage SOI integrated circuits

International Business Machines Corporation


A lighting switch for use in a vehicle lighting system that comprises a switch housing, a plurality of electrical contacts on the switch housing and a manually operable contact engaging means. The manually operable contact engaging means, when in a first position, prevents electrical energy from flowing to either the headlights or the parking lights; when in a second position, permits electrical energy to flow from the battery to the parking lights with the headlights being electrically isolated from the battery and the ignition switch; and, when in a third position, permits electrical energy to flow from the ignition switch to the headlights and parking lights such that when the ignition switch is turned off no electrical energy flows to either the headlights or parking lights.

The draining of an automobile battery through inadvertently leaving the automobile lights in their on position is a problem that has plagued motorists since practically the time the automobile was invented. Through haste and oversight motorists commonly leave their vehicles without turning their lights off, only to return to find their vehicle with a dead battery. The recent popularity of timers and daytime running light mechanisms for headlights have only added further to this problem on account of motorists mistakenly believing that their automobile headlights remain on due to the operation of such timers or running lights.
Others have developed numerous mechanisms and lighting systems in an attempt to combat this problem. Such devices include warning chimes, to indicate that a vehicle's lights remain on after the ignition key has been removed, and complex relays and electronic circuitry that prevent a vehicle's lights from remaining on when the ignition has been turned off. While warning chimes provide an audible indicator they do not actively prevent a vehicle's lights from being left on. Chimes only provide limited assistance and suffer from inherent problems. First, since they comprise electronic components they are susceptible to failure. Secondly, in some instances background noise is sufficient to prevent a motorist from realising that the warning chimes are in operation. In the case of individuals with hearing impairment, the warning chimes may serve no purpose whatsoever.
With respect to the use of other electronic components (which may include relays and similar devices) to ensure that headlights do not remain on, they too suffer from inherent problems. First and foremost is the fact that such a systems usually involve relatively complex electrical and electronic circuitry and components, any part of which is subject to failure. In the event that any aspect of such a system fails a motorist may not be aware that the system is no longer working properly and falsely rely upon it to ensure that the automobile headlights are turned off. Furthermore, in the event of failure of part of the system, the cost of locating the failed component and fixing the system can often be very significant. Finally, as the complexity of such electronic systems increases so do the overall vehicle costs.


A transport apparatus comprises: transport means 150 which is equipped with transport members 152 for holding preforms 200 to be rotatable in a horizontal direction and transports the transport members 152 along a transport line 151; and positioning means 300 for aligning the preforms 200 in a predetermined direction. The transport members 152 include regulation members for regulating the rotation of the preforms 200 aligned in the predetermined, direction by the positioning means 300.

An injection stretch blow molding apparatus called a 1.5-stage one, has been known as a blow molding apparatus in which a preform is disposed in a blow cavity mold, and the preform is blow-molded to form a hollow container (see, for example, Patent Document 1).
Such a blow molding apparatus is equipped with a transport apparatus for continuously transporting the preforms. The transport apparatus described in Patent Document 1, for example, has a plurality of sprockets, a plurality of transport members engageable with the plurality of sprockets for holding the preforms, and a guide rail for guiding the transport members along a transport direction.
In the above blow molding apparatus provided with such a transport apparatus, when a flat container of a nearly circular shape in a plan view or an in-mold labeled container, for example, is to be formed as a hollow container, it is necessary to align the respective preforms circumferentially in a constant direction and arrange them in a blow mold. Various transport apparatuses equipped with mechanisms for aligning the preforms, which are continuously transported, in a constant direction have been proposed (see, for example, Patent Document 2).


This disclosure relates to trans-cyclooctene compounds and methods of using the same in bioorthogonal labeling experiments.

The introduction of the tetrazine-based inverse electron demand Diels-Alder (iEDDA) reaction was a major breakthrough in bioorthogonal chemistry (see, e.g., Blackman, M. L. et al., J. Am. Chem. Soc. 2008, 130, 13518-13519; and Devaraj, N. K. et al., Bioconjugate Chem. 2008, 19, 2297-2299). The stability of the reaction partners and the excellent kinetics, in particular when employing trans-cyclooctene as the dienophile, has made these reagents a useful tool for bioorthogonal labeling experiments (see, e.g., Blackman, M. L. et al., J. Am. Chem. Soc. 2008, 130, 13518-13519; and Devaraj, N. K. et al., Bioconjugate Chem. 2008, 19, 2297-2299; Rossin, R. et al., Angew. Chem. Int. Ed. 2010, 49, 3375-3378; Devaraj, N. K. and Weissleder, R. Acc. Chem. Res. 2011, 44, 816-827; and Keliher, E. et al., ChemMedChem 2011, 6, 424-427). Early research on this cycloaddition chemistry focused on optimization of the cycloaddition reaction kinetics via modification of tetrazine. More recently, additional trans-cyclooctene derivatives with significantly improved cycloaddition kinetics have been reported (see, e.g., Blackman, M. L. et al., J. Am. Chem. Soc. 2008, 130, 13518-13519; and Devaraj, N. K. et al., Bioconjugate Chem. 2008, 19, 2297-2299), but at the expense of decreased chemical stability or significantly increased molecular weight of the reactants.

Cyclooctenes for bioorthogonol reactions


A steering system for a motor vehicle includes a steering column and a device for adjusting the steering column. The device includes a bearing block, a first guide mechanism, and a second guide mechanism. A housing of the steering column is adjustably mounted in the bearing block. The first guide mechanism is configured to adjust a height of the steering column in the bearing block. The second guide mechanism is configured to adjust an inclination of the housing, and includes at least one first guide plate and at least one second guide plate that are each movably connected to the housing of the steering column and to the bearing block so as to be axially movable with an adjustment of the inclination of the housing.

Steering column mountings which can be of fixed or else adjustable design are considered to be well known. Steering column mountings having adjustment devices which are operated by electric motor and permit adjustment of the height and/or inclination of the steering column are known in particular in the passenger vehicle sector. Such steering column mountings are also known in the utility vehicle sector. However, the electric motor adjustment has proven to be very slow and is also limited to a comparatively small adjustment range. In particular in the utility vehicle sector, however, steering column mountings which have a large adjustment range are required. For this purpose, use is customarily made of constructions in which the steering column can generally be pivoted manually into an approximately vertical position in order therefore to simplify the entry into or the exit from the vehicle.
DE 10 2009 001 324 A1 discloses a steering column mounting with a support housing for a steering column which is mounted in an at least rotatably arranged steering column holder, as a result of which at least the inclination of the steering column is changeable, and wherein at least one first latching mechanism and at least one second latching mechanism are provided, which latching mechanisms are connectable to the support housing, and that a rapid clamping device is provided for latching in one of the latching mechanisms, as a result of which the steering column is latchable in a first inclination position or in a second inclination position.
It is desirable here for the steering column mounting to have as small dimensions as possible, for an adjustment of the height and inclination of the steering column to have an increased adjustment range and for guide elements for adjusting the steering column to be able to be produced cost-effectively.
This object is achieved with a device for adjusting a steering column of a motor vehicle with the features of patent claim 1. Furthermore, the object is achieved with a steering column for a motor vehicle with the features of patent claim 15.

Device for adjusting a steering column of a motor vehicle, and steering system


A processing element for an advanced processing apparatus. The processing element comprises a silicon-insulator interface and a confining arrangement for confining one or more quantum dots in the semiconductor. The processing element has also a control arrangement for controlling a quantum property of the one or more quantum dots and operate the one or more quantum dots as a qubit to perform quantum processing.

The power and capacity of computing components such as microprocessors and memory circuits has been increasing for the last 50 years, as the size of the functional units, such as transistors, has been decreasing. This trend is now reaching a limit, however, as it is difficult to make the current functional units (such as MOSFETs) any smaller without affecting their operation.
The technology employed to manufacture conventional silicon integrated circuits has developed over the last 50 years and is today well established. Current microprocessors feature several hundreds of millions of transistors which are manufactured in high throughput lines.
Developments are ongoing to implement new types of advanced processing apparatus that can implement powerful computations using a different approach than current processors. Such advanced processing apparatus promise computational capacities well beyond current devices. For example, quantum processors are being developed which can perform computations according to the rules of quantum mechanics. Approaches to the realisation of devices for implementing quantum bits (qubits), the basic computational unit of a quantum processor, have been explored with different levels of success.
For example, semiconductor based qubits have been developed and described in a number of earlier patent publications, including U.S. Pat. No. 6,472,681 (Kane), U.S. Pat. No. 6,369,404 (Kane). These qubits are based on the exploitation of the quantum effects of a single dopant atom in a silicon crystalline lattice. Although, the properties of a single dopant atom in silicon are promising to implement qubits, the techniques for manufacturing these devices include complex nanofabrication solutions, as discussed for example in U.S. Pat. No. 7,547,648 (Ruess et al.).
It has also been proposed to encode quantum information using the spin states of semiconductor quantum dots (Loss and DiVincenzo (Loss, DiVincenzo, DP quantum computation with quantum dots. Phys Rev. A56, 120; 1998)). This proposal primarily envisaged the use of quantum dots formed using electrostatic gates on a GaAs/AlGaAs heterostructure. However, the limited coherence time and the associated fidelity of the quantum state in these systems represent a significant hurdle to application of quantum dots in a quantum processor. Experimental work has been done in GaAs/AlGaAs on quantum dot qubits, but to realise large-scale arrays of such structures will require new manufacturing process technologies to be developed. More importantly, these materials suffer from problems with fidelity and dephasing time due to the presence of nuclear spins that are inherent to the GaAs crystal lattice.