Membrane translocation peptides, compositions comprising them, chimeric molecules comprising them, and methods of using them to achieve transmembrane transport of various agents.

The epithelium lining the gastrointestinal tract (hereinafter, "GIT") is a major barrier to absorption of orally administered pharmaceutically active agents (hereinafter, "active agents"). Absorption across the GIT epithelium can be by transcellular transport through the cells and by paracellular transport between the cells. Transcellular transport includes, but is not limited to, receptor-mediated, transporter-mediated, channel-mediated, pinocytotic and endocytotic mechanisms and to diffusion. Paracellular transport includes, but is not limited to, movement through tight junctions. Of particular interest is the development of non-invasive methods for enhancing uptake of active agents across the GIT epithelium into the body (Evers, P. Developments in Drug Delivery: Technology and Markets, Financial Times Management Report, 1995).
To develop non-invasive methods, phage display libraries have been used to identify specific peptide sequences, which bind preferentially to specific GIT membrane receptor, transporter, channel, pinocytotic or endocytotic target pathways (hereinafter, "targeting peptides") within the GIT. Included among the target pathways, which have been screened with phage display libraries, are the GIT membrane transporters HPT1, hPEPT1, D2H and hSI. HPT1 and hPEPT1 transport dipeptides and tripeptides. D2H transports neutral and basic amino acids and is a transport activating protein for a range of amino acid translocases. hSI is involved in sugar metabolism and comprises 9% of the brush border protein in the jejunum. Specific peptide sequences, which interact with the HPT1, hPEPT1, D2H and hSI membrane transporters have been identified in the following 4 applications, each of which is incorporated herein in its entirety: U.S. patent application Ser. Nos. 09/079,819, 09/079,723 and 09/079,678, and PCT application, PCT/US98/10088, published as WO 98/51325.
Non-target pathway based assays have been used to identify peptides with inherent cell membrane translocating properties. These cell membrane translocating peptides interact directly with and penetrate the lipids of cell membranes (Fong et al. Drug Development Research 33:64, 1994). The central hydrophobic h-region of the signal sequence of Kaposi's fibroblast growth factor, AAVLLPVLLAAP (SEQ ID NO: 1) is considered to be a membrane translocating peptide. This peptide (SEQ ID NO: 1) has been used as a carrier to deliver various short peptides (<25 mer), through the lipid bilayer, into living cells in order to study intracellular protein functions and intracellular processes (Lin et al. J. Biol. Chem. 271:5305, 1996; Liu et al. Proc. Natl. Acad. Sci. USA 93:11819, 1996; Rojas et al. J. Biol. Chem. 271:27456, 1996; Rojas et al. Biochem. Biophys. Res. Commun. 234:675, 1997). A 41-kDa glutathione S-transferase fusion protein containing SEQ ID NO: 1 (GST-Grbs-SH2 fused to SEQ ID NO: 1) has been shown to be imported into NIH 3T3 fibroblasts and to inhibit epidermal growth factor induced EGFR-Grb2 association and MAP kinase activation (Rojas et al. Nature Biotechnology 16:370, 1998). However, these studies do not address the use of membrane translocating peptides to enhance active agent uptake into a cell, into and out of an intracellular compartment, or across a cell layer when the active agent is complexed to a membrane translocating peptide or when the active agent is incorporated into a particle and the particle is modified with (hereinafter, "complexed to") a membrane translocating peptide.
The ability to enhance movement of an active agent across a cell membrane is important because, although an active agent can be administered to an animal by a variety of routes including, but not limited to, oral, nasal, mucosal, topical transdermal, intravenous, intramuscular, intraperitoneal, intrathecal and subcutaneous, oral administration is the preferred route. Nasal, mucosal, topical and transdermal administration depend on drug absorption through the mucosa or skin into the circulation. Intravenous administration can result in adverse effects from rapid accumulation of high concentrations of drug, in patient discomfort and in infection at the injection site. Intramuscular administration can cause pain at the injection site. Subcutaneous administration is not suitable for large volumes or for irritating substances. Although oral administration is the preferred route, many active agents are not absorbed efficiently across the GIT epithelium. This results from enzymatic degradation of active agents within the lumen of the GIT, from the limited permeability of the GIT epithelium to active agents, from the large molecular size of active agents and from the hydrophilic properties of active agents (Fix, J A. J. Pharmac. Sci. 85:1282, 1996). To develop an oral formulation, an active agent must be protected from enzymatic digestion within the lumen of the GIT, presented to the absorptive epithelial cells of the GIT in an effective concentration and "moved" across the epithelium in an apical to basolateral direction.
Therefore, because of the advantages of oral drug administration, there is a need for delivery systems, which protect orally ingested active agents from enzymatic degradation within the lumen of the GIT and which promote the absorption of orally ingested active agents into and across the epithelial cells lining the GIT.

Conjugates of membrane translocating agents and pharmaceutically active agents


A door locking mechanism for an appliance provides a bolt that may be moved by an actuator between an extended and retracted position. A bolt stop mechanism blocks movement of the bolt in retraction at one of two positions, depending on how the bolt was extended before the retraction. In this way the bolt automatically retracts when the door is not present because this causes extra extension of the bolt and an over-travel position need not be directly sensed reducing controller complexity or wiring.

The spin cycle of a washing machine removes water centrifugally from wet clothes by spinning the clothes at high speed in a spin basket. In order to reduce the possibility of injury to the user during the spin cycle, it is known to use an electronically actuated lock for holding the washing machine door in the closed position.
U.S. Pat. Nos. 6,363,755; 5,823,017; and 5,520,424, assigned to the present assignee and hereby incorporated by reference, describe several locking mechanisms. Desirably, the locking mechanism minimizes projecting parts on the washing machine door which might snag clothing or reduce access to the spin basket, and is simply integrated into the washing machine housing.
A signal indicating the state of the washing machine door as opened or closed may be used to ensure the door is closed before the lock bolt is engaged. Such a signal may be provided by a switch communicating with the washing machine door. Ideally such a switch could not be easily defeated, would operate reliably when used with other washing machine components with normal manufacturing tolerances, and would be resistant to contamination by water and dirt.
U.S. Pat. No. 7,493,783, hereby incorporated by reference, describes a door lock that can sense whether the door is closed by distinguishing between an "over-travel" position of the bolt that can occur when the bolt is extended and the door is up and so does not block the extension of the bolt, and an "engagement" position of the bolt that occurs when the door is down and the bolt is received by the door blocking overextension of the bolt. An appliance controller, by distinguishing between three electrical signals indicating, respectively, the unlock position, the over-travel position, and the lock position, can determine that the door is properly locked with the bolt engaging the door.
Many existing controllers do not have the capability to accommodate additional signals and respond to those signals by retracting the lock. Alternatively, it may be desirable to avoid the extra wiring necessary to communicate an over-travel position to the appliance controller.

Appliance latch with door presence sensing


An electrical joint monitoring device including a mounting assembly and a wireless transponder unit. The mounting assembly includes a first conductive contact structured to electrically connect to a first conductive member of an electrical joint and a second conductive contact structured to electrically connect to a second conductive member of the electrical joint. The wireless transponder unit includes a control unit electrically connected to the first and second conductive contacts and an antenna electrically connected to the control unit. The wireless transponder unit is configured to sense a voltage difference between the first and second conductive contacts, to generate information based on the voltage difference, and to output the information to a wireless reader unit via the antenna.

1. Field
The disclosed concept pertains generally to electrical joints and, more particularly, to electrical joint monitoring.
2. Background Information
Some typical types of electrical joints are formed by securing two conductive members together with, for example, a fastener. The electrical performance of the joint, and in particular, the conductivity of the joint, depends partially on the conductive members being secured together tightly. A loosening of the electrical joint reduces the conductivity of the electrical joint and can cause additional problems such as overheating.
Due to the aforementioned problems, it is desirable to determine whether the conductive members in an electrical joint are properly secured together. However, verifying whether the conductive members in an electrical joint are properly secured together can consume a technician's time. In particular, when an electrical system includes numerous electrical joints, or if it is difficult to reach electrical joints, a large amount of technician's time can be taken verifying whether conductive members in electrical joints are properly secured together.
There is room for improvement in the area of monitoring electrical joints.

Electrical joint monitoring device and electrical joint monitoring system employing the same


Embodiments of the present disclosure disclose a gate driving circuit, a method for driving the same, and a display apparatus. The gate driving circuit includes N stages of cascaded shift registers, N being an integer greater than or equal to 4. In the N stages of shift registers, an output signal terminal of an nth stage of shift register is connected to an input signal terminal of an (n+I/2)th stage of shift register, and a reset signal terminal of the nth stage of shift register is connected to an output signal terminal of an (n+K)th stage of shift register, wherein n is an integer greater than or equal to 1 and less than (N−I/2), K is an integer greater than I/2 and less than I, and I is a number of clock signal lines connected to the gate driving circuit, which is an even number greater than or equal to 4.

In a Thin Film Transistor (TFT)-based Liquid Crystal Device (LCD), a gate driving circuit for driving a gate may be formed on a display panel to form a Gate drive On Array (GOA) panel. The gate driving circuit comprises a plurality of cascaded shift register units. In a conventional gate driving circuit, an output signal of a next stage of shift register unit is usually used as a reset signal of the stage of shift register unit, and an output signal of a previous stage of shift register unit is usually used as an input signal of the stage of shift register unit.
However, in a case of a conventional gate driving circuit, especially where a plurality of clocks are used, a display apparatus may exhibit a flash screen phenomenon.

Gate driving circuit, method for driving the same, and display apparatus

HEFEI BOE OPTOELECTRONICS TECHNOLOGY CO., LTD.


The invention provides a method of using pregnadienones and pregnadienols represented by the structural formula (I):

This invention relates to the novel use of D-ring unsaturated pregnadienols/pregnadienones represented by general formula I as shown in the accompanying drawings, possessing both pronounced hypolipidemic and hypoglycemic activities and devoid of androgenic and progestational activities. More particularly this invention relates to the novel use of 3xcex2-hydroxy-pregna 5,16-dienone important prototype of this class, represented by the formula (II) as shown in the accompanying drawings, for the treatment of diabetes and pronounced hypolipidemic and hypoglycemic activities.
High plasma cholesterol and related lipids are known to be one of the factors that predispose and individual to atherosclerosis and thus to myocardial infraction. Diabetes mellitus, which eventually impairs the function of kidneys, eyes, nervous and vascular systems, is quite often associated with lipid disorders. Both hyperlipidemia and diabetes mellitus require long term management and pose problems in choice of pharmacotherapeutic interventions when these conditions manifest together. Though a number of drugs are known separately to treat these conditions, there are a number of side effects associated with them which limit their long term use.
The most important hypolipidemic drugs available today belong to the strain and fibrate classes [McCarthy, P. A., Med. Res. Rev., 13, 139-59 (1993)] whereas hypoglycemic drugs fall into the category of sulphonylureas, biguanidines and amidines [Wolff, M. E. (Ed), Burger""s Medicinal Chemistry Part II, 1045 (1981), John Wiley and Sons, New York]. However, these therapeutic agents are not free of side effects-statins (HMG-CoA reductase inhibitors) the most widely used drugs today which hitherto were thought to be very safe drugs, have exhibited side effects following long term therapy [Carrier, M. et al.; Ann. Thorac. Surg., 57, 353-6 (1994)]. The adverse effects which have become the source of concern, are increases in hepatic transaminases and myopathies [Witztum, J. L., In Goodman and Gilman""s The Pharmacological Basis of Therapeutics, eds. Hardman, J. et al., 9th edition, McGraw Hill, New York pp 875-98, Fukami, M. et al; Res. Exp. Med., 193, 263-73 (1993); Appelkvist, E..; et al.; Clin. Invest., 71 (suppl 8), 597-102 (1993), Wills, R. A. et al.; Proc. Natl. Acad. Sci. (US), 87, 8928-30 (1990)] and carcinogenesis specially breast cancer in subjects undergoing treatment with pravastatin [Braunwald, E.; Scrip, 2117, 33 (1996)); Ciaravino, V. et al.; Mutat. Res.; 353, 95-107 (1995)]. The incidence of myopathy associated with rhabdomyolysis and renal failure is increased subsequent to such treatment [East, C. et al.; N. Engl. J. Med., 318, 47-48 (1998); Pierce L. R. et al.; J. Am. Med. Assoc., 265, 71-75 (1990)]. Also, the HMG-CoA inhibitors block mevalonate production which occurs at an early stage in cholesterol synthetic pathway. Meyalonate is a common precursor for all isoprenoids such as ubiquionones (Co-enzyme Q-10), the dolichols, isopentenyl t-RNA etc. Therefore, long term blockade of mevalonate synthesis leads to Q-10 deficiency. Serum Co-enzyme Q-10 is important for cardiac function [Laaksonen, R. et al., Eur. J. Clin. Pharmacol. 46,313-7 (1994); Bargossi, A. M. et al; Int. J. Clin. Lab. Res., 24, 171-6 (1994)]. The commonest side-effects of fibrates and particularly clofibrate therapy are gastrointestinal upsets including nausea, vomiting, diarrhoea, dyspepsia, flatulence and abdominal discomfort [Oliver, M. F. et al.; Br. Heart J., 40, 1069-1118 (1978)]. Elevated creatine phosphokinase concentration during clofibrate therapy may be associated with a syndrome of muscle pain and weakness. Large-scale long-term studies have demonstrated an increased incidence of cholecystitis, gallstones and sometimes pancreatitis in patients receiving clofibrate and some studies have indicted cardiovascular disorders [The coronary Drug Project Research Group; N. Engl. J. Med., 296, 1185-90 (1977)]. The unexpected finding of an increased mortality rate in patients taking clofibrate in the WHO study produced serious concern over the long-term safety of clofibrate and ultimately led to its withdrawal in many countries [Oliver, M. F. et al; Lancet, ii, 600-604 (1984)].
The adverse effects of biguanidine antidiabetic agents include gastro-intestinal disturbances like diarrhoea and lactic acidosis [Paterson, K. R. et al.; Adverse Drug React Acute Poisoning Rev., 3, 173-82 (1984)]. With sulphonylureas the commonly associated adverse effects are hypoglycemia, gastrointestinal disturbances, hypersensitivity and vascular complications [Paice, B. J. et al., Adverse Drug React. Acute Poisoning, 4, 23-26 (1985)]. As diabetes and hyperlipidemia are quite commonly manifesting together, it would be great clinical benefit if the same compound could have both these activities together because the available drugs are not free of toxic effects and neither data regarding toxic manifestations are available when drugs for two clinical conditions are mixed together.
Two approaches currently being pursued in search of drugs with hypolipidemic and hypoglycemic activities together. The first approach emerged during detailed study of antihypertensive action of adrenergic receptor modulators. The study revealed that xcex11-adrenergic blockers (particularly Doxazosin and Prazosin) [Lithell, H. O.; J. Hypertens, 15 (Suppl 1), S 39-42 (1997); Poliare, T. et al.; Diabetologia, 31, 415-420 (1988); Anderson, P. E. et al.; Am. J. Hypertens, 9, 323-333 (1996)] and xcex23-adrenergic agonist (BTA-243, BRL-37344, CGP 12177, CL 316243 [Arch, J. R. S. et al.; Med. Res. Rev. 13, 663-729 (1993); Largis, E. E. et al; . Drug Dev. Res., 32, 69-76 (1994)] also affect plasma lipoprotein metabolism and increase insulin sensitivity. As a result such antihypertensive drugs exhibit lipid lowering and hypoglycemic actions together, xcex11-adrenergic receptor blockers, however have the inherent limitations of causing orthostatic hypotension and syncope [Matyus, P.; Med. Res. Rev., 17(6), 523-35 (1997)]. The essential requirement of xcex23-agonist for antiobesity and antidiabetic actions is the need for high selectivity for xcex23xe2x80x94adrenoceptor. Any substantial xcex21- or xcex22-agonism would likely cause increased heart rate and muscle tremor respectively which are unacceptable in a drug which could be administered on long term basis [Connacher, A. A. et al.; Brit. Med. J., 296, 1271-20 (1988); Mitchell, T. H. et al; Int. J. Obesity., 13(6), 757-66 (1989)]. The second line of approach for dual activity came into light during the study of anti-oxidant property of drugs. There have been many reports describing relationships between peroxidantion and disease such as diabetes mellitus, atherosclerosi and myocardial ischemia in terms of radical oxidation. Troglitazone, an antioxidant drug has been developed as an oral hypoglycemic agent which enhances the action of insulin in peripheral tissues and liver besides its hypolipidemic effects. However, troglitazone is also not free of major side effect causing liver damage. The drug, troglitazone, has been implicated in 35 cases of liver disease leading to one transplant and one death [Warner-Lambert; Chem. and Ind., No.22, 897 (1997)]. Thus to the best of our knowledge no class of compound is yet available which has both effects together as the main action and have fair safety margin.
We, in early eighties started our work for search of such compounds which have effect on endogenous transportation of lipids and glucose rather than interfering with exogenous transportation. Our research was mainly based on secondary metabolic actions of progesterone.
Progesterone, apart from its clinical hormonal action on the reproductive system, is known to modulate lipid, carbohydrate, insulin and protein metabolism. The rise in the level of progesterone in the first trimester of pregnancy causes hyperphagia, pancreatic islet hypertrophy, hyperinsulinemia and body fat and glycogen deposition, when the metabolic demands of the fetus are very low. However, in the latter half of pregnancy, although the progesterone levels are still high, the carbohydrate, lipid and protein reservoirs shift into circulation to meet the needs of the growing fetus [Kalhoff, R. K.; Am. J. Obstet. Gynecol., 142, 735-38 (1982)].
Progesterone thus, having actions both on the reproductive and the metabolic systems, seemed to offer the possibility of dissociating these two biological activities by structural modifications. The experience of the development of second generation progestins supported this contention. The first generation progestins such as levonorgestrel exhibited undesirable pharmacologic effects like alteration in carbohydrate and lipoprotein metabolism, weight gain and hypertension, which was shown to be related to their intrinsic androgenic/anabolic activity and ability to bind with androgen receptors. The androgenic affinity has been attributed to C-17 hydroxy functionality which makes these molecules resemble androgens. In recently discovered second generation progestins such as gestodene and 3-keto-desogestrel, an additional olefinic bond either in C- or D- ring brought a dramatic decrease in their affinity to androgen receptors (Table 1). As a result these compounds have a very high order of progestational effect with practically no androgenic activity and did not cause hyperlipidemia [London, R. S.; Obstetrical and Gynocological Survey, 47, 777-81 (1992)].
It is an object of the invention to explore the possibility of designing pregnadienones which while preserving the ability to modulate lipid and carbohydrate metabolism would not have any progestational effect. It would be pertinent to point that earlier, the applicants had isolated a D-ring modified pregnenolone, named Gugulsterone represented by formula (9) as shown in Table 2, from guggul resin obtained from Commiphora mukul, which had potent hypolipidemic effect without any progestational effect [Arya, V. P.; Drugs Fut. 13, 618 (1998)].
It is another object of the invention to explore the possibility of dissociating the hypolipidemic and insulin sensitizing activities of progesterone from its hormonal actions. Accordingly, the applicants focussed their attention to prepare and investigate analogues/prototypes with additional substituents in ring-D of pregnadienones.

Method of treating hyperlipidemic and hyperglycemic conditions in mammals using pregnadienols and pregnadienones

Abstract: containing at least one olefinic bond in or on their D-ring for the treatment of hyperlipidemic and hyperglycemic conditions in mammals wherein Xxe2x95x90OH or O and the olefinic bonds are at 4(5); 5(6); 16(17); or 17(20) or various combinations, and wherein the compounds contain at lest one olefinic bond in or on their D-ring. The method comprises administering an effective amount of said compounds to recipient mammals.

Council of Scientific and Industrial Research


A fluidized bed reactor includes a bottom portion, a roof portion, and side walls vertically extending between the bottom portion and the roof portion, forming a reaction chamber of the reactor. At least one side wall of the reaction chamber forms at least one vertical indentation in the reaction chamber, which indentation extends from the plane of the at least one side wall towards the reaction chamber. The indentation extending from the plane of the at least one side wall towards the reaction chamber is formed of a portion of the at least one side wall, protruding from the plane of the at least one side wall towards the reaction chamber, and the portion of the at least one side wall includes at least two substantially vertical indenting wall portions deviating from the plane of the at least one side wall at vertical lines within a distance from each other.

The reaction chamber of a fluidized bed reactor typically comprises an inner portion having a rectangular horizontal cross section, defined by four side walls, a bottom portion and a roof portion, wherein solid material and bed material containing, for example, fuel, are fluidized by means of fluidizing gas introduced through the bottom, the fluidizing gas usually being oxygenous primary gas required for exothermic chemical reactions taking place in the reaction chamber. The inner portion of the reaction chamber is usually called a furnace and the reactor a fluidized bed boiler, when a combustion process is performed in the reactor. The side walls of the furnace typically also have connections for the introduction of, at least, fuel and secondary air.
The side walls of the furnace are usually manufactured of panels formed of tubes and fins therebetween, whereby energy being released in the chemical reactions of the fuel is used for evaporating water flowing in the tubes. Often, there are also superheating surfaces arranged in the fluidized bed reactor to further increase the energy content of the steam.
When aiming to manufacture a high capacity boiler, for example, one on the order of several hundreds of megawatts, a large reaction volume and a lot of evaporating and superheating surfaces are required. Such a high capacity fluidized bed boiler is disclosed in U.S. Pat. No. 6,470,833 B1. The basal area of the boiler is directly proportional to the capacity of the boiler, on the basis of the required volume and velocity of the fluidization air. As it is at least structurally disadvantageous to have a very long and narrow bottom of the furnace, the height of the boiler and the width of the boiler bottom also have to be increased in order to have enough evaporation surfaces on the side walls. The increase of the height may significantly lead to constructional difficulties, and the increase of the width can make it difficult to arrange homogeneous feed of the fuel and secondary air. It can be difficult to form sufficiently strong and rigid side walls extending from the bottom to the roof of a high furnace, as the side walls are considerably thin relative to their height.
It is especially challenging to realize a high-efficiency once-through fluidized bed boiler. The increase of the cross-sectional area of the furnace makes it challenging to maintain uniform behavior of the fluidized bed. This means, in practice, that the heat surfaces of the furnace tend to be affected by a varying fluidized bed, depending, for example, on the structures of the grid and the lower portion of the furnace and the control of the process. It is important for the reliable operation of the once-through fluidized bed boiler that the evaporation of water in the tubes of the evaporator surfaces is homogeneous enough in the different portions of the furnace walls. In large fluidized bed boilers, especially, in the once-through fluidized bed boilers, the uniformity of the fluidized bed has an even bigger meaning. Especially, the inner corners of a large boiler are areas, in which the effect of the fluidized bed on the evaporation is easily different from that in the other areas.


A Zener diode—capacitor combination wherein a Zener diode is mounted in the capacitor body and connected in parallel with the capacitor after the capacitor has been voltage tested. A welded strap or jumper wire completing the diode circuit or a connection of separate terminations during soldering may be used to complete the circuit.

Overvoltage, especially from current surges, can cause capacitors to fail and render entire circuits non-functional.
For example, in automotive applications, the normal DC voltage is between 14 and 12 VDC. Surge conditions such as battery dropout can create overvoltage voltage levels to appear across the bus as high as 37 VDC.
For the regulated 12 VDC applications the recommended capacitor of choice would be a 25 WVDC capacitor. This follows manufacturer's recommendations that the voltage rating of the capacitor be at least twice the rated voltage. This headroom between rated and application voltage allows faults created during surface-mount solder reflow exposures to be undetected during application. If the voltage will be at 14 VDC nominal, such as in typical automotive use, then the recommended capacitor voltage would be at 35 WVDC.
As long as the voltage across the capacitor is maintained near that 50% of rated voltage level, the failure rates will be in the very low PPM. Once that voltage is exceeded, then the PPM level will rise geometrically with the applied voltage level.
All too often this overvoltage is overlooked, and because sample test of 20 to 100 units may not disclose high PPM failure rates, there are many opportunities to dismiss this failure. Ideally, every capacitor should be protected against overvoltage.
In conventional circuit designs, Zener diodes have been used in parallel with capacitors, such as in U.S. Pat. No. 4,100,479.
Combining a Zener diode in parallel with the capacitor, especially a polar capacitor, two potential faults to the capacitor are protected. Firstly, the Zener diode will clamp the voltage to a very specific voltage and prevent voltages above the level from being applied to the capacitor. Secondly, because the Zener depends on reverse or breakdown voltages for the Zener action, it will be forward biased for any reverse voltages, thereby eliminating the potential of applying a reverse voltage to the polar capacitor.
The concept of using a diode in the package with a capacitor to prevent reverse voltages has been presented with the diode in series with the capacitor. Using a Zener in parallel with the capacitor presents a problem in that if these devices are electrically connected before they are packaged the Zener prevents certifying any "headroom" for the capacitor over the Zener's breakdown voltage. The device would be effectively cleared up to the Zener voltage, and subsequent fault sites during the solder process could create faults activated before the Zener voltage is achieved. It is imperative that the capacitor and Zener remain independent of each other until the device is packaged into the packaging system or thereafter. The capacitor must be burned-in and tested to voltages well above the Zener voltage to create the required headroom. Any fault created in the dielectric during the solder process would be highest at the rated voltage of the capacitor, but the Zener is selected in such a manner that the maximum voltage applied to the in-circuit capacitor would be restricted to the Zener voltage, well below the rated voltage of the capacitor.

Multiple electronic components: combination capacitor and Zener diode


A system and method retrieve a robust customer profile of a user accessing a website and generate a custom webpage that include in a first area graphical user interface elements and objects representative of products owned by a first entity having stored attributes that correlate with attributes of the user stored in the robust customer profile. A state of a secondary market is determined and the custom webpage is generated to include in a second area graphical user interface elements and objects representative of items owned by a second entity in the secondary market that correlate with the products in the first area.

In most customer interactions, a customer may be faced with various barriers, or elements of friction, that may prevent them from proceeding with the interaction, where the particular barriers may vary from interaction to interaction. In the context of a purchase transaction, for example, customers may wonder if they can afford to make the purchase, or whether they need to make the purchase. For instance, a customer looking to purchase a pair of designer jeans may assess whether they can afford the purchase based on their budget or determine whether they have enough space in their wardrobe. Customers may also face mental barriers regarding a transaction, for example, "shopping guilt" or for those customers who are environmentally conscious, questions regarding the sustainability of the product. It is often the case that the mental barriers are subjective in nature, and may be influenced by various externalities. For example, a customer may assess whether they truly have a need for a product, or whether they strongly desire the product. This assessment may involve additional subjective considerations, for example whether the customer owns the same or similar products. By removing these barriers, customers are more likely to engage in the interaction (i.e., proceed with the purchase transaction). For example, if a product is on sale, a customer may be more inclined to make the purchase.
Customers have turned to secondary markets to address some of these barriers, as secondary markets can allow a customer to off-load or sell certain items. By way of example, a customer can sell a coat that he/she owns, which can provide additional funds to the customer as well as free up space in their wardrobe. Increasing a customer's purchasing power may influence whether the customer is able or willing to conduct future transactions, e.g., additional purchases. Similarly, a customer may choose to purchase an item from a secondary market because it is being offered at a significant discount.
However, secondary markets themselves present barriers to access, as it is often time and labor intensive process to participate in the market, which most customers are simply unwilling or unable to commit to. For example, participating in flea markets is a time consuming activity and has no guarantee of success. This is particularly problematic for customers who are only looking to off-load one or two individual items. While electronic secondary markets (e.g., eBay and Amazon) allow for more sporadic access to secondary markets, they still require a significant amount of effort on the part of the customer, who must prepare a detailed product listing for the product, including a description, staged photos, and the like. Moreover, existing electronic secondary markets are difficult to navigate by potential purchasers looking for a particular product, significantly diminishing the chances for a successful transaction. Furthermore, from the perspective of a product retailer, secondary markets can be extremely harmful to product branding, as the product retailer has no control over how products are presented (e.g., visually or descriptively) through these secondary markets.

Secondary market integration within existing data framework


Lightweight sectional doors for cargo bodies and the like are reinforced by a reinforcing member supported on an inner wall surface of at least alternate ones of the panels of a multipanel door. The reinforcing member comprises an elongated, preferably extruded member having spaced apart coplanar flanges and an arcuate web interposed the flanges. An integral rib is disposed at the midpoint of the arcuate web to provide additional stiffness for the reinforcing member. The reinforcing member may be secured to selected door panels by conventional mechanical fasteners.

Sectional upward acting doors are ubiquitous in applications for cargo bodies of freight vehicles, including motor trucks, for example. Mobile cargo bodies are, of necessity, fabricated of components which are required to be as light in weight as possible in order to reduce the tare weight of the vehicle. However, such components must also be of sufficient structural integrity as to not fail in normal use. Sectional upward acting doors for cargo bodies are preferably manufactured of lightweight extruded materials including aluminum and plastics. One problem associated with the design and manufacture of sectional doors for cargo bodies pertains to the stiffness of the door panels required to resist damaging deflections due to rough treatment, wind loads and impacts from shifting cargo. A related problem with regard to cargo pertains to that wherein cargo items may shift during transport and lodge against the inside surface of the door and engage with projections, such as hinge components and the like which can prevent opening the door.
Accordingly, there has been a need to provide lightweight sectional doors for cargo bodies and the like which can be conveniently reinforced, when needed, by reinforcing members which in themselves are lightweight while adding the requisite rigidity to the door panels and wherein the reinforcing members do not aggravate but alleviate problems associated with cargo shifting against the door which would prevent the door from being opened. It is to these ends that the present invention has been developed.

Reinforced sectional door for cargo body


According to one embodiment, a mask includes a substrate, first and second pattern portions. The substrate includes a first surface, and the substrate is light transmissive. The first pattern portion includes first optical members. The first optical members are provided on the first surface. A light transmittance of the first optical members is lower than a light transmittance of the substrate. A distance between the adjacent two first optical members is a first distance. The second pattern portion includes second optical members. The second optical members are provided on the first surface. A light transmittance of the second optical members is lower than the light transmittance of the substrate. A distance between the adjacent two second optical members is a second distance. A first phase of a light penetrating the first pattern portion is different from a second phase of a light penetrating the second pattern portion.

A mask having a repeated pattern is irradiated with light, and thereby a substrate to be transferred is exposed by light intensity according to an opening ratio and a gray level exposure region (gray region) can be formed on the substrate to be transferred. For the mask used for forming such a gray region, a high accuracy pattern is desired to be formed easily.


A FET device for sensing a magnetic field, the FET device comprising: a semiconductor material having a source at a first position therein and receiving means at a second position therein for receiving charge carriers; bias voltage means for providing a bias voltage between the source and the receiving means to produce a movement of charge carriers between the source and the receiving means; a channel layer disposed within the semiconductor material between the source and the receiving means through which the charge carriers move as a function of the bias voltage and the magnetic field being sensed; a resistive gate disposed between the source and the receiving means and above the channel layer; a first resistive gate contact disposed in a first preselected position with respect to the source; a second resistive gate contact disposed in a second preselected position with respect to the receiving means; a resistive gate voltage means for providing a resistive gate bias voltage between the first and second resistive gate contacts to establish a longitudinal electric field in the channel layer; and output means disposed in the semiconductor material for providing a signal related to the strength of the magnetic field sensed by the FET device.

A conventional method of implementing a magnetic field sensor is to use a MOSFET semiconductor device comprising a source, a drain, and a gate, located between the source and the drain, which provides a control of charge carrier movement in a channel region between the source and drain. One common MOSFET device for sensing a magnetic field (sometimes referred to as a MAGFET) is the MOSFET Hall effect sensor which uses the basic MOSFET structure with Hall electrodes applied on either side of the channel so as to measure a voltage between the electrodes developed by the charge carrier movement in the channel. Another technique of implementing a MOSFET magnetic field sensor is to use split drains in a conventional MOSFET structure that includes a source and a gate.
In both types of known devices, the Lorentz deflection of charge carriers caused by a magnetic field perpendicular to the top surface of the MOSFET is used to sense the magnetic field strength. The deflection of carriers in the y-direction, for example, is proportional to the carrier velocity in the x-direction times the magnitude of the magnetic field in the z-direction. In the MOSFET Hall effect sensor, this deflection causes a change in voltage at the Hall electrodes, while in the split drain device, the deflection causes a differential change in the current at the output of the split drains.
The carrier deflection in the y-direction is a function of the electric field in the y-direction, E.sub.Y, which is given by: EQU E.sub.Y =k.sub.H .mu. B.sub.Z E.sub.X ( 1)
where k.sub.H is the Hall coefficient, .mu. is the carrier mobility, B.sub.Z is the magnitude or strength of the magnetic field in the z-direction and E.sub.X is the longitudinal electric field in the x-direction.
One adverse factor affecting the use of a MOSFET as a magnetic field sensor is the associated undesirable noise sources that affect the sensitivity of the device. Examples of this include the "Johnson noise" produced by a circuit resistor, such as a load resistor or a bias resistor in the sensor circuitry, and signal noise of the receiver used with the sensor. Studies have been conducted in these areas with a view towards improving sensitivity. In my companion application Ser. No. 07/560,700, filed Jul. 31, 1990 and entitled "A Floating Gate Magnetic Field Sensor", an improved MOSFET sensor is described that offers increased sensitivity and combats the effect of noise sources typically associated with the load and bias resistances and with the sensor receiver.
However, in addition to noise considerations, carrier density has also been found to be a significant factor in the effectiveness of a MOSFET when used as a magnetic field sensor, as is evident from the following brief review of the basic MOSFET operation.
MOSFET devices operate in general in either a pentode or a triode mode. In the pentode mode, the channel (or gate) is pinched-off near the drain, and the region of high electric field is in the region from the pinch-off point to the drain. Thus, only a small region of the channel, i.e., the gate of the MOSFET, has a high electric field and, as can be observed from equation (1), the majority of the deflection will occur in the region near the drain. In the triode mode, a uniform longitudinal electric field, E.sub.X, will exist in the channel with a value given by: ##EQU1## where V.sub.D is the drain voltage and L is the channel length. However, the condition for triode operation requires that: EQU V.sub.G -V.sub.t >>V.sub.D ( 3)
where V.sub.G is the gate voltage, V.sub.D is the drain voltage and V.sub.t is the threshold voltage. The requirement for a large gate voltage V.sub.G means that a large carrier density will exist in the channel since the carrier density per unit area, n, at the source is a function of V.sub.G, namely: EQU n=C.sub.OX (V.sub.G -V.sub.t) (4)
where C.sub.OX is the oxide capacitance.
A low carrier density in the channel for a MOSFET used as a magnetic field sensor is important for two reasons. First, the mean-square thermal noise current at the drain of a MOSFET, I.sup.2.sub.n, depends on the carrier density n according to the relation: ##EQU2## where e is the charge of an electron, =1.6.times.10.sup.-19 coulombs, K is the Boltzman's constant, T is absolute temperature, W is the width of the MOSFET gate and .mu. is mobility of the charge carriers. Thus, a smaller carrier density results in a smaller noise current.
Secondly, an important parameter for the performance of a MOSFET as a magnetic field sensor is relative sensitivity, S.sub.r, of the device, which can be expressed as follows: ##EQU3## where the symbols are as indicated earlier, and with J.sub.X =current density in the x-direction. Thus, a smaller carrier density yields an improvement in relative sensitivity of the MOSFET. The MOSFET sensitivity relationship is more fully discussed in an article entitled "A MOS Hall Device Free from Short-Circuit Effect," by R. S. Popovic, Sensors and Activators, Vol. 5, pp. 253-262 (1984).
The disadvantages discussed above in connection with large carrier densities associated with the use of a MOSFET as sensor device have limited its applicability. In particular, the large gate voltage heretofore required and the associated larger carrier density continue to restrict the sensitivity, and hence the effectiveness, of this type of sensor.
One approach to controlling carrier density is described in a publication entitled "A Magnetic Field Sensor Using A Graded Gate Potential" by D. S. Gill et al., Solid State Devices, at pages 523-526 (1988). The article describes the fabrication of a MOSFET-like structure, termed a Graded-gate FET (GFET), having a resistive gate made of undoped polysilicon, and diffused gate contacts at either end of the device. The gate contacts are biased separately so that a resulting voltage gradient is produced along the gate so as to provide a uniform longitudinal electric field that varies linearly along the entire length of the channel. The separation between diffused gate contacts is approximately 100 .mu.m. Carrier collection is accomplished by relatively long (approximately 60 .mu.m) lateral drain contacts. The article describes results with respect to both dual drain and triple drain GFET devices and based on the results, these devices appear to exhibit significantly better sensitivities than corresponding MAGFET devices.
The drain contacts used in the GFET described in the Gill et al. article are, as stated, located along the channel, and serve to increase the area over which carrier collection can take place, while preventing the development of a Hall electric field so that the charge collection, i.e. sensitivity of the device, is, based solely on carrier deflection. The application of a magnetic field perpendicular to the current flow through the channel produces an imbalance, or an asymmetry, in the two drain currents produced by the collection of charge carriers under each of the split drains, which provides an output as a measure of the strength of the magnetic field. The results described in the article indicate that the maximum measured sensitivity of the GFET device using a differential bias, delta V.sub.G, on the gate of approximately +19 volts which is a factor of 5 greater than that obtained with delta V.sub.G =0.
It is noted that the triple drain GFET structure described collects undeflected charge carriers in a central drain region, and difficulties are acknowledged in the article in establishing a balanced current between the lateral drains from which the magnetic field measurement is made, thus indicating that the triple drain GFET structure may be impractical in the form described.
While the GFET device described in the above-referenced article provides a uniform longitudinal electric field along the entire length of the channel for increasing of sensitivity of the device, the device has certain disadvantages. For example, a distance of approximately 100 .mu.m, is required between gate contacts with the channel length being on the order of 40 .mu.m and the split drain length being 60 .mu.m. The longitudinal electric field E.sub.X in the GFET device is given by: EQU E.sub.X =.DELTA.V.sub.G /L.sub.G ( 7)
where .DELTA.V.sub.G is the bias voltage difference between the gate contacts and L.sub.G is the separation between the gate contacts. In accordance with equation (7), increasing the gate contact separation reduces the longitudinal electric field E.sub.X. This affects the amount of carrier deflection, i.e. the sensitivity of the device, which is directly proportional to the longitudinal electric field, as shown by equation (1). For a large separation between gate contacts, a higher differential gate voltage must therefore be applied to maintain the same electric field within the channel.

The United States of America as represented by the Secretary of the Navy


As a method for constituting a pre-metal interlayer insulating film, such method is considered as forming a CVD silicon oxide-based insulating film having good filling properties of a silicon oxide film by ozone TEOS, reflowing the film at high temperatures to planarize it, then stacking a silicon oxide film having good CMP scratch resistance by plasma TEOS, and, further, planarizing it by CMP. However, it was made clear that, in a process for forming a contact hole, crack in the pre-metal interlayer insulating film is exposed in the contact hole, into which barrier metal intrudes to cause short-circuit defects.

The present invention relates to a semiconductor integrated circuit device formed by mainly integrating MISFETs (Metal Insulator Semiconductor Field Effect Transistor) or MOSFETs (Metal Oxide Semiconductor Field Effect Transistor), and to a technology that is effective when applied to a technology for forming an insulating film, in particular, to a technology for forming a pre-metal interlayer insulating film, in a method of manufacturing the semiconductor integrated circuit device (or a semiconductor device).
Japanese patent laid-open No. 5-21620 discloses a technology in which a SOG (Spin-On-Glass) silicon oxide film is coated over a TEOS (Tetra-Ethyl-Ortho-Silicate)-CVD (Chemical Vapor Deposition) silicon oxide film using TEOS to be planarized and these are etched back by dry etching, as a technology for forming a pre-metal interlayer insulating film.
Japanese patent laid-open No. 5-206474 discloses a technology in which a TEOS-CVD silicon oxide film using TEOS is reflowed for planarization and then etched back.
Japanese patent laid-open No. 2002-110666 discloses a technology in which a CVD silicon oxide film by P-TEOS (Plasma-TEOS) is formed over a CVD silicon oxide film by HDP (High Density Plasma), and the CVD silicon oxide film by P-TEOS is subjected to CMP (Chemical Mechanical Polishing) or to etching back for planarization, and then, a CVD silicon oxide film by P-TEOS is formed as a cap film.
Japanese patent laid-open No. 2000-208624 discloses, as a technology for forming a pre-metal interlayer insulating film, a technology for forming a silicon oxide film by a plasma CVD method using O3-TEOS, then, polishing the silicon oxide film by a CMP method until the conductive layer of the gate electrode is exposed, and further forming a silicon oxide film on it by a CVD method using PH3—SiH4—O2.
Japanese patent laid-open Nos. 7-147281 and 3-194932 disclose a technology for forming a silicon oxide film between wirings by CVD using O3-TEOS, then removing the silicon oxide film by etching back or CMP until the upper portion of the wiring is exposed, and further forming a silicon oxide film on it by plasma CVD using TEOS.
Japanese patent laid-open No. 7-221179 discloses a technology for filling an area between wirings with an O3-TEOS NSG silicon film (which generates in-situ reflow at the deposition), then forming a silicon oxide film by plasma CVD, and then planarizing it by CMP.

Semiconductor integrated circuit device and a method for manufacturing a semiconductor integrated circuit device

Abstract: In the present invention, in the pre-metal process, after forming the ozone TEOS film over an etch stop film, the ozone TEOS film is once etched back so as to expose the etch stop film over a gate structure, and, after that, a plasma TEOS film is formed over the remaining ozone TEOS film, and then the plasma TEOS film is planarized by CMP.


The invention concerns the use of a recombinant nucleotide sequence containing a cDNA coding for a lactoferrin, in particular human lactoferrin, or the derived proteins, and elements enabling a plant cell to produce lactoferrin or the derived proteins, coded by the cDNA, in particular a transcription promoter and terminator identified by the plant cell transcription machinery, to transform plant cells in order to obtain, from these cells, or plants obtained therefrom, lactoferrin or derived proteins.

The present invention relates to recombinant lactoferrins (rLf), their production from plants, and uses thereof.
The use of certain proteins found in mammals has been questioned due to the possibility of contamination by non conventional infectious agents, particularly of the prion type. The impact on marketing and regulations is great. The development of proteins free of all animal contamination is, therefore, a new possibility but one which faces new difficulties depending on the protein and the plant matter chosen.
Prior art includes the publication by Mitra et al. (1994), which describes the transformation of tobacco cells with the DNA sequence which codes for human lactoferrin. However, this publication is limited to plant cells, and does not allow for the production of regenerated plants from these cells. Furthermore, the protein expressed is not purified, and seems, in any case, imperfect as only a part (48 kDa) is detected, and not the entire protein.
In the prior art, application WO 9637094 is also known; this describes the production of plants which are resistant to viruses, by means of transforming them with a gene which codes for lactoferrin. However, in this document as well, the protein is not purified and the only indication of its presence is a Weston blot test.
As a result of the complexity of lactoferrin and the characteristics of the plant matter used, the extraction and purification procedures also represent major obstacles in the production of lactoferrin from plants. The difficulties posed by these two procedures can represent a new set of problems for each protein which one wishes to produce from a plant.
Lactoferrin is a glycoprotein of the transferrin family. Following its discovery in human milk, lactoferrin was shown to be present in many other species such as cows, goats, pigs, mice and guinea pigs, but a highly variable concentrations. In human milk, the concentration of lactoferrin is in the range of 1 to 2 g/l; the concentration is particularly high in colostrum and diminishes over the course of lactation. In milk, lactoferrin is present primarily in the apo form, that is to say, unsaturated in iron. Lactoferrin has also been found in many other secretions, such as the saliva, bile, pancreatic fluid, and secretions of the small intestine. It is found in most mucus, such as bronchial, vaginal, nasal and intestinal secretions.
Lactoferrin is also present in polymorphonuclear neutrophilic leucocytes, where it is localized in the secondary granules of cells that do not contain myeloperoxidase. Leucocytic lactoferrin is synthesized during granulopoiesis of the promyelocyte stage of the metamyelocyte stage. When the neutrophils degranulate, lactoferrin is released into the plasma at a relatively low concentration (0.4 to 2 mg/l) as compared with the level of transferrin found in the blood (2 to 3 g/l).
The peptide sequence for human lactoferrin (hLf) was determined in 1984 by Metz-Boutigue et al. This sequence of 692 amino acids was confirmed by way of cloning of the cDNA for lactoferrin of the human mammary gland (Powell and Ogden, 1990, Rey et al., 1990). Lactoferrin and serotransferrin have very similar primary structures and spatial configurations. Their polypeptide chains are formed of two lobes (N terminal lobe and C terminal lobe) joined by a small alpha helix peptide. Sequence similarities between the N and C terminal halves of human lactoferrin reach 37%. Trypsic hydrolysis of human lactoferrin allowed Legrand et al. (1984) to produce the 30 kDa N trypsic (N-t) fragment (residues of amino acids 4 to 283), and the 50 kDa C trypsic (C-t) fragment (residues of amino acids 284 to 692). At equimolar proportions, these fragments can reunite to form a non-covalent N-t/C-t complex which has electrophoretic and spectroscopic characteristics similar to those of human lactoferrin (Legrand et al, 1986).
Lactoferrin can reversibly bind two ferric ions which results in a salmon-pink coloration, the maximum absorption of which is centered at 465 nm. The binding of each ferric ion requires the same of a carbonate ion. At a pH of 6.4, the association constant of the complex [Fe3+]2-Lf is in the range of 1024 Mxe2x88x921, which decreases with pH. X-ray diffraction study of human lactoferrin at 3.2 xc3x85 to 2.8 xc3x85 and at 2.2 xc3x85 show that each ferrous ion is coordinated with 2 tyrosine residues, a histidine, an aspartic acid and a carbonate ion. These amino acids are the same in both lobes. Both lactoferrin iron binding sites have a strong affinity for this metal, but they release it at different pH levels. The N-t lobe releases its iron at pH 5.8 (acid labile lobe), while the C-t lobe (acid stable lobe) releases its iron at pH 4. Other ions may bind to the protein, in particular gallium. Researchers interested in the use of a 67Ga-Lf complex as a tracer in cancer diagnostics have shown that following injection with 67Ga, the complex is preferentially found in the mammary tissues, in physiological and pathological secretions and in Burkitt and Hodgkin lymphomas.
In terms of glycosylation, lactoferrin isolated from human milk has three glycosylation sites, Asn138, ASN479 AND Asn624, the first located on the N-t lobe and the other two on the C-t lobe. Glycosylation occurs preferentially at two sites (Asn138 and ASN479) in 85% of molecules, while glycosylation of one site (Asn479) and of the three sites simultaneously happens in 5% and 9% of cases, respectively. Lactoferrin glycans are of the mono or disialylated and fucosylated N-acetyllactosamine type (Spik et al, 1982). The fucose residues are a (1,6) branched on the N-acetylglucosamine 5xe2x80x2 of the attachment point, or are xcex1 (1,3) branched on the N-acetylglucosamine 5xe2x80x2 of the antenna. Leucocytic lactoferrin differs from that above by the total absence of fucose.
While serotransferrin is unquestionably the principal transporter of iron in all the cells of the organism, the roles played by lactoferrin appear to be essentially linked to defense of the organism and inflammatory mechanisms, working either directly on pathogenic micro-organisms, or indirectly on the effector immune cells.
Lactoferrin is an anti-microbial agent which works by way of several mechanisms. The first of these is the bacteriostatic effect of lactoferrin by means of iron deprivation (Spik et al., 1978). By taking up iron from its surroundings, lactoferrin inhibits bacteria division, as iron is an indispensable element in the biosynthesis of DNA. Furthermore, a more complex mechanism which causes antibodies to act has been shown. The bacteriostatic activity of lactoferrin increases in the presence of the specific IgA and IgG of the pathogenic bacterium. At the same time, lysozyme can associate its lytic activity on the walls of Gram+ bacteria with the action of lactoferrin. Thus, in milk, lactoferrin, lysozyme and antibodies can act synergistically in case of microbe attack.
The second anti-bacterial effect of lactoferrin is linked to it bactericidal capacity. Lactoferrin appears to bind to the walls of Gramxe2x88x92 bacteria, which appears to destabilize them and to provoke the release of lipopolysaccharides (LPS). Thus it would seem that the walls become more fragile and more susceptible to the effects of hydrophobic antibiotics. These theories have been confirmed by use of electron microscopy which shows the destabilizing effects of lactoferrin on Gramxe2x88x92 bacteria, including E. coli. A hypothesis has been made to the effect that the binding of lactoferrin occurs on the A lipid of the LPS, and that this is followed by the extraction of these LPS from the external membranes of the bacteria, irreparably damaging them. The bactericide regions of human lactoferrin (lactoferrin A) and bovine lactoferrin (lactoferrin B) have recently been identified. They are both found in an N-terminal lobe loop comprising 18 amino acids. This loop is formed by a disulphur bridge between the residues Cys 30 and 37 for human lactoferrin, and 19 and 36 for bovine lactoferrin. In addition, the importance of the loop formed by residues 28-34 of human lactoferrin in its binding to LPS has been demonstrated.
Thus, due to its bacteriostatic and bactericide activities, lactoferrin present in human milk protects nursing infants from infantile diarrheas.
An anti-fungal effect has been established for lactoferrin with respect to several strains of Candida. Studies have also been carried out with bovine lactoferrin showing this action both on yeasts and on filamentous fungi. Also, the effect of bovine lactoferricin appears to be greater than that of whole bovine apolactoferrin and similar to that of polymyxin B, an antibiotic of the cationic peptide type, known for its membrane destabilisation properties. It has also been shown that lactoferrin B interacts directly with the surface of the fungus, thereby introducing changes to its ultrastructure.
Recently, an antiviral activity has been demonstrated for lactoferrin by several authors. Certain types of virus penetrate the cells by means of a mechanism which causes absorption of proteoglycans by the membranes of the target cells, followed by binding at a specific receptor and fusion of the viral membrane with that of the host. As it is highly basic, lactoferrin binds to the heparan sulphates of cells, and is thereby able to inhibit the adsorption of several types of virus. Highly conclusive in vitro studies have been carried out using HIV (human immunodeficiency virus) and HCMV (human cytomegalovirus) with a CI50 in the range of 10 xcexcg/ml. Similar results have been achieved with HSV-1 (herpes simplex virus type 1). This work showed not only blocking of virus receptors (heparan sulphates, proteoglycans, LDL receptor), but also a possible interaction between lactoferrin and the virus. These recently discovered roles represent new possibilities for prevention and treatment, particularly in terms of immunodeficiency illnesses or recurrent illnesses, in terms of these viral infections.
One of the consequences of tissue inflammation is the formation of free radicals and the peroxidation of lipids. The formation of these free radicals results particularly from the phagocytosis mechanisms of the micro-organisms. According to the Haber-Weiss reaction, free radicals are created as the result of ferric iron, which acts as a reaction catalyst. It has been shown in vivo that lactoferrin, coming from the degranulation of neutrophils, stops the formation of extra-cellular free radicals by immediately taking up the iron which would catalyse the formation of these radicals. As the result of this action, lactoferrin prevents tissues from being damaged. By means of a similar mechanism, lactoferrin inhibits the peroxidation of lipids and thus protects the cellular membranes to which it binds. These studies also showed that lactoferrin has anti-oxidising and anti-inflammatory effects if the protein is in the form without iron.
Lactoferrin released by leucocyte granules has been identified as an inhibitor of granulocyte and macrophage colonies by reducing the production of GM-CSF (granulocyte and macrophage colony stimulation factor). The mechanism involved seems complex, as lactoferrin appears to act by inhibiting the release of a monokine, which is itself responsible for the release of GM-CSF by the lymphocytes, the fibroblasts and the endothelial cells. This monokine has been identified at IL1.
Many of the roles played by lactoferrin, such as the suppression of the production of antibodies, regulation of complement activation and regulation of NK (natural killer) cells activity, suggest mechanisms which are regulated by cytokines. Studies show that lactoferrin can exert a negative retrocontrol on certain cytokines such as the IL1, the IL2 and the TNFa, so as to prevent the activation of leucocytes in inflammation areas.
Zimecki et al (1991) showed that immature CD4xe2x88x92 CD8xe2x88x92 thymocytes incubated in the presence of lactoferrin acquire the marker CD4+ characteristic of auxiliary lymphocytes. These authors also point out various phenotypic and functional changes in B cells in the presence of lactoferrin (Zimecki et al., 1995). A specific receptor for human lactoferrin has been defined for activated lymphocytes (Mazurier et al., 1989). In addition, the site of interaction between lactoferrin and its lymphocytic receptor has been described: Legrand et al. (1992) showed that it was contained in the N terminal region, and more specifically, in the first 50 residues of lactoferrin.
Lactoferrin appears to regulate the cytotoxic activity of NK (natural killer) cells and LAK cells at very low quantities (0.75 xcexcg/ml). Lactoferrin significantly increases the cytotoxic activity of NK cells with respect to tumour cells and cells infected by retroviruses. Lactoferrin also effects, the cytotoxicity of monocytes. The cause of this stimulation by lactoferrin of the cytotoxic activity of NK cells, of lymphocytes and also adherent cells may be the result of either activation of the killer cells following the internalisation of lactoferrin, or of a modification of the target cells which then become more susceptible to lysis.
Lactoferrin also seems to play a immunoregulatory role in inflammatory responses (Elass-Rochard et al., 1995; confirmed by Elass-Rochard et al., 1998). Demonstration of anti-tumour activity was also the object of studies by Salmon et al. (1998).
Lactoferrin has a growth factor effect on various cells in environments lacking in foetal veal serum. This activity has been demonstrated, particularly on the B and T lymphocytic strain with respect to a macrophage murine strain (P388 DI). Lactoferrin also stimulates the incorporation of thymidine tritiate in the DNA of rat enterocytic cells.
The role of iron in growth factor activity is still an object of controversy. According to some authors, lactoferrin works by providing the iron necessary to cellular proliferation. Others hold that iron is not involved, and that the mitogen activity is due solely to the protein itself.
The hypothesis to the effect that lactoferrin is involved in the intestinal absorption of iron results from the observation that amongst breast-fed infants, the incidence of iron deficiency is very low. In fact, only such children maintain a major supply of iron up to the age of 6 months, which implies high bioavailability for iron contained in human milk. The percentage of absorption can reach 81% during the first three months of life, and diminishes rapidly thereafter. Amongst the various components of human milk, lactoferrin is the best candidate for explanation of both the great bioavailability of iron in milk and regulation of its absorption. Cox et al. studied the importance of lactoferrin in the absorption of iron by the human intestine as early as 1979. The enterocytic receptor for lactoferrin was first shown to be present in rabbits, then in mice. Finally, the human enterocytic receptor was studied. It was shown that, with HT29 enterocytic cell cultures, the number of lactoferrin receptors doubled in the presence of iron chelator (Mikogami et al., 1994, 1995). This increase is due to a de novo synthesis of receptors. The expression of the lactoferrin receptor is, therefore, regulated by a lack of iron, and this lack also induces an increase in the internalisation of the lactoferrin receptor by the enterocytes. Thus, lactoferrin seems to be involved in iron nutrition, in particular, in case of iron deficiencies.
Not only has the cDNA sequence for human lactoferrin been determined, but the cDNA sequence for various animal species has been established. Specifically, sequences have been found for:
bovine lactoferrin (Pierce et al., 1991)
porcine lactoferrin (Alexander B. F. et al., 1992)
murine lactoferrin (Shirsat N. V. et al., Gene, 1992)
caprine lactoferrin (Le Provost F. et al., 1994).
Analysis of peptide sequences corresponding to cDNA sequences indicates major similarities. In particular, the human lactoferrin sequence shows a 69% correspondence with that of cows. As with human lactoferrin, the nucleotide sequence of bovine lactoferrin cDNA contains a signal peptide composed of 16 amino acids.
This structural similarity results in functional similarities. In particular, as the N-terminal end of both bovine and human lactoferrin have a great number of basic amino acids, these two lactoferrins are recognised in a similar way by many constituent acids. It should be noted, for example, that these two proteins have similar interactions with the lipopolysaccharides of Gramxe2x88x92 bacteria and the proteoglycans which are found on the surface of many cells. (Elass-Rochard E., et al., 1995).
These interactions appear to imply that these two lactoferrins may play the same role in the inhibition of release of cytokines of macrophages activated by lipopolysaccharides, and therefore in inflammatory reaction mechanisms.
In the same manner, these two lactoferrins show the same binding characteristics for enterocytic cells and, therefore, play the same role in intestinal iron absorption and various anti-bacterial and anti-viral activities.
Thus, the many roles played by lactoferrin, and especially its antioxidant, anti-microbial and anti-viral activities make this protein of major importance in terms of treatment, and above all prevention, of bacterial, fungal and viral infections, and also in terms of the prevention of septic shock which, classically, occurs after surgical operations.
The immunoregulatory and anti-tumour activities of lactoferrin can also be used in the treatment of inflammation and cancer (Denis et al.; Zimecki et al.).
Lactoferrin can also be used in dermo-pharmaceutical and cosmetic treatments, for example in a cosmetic anti-free-radical treatment, or to protect hair keratin against atmospheric damage.
The invention concerns:
the use of a recombinant nucleotide sequence containing both: a cDNA coding for a lactoferrin, particularly for mammalian lactoferrin, preferably bovine, porcine, caprine or human lactoferrin, or derived proteins (derived protein meaning any protein having at least 70% correspondence with the target protein, particularly at least 80%, for example between 85 and 100% correspondence and/or having a different glycosylation profile while maintaining the functional characteristics of the reference lactoferrin); and the elements required by a plant cell to produce the lactoferrin or derived proteins coded by said cDNA, particularly a transcription promoter and terminator recognised by the transcriptional machinery of plant cells, so as to produce from these cells, or from plants produced therefrom, lactoferrin or derived proteins.
a recombinant nucleotide sequence characterised in that it contains both: a sequence coding for lactoferrin, particularly for mammalian lactoferrin, preferably bovine, porcine, caprine or, human lactoferrin, or derived proteins; and the elements required by a plant cell to produce the lactoferrin or derived proteins coded by said cDNA, particularly a transcription promoter and terminator recognised by the transcriptional machinery of plant cells. Advantageously, the nucleotide sequence contains a sequence coding for a signal peptide responsible for the secretion of recombinant polypeptides.
a vector, particularly a plasmid, containing a nucleotide sequence according to the invention inserted, as necessary, at a site which is not essential for its replication.
a cellular host, particularly any bacteria such as Agrobacterium tumefaciens transformed by a vector according to the invention,
a method of producing lactoferrin, particularly human lactoferrin, or derived proteins, characterised in that it comprises:
transformation of plant cells, particularly by means of a cellular host according to the invention, this itself having been transformed by a vector according to the invention, so as to integrate a recombinant sequence according to the invention within the genome of these cells,
as necessary, the production of transformed plants from the aforementioned transformed cells,
recuperation of recombinant lactoferrin, particularly human lactoferrin, or derived proteins produced in said aforementioned transformed cells or plants, particularly by extraction followed, as necessary, by purification,
a genetically transformed plant, plant extract or part of a plant, particularly leaves and/or fruits and/or seeds and/or plant cells, characterised in that it contains one (or several) recombinant nucleotide sequence(s) according to the invention which is (are) integrated in a stable manner in the genome thereof, these plants being particularly chosen from amongst rape, tobacco, maize, peas, tomatoes, carrots, wheat, barley, potatoes, soy, sunflower, lettuce, rice, alfalfa and beets.
a lactoferrin, particularly a human lactoferrin, or a derived protein, characterised in that it is obtained by means of the method of the invention,
a genetically transformed plant, plant extract or part of a plant, particularly leaves and/or fruits and/or seeds and/or plant cells, characterised in that it contains a lactoferrin, particularly a human lactoferrin or a derived protein, according to the invention, these plants being particularly chosen from amongst rape, tobacco, maize, peas, tomatoes, carrots, wheat, barley, potatoes, soy, sunflower, lettuce, rice, alfalfa and beets.
the use of plants, plant extracts or parts of plants and/or proteins (lactofrrrin, particularly human lactoferrin, or derived proteins) according to the invention, for the production of pharmaceutical, medical, odontological, cosmetic or biotechnological compositions,
a biomaterial or a pharmaceutical, medical, odontological, cosmetic or biotechnological composition characterised in that this comprises plants, plant extracts or parts of plants according to the invention, and/or proteins (lactoferrin, particularly human lactoferrin, or derived proteins) according to the invention.
A pharmaceutical composition according to the invention includes particularly any composition according to the invention which constitutes or is used in the manufacture of a composition allowing for the detection or treatment of a pathology or a symptom of bacterial, fungal or viral origin, an inflammation or a pathology having an inflammatory component, septic shocks, a pathology related to a cellular growth phenomenon or an iron deficit, such as anaemia.
A cosmetic composition according to the invention includes particularly any composition according to the invention constituting (or used in the manufacture of) an additive for preparations (creams, ointments, makeup, salves).
Advantageously, the recombinant sequences according to the invention contain one (or several) sequence(s) which code for a peptide responsible for addressing recombinant polypeptides in a specific compartment of the plant cell, particularly in the endoplasmic reticulum or in the vacuoles, or even outside the cell in the pectocellulosic wall or in the extracellular space know as the apoplasm.
Amongst the transcription terminators which can be used for the transformation of plant cells within the framework of the present invention, examples include terminator polyA 35S of the cauliflower mosaic virus (CaMV), or the terminator polyA NOS, which corresponds to the non-coding 3xe2x80x2 region of the nopaline synthase gene of the plasmid TI of the nopaline strain of Agrobacterium tumefaciens.
Accordingly, the invention takes as its object any recombinant nucleotide sequence such as described above which contains the terminator polyA 35S of the CaMV, or the terminator polyA NOS of Agrobacterium tumefaciens downstream of said cDNA or a derived sequence thereof.
Amongst the transcription promoters which can be used for the transformation of plant cells in the framework of the invention, examples include:
the promoter 35S (P35S), or advantageously the double constitutive promoter (Pd35S) of the CaMV: these promoters allow for expression of the recombinant polypeptides of the invention in the entire plant produced from transformed cells according to the invention, and are described in the article of Kay et al., 1987,
the promoter PCRU of the radish cruciferin gene allows for the expression of the recombinant polypeptides of the invention in only the seeds (or grains) of the plant produced from transformed cells according to the invention and is described in the article by Depigny-This et al., 1992;
the promoters PGA1 and PGA6, which correspond to the non-coding 5xe2x80x2 region of the seed reserve protein genes, GEA1 and GEA6 respectively, of Arabidopsis thaliana (Geubier et al., 1993) allow for specific expression in seeds,
the chimeric promoter super-promoter PSP (Ni M. et al., 1995), which is constituted from a triple repetition of a transcription activation element of the Agrobacterium tumefaciens octopine synthase gene promoter, of a transcription activation element of the mannopine synthase gene promoter, and of the mannopine synthase promoter of Agrobacterium tumefaciens,
the rice actin promoter followed the actin intron (PAR-IRA) contained in the plasmid pAct1-F4 described by McElroy et al., (1991),
the barley HMWG (high molecular weight glutenin) promoter (Anderson O. D. et al., 1989),
the maize xcex3zein gene promoter (Pxcex3zein) contained in plasmid pxcex363 described in Reina et al., (1990) which allows for expression in the albumen of maize seed.
Accordingly, the object of this invention extends to any recombinant nucleotide sequence such as described above containing the double 35S constitutive promoter (Pd35S) of the CaMV, the promoter PCRU of the radish cruciferin gene, the promoters PGA1 or PGA6 of Arabidopsis thaliana, the chimeric promoter super-promoter PSP of Agrobacterium tumefaciens, the rice PAR-IRA promoter, the barley HMWG promoter, or the maize Pxcex3zein promoter, upstream of said cDNA or a sequence derived therefrom.
Sequences coding for an addressing peptide in the framework of the present invention may be of plant, human or animal origin.
Amongst sequences coding for an addressing peptide originating in plants, examples include:
the nucleotide sequence of 69 nucleotides (shown in the examples which follow) which codes for the 23 amino acid prepeptide (signal peptide) of sporamin A in sweat potatoes, this peptide signal allows the recombinant polypeptides of the invention to enter the secretion system of the plant cells transformed according to the invention (that is to say, principally in the endoplasmic reticulum),
the nucleotide sequence of 42 nucleotides (shown in the examples which follow) which codes for the vacuolar addressing N-terminal propeptide of 14 amino acids of sweet potato sporamin A, which allows for the accumulation of recombinant polypeptides according to the invention in the vacuoles of plant cells transformed according to the invention,
the nucleotide sequence of 111 nucleotides (shown in the examples which follow) which codes for the prepropeptide of 37 amino acids of sporamin A comprising the N-terminal part nearest the C-terminal part comprising the 23 amino acids of the aforementioned signal peptide, followed by the 14 amino acids of the aforementioned propeptide: this prepropeptide allows for entry of the recombinant polypeptides of the invention in the secretion system, and their accumulation in the vacuoles of the plant cells transformed according to the invention; the three aforementioned sequences are described in the articles of Murakami et al., 1996, and Matsuoka et al., 1991,
the barley lectin carboxy terminal propeptide, particularly as described in the articles of Schroder et al., 1993, and Bednarek et al., 1991,
and PRS (pathogenesis related protein, Corenlissen et al., 1986) which allows for secretion.
Amongst sequences which code for an addressing peptide, examples also include those coding for the peptides KDEL (SEQ. ID. NO.: 1), SEKDEL (SEQ. ID. NO.: 2) and HDEL (SEQ. ID. NO.: 3), and allowing for addressing in the endoplasmic reticulum.
The object of the invention also extends to any recombinant nucleotide sequence such as described above which contains a sequence coding for all, or part, of a vacuole addressing peptide, particularly that of sweat potato sporamin A; where this sequence codes for a vacuole addressing peptide which is located, in said recombinant nucleotide sequence, between the sequence coding for a signal peptide and that coding for said cDNA or a derived sequence thereof, in such a way that the first N-terminal amino acid of the vacuole addressing peptide is joined to the last C-terminal amino acid of the signal peptide, and wherein the last C-terminal amino acid of said addressing peptide is joined to the first N-terminal amino acid of the polypeptide coded by said cDNA or a derived sequence thereof, in the protein coded by said recombinant nucleotide sequence.
The object of the invention also extends to any nucleotide sequence such as described above which contains a sequence which codes for all or part of a vacuole addressing peptide, particularly that of barley lectin, wherein this sequence codes for a vacuole addressing peptide which is located upstream of the sequence coding for said cDNA or a derived sequence thereof, so that the first N-terminal amino acid of the vacuole addressing peptide is joined to the last C-terminal amino acid of the polypeptide coded by said cDNA or a derived sequence thereof, in the protein coded by said recombinant nucleotide sequence.

Recombinant lactoferrin, methods of production from plants and uses


A method of fabricating a semiconductor device is provided. A substrate is provided. The substrate includes a first region, a second region and a third region. An isolation structure is formed on the substrate in the first and the second region. A removing process is performed to remove the isolation structure in the first region, so as to form a first opening exposing a top surface of the substrate. A gate structure is formed on the substrate, covering a part of the substrate in the first region and a part of the isolation structure in the second region. A first doped region of a first conductive type is formed at one side of the gate structure in the first region, and a second doped region of the first conductive type is formed in the substrate in the third region.

1. Field of the Invention
The embodiments of the invention relate to a semiconductor device and a fabricating method thereof, and particularly relates to a laterally diffused metal oxide semiconductor (LDMOS) device and a fabricating method thereof.
2. Description of Related Art
A laterally diffused metal oxide semiconductor (LDMOS) device is a typical high voltage device and the process of fabricating the same may be integrated with the process of fabricating a complementary metal oxide semiconductor (CMOS) to fabricate control circuits, logic circuits and power switches on a single chip. When operating a LDMOS device, a high breakdown voltage and a low on-state resistance (Ron) must be provided. The LDMOS device having a high breakdown voltage and a low on-state resistance (Ron) has a lower power consumption when being operated under a high voltage condition. Furthermore, a lower on-state resistance (Ron) allows the transistor have a higher drain current in saturation state to improve the operating speed of the device. However, the on-state resistance of the conventional LDMOS transistors cannot be further reduced to present a more preferable device characteristic. Therefore, it is necessary to develop a LDMOS transistor having a high breakdown voltage and/or low on-state resistance, so as to improve the device characteristic of the LDMOS transistor.

Semiconductor device and method of fabricating the same


Output waveform of the generator is improved through stabilization of field current by removing flywheel diode used to be required for automatic voltage regulator. Output electric current of excitation winding 3 is rectified by rectifier 8 and is supplied to field winding 5 of rotor 4. Impedance adjustment circuit 12 is provided to circuit where field current flows. Target electric current determination unit 10 determines target electric current (target field current) used to control output voltage of power generation winding 2 to the reference voltage. Impedance adjustment circuit 12 increases or decreases the impedance of field current circuit so that the field current detected by electric current detector 11 converges with target electric current.

1. Field of the Invention
The present invention relates to an output control apparatus of a generator, and particularly to an output control apparatus of a generator suitable for further improvement of output voltage waveform by maintaining an electric current flowing a field winding constant.
2. Description of the Related Art
In a power generation control apparatus of an alternating-current (AC) generator which includes a power generation winding, excitation winding, and field winding, and rectifies electric current generated in the excitation winding and supplies the same to the field winding, automatic voltage regulator is known in the art which maintains a voltage output from the power generation winding to a predetermined voltage by controlling the electric current supplied to the excitation winding.
FIG. 6 is a drawing showing composition of primary components of the AC generator equipped with conventional automatic voltage regulator. In FIG. 6, a generator 100 includes a field winding 102, a power generation winding 103, and an excitation winding 104. A permanent magnet 106 is provided to a rotor 105 around which the field winding 102 is wound. An automatic voltage regulator (AVR) 107 are provided with a rectifier 108, a voltage detection circuit 109, and a transistor 110. Output of the rectifier 108 is connected to the field winding 102 via a brush 111, and a flywheel diode 112 and a capacitor 113 are connected in parallel with the field winding 102. The excitation winding 104 is connected to input side of the rectifier 108. The rotor 105 is driven by a driving source such as engine (not shown).
In FIG. 6, when the rotor 105 is driven by the engine or the like, an electric current is generated to the excitation winding 104 by the permanent magnet 106. This electric current is rectified by the rectifier 108 and is supplied to the field winding 102 in the form of direct-current (DC) excitation current. The voltage detection circuit 109 compares an output voltage of the power generation winding 103 with a predetermined voltage and executes ON/OFF control of the transistor 110 depending on magnitude of the output voltage with regard to the reference voltage. When the transistor 110 is ON, electric current flows through the field winding 102 thereby increasing output of the power generation winding 103, and when the transistor 110 is OFF, electric current does not flow through the field winding 102 and output of the power generation winding 103 is decreased. Output of the generator 100 is maintained constant by ON/OFF control of the transistor. An example of such AC generator equipped with the automatic voltage generator is described in Japanese Patent Application Laid-Open (JP-A) No. 08-140400.
In the above-mentioned generator, by flowing an electric current through the field winding 102, an induced current is generated to the power generation winding 103, then a back electromotive force is induced to the field winding 102 by magnetic field generated by the electric current. Since the electric current flowing through the field winding 102 is increased or decreased by the back electromotive force, output of the power generation winding 103 fluctuates. However, with conventional automatic voltage regulator 107 which is based on the principle that current increase in constant direction is stopped by the transistor 110, electric current flowing through the flywheel diode 112 connected in parallel with the field winding 102 can not be decreased. When field current is PWM controlled based on voltage detection in the voltage detection circuit 109, the flywheel diode 112 is indispensable to absorption of surge voltage generated at energizing stop and smoothing of the field current.
Therefore, with the control apparatus having the flywheel diode 112, it is not easy to maintain the electric current flowing through the field winding 102 constant. When the electric current flowing through the field winding 102 can not be maintained constant, output voltage of the power generation winding 103 has distortions with respect to the sinusoidal wave. Hence, further improvement of the output voltage waveform is desired.


A DC or AC power conversion and regulation system in which DC or rectified AC is applied to a voltage controlled oscillator (VCO). The output of the VCO is applied to a frequency sensitive filter whose frequency response is such that for a fixed input voltage the output voltage is a function of the input frequency. The output of the filter is applied to a transformer whose output may be rectified to provide a regulated DC output. A portion of the rectified DC is sampled and compared with a reference voltage to generate an error signal which is used in a feedback loop to control the operating frequency of the VCO.

The invention relates to the field of electrical power conversion and regulation systems.
Various types of power conversion and regulation systems are well-known in the art. Modern electronic equipment which use microelectronic circuits or transistors generally require a low-voltage high-current power supply. Especially in devices which use digital logic, such as computers or microprocessors, there is a need to provide high power levels at a very precise voltage since in many such systems the difference in logic states is less than one volt.
Present techniques for regulating power involve the use of either dissipative regulators or switch mode regulators. Linear power supplies and associated dissipated regulators are highly inefficient and wasteful of energy and require bulky magnetics and massive heatsinks.
The basic techniques of switching power supplies are well-known, as shown in the article "Focus on Switching Power Supplies", Electronic Design, Vol. 26, No. 17, August 16, 1978, pp. 72-83. It is known that switching power supplies are highly efficient. In DC to DC converters, a switching power supply can deliver 60-90% efficiency as compared to linear supplies ' 20-50% efficiences. Since most switching power supplies operate at around 20 kHz, components can be made smaller and lighter than in linear supplies.
However, prior art switching supplies suffer from several disadvantages. Chief among them that power regulation is generally poorer than with linear supplies. Also, prior art switching supplies produce a considerable amount of electromagnetic interference due to approximately 50 mv peak-to-peak noise pulses. Prior art switching supplies are limited in their power handling capabilities since the components capable of handling high power levels are intrinsically "slow" (i.e. have a long recovery period between power saturation cycles). This limits the use of high power components to lower switching frequencies (e.g. below 20 KHz) which lower the overall efficiency of the system and results in greater component size and high levels of acoustic noise. Typically rise and fall times of high power switching SCRs are limited to .apprxeq.10 .mu.sec or more which limits their dynamic range when operated at pulse width modulation (switching) frequencies above the audio range (20 KHz). Of course, switching transistors could be paralleled for high power handling; however, the matching and balancing requirements for a high power system renders this solution impractical.
Prior art switching supplies such as that shown in the Electronic Design article at page 78 comprise a DC input applied to a switching circuit (typically a number of SCRs driven at 20 KHz) with the high frequency square wave output of the switching circuit being applied to a voltage conversion device such as an inductor or transformer. The output of the transformer is then rectified and filtered to produce pure DC without a high frequency ripple. In order to regulate the output voltage, a portion of the DC output is sampled and compared with a reference voltage to produce an error signal which controls a pulse modulation circuit. The modulation circuit controls the firing of the SCR switching transistors to produce a regulated DC output.
U.S. Pat. Nos. 3,416,062 and 3,205,424 are representative of prior art pulse width modulated (switching) power supplies having a feedback loop from the output to the switching oscillator. The pulse train generated by the oscillator generally comprises a series of square waves accompanied by spurious harmonics. These harmonics are eliminated by a band pass filter placed in the output of the oscillator.
U.S. Pat. No. 4,042,873 discloses a phase-locked loop voltage regulator having a voltage controlled oscillator (VCO) which controls the firing of an SCR pulse driving circuit through a ramp generator and comparator circuit. An AC input is applied to a phase detector which compares the phase angle of the applied power with the phase angle of the VCO output. A detected phase difference is filtered through a low pass filter and used to control the VCO. A separate comparator circuit detects the voltage output of the VCO and compares it with a reference voltage to control the conduction of the VCO output to the SCR pulse driving circuit.
It is known to employ an active harmonic filter in a Class C inverter circuit. In a Class C inverter pure DC is converted to pulsed DC by a capacitor or LC network switched by a load-carrying SCR. An active harmonic filter, such as that described in the GE SCR Manual, 4th ed, 1967, pp. 235-236 and 248, has a frequency response such that for a fixed input voltage the output voltage is a function of the input frequency. Such a filter is also known as an OTT filter, after its inventor. However, in the circuit described the OTT filter merely acts as a harmonic filter to provide a sine wave output to a load. The filter provides good load regulation while maintaining a capacitive load to the Class C inverter over a large range of load power factors. It will be noted however, that the described OTT filter is employed merely as an active harmonic filter and load regulator and plays no part in the voltate regulation scheme of its associated Class C inverter. Indeed, it is noted on p. 226 of the GE SCR Manual that due to design and component limitations a Class C inverter is only useful for switching frequencies below 1000 Hz.
It can thus be seen that there is a need for a simple, efficient and economical power conversion and regulation system which can employ high power and high frequency switching techniques with good output regulation and low noise.