Compounds of Formula (I),

This invention relates to inhibitors of beta amyloid production, which have utility in the treatment of Alzheimer's disease.
Alzheimer's Disease (AD) is the most common form of dementia (loss of memory) in the elderly. The main pathological lesions of AD found in the brain consist of extracellular deposits of beta amyloid protein in the form of plaques and angiopathy and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein. Recent evidence has revealed that elevated beta amyloid levels in brain not only precede tau pathology but also correlate with cognitive decline. Further suggesting a causative role for beta amyloid in AD, recent studies have shown that aggregated beta amyloid is toxic to neurons in cell culture.
Beta amyloid protein is composed mainly of 39 to 42 amino acid peptides and is produced from a larger precursor protein called amyloid precursor protein (APP) by the sequential action of the proteases beta and gamma secretase. Although rare, cases of early onset AD have been attributed to genetic mutations in APP that lead to an overproduction of either total beta amyloid protein or its more aggregation-prone 42 amino acid isoform. Furthermore, people with Down's Syndrome possess an extra chromosome that contains the gene that encodes APP and thus have elevated beta amyloid levels and invariably develop AD later in life.
There continues to be a need for compositions useful in inhibiting beta amyloid production and in the treatment of the effects of conditions associated therewith.

Fluoro- and trifluoroalkyl-containing heterocyclic sulfonamide inhibitors of beta amyloid production and derivatives thereof

Abstract: Compounds of Formula (I),

Abstract: are provided where T is CHO, CON, or C(OH)R1R2; R1 and R2 are hydrogen, optionally substituted lower alkyl, CF3, optionally substituted alkenyl, or optionally substituted alkynyl; R3 is hydrogen or optionally substituted lower alkyl; R4 is (CF3)nalkyl, (CF3)n(substitutedalkyl), (CF3)nalkylphenyl, (CF3)nalkyl(substitutedphenyl), or (F)ncycloalkyl; n=1-3; R5 is hydrogen, halogen, CF3, diene fused to Y when Y═C, or substituted diene fused to Y when Y═C; W, Y and Z are C, CR6 or N where at least one of W, Y or Z are C; R6 is hydrogen, halogen, or optionally substituted lower alkyl; X is O, S, SO2, or NR7; R7 is hydrogen, optionally substituted lower alkyl, optionally substituted benzyl, or optionally substituted phenyl; and R8 is lower alkyl, CF3, or optionally substituted phenyl. Methods of preparing and using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer's Disease and Down's syndrome are also described.


In a motor vehicle with an adjustable coupling (intermediate device) between the (crank)shaft and floor contact elements (wheels), wherein the coupling is set in trailing throttle mode in such a way that the rotational speed of the shaft is reduced, in particular is adjusted to a predefined value, in order to reduce the internal losses of the drive, in particular an internal combustion engine.

The invention relates to a method for operating a motor vehicle. A prerequisite is that the motor vehicle has a primary drive for rotating a shaft, for example an internal combustion engine with a crank shaft. The primary drive in this case is coupled with ground contact elements, in particular wheels of the motor vehicle, via an intermediate device. The intermediate device includes a clutch and as the case may be a transmission, wherein the clutch can be integrated into the transmission. A prerequisite is an adjustable intermediate device, in particular an adjustable clutch, i.e. the torque which is transferred via the intermediate device is to be changeable by varying a regulating variable (which in the example more or less directly relates to the clutch) so that a defined rotational speed of the primary drive can be set. In the example, such a clutch can be caused to assume intermediate states between a state of being decoupled and a state in which a maximal torque is transferred, the clutch is completely engaged.
It is known to detect during the drive of such a motor vehicle whether the movement of the motor vehicle occurs in coasting mode, i.e., whether the force flow proceeds from the wheels or other ground contact elements such as a chain, to the (crank)shaft and not vise versa as in the traction mode. Such a trailing throttle phase can for example be detected by way of the position of the gas pedal: in particular when the driver no longer actuates the gas pedal no active forward drive is generated any more by the primary drive (for example internal combustion engine). There is also the so called trailing throttle fuel cutoff: in trailing throttle mode the primary drive is only supplied with the kinetic energy which is inputted via the ground contact units by the clutch, in the example of a motor vehicle with internal combustion engine and transmission the fuel supply to the internal combustion engine is interrupted which saves fuel, the clutch is not engaged, the rotational speed of the crank shaft corresponds to the rotational speed on the transmission side and is thus proportional to the drive output rotational speed of the intermediate device. Small differences in rotational speed result due to a principally possible micro slip which for reasons of simplicity is disregarded in the following description. Due to the fact that the shaft of the primary drive still rotates with sufficient rotational speed an acceleration can be provided again relatively quickly when there is a corresponding demand by the driver for example via the gas pedal.
The trailing throttle fuel cutoff also involves that when exceeding a threshold value for the rotational speed of the primary drive shaft, supply with primary energy (in the case of an internal combustion engine with fuel) is initiated again in order to not allowing the rotational speed of the primary drive to become too low. At this threshold rotational speed the clutch is disengaged.
During the trailing throttle fuel cutoff the primary drive has a decelerating effect on the drive due to internal losses (for example compression in the internal combustion engine, mechanical losses etc.), wherein the kinetic energy which is inputted via the drive is predominantly converted into non-usable energy forms (for example heat). In the following, this no longer usable energy is referred to as loss energy. It would be desirable to be able to convert at least a portion of this energy into electric energy, for example via an electric machine.
As alternative to the trailing throttle fuel cutoff it is also known to disengage the clutch during trailing throttle mode and to operate the primary drive in neutral mode. This prevents that the primary drive absorbs kinetic energy. In addition, no renewed starting process is required for the primary drive in case of acceleration. A disadvantage is here the consumption of primary energy (for example fuel consumption when using an internal combustion engine as primary drive) for the neutral mode.
It is also possible to disengage the clutch during trailing throttle mode and to turn off the primary drive. As a result, neither primary energy nor kinetic energy is absorbed by the primary drive. This has the disadvantage that the primary drive has to be restarted again when accelerating.
It would thus be desirable to find a compromise so as to minimize the disadvantages of the mentioned possibilities of a trailing throttle mode.

Method for operating a motor vehicle in trailing throttle mode


Processing of a digital image that has been recorded through an optical system is described, the image being in a raw format matrix of picture elements and comprising a plurality of subsets of picture elements, each subset corresponding to a color component. The method comprises analyzing values of picture elements of the color components in terms of spatial features, resulting in at least one calculated parameter that is representative of aberration caused by the optical system, and performing demosaicing of the digital image by, for each picture element under consideration, defining a kernel comprising picture elements that are to be considered during the demosaicing, the definition of the kernel being dependent on the at least one parameter that is representative of the aberration.

In the process of image acquisition using an optical camera (from scene to image display), the image is degraded by the atmosphere, object or camera motion, the camera system's lens, internal optics and image sensors, processing, color interpolation and further post-processing. Thus, the displayed image may look distorted, defocused, color mixed, etc. In other words, the acquired image does not seem realistic compared to that of the scene of interest.
Optical aberrations are defined as the departures of the performance of an optical system from the predictions of paraxial optics (i.e. the ideal optical approximation of the image formation). Indeed, the light wave front, assumed ideally spherical before the optical system, is modified by it, yielding an aberrated image.
Optical aberrations may be divided into two main categories: monochromatic aberrations and chromatic aberrations. Monochromatic aberrations, which occur even when the light is quasi-monochromatic, are in turn divided into those that degrade the image making it unclear and those that deform the image. On the other hand, chromatic aberrations arise from the fact that refractive index of the lens is a function of frequency or color and therefore different "colored" rays will traverse a system along different paths. The aberrations may be summarized as follows.
Monochromatic spherical aberration occurs in a spherical lens or mirror because such lenses do not focus parallel rays to a single point, but instead along the line containing the center of the lens and the focal point, decreasing the contrast and degrade the details of an image.
Monochromatic coma occurs when a ray bundle originated at an object point is oblique with regard to the lens plane. Then, different rays will focus at different positions in the object plane. In images, the effect of coma produces the so-called coma flare, i.e. the repetition of the same object at different positions and with different magnifications.
Monochromatic astigmatism is the lens aberration in which tangential and sagittal lines are focused at two different points along the optical axis. The image is clearest somewhere between these two points, though edges have a certain amount of inevitable blur.
Monochromatic field curvature corresponds to the inability to bring the centre and the border of the image into focus at the same time, with the border out of focus when the centre is sharply focused and vice-versa. This aberration is closely related to astigmatism.
Monochromatic distortion appears because the transverse magnification is a function of the distance between the image center and the pixel under consideration. In the absence of any other aberrations, images as a whole appear as misshaped, even though each point is sharply focused.
Longitudinal chromatic aberration is such that the redder (i.e. longer wavelengths) components of the white light will be focused further away from the lens than the bluer (i.e. shorter wavelengths) components. This phenomenon produces a color halo around the spot in the generated images.
Lateral chromatic aberration appears in scene points which are not in the center of the image. In this case, the magnification and focus are wavelength dependent. In an image, this will result in a different magnification of every "colored" ray and different sharpening. Succinctly, the image will consist of a continuum of more or less overlapping images, varying in size, color and focus.
In images, there may be a predominant aberration with regard to others. However, the resulting image is typically a compound of all the aberrations. It is to be noted that the aberrations described here correspond to the primary aberrations and that higher-order aberrations may also be present in an image. Nevertheless, primary aberrations are the most representative.
In the prior art, the major amount of work on aberration correction involves modification of the optical system, by adding or deleting optical devices. The principle is fairly simple. For instance, if a positive lens introduces a specific aberration (e.g. certain amount of chromatic aberration), then a negative lens introduces the inverse aberration. Therefore, if these two reciprocal lenses are combined, the aberration should be eliminated. There are, however, many other problems, since the introduction of a new lens modifies other properties of the optical system. Thus, a compromise is needed between the amount of aberration that is eliminated and the properties that are desirable in the optical system.
Correction of optical aberrations has also been done by using software-based techniques. Such techniques are in principal similar to optical corrections, i.e. recovering the ideal light wave front by modifying the wave front generated after passing through an optical system. This can be performed, for example, by using the modulation transfer function (MTF), which characterizes uniquely the optical system. This implies a-priori knowledge on the system, either by means of manufacturer data or by experimental calibration.
An example of a software-based correction can be found in U.S. Pat. No. 7,221,793 to Stavely et al. where spatially-varied demosaicing is used to correct lateral chromatic aberration. A drawback of the methods and systems described in U.S. Pat. No. 7,221,793 is that it requires some a-priori knowledge regarding the optical system.

Image processing for aberration correction


A resin ring is integrally formed on an outer peripheral face of a metal ring to form a hub. On a lower end portion side of the resin ring, a step portion exposing the metal ring is formed. A positioning portion with which the step portion of the hub can be fitted is formed at a central portion of a lower flange. Positions in a height direction of lower end faces of the resin ring and the metal ring are different from each other. Even if a minute gap exists between the metal ring and a metal mold for molding the hub and fluid resin flows into the gap to produce a burr, the burr does not reach the lower end face of the metal ring. Therefore, variations due to the burr do not occur in the lower end face of the hub for positioning in dimension of product.

1. Technical Field
The present invention relates to a reel wound with recording tape such as magnetic tape and a recording tape cartridge.
2. Related Art
As an external recording medium for a computer or the like, a recording tape cartridge formed by housing a reel wound with magnetic tape in a case is known, for example. The reel includes a hub forming an axial center portion and wound with the magnetic tape around its outer periphery and an upper flange and a lower flange extending radially outward from axial opposite ends of the hub, respectively.
Conventionally, there is a known recording tape cartridge formed by winding recording tape such as magnetic tape on a single reel and rotatably housing the reel in a case made of synthetic resin, the tape used as a data recording and playback medium for a computer or the like. At a tip end (free end) of this recording tape, a leader member such as a leader pin, a leader tape, and a leader block is provided. A pull-out means provided to a drive device pulls out the leader member from an opening of the recording tape cartridge to thereby wind the recording tape fixed to it around a winding reel of the drive device.
In such a reel of the recording tape cartridge, the recording tape is normally wound around an outer peripheral face of its hub. An upper flange and a lower flange are provided above and below the hub, respectively. With the upper and lower flanges, the recording tape is restricted in its vertical height position, held to enhance a roll appearance and to improve traveling stability, and moreover protected from excessive damage when the tape is not in use.
Meanwhile, in many cases, the hub is formed into a cylindrical shape which has a bottom and in which axial one side is opened and the other side is closed. The hub in such a cylindrical shape with the bottom is likely to be deformed on its open end side having lower strength due to winding pressure of the magnetic tape. If the hub is deformed in this manner, the flange provided on the open end side of the hub is deformed in such a direction as to come in contact with a widthwise end portion (edge) of the magnetic tape.
Therefore, a configuration for reinforcing the hub with a metal ring so as to prevent deformation of the hub is conceivable as in Japanese Patent Application Laid-open (JP-A) No. 2004-14022 and JP-A No. 2005-116163, for example. However, in covering an outer peripheral face of the metal ring with resin and integrating the metal ring and resin with each other by insert molding, fluid resin may flow into a minute gap (of several tens of microns) existing between the metal ring and a metal mold in molding to thereby produce a resin burr on an end face of the metal ring and the burr causes variations in heights of hubs in dimensions of products.


The present invention is generally directed to an oral pharmaceutical tablet composition comprising a sulfate salt, for example, sodium sulfate, wherein the composition is capable of administration by direct oral ingestion and by disintegration in water prior to oral ingestion. The present invention is further directed to use of such oral pharmaceutical tablet formulations to induce laxation or to treat or prevent constipation.

Dosage Forms
Delivery of medication to a patient is often in the form of a tablet, liquid formulation or powder for reconstitution. Each dosage form has disadvantages. Patients are often unwilling, or unable, to swallow tablets, especially when the tablets are relatively large, or when an effective dose requires ingestion of multiple tablets. Challenges associated with swallowing tablets are particularly relevant for children and older adults. Likewise, some patients are unwilling, or unable, to drink liquid pharmaceutical formulations due to an undesirable taste and/or mouth feel.
When the amount of a specific active ingredient to be administered exceeds the amount that can be conveniently formulated in a tablet, the dosage is often provided as a powder or liquid concentrate. The powder or concentrate is then reconstituted for administration as an oral liquid, syrup or powder suspension. The preparation of a liquid formulation from a powder or liquid concentrate can be inconvenient or cumbersome, especially when the patient must take the medication chronically or frequently. This may result in reduced patient compliance and ultimately, in reduced effectiveness of the treatment regimen.
A single dosage form that can be administered as either an immediate release tablet or liquid provides options for patients, caregivers and hospitals when administering a medication to patients who prefer, or are unable, to take one form of medication or the other. For instance, a dual purpose tablet that can be swallowed whole or disintegrated in liquid prior to ingestion would be useful for patients able to swallow tablets, or for patients who prefer or require a medication in a liquid form, or for patients to whom the liquid is directly administered (e.g. delivery through a feeding tube).
Sodium Sulfate
Sodium sulfate is an abundant, naturally occurring salt known to have a laxative effect. However, formulating sodium sulfate in dosage forms, either for direct oral ingestion or in aqueous solution is quite challenging, stemming, at least in part, from the levels of salt required to achieve the desired laxative effect and, further, from the extreme hygroscopic nature and unique solubility profile of sodium sulfate.
With respect to formulating sulfate salts in tablet form for direct oral ingestion, the challenge stems, at least in part, from formulating a convenient dosage form containing a high level and/or effective amount of sodium sulfate to achieve the desired laxative effect. The laxative effect of sulfate salts requires approximately between 2 to 7 grams of sulfate ion and/or 3 to 11 grams of sulfate salts. However, until now, formulating tablets with a high level of sodium sulfate at a size appropriate for direct ingestion while minimizing the number of tablets required to induce laxation has proved challenging.
In addition, the extreme hygroscopic properties of sodium sulfate make the provision of a tablet formulation difficult. When placed in the mouth, the sodium sulfate immediately scavenges all available saliva creating an undesirable mouth feel and dry mouth, thereby making swallowing difficult.
With respect to formulating a tablet dosage form of sodium salt for disintegration in water, the chemical properties of sodium sulfate present significant challenges. Sodium sulfate exhibits unusual water solubility characteristics in that its solubility increases more than 10-fold from 0° C. to 32.384° C. At 32.384° C. the solubility curve changes and crystal water is released and the hydrated salt melts. In contrast to other salts (e.g., potassium, magnesium), the solubility of sodium sulfate does not increase with increasing temperature above 32.384° C. Due to these solubility characteristics, sodium sulfate will crystallize when concentrated and/or cooled.
The reaction of sodium sulfate and water is exothermic, generating heat during hydration and causing the localized water temperature to increase significantly. When sodium sulfate is added to ambient temperature water with no agitation, the water wets the sodium sulfate which is converted to sodium decahydrate and creates an exothermic reaction in the immediate physical area. The exothermic reaction can increase the temperature of the localized wetted salt by as much as 10° C. This results in a portion of the sodium sulfate dissolving to form a localized concentrated solution. However, as the heat from the reaction dissipates into the surrounding solution, the temperature of the localized high concentration sodium sulfate solution decreases and the sodium sulfate recrystallizes forming a very hard mass of sodium sulfate decahydrate (i.e., mirabilite).
Until now, acceptable tablets capable of rapidly disintegrating in water could only be achieved with the inclusion of a high level of inactive ingredients and excipients, which significantly increases the weight and mass of the final dosage formulation and potentially doubles the number of tablets needed to deliver an effective dose. Indeed, formulating tablets of sulfate salts for dispersion in water required about 50% to 90% of excipient, thereby limiting the levels of sulfate salts present therein.
For these reasons, formulation scientists have sought to formulate sulfate salts at the dosage levels necessary to achieve laxation in a powdered form for reconstitution or as a liquid or syrup.
Other forms of tablets include buccal tablets, sublingual tablets, chewable tablets and effervescent tablets. However, these formulations fail to address (i) the need for a versatile and convenient formulation to address patient compliance issues, and (ii) the need for a formulation of a high dose of sodium sulfate to achieve the desired laxative effect.
Dual use tablets of tetracycline have been proposed (see, U.S. Pat. No. 5,211,958; "Pharmaceutical Composition and Process for its Preparation"). However, the unique properties of sodium sulfate as described above do not allow for mere application of the teachings of proposed dual use tablets of alternative active agents to formulating dual use sodium sulfate tablets having a high level of active agent. In addition, the proposed tetracycline tablets include greater than 50% by weight of excipient. Moreover, the tetracycline tablets previously proposed have not been shown to be capable of disintegration in cool or cold water. Typical drinking water sources provide water at temperatures less than 20° C. An acceptable dual use tablet composition should perform as claimed throughout all typical drinking water temperatures.

Dual use oral pharmaceutical composition tablets of sulfate salts and methods of use thereof


A closure (10) that is suitable for attachment to a container (20) having an end portion defining an opening of the container. The closure (10) comprises a top portion (11) and a skirt portion (12) depending from the top portion. The closure (10) also has a sealing rib (14) having a first sealing portion (15) which is contiguous with the top portion (11). The first portion (15) has an inner surface made up of at least a first substantially cylindrical surface portion (17) lying radially inwardly of the first surface portion (17). The rib (14) further includes a second sealing portion (16) that is separated from the top portion (11) by the first portion (15) and which, prior to attachment of the closure to the container, extends inwardly to a free edge. The closure (10) further has a continuous nub member (28) extending downwardly and outwardly from the underside of the top portion (11) and positioned radially inwardly of the first sealing portion (15). On relative attachment of the closure to the container end portion, the nub member (28) seals with an inner surface of the container end portion and the sealing rib (14) seals with at least an outer surface of the container end portion.

U.S. Pat. No. 5,423,444 discloses a plastics closure for a container having an externally screw threaded neck, the closure including a top portion and an internally threaded skirt. The closure has an annular sealing rib which projects downwardly from the underside of the top portion. The rib includes a first substantially cylindrical portion contiguous with the underside of the top portion and lying adjacent to or abutting with the skirt, and a second, frusto-conical, portion contiguous with the end of the first portion distal to the underside of the top portion and extending radially inwardly to a circular free edge. During threaded attachment of the closure with the neck, the second, frusto-conical, portion is engaged by a free end of the neck and folded back toward or against the first, substantially cylindrical portion of the rib to form a gas tight seal between at least the outer surface of the neck of the container and the closure.
U.S. Pat. No. 5,609,263 discloses a variant of the above closure in which there is at the free end of the second portion of the rib a thick seal ring of substantially circular cross-sectional shape. The rib and the seal ring are dimensioned to engage the free end of the neck when the closure is threaded onto the neck such that when the neck is fully screwed into the closure its free end crushes the seal ring directly against the inside surface of the top portion of the closure.
International Patent Application No PCT/AU98/00510 (WO 99/03746) discloses still further variants of the closure described in U.S. Pat. No. 5,423,444. In one variant, the sealing rib of the closure has a third portion connected to the second portion at or adjacent its circular edge and extending generally in a direction away from the top portion. The third portion is substantially no thicker than the second portion and has a length longer than its thickness. On attachment of this closure to a container, the third portion is positioned between the neck of the container and the underside of the top portion of the closure.
The present invention is further directed to a sealing rib arrangement for closures. In particular, the sealing rib arrangement finds use in circumstances where the container neck has suffered damage prior to application thereto of the closure. Such damage can arise in situations where the container is a reusable container and as such has been used at least once before.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.


A component carrier may include a carrier front wall and a plurality of carrier side walls extending in a substantially parallel orientation to each other from opposite edges of the chassis front wall, and defining a component channel between them. The carrier side walls may include respective guide flanges extending substantially perpendicularly therefrom such that the guide flanges are in a substantially parallel orientation to each other and the guide flanges are oriented relative to the remainder of the component carrier such that when a component is mounted within the component channel to the component carrier, and the guide flanges may define a plane whereby a combined mass on a first side of the plane of the component carrier and the component is approximately equal to a combined mass on a second side of the component carrier and the component.

As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option available to users is information handling systems. An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling systems may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in information handling systems allow for information handling systems to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, information handling systems may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
Some information handling systems such as, for example, servers and storage systems, sometimes include a chassis that houses the components of the system. For example, some servers include a chassis that defines a component enclosure for coupling a plurality of storage drives (e.g., hot-plug hard drives) adjacent a front entrance of the chassis, and that houses the other server components of the server opposite the storage drives from the front entrance of the chassis. Oftentimes, certain components, in particular storage drives, having motors or other mechanical devices that cause vibration between such components and portions of the chassis. Because such vibration can cause undesirable side effects, such as inoperability, vibrational interference with other server components, and undesired acoustic noise, it may be desirable to provide a component carrier and guiding system to minimize or eliminate such vibration.

Systems and methods for reducing vibration associated with a component in an information handling system


An atmospheric leach process for the recovery of nickel and cobalt from lateritic ores includes providing limonitic and saprolitic ore fractions of a laterite ore; separately slurrying the limonitic and saprolitic ore fractions to produce a limonitic ore slurry and a saprolitic ore slurry; separating any limonitic type minerals from the saprolitic ore slurry to produce a saprolitic feed slurry; milling or wet grinding the saprolitic feed slurry; leaching the limonitic ore slurry with concentrated sulfuric acid in a primary leach step; introducing the saprolitic feed slurry to the leach process in a secondary leach step by combining the saprolitic feed slurry with the leached limonite slurry following substantial completion of the primary leach step, and releasing sulfuric acid to assist in leaching the saprolite feed slurry.

A laterite (nickeliferous) ore body essentially contains three fractions: the limonite fraction beneath surface soil, the saprolite fraction above the bed rock, and ores in the transitional zone between limonite and saprolite. The nickel-containing mineral in limonite is goethite and/or hematite, which are soft and fine in particle size. The nickel-containing minerals in saprolite are mostly coarse siliceous phases such as serpentine, garnierite, chlorite, nontronite, and smectite. The ore in transition zone contains both limonite and saprolite. With the aid of geological data and mining program, it is possible to separate limonite and saprolite via screening with designed cut-off particle size. However, in mining practice, it is difficult to have a clean separation of limonite and saprolite fractions. Consequently, the cross-entrainment of limonite and saprolite exists to a certain extent with the run-of-mine saprolite and limonite fractions.
PCT/AUO3/00309 (H. Liu et al, QNI Technology PTY LTD) describes an Atmospheric Acid Leach (AAL) process that processes the whole laterite ore deposit across the three ore zones. In the process described the limonite slurry (or the low Mg containing fraction) was mixed and leached with concentrated acid at temperatures up to 105° C. (or the boiling point at atmospheric pressure). The iron content in the tested limonite in the Examples of this application was generally from 40-43%, and the dose of sulfuric acid, in terms of the weight ratio of sulfuric acid to dry limonite ore, was 1.32 to 1.43. This is shown in each of the eleven Examples. At the equilibrium acidity of 0-10 g/L to form goethite, the saprolite (or the high Mg containing fraction) used showed good leaching reactivity and neutralization capacity. This was due to the fact that it was not significantly contaminated with limonite.
The mineralogy of laterite ore components varies depending upon from which region the ore is sourced. Table 1, in PCT/AU03/00309 shows the characterisation of various laterite ore bodies from different parts of the world. The ore which is used in the Examples of PCT/AU03/00309 was sourced from Gag Island, Indonesia. Because of the wide characterisation of different laterite ore bodies, the process to recover the nickel and cobalt from within the ore body must be tailored to maximise the recovery.
The Applicants have found that with a laterite ore body with high iron content, particularly a high iron content in the limonite fraction and a high goethite and/or hematite content in the saprolite fraction, the nickel recovery is compromised in an atmospheric leach process as the saprolite fraction has less leaching reactivity and neutralisation capacity. This is thought to be due to a higher goethite or hematite content in the saprolite fraction.
The present invention aims to overcome or alleviate some of the problems that may occur when processing a high iron content laterite under atmospheric pressure conditions.
A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims.

Atmospheric acid leach process for laterites


A computerized method for controlling the operation of a laser therapy device is disclosed. A laser therapy device comprising laser diodes has a microprocessor for storing and executing instructions pertaining to the operation of the laser diodes within certain parameters. The computerized method detects the movement of the laser therapy device and alters the output of the laser diodes when a movement signal exceeds predetermined threshold parameters. The computerized method detects difference in temperature in certain areas, and patterns in temperature differences, for assistance in diagnosing ailments. The computerized method also detects differences in skin color to determine treatment areas. The computerized method also measures the distance of the laser therapy device to a treatment area. The microprocessor executes instructions then which can alter the output of the laser diodes or generate an alarm signal based on measurements received.

Laser therapy is used in many different treatment scenarios, from Acupuncture through to surgery recovery. The therapeutic value of laser light was discovered by accident. Surgeons noticed that surgeries that were performed using laser scalpels healed faster and better than when using traditional metal scalpels. Furthermore, surgical laser devices required only a simple defocusing of the beam to be used effectively for therapy. Due to this simple re-purposing of existing technology, modern therapy lasers retain much of the engineering design of their surgical cousins.
While each treatment modality uses the same basic laser technology to produce laser light, each has a different requirement for how the light is emitted from the treatment device. Some modalities require tight focus of the beam down to a point (acupuncture), others prefer a larger diffused beam (pain management, wound healing) and certain specialized cases require that the laser light projects the shape of the physiology being treated (for example a long rectangle for treating the spine). Laser beam geometries and the limited capabilities of lenses make it difficult to achieve ideal projections patterns or shapes. Lenses simply take the poor geometry of the laser beam and expand it to a larger version of the poor geometry. Traditionally laser therapy devices use lenses to expand the laser beam, but have limited ability to alter the geometry. Minor differences in the energy level across a laser beam's geometry is magnified as the lens expands the beam. Thus the energy used across the larger area of treatment is not uniform and treatment efficacy is diminished. The operator has to compensate for these deficiencies by "painting" the treatment area. Some devices automatically move the treatment head during use but this approach is costly. Finally, some devices use multiple laser diodes to produce a shotgun effect to cover a larger area of treatment. What is needed is a laser therapy device which can expand the energy of the laser beam into a specific geometric area while at the same time creating a uniform energy distribution across the chosen area.
Laser therapy devices are also becoming increasingly powerful. While this enables greater treatment efficacy, it increases the attendant risks of operating such devices. There are legitimate concerns about using such devices because of the potential to inadvertently injure patients if misused. The high energy level of the beam, if not properly administered, may burn the patient. What is needed is a laser therapy device which automatically regulates the energy output of the laser therapy device during treatment to reduce the risk of such injury.
The present invention is directed toward a cordless, high-powered, laser therapy device. Current high power therapy lasers are based upon surgical lasers, due to the maturity of surgical laser technology. However, surgical lasers were developed to be stationary since they were intended to be used on immobile patients in an operating room environment. There was no requirement to make a surgical laser as a handheld or cordless device.
Although surgical and therapy lasers are almost identical in construction, their uses are very different. These different uses give rise to opportunities for an improved design of a laser device for therapy, but also present engineering hurdles. Specifically;
(1) Surgical lasers are single-modality devices with correspondingly limited operating parameters. Surgical lasers are required to cut tissue to a limited depth. Therapeutic laser devices on the other hand are used for many different inidications.
(2) When used for therapy, laser treatment exhibits so-called "dose dependence". This means that higher treatment doses generally produce an improved therapeutic outcome. Thus there is a tendency to use higher power laser therapy devices as this improves both treatment outcomes and the time (and cost) efficiency of treatment.
(3) Surgical lasers require a single narrow beam of light. Therapy lasers require a dispersed beam. Additionally, therapy lasers with a dispersed beam improve safety.
(4) Surgical lasers require exact control of power output as this determines the depth of cut. Therapy lasers are concerned more with "dose" or accumulated radiation, so lower power can be used at the expense of longer treatment time.
(5) Surgical lasers are required to heat tissue so hot that it evaporates, whereas therapy lasers must not be allowed to cause discomfort or tissue damage.
(6) Surgical lasers are directed at a very small area, whereas therapy lasers are frequently used to "paint" a treatment area. This results in higher probability of stray radiation.
Laser therapy devices vary principally in output power. The range is a few milli-Watts to tens of Watts. Like any light source, a laser diode is not 100% efficient. Waste energy is liberated as heat, so thermal management for high-power laser therapy devices is a significant engineering hurdle. Modern laser diodes are around 50% efficient. Thus 50% of the electrical power is converted to light output and the other 50% is converted to heat. In high power laser therapy devices, this "waste" heat presents two engineering concerns. The first is that a laser diode's efficiency and life degrade at elevated temperatures. The second is that dumping heat into the surrounding air requires a bulky cooling apparatus. Device overheating and optical fiber coupling problems are the major causes of device failure.
High power laser therapy devices consume significant electrical power. In order for a laser therapy device to operate as a cordless device, large batteries are required. This causes such a device to be overly bulky and perceived as impractical. Because of these hurdles, laser therapy devices have historically been tethered to a base station.
Therapy lasers have historically been repurposed surgical lasers. Manufacturers have simply applied different optical heads and software to these devices to diverge the beam. Although some of these devices are portable, they are only portable in that all the components can be moved from one location to another with relative ease. There has been no self-contained, high power, handheld laser therapy unit. No manufacturer has yet designed and implemented a therapy laser from scratch because of the comparative ease of repurposing surgical lasers. For this reason, the invention and advances described herein are nonobvious. Otherwise the advances described herein would already be available on the market.
The present invention overcomes these limitations. One embodiment of the invention is directed toward a cordless, high-powered, laser therapy device. "High-powered" means any optical power output by the laser therapy device that emits light output of five (5) Watts or higher, although the same technology can be employed to benefit lower power devices. The cordless, handheld, embodiment of the laser provides a great advantage in situations where a patient requires treatment in a specific position which would be awkward or impractical to treat with a corded device. Likewise, a cordless, handheld, laser therapy unit would be beneficial for treating animals in the care of a veterinarian.
Due to the limitations in the current state of the art, handheld laser therapy devices are unable to be high powered. Laser diodes typically require around 20% of the maximum electrical power before they start emitting light. Therefore at low output power levels the conversion rate of electrical power to optical power is very low. The power requirement therefore becomes overtly high just to be able to emit a small amount of light.
The current invention uses a novel approach for improving efficiency of the laser diodes at lower output power requirements (and therefore minimizing electrical consumption). The maximum efficiency of the laser diodes is when they are operating at maximum specified output power. The invention employs two mechanisms for adjusting the total output power of the device while the laser diodes are running at maximum output. Firstly, the invention disables a portion of the array of diodes. Those laser diodes that are switched on are operating at 100% of output but since there are fewer, the net light output is reduced. The second mechanism is to pulse the diodes between off and on at high frequency and to vary the percentage of time that the diode is in the "on" state. This technique of "Pulse Width Modulation" is used to provide a much finer degree of control than selective disabling of parts of the laser diode array. These two power control methods are using in addition to the typical proportional control of the laser diode's output.
The current invention also allows the laser to be controlled by a computer to allow for easier use by an operator. The invention controls the operation of the laser diode array only within specific parameters. This allows an operator to utilize the laser therapy device without risk of injury to a patient and thus improves the operation of the laser therapy device.


An electric motor consisting of an inside stator part and a rotor part placed outside and concentrically in relation to the stator part, has a high number of permanent magnets (13) on the inside of the rotor part. The magnetic fields from these permanent magnets interact with magnetic fields between flux-conducting lamella blocks (30, 35) engaging the coil cores (8) on the stator. The lamella blocks (30, 35) are T- and .GAMMA.-shaped with top beams (25, 27) pointing in directions parallel to the axis, and the top beams (25, 27) are positioned to provide substantially circumferentially directed magnetic fields in flux gaps (36) therebetween. The magnetic fields in the flux gaps (36) between the top beams (25, 27) are reversed in successive order, and under time control from an electronic regulator.

There is previously known from U.S. Pat. No. 4,280,072 a motor with some features which exhibit similarity with the present invention. According to the embodiment shown in FIGS. 9 and 10 of said U.S. patent, an outer rotor part is used which comprises four inside-mounted magnets, each covering an angular range of 90.degree. of the entire circumference. The inside stator part comprises four components which are similar to cog rims, however these components do not comprise circumferentially uniformly distributed flux conducting elements or "fingers". There are two so-called "poles" on each component, each respective pole being divided into three "teeth", and each such pole range covers about 90.degree.. Three "teeth" extend in between three corresponding "teeth" on an oppositely facing component, and a corresponding set of two components are found right next to the first two components, with a 45.degree. shift in relation to the first set.
A serious question must be asked regarding the ability of the above mentioned motor regarding achieving a successively and uniformly increasing rpm from standstill to the desired rotation speed, due to the small number of magnets in the rotor part and the correspondingly small number of "poles" on the stator part, i.e. with only two "pole ranges" on each cog rim-like component. However, it appears from said U.S. patent that the electric machine primarily is a sort of asyncronous generator, so that the motor aspect is a secondary consideration, at least regarding the ability to provide a high torque. In the motor function, said U.S. patent attaches most importance to a smooth and "ripple"-free running. Besides, a main feature of said U.S. patent is that the angle between the "step intervals" in the "poles" on the stator part should not be equal to the angle between the magnet pole centers on the rotor part. This is an unfortunate feature regarding achieving a high torque.
From British patent application, publication no. 2,211,030 is previously known a stepper motor based upon some of the same principles as the present invention, but which as a starting point has a reversed construction, i.e. with the rotor placed in center and the stator on the outside. Thus, the motor is not directly usable in the manner mentioned in the first section of this specification. Besides, the construction of the flux-conducting elements in the stator part is more similar to an abandoned development stage of the the present invention, with axially inward bent fingers from annular plates conducting flux from the stator coils.


The present invention is situated in the field of multimers used for targeted therapies. More particularly, the invention relates to methods for preparing multifunctional heteromultimeric protein complexes with a defined ratio of functional components and to multifunctional heteromultimeric protein complexes for directing complement-dependent cytolysis, optionally comprising a scaffold, which display three or more different functional components present in a defined relative ratio, of which one is a tracking component.

Multimeric systems offer the opportunity to combine several functional components, such as components with a therapeutic and a targeting functionality, into one molecule, allowing targeted therapy which often increases effectiveness and reduces unwanted side-effects. Joint delivery of different therapeutic components can lead to a synergistic therapeutic effect. In addition or alternatively, the combination of different targeting components may increase the binding specificity and affinity.
In most cases, the functional components are attached to a scaffold or backbone composed of, for example, dendrimers, antibodies and poly lysine. Although highly efficient, these multimeric systems have some drawbacks. First, their chemical formulation is not precisely defined. Second, the number of functional components being added to a polymer molecule is often random and cannot be controlled. This is particularly troublesome when it is of interest to load a combination of functional components on such a polymer. An example is given below.
The main actor of the innate immunity is the complement system, acting as a fast and efficient immune surveillance system able to discriminate among healthy host tissue, cellular debris, apoptotic cells and foreign intruders by promoting inflammation through the modification of the status of the target membrane surfaces that become the siege and focus of opsonisation by the central C3 complement component. Subsequent events of the complement-directed inflammatory cascade lead to the generation of C3- and C5-convertases that orchestrate the assembly of the membrane attack complexes C5b-9 (MAC), leading to direct cell killing. Complement-mediated tumour cell killing is not the principal cytotoxic mechanism, while C3b degradation products (e.g. iC3b, C3d,g, C3d) on opsonised tumour targets are ligands for complement CR3, CR4 complement receptors on host phagocytic cells (e.g. macrophages, neutrophils, NKs, mast cells). Furthermore, anaphylatoxins (C3a, C5a) released from the generation of C3-105-convertases attract towards the sites of opsonisation further host immune cells of the adaptive immunity, thus reinforcing the host immune response towards opsonised tumour cells.
Directing complement activation exclusively towards unwanted cells to promote a host destructive cell targeting is thus an attractive strategy.
The first therapeutic application involving complement activation was the development of monoclonal antibodies in cancer therapy, aiming at promoting antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of tumor cells. However, the focus of the therapeutic effect of most of these antibodies lies mainly on eliciting ADCC. The contribution of CDC in the therapeutic potency of mAbs remains controversial, with some exceptions such as anti-CD20 mAbs Rituximab (RTX) and Ofatumumab (OFA) activating the complement classical pathway (CCP) which is regulated by C4b binding protein (C4bp) and C1-inhibitor further merging to the C3b amplification loop.
In 2000, Vuagnat et al. showed that a membrane-anchored version of the human Properdin factor expressed on HEK293 cells, was able to promote the C3b assembly on Properdin-expressing cells (1), although direct lysis was less than 10% of PI-positive cells. Spitzer et al. generated a fusion protein combining an anti-human glycophorin A (GYPA) scFv and human Properdin and demonstrated that the fusion molecules bound human erythrocytes and triggered C3b deposition in the presence of autologous serum, but not to levels leading to the lysis of erythrocytes (2). They concluded that the presence of CD59 prevented the formation of MACs. Thus, monovalent bifunctional fusion proteins directing CDC on erythrocytes, were unable to lyse erythrocytes.
EP1951313 B1 describes the use of protein constructs for targeting and lysis of cells. More specifically, it describes heteromultimeric molecules comprising anti-GYPA scFv to target erythrocytes or anti-carcinoembryonic antigen (CEA) VHH to target certain tumor cells and fragment C of Tetanus toxin (TTfC) as an effector component. The use of TTfC-C4bpα/anti-GYPA scFv.C4bpα multimers directed against erythrocytes resulted in a partial cytolysis of the erythrocytes. After transfection and expression of TTfC-C4bpα/anti-GYPA scFv.C4bpα protein constructs in 293T cells, multimers with a variable valence were secreted. The main disadvantage of such uncontrollable valence is that the success of binding the target cell and recruiting the complement is mostly dependent on luck, which results in low reproducibility.
In view of the above, there remains a pressing need for an improved method for preparing multifunctional heteromultimers so that the number of functional components within the multimers can be better controlled.

Université de Reims Champagne Ardenne URCA


A structure for extracting light, which improves light extraction efficiency by enhancing a scattering effect and improves power efficiency and thus increases the lifetime of an organic electroluminescent lighting device, is provided, and an organic electroluminescent lighting device including the structure for extracting light is also provided.

An organic light-emitting device has recently increased in utilization in that it may be flexibly implemented as a self-luminescent device.
The organic light-emitting device is mainly used as a display device having a plurality of pixels to implement an image.
When the organic light-emitting device is used as a surface luminescent lighting device, since light generated in an emission layer has to pass through many interfaces until the light is emitted to a light extraction surface, there is a lot of light loss in this process, and thus, light extraction efficiency may be lowered. This lowering in light extraction efficiency increases power consumption, which in turn has the side effect of reducing the lifetime of the lighting device.

Structure for extracting light and organic electroluminescent lighting device


Direct digital QAM modulation at an RF frequency is obtained from digitally synthesized RF signals which are generated for use as the two vectors. The two vectors are individually controlled in phase and summed to provide a combined phase and amplitude modulation that forms the modulated signal. The synthesized RF signal is generated from a higher reference frequency using a variable pulse stretching technique implemented with programmable delay lines. The amount of the pulse stretch in each cycle is controlled by a phase increment value. Pulse stretching can be extended beyond one cycle by pulse swallowing, allowing the generation of an RF signal from DC up to and including the input reference frequency. Phase modulation is added by digital control of the pulse stretching according to the phase modulation data bits.

A prior art arrangement is shown and described hereinafter and has a number of disadvantages which will become apparent from the description hereinafter.
A search has revealed the following US patent references:
U.S. Pat. No. 5,329,259 Stengel, "Efficient Amplitude/Phase Modulation Amplifier"
U.S. Pat. No. 5,612,651 Chethik, "Modulating Array QAM Transmitter"
U.S. Pat. No. 5,659,272 Linguet, "Amplitude Modulation Method and Apparatus using Two Phase Modulated Signals"
U.S. Pat. No. 5,867,071 Chethik, "High Power Transmitter Employing a high Power QAM Modulator"
U.S. Pat. No. 6,366,177 McCune, "High-Efficiency Power Modulators"
U.S. Pat. No. 5,852,389 Kumar, "Direct QAM Modulator"

Method and apparatus for digital vector QAM modulator


The present invention includes a holding stay made of a heat conductive material that is the same as that of an isolator holder, the holding stay being in contact with a radiation stay made of a member having good thermal conductivity, the radiation stay being in contact with radiation fins extracted from the inside of the isolator holder through an external opening for extraction, columnar welded portions bond the holding stay and the isolator holder through openings for welding, the welded portions apply tensile force toward the isolator holder to the radiation stay via the holding stay, and the radiation stay presses the radiation fins by means of the above-described tensile force to be fixed to the isolator holder.

The present applicant proposed a product described in Japanese Patent No. 4077867 (issued date: Apr. 23, 2008) as a heat-dissipating structure that suppresses an increase in temperature caused by light absorption in a Faraday rotator used for an optical isolator. This heat-dissipating structure includes: an isolator holder within which component elements of an optical isolator main body such as a magnetic garnet crystalline film being a magnetooptical crystalline film, a polarizer, and a magnet are arranged respectively; an external heat conducting cover member covering this isolator holder; first and second heat conductive members provided within the above-described isolator holder; and flexible radiation fins formed at a part of the second heat conductive members. The above-described isolator holder is formed in a pipe shape made of a stainless steel, or the like, and has guide openings for radiation fins, which are opened toward the above-described external heat conducting cover member, formed in an upper portion thereof. The above-described external heat conducting cover member is made of copper or the like, and has an extracting opening for radiation fins, which is opened on the side of the above-described guide openings, formed therein. The above-described first heat conductive members each have a plate shape and are provided on both sides of the above-described magnetic garnet crystalline film with the magnetic garnet crystalline film being in the middle, and the above-described second heat conductive members each also have a plate shape, are positioned opposite to the above-described magnetic garnet crystalline film across the above-described first heat conductive members, are provided adjacently to the above-described first heat conductive members, and each have a hole for a light path. The above-described radiation fins extend laterally with a gap left relative to the above-described magnet to be extracted from the above-described guide openings to the outside of the above-described external heat conducting cover member through the extracting opening and have their outer end portions in contact with the above-described outside. Further, on the occasion of practical use, a pressure plate disposed on the upper side of the above-described external heat conducting cover member and a supporting plate disposed on the lower side thereof are used to sandwich the above-described external heat conducting cover member from the upper and lower sides, and the above-described pressure plate comes in pressure contact with upper surfaces of the outer end portions of the above-described radiation fins, and at the same time, bolts are screwed into holes in four corners of this pressure plate, and thereby the above-described pressure plate secures and fixes a contact between the outer end portions of the above-described radiation fins and bottom surfaces of outer grooves of the above-described external heat conducting cover member. Further, bolts are screwed into holes in four corners of the supporting plate, and thereby the supporting plate receives bolt-screwed forces of the four corners of the above-described pressure plate on the lower side.
Heat dissipation of the optical isolator is explained, and heat produced in the above-described magnetic garnet crystalline film is directly led to the second heat conductive members through the first heat conductive members and further led to the outside of the external heat conducting cover member by the respective radiation fins. Then, the led heat is dissipated to the outside through the radiation fins, which are out of contact with the principal parts of the heat-dissipating structure other than the isolator holder and the first and second heat conductive members, and as a result, in the optical isolator, an increase in temperature is suppressed and adverse effects caused by the heat, which are deterioration of optical characteristics and the like, are suppressed.

Heat-dissipating structure for optical isolator