Dynamic fly height (DFH) controlled read/write heads using multiple heaters have their heater powers set within a range of ratios that allows minimum clearances to be set between the read-gap and the write-gap and the surface of a disk, thereby providing improved touch-down detection. Determining the correct range of power ratios requires varying the ratio to create an adjustable protrusion profile for the read and write elements in the head and measuring values of the ratio and corresponding values of read gap and write gap clearances that create points of minimum clearance. By adjusting the ratio of power supplied to the heaters, different protrusion profiles can be produced, clearance control for sigma reduction can be obtained and read/write readiness and operation consistency and reliability can be improved.

1. Field of the Invention
This invention relates to the fabrication of hard disk drives (HDD), particularly to a method of measuring head protrusion in a slider produced by the controlled use of heater elements.
2. Description of the Related Art
As magnetic read/write heads have been required to deal with magnetic media having increasingly higher area density of recorded information, various methods have been developed to improve the capabilities of the head to read and write at those levels. Traditionally, the direction taken in trying to achieve the reading and writing of this high density information has been to decrease the spacing (i.e. the static fly height) between the disk and the slider in each new generation of products.
FIG. 1 is a schematic illustration showing a single suspension-mounted slider (the combination collectively termed a "head gimbals assembly (HGA)") positioned above a rotating magnetic hard disk during disk-drive operation in a hard disk drive (HDD) at ambient operating temperature. The suspension (101) holds the slider (10) at an angle above the surface of the spindle-mounted magnetic disk (400), producing a static "fly height" between the air bearing surface (ABS) (100) of the slider and the disk. A read/write head (600) is mounted within the slider. The rotation of the disk (400) is, by definition, into the leading edge of the slider, while the read/write head (600) is located at the trailing edge of the slider. The write-gap (from which the write magnetic field contacts the disk) of the head (90) is "above" (i.e. to the trailing edge side of) the read-gap portion (30). The hydrodynamics of the air layer between the ABS and the rotating disk surface supports the slider at a static fly height above the disk. In the two-heater dynamic flying height (DFH) type of system to be discussed herein, separately controllable heater elements (35), (95) are located adjacent to the two gaps (30) and (90) and, by heating the region surrounding the gaps, can cause protrusions (not shown) of the ABS (200) of the head portion relative to the undisturbed shape of the ABS. These protrusions will produce a characteristic shape (the protrusion profile) across the ABS, which will manifest itself in a corresponding profile of the flying height of the ABS above the disk (the flying height profile).
Although FIG. 1 illustrates one dual-heater DFH head, single-heater heads are common and multi-heater heads with more than two heaters can also be envisioned. It is further noted that hard disk drives (HDD) in the current art will typically include a plurality of adjacent, independently operating suspension mounted sliders exactly as shown in FIG. 1, each located adjacent to its own disk, which are mounted in a stack configuration. Although such an arrangement is not illustrated herein, it is easily visualized.
The limit of the total clearance budget (i.e. the sum of all factors entering into the total clearance between the head and the disk) prohibits a continuous reduction of this static fly height beyond a certain point. In addition to the static fly height variations resulting from the ABS and HGA/HSA (head gimbal assembly/head stack assembly) manufacturing processes, other factors also contribute to the total clearance between the head and the disk. A simple example is the drop in static fly height when the HDD is moved from sea level to a higher altitude. Yet another example is the isothermal PTP (pole tip protrusion) associated with the change in ambient temperature of the environment in which the HDD is located. Furthermore, the writer coil induced PTP (protrusion caused by joule heating of the coil) also diminishes the fly height clearance when the coil is activated to produce magnetic flux in a HDD write operation. There is a clear necessity to have a method of producing DFH (dynamic fly height) control, i.e. a method of providing a controllable head-disk spacing under various operational conditions, to avoid incidental contacts between the head and the disk that result from these inevitable variations in static fly height.
A common prior art approach to introducing such a "dynamic" control of fly height spacing is to embed a thin layer of heater film inside the magnetic recording head to produce single or multiple heater elements. The heater film is electrically connected to the pre-amplifier within which a heater current is activated to increase the heater film temperature and, thereby, to increase the temperature of the surrounding materials of the head structure. When subjected to this increased temperature, the materials forming the head begin to expand in accordance with their respective thermal expansion characteristics. This leads to a thermally deformable ABS and a resulting protrusion profile that achieves a lower spacing (less clearance) between the disk surface and the RG (read gap) and WG (write gap), thus greatly improving head performance.
When the read/write operation is not required, the heater current is turned off so that the ABS is elastically returned to its original, non-deformed state. The induced rise in temperature produced by the heating is sufficiently mild that the reliability of the head is not detrimentally affected. In addition, the heater activation has not shown a degrading effect on the magnetic reader in terms of noise and stability, since the magnetic fields produced by the heater activation currents is minimal.
The utilization of the DFH heater (or heaters) shows an unequivocal improvement in HDD performance. However, the same DFH power setting cannot be expected to deliver the same changes in spacing for each individual head due to the inevitable variations in the manufacturing process.
Single heater induced head element protrusion height is proportional to heater power and there is a fixed protrusion profile shape. Referring to FIG. 2, there is shown, schematically, a protrusion profile produced by a single heater as a function of distance along the ABS measured in microns from the edge (at x=0) between the alumina of the head element and the slider substrate edge (see (600) in FIG. 1). Different heater powers are shown, ranging from a low of 20 mW (milliwatts) (20) to a high of 100 mW (100). Each profile has a similar shape, displaying a flat region between the location of the read-gap and the write-gap and gradual increase and decrease in the protrusion to either side of the flat region. Typically the head element also includes a head-disk interference (HDI) sensor. This sensor is a resistive temperature sensor used to detect a temperature change in the head that is induced by changes in clearance during head vibrations caused by contact with disk asperities. In the single heater DFH, the head element flying profile is fixed between DFH touch-down and the flying operation.
Referring to FIG. 3, there is shown, schematically, a flying height profile graph with a single heater DFH, in which the height of the head above the medium (the ordinate) is measured in nanometers (nm) and length along the ABS of the head (abscissa) is measured in microns, exactly as in FIG. 2. The upper graph (5), representing a condition of no DHF (no heater activation), shows the passive flying height of the read gap and write gap above the medium surface. The lower graph, broken line (7), shows the effects of activating DFH during operation, which, in the case of a single heater, produces a fixed protrusion shape whose height above the medium is proportional to the power supplied to the single heater. Since the head touch-down point and the operational minimal fly height point are the same and cannot be adjusted, DFH touch-down detection and operational read-gap and write-gap clearances cannot be optimized. The solid line (9) beneath the broken line (7) shows the head touch-down used to calibrate the touch-down DFH power and to determine the operational DFH power. Due to the effects of head manufacturing tolerances on passive flying height and pole tip recession (PTR), head element DFH touch-down locations will be tolerated. This affects the head touch-down vibration and DFH touch-down detection by HDD or HDI sensor. Moreover, read gap and write gap clearances associated with variations in head element TD locations are also tolerated.
Referring to FIG. 4, there is shown a histogram of flying height (FH) clearance differences ("deltas"), defined as read-gap fly height (RG/FH) minus write-gap fly height (WG/FH), (delta=RG/FH−WG/FH) between read-gaps and write-gaps and the medium surface during touch-down and head flying operation. Not unexpectedly, the histogram is well represented by a Gaussian curve and shows that the greatest number of read/write heads show a clearance difference of 1.0 nm.
This distribution of clearance differences in single heater DFH that results from normal manufacturing tolerances directly affects the magnetic performance or recording density due to the variation in magnetic spacing between the reader and the disk. Read-gap and write-gap operation clearance sigma (standard deviations) would be increased by the touch-down detection error and head manufacturing tolerances (eg. PTR tolerances). Moreover, the distribution also exacerbates head vibration inconsistencies during DFH touch-down, causes HDI sensor touch-down detection error and ultimately affects head reliability.
To improve the operation clearance sigma and the HDI sensor touch-down detection accuracy, an adjustable DFH protrusion shape can be applied to the head element through multi-heater fly height (DFH) control or other features. Although such adjustable DFH protrusion shape is available, there is no methodology to calibrate suitable DFH protrusion shapes in order to obtain data necessary for establishing read and write gap clearances, to optimize the write-gap clearance, during reading, for 1st sector writing readiness, and to have a consistent level of DFH touch-down vibration.
To achieve the required improvement of DFH head performance, an effective calibration methodology of a variable DFH protrusion is a necessity. Although the following prior arts have considered aspects of these problems, they have not considered aspects addressed by the present invention nor have they arrived at the solution method of the present invention.
U.S. Pat. No. 7,492,543 (Mitsunaga et al) discloses a method to measure heater control values for each head. A clearance control unit varies electric power distribution to a heater to vary the protrusion value of the head to control the clearance.
U.S. Pat. No. 7,903,365 (Watanabe) teaches that clearances between the ABS surfaces and magnetic heads can be adjusted by respective heaters. A vibration detection sensor is disclosed.
U.S. Pat. No. 7,817,372 (Takahashi) shows a flying height control method including measuring saturation characteristics and adjusting flying height based on the measurements.
U.S. Pat. No. 7,468,854 (Yamashita et al) describes accurate measurement of flying height by controlling power distribution to the heaters in the heads.

Head DFH protrusion shape calibration by HDI sensor


An image recording medium includes: a support which is transparent to radiation for use in recording, and resistant to shock; a wavelength conversion layer which contains an organic binder and a fluorescent material which converts the radiation into visible light; a first electrode layer which is transparent to the visible light; a recording-side photoconductive layer which exhibits photoconductivity when the recording-side photoconductive layer is exposed to the visible light; a charge storage region which stores electric charges which are generated in the recording-side photoconductive layer in response to exposure to the visible light; a reading-side photoconductive layer which exhibits photoconductivity when the reading-side photoconductive layer is exposed to reading light; and a second electrode layer which is transparent to the reading light.

1. Field of the Invention
The present invention relates to a radiographic-image recording medium which records radiographic-image information by storing electric charges generated in response to exposure to radiation.
2. Description of the Related Art
The following documents (1) and (2) disclose information related to the present invention.
(1) U.S. Pat. No. 6,268,614 issued to the present inventor (Shinji Imai) and corresponding to Japanese Patent Applications Nos. 10-215378 and 10-232824 (which are laid open as Japanese Unexamined Patent Publication No. 2000-105297)
(2) U.S. Pat. No. 6,121,620 corresponding to Japanese Patent Application No. 8-34903 (which is laid open as Japanese Unexamined Patent Publication No. 9-230054)
Conventionally, radiographic-image recording mediums, which record radiographic images by storing in a charge storage region electric charges the amounts of which respectively correspond to doses of radiation such as X-rays, are used in many applications such as medical radiography. Various types of radiographic-image recording mediums basically operating as above have been proposed.
In aforementioned document (1), the present inventor has proposed a radiographic-image recording medium which can concurrently realize high speed response in reading and efficient readout of signal charges. In the proposed radiographic-image recording medium, a first electrode layer, a recording-side photoconductive layer, a charge transportation layer, a reading-side photoconductive layer, and a second electrode layer, stacked in this order. The first electrode layer is transparent to radiation for use in recording or light emitted due to excitation by the radiation for recording, the recording-side photoconductive layer becomes conductive when the recording-side photoconductive layer is exposed to the above radiation or light, the charge transport layer behaves substantially as an insulator against latent-image charges and substantially as a conductor of charges having the opposite polarity to the latent-image polarity, the reading-side photoconductive layer exhibits conductivity when the reading photoconductive layer is exposed to an electromagnetic wave for reading, and the second photoconductive layer is transparent to the electromagnetic wave for reading. Thus, when the radiographic-image recording medium is irradiated through the first electrode layer with the radiation for recording, a radiographic image is recorded by storing in a charge storage region electric charges the amounts of which correspond to the doses of the radiation. The charge storage region is formed substantially at an interface between the recording-side photoconductive layer and the charge transport layer.
Further, in document (1), the present inventor has also proposed a radiographic-image recording medium in which a wavelength conversion layer containing a fluorescent material (CsI) is arranged, where the fluorescent material emits visible light in the blue wavelength range in response to exposure to radiation for recording.
In each of the above radiographic-image recording mediums disclosed in document (1), information on the radiographic image recorded in the radiographic-image recording medium can be read out by scanning the radiographic-image recording medium with a laser light beam or a light beam having a linearly-shaped cross section.
Meanwhile, aforementioned document (2) discloses a radiographic-image recording medium includes a fluorescent sheet and a glass substrate on which a plurality of photoelectric conversion elements are arranged, and the glass substrate and the fluorescent sheet are bonded together. Each photoelectric conversion element on the glass substrate is constituted by a photodiode and a TFT (thin-film transistor) switch, and the fluorescent sheet emits fluorescent light in response to exposure to radiation. In this radiographic-image recording medium, each photodiode photoelectrically converts the fluorescent light emitted from the fluorescent sheet into an electric charge. Then, the electric charge is stored and read out by controlling the TFT switches on and off.
The above radiographic-image recording mediums are mainly used in hospitals and the like. It is desirable that each radiographic-image recording medium is contained in a cassette or the like so as to be portable, and is shock resistant so that the radiographic-image recording medium is not damaged even when the radiographic-image recording medium is unintentionally dropped. Further, since the radiographic-image recording mediums may be used outside the hospitals, for example, in a mobile van service, there are intense demands for portability and shock resistance of the radiographic-image recording mediums.
However, the radiographic-image recording mediums disclosed in documents (1) and (2) have the following drawbacks (i) and (ii).
(i) The recording-side photoconductive layer in each radiographic-image recording medium disclosed in document (1) is made of a-Se. The thickness of the a-Se film required for satisfactorily detecting applied radiation is as much as about 1,000 micrometers. a-Se films having such a thickness are susceptible to damage when dropped. When the aforementioned wavelength conversion layer is used, the thickness of the recording-side photoconductive layer can be reduced, and the recording-side photoconductive layer can be made less susceptible to damage. However, since the above wavelength conversion layer is produced by vapor deposition of CsI, which forms a needle crystal, the wavelength conversion layer per se is very susceptible to damage.
(ii) In the radiographic-image recording medium disclosed in document (2), in order to form the TFTs on the substrate, the substrate is required to be made of heat resistant non-alkali glass or quartz glass, and the thickness of the substrate is required to be 0.7 to 3 mm. However, such a glass substrate also breaks easily upon impact, such as that applied when dropped.

Radiographic-image recording medium containing shock-resistant member


The present invention provides a device, method and program for selecting genes or proteins from a set of candidate genes or proteins so that the selected genes or proteins have a stronger relevance to a specific subject. The device of the present invention contains a storage device, an input device and a processor. The storage device stores a data warehouse that contains a data about a collection of genes or proteins, with which annotations are associated. The input device receives an input of the set of candidate genes or proteins. The processor (a) gathers annotations that are associated with the candidate genes or proteins, (b) chooses annotations that are associated with the candidate genes or proteins more than a threshold number of times or frequencies, and (c) selects genes or proteins, with which at least one of the chosen annotations is associated.

Knowledge about genes and proteins has been being accumulated due to recent developments of molecular biology. Many findings related to genes and proteins are now available through various public databases such as NCBI (National Center for Biotechnology Information), Entrez Gene, and DDBJ (DNA Data Bank of Japan).
Along with the development of public databases, technologies to predict functions of genes and proteins utilizing the information obtained from such databases have also been developed. For example, there is a method of determining G-protein coupled receptors based on amino acid sequences or nucleotide sequences (Japan Patent Application Publications JP2006-003970 and JP2002-112793). There is also a method of predicting protein-protein interactions based on a supervised machine-learning using characteristic vectors defined by attributes about protein structures and about drugs and compounds, which interact with proteins (Japan Patent Application Publication JP2010-165230).

Device and method for selecting genes and proteins

NATIONAL INSTITUTE OF BIOMEDICAL INNOVATION


A bi-directional overrunning clutch assembly employed in connection with a reduced capacity low friction clutch to provide low and reverse gears in a transmission. The clutch assembly including an inner race, an outer race, and engagement members supported therebetween. The inner race is operatively coupled to the transmission casing and the outer race is operatively coupled to the ring gear of the gear set as well as the inner race of the friction clutch assembly. The clutch assembly further includes at least one actuating cam. The actuating cam operates to actuate the engagement members to provide four separate modes of operation between the inner and outer races of the clutch assembly. More specifically, the cam is operable to (1) disengage the engagement members to provide freewheeling between the inner and outer races in both rotational directions; (2) to actuate engagement members so that torque is translated in one rotational direction but to allow freewheeling in the opposite rotational direction; (3) to actuate the engagement members so that torque is translated in a direction opposite to that in mode (2) above, but allow freewheeling in the rotational direction opposite to that in which torque is translated in this mode; and (4) to actuate the engagement members so that the inner and outer races are locked relative to each other and torque is translated in both rotational directions.

1. Field of the Invention
The present invention relates, generally, to bi-directional overrunning clutch assemblies and, more specifically, to an actively controlled, bi-directional, overrunning clutch assembly having four modes of possible operation for use in providing low and reverse gear ratios in a transmission.
2. Description of the Related Art
Generally speaking, land vehicles require three basic components. These components include a power plant (such as an internal combustion engine), a power train and wheels. The power train's main component is typically referred to as the "transmission." Engine torque and speed are converted in the transmission in accordance with the tractive-power demand of the vehicle. Transmissions include one or more gear sets which may include an inner gear, intermediate planet or pinion gears that are supported by their carriers, and outer ring gears. Various components of the gear sets are held or powered to change the gear ratios in the transmission. In addition to such planetary gear sets, driveline components may further include multi-disc friction devices that are employed as clutches or brakes. The multi-disc pack clutch is a friction device that is commonly employed as a holding mechanism in a transmission.
The multi-disc pack clutch or brake assembly has a clutch sub-assembly including a set of plates and a set of friction discs that are interleaved between one another. The plates and friction discs are bathed in a continual flow of lubricant and in "open pack" mode normally turn past one another without contact. The clutch or brake assembly also typically includes a piston. When a component of a gear set is to be held, as for example during a particular gear range, a piston is actuated so as to cause the plates and friction discs to come in contact with respect to one another. In certain applications, it is known to employ several multi-disc pack clutch devices in combination to establish different drive connections throughout the transmission to provide various gear ratios in operation, or to brake a component.
When the discs are not engaged, there often remains a differential rotational speed between the drive and driven members that the clutch or brake bridges. Relative rotation between the friction discs and the plates during open-pack mode creates drag. This condition results in parasitic energy losses, reduces the efficiency of the transmission, and ultimately results in lower fuel efficiency.
In addition to multiple friction devices, one-way clutches are frequently employed in transmissions to selectively transmit torque in one rotational direction, but not in the opposite rotational direction. To this end, one-way clutches typically include an inner race, an outer race, and an engagement mechanism disposed therebetween. The engagement mechanism is operable to lock the inner and outer races together thereby transmitting torque in one relative direction. The engagement mechanism is further operable to allow freewheeling rotation between the inner and outer races in the opposite rotational direction. Engagement mechanisms commonly used in one-way clutches of the related art include pawls, sprags, and rollers. A cage, along with biasing members, such as springs, are also sometimes employed to retain the pawls, sprags, or rollers between the inner and outer races as well as to selectively assist in the change of operational modes between torque translation and freewheeling actuation of the clutch, depending on the direction of rotation between the inner and outer races.
As noted above, one-way clutches of this type have been employed in numerous applications in transmission, transfer cases, and differentials. For example, one-way clutches have been employed in conjunction with multiple friction clutches and planetary gear sets to effect low and reverse gear ratios in conventional transmissions. While this arrangement has worked well for its intended purpose, some disadvantages remain. For example, the friction clutch remains a source of significant parasitic losses due to inherent drag between the friction plates when the clutch is operating in "open pack" mode. Still, the clutch is necessary for providing the proper holding torque in low and reverse gears. Accordingly, there remains a need in the art for a mechanism that can provide the appropriate holding torque for both low and rear gears in the transmission and yet results in less parasitic losses which are presently attributable to the multiple plate friction clutch used for this purpose. In addition, there is a need in the art for a device that continues to perform the functions of the one-way clutch as described above, particularly where the output speed of the transmission exceeds the input speed resulting in engine compression braking.
Partially in response to this problem, bi-directional overrunning clutches have been proposed in the related art for use in these circumstances. These bi-directional overrunning clutch assemblies typically employ an inner race, an outer race, and a plurality of rollers as the engagement mechanism disposed therebetween. An actuator is employed to bias the rollers in one direction or another to allow freewheeling or torque translation in either rotational direction depending upon the position of the rollers. However, and while they appear to present a solution to certain problems identified above, bi-directional overrunning clutches have not been widely employed in transmissions of the related art. They are relatively mechanically complex and therefore generally more expensive than conventional one-way clutches. In addition, many of the designs considered in the related art simply do not operate at an acceptable level that meets the standards of today's sophisticated driving public.
Accordingly, there remains a need in the art for a bi-directional overrunning clutch assembly that can provide torque translation in either rotational direction as well as one that may be employed to assist a multi-disc friction device to provide low and reverse gear action in a transmission while at the same time reducing parasitic losses attributable to the friction devices known in the related art.

Bi-directional four-mode clutch for providing low and reverse gear ratios in a transmission


An article made of a metallic material having its constituent elements is made by furnishing at least one nonmetallic precursor compound, wherein all of the nonmetallic precursor compounds collectively include the constituent elements of the metallic material in their respective constituent-element proportions. The precursor compounds are chemically reduced to produce particles comprising the metallic material, without melting the precursor compounds and without melting the metallic material. The particles may be consolidated into a rod, which may be used as a welding rod in a welding operation. Alternatively, the nonmetallic precursor compounds may be consolidated prior to the chemical reduction.

Welding is used to join two or more pieces of material together, to repair defects in the surface of a single piece of material, and to build up structures. In the first two applications, the welding may be accomplished by heating the piece(s) to either join them or to heal the defect, without adding additional material. The welding in each case may instead be accomplished by melting additional material, termed a filler metal, that subsequently is solidified to join the pieces or to fill the defect in the single piece or to build up a structure. The filler metal is usually supplied as a powder that is injected into the heated region being welded, or as a welding rod that is gradually fed into the heated region. The filler metal may be of the same composition as the piece or pieces being welded, or of a different composition.
There is sometimes a distinction made between "welding rod", taken to be of larger diameter, and "welding wire", taken to be of smaller diameter. As used herein to avoid any arbitrary distinction between them, the terms "rod" and "welding rod" include both larger-diameter and smaller-diameter forms of rod and welding-feed materials, and thence includes both what is sometimes referred to as welding rod and what is sometimes referred to as welding wire.
Most welding rod is made by melting the metallic alloy that is to form the welding rod, casting the molten alloy into a cast form, and then wire drawing the cast form to its final diameter and length. However, this approach is limited to those metallic alloys that are sufficiently ductile to be wire drawn without failing. For less-ductile alloys, such as some high-gamma-prime superalloys that are to be used as welding rod, the cast or powder-processed metallic alloy is extruded to its final form.

This patent is subject to a terminal disclaimer.

Method for meltless manufacturing of rod, and its use as a welding rod


Process and apparatus for the mass production of compound cigarette filters function to deposit granular filter material into the open ends of vertically oriented filter tubes. Predetermined amounts of diverse granular material are withdrawn by suction from sources of such material, and these amounts are deposited into the tubes. Solid filter segments seal the granular material within the tube. After one half of each filter tube is filled with granular material and sealed, the tube is inverted and the opposite end is filled in substantially the same manner. When cut in half each filter tube produces two cigarette filters.

U.S. Pat. Nos. 3,517,480 and 3,603,058 illustrate and describe machines for the production of composite cigarette filters by directly flowing granular filter material from a storage hopper into a vertically oriented filter tube made of paper. Similarly, US Patent Application Publication 2002/0119874A1 describes another machine for producing compound cigarette filters that includes a series of rotating plates with cavities therein into which the granular filter material is deposited. The cavities ultimately are aligned with an open paper ended filter tube to facilitate deposit of the granular material into the tube. These machines have the disadvantage of often destroying the integrity of the paper filter tubes into which filter materials are deposited. They also deposit imprecise amounts of granular material and produce undesired amounts of fine dust and the like.

Vertical filter filling machine and process


The present disclosure provides substituted 9H-pyrimido[4,5-b]indoles and 5H-pyrido[4,3-b]indoles and related analogs represented by Formula I:

Field of the Invention
The present disclosure provides BET bromodomain inhibitors and therapeutic methods of treating conditions and diseases wherein inhibition of one or more BET bromodomains provides a benefit.
Background Art
The genomes of eukaryotic organisms are highly organized within the nucleus of the cell. The long strands of duplex DNA are wrapped around an octamer of histone proteins (usually comprising two copies of histones H2A, H2B, H3, and H4) to form a nucleosome, which then is further compressed to form a highly condensed chromatin structure. A range of different condensation states are possible, and the tightness of this structure varies during the cell cycle. The chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin. The chromatin structure is controlled by a series of post translational modifications to histone proteins, notably histones H3 and H4. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation.
Histone acetylation usually is associated with the activation of gene transcription, as the modification loosens the interaction of the DNA and the histone octamer by changing the electrostatics. In addition to this physical change, specific proteins bind to acetylated lysine residues within histones to read the epigenetic code. Bromodomains are small (about 110 amino acids) distinct domains within proteins that bind to acetylated lysine resides commonly, but not exclusively, in the context of histones. There is a family of about 50 proteins known to contain bromodomains, which have a range of functions within the cell.
The BET family of bromodomain-containing proteins ("BET bromodomains") includes four proteins, i.e., BRD2, BRD3, BRD4, and BRD-t, which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, thereby increasing the specificity of the interaction. BRD2 and BRD3 associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation, while BRD4 may be involved in the recruitment of the pTEF-β complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output. BRD4 or BRD3 also may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia. Data suggests that BRD-NUT fusion proteins contribute to carcinogenesis. BRD-t is uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division, which suggests a role in the maintenance of epigenetic memory. In addition, some viruses make use of these proteins to tether their genomes to the host cell chromatin as part of the process of viral replication.
A discussion of BET proteins can be found in WO 2012/075456, WO 2012/075383, and WO 2011/054864. A discussion of BET bromodomain inhibitors, e.g., I-BET-151 and I-BET-762, can be found in Delmore et al., Cell 146:904-917 (2011) and Seal et al., Bioorg. Med. Chem. Lett. 22:2968-2972 (2012). Small molecule inhibitors of BET bromodomains have therapeutic potential for the treatment of many diseases and conditions in which BET bromodomains have a role, including cancer. BET bromodomain inhibitors are disclosed in the following U.S. Pat. No. 8,044,042, U.S. Pat. No. 8,476,260, U.S. Pat. No. 8,114,995, U.S. Pat. No. 8,557,984, and U.S. Pat. No. 8,580,957; the following U.S. patent application publications: US 20120059002, US 20120208800, US 2012202799, US 2012252781, US 20130252331, US 20140011862, US 20130184264, US 2013079335, US 20140011862, US 20140005169, US 20130331382, US 20130281450, US 20130281399, US 20120157428, and US 20100286127; and the following international applications: WO 1998011111, WO 2006129623, WO 2008092231, WO 2009084693, WO 2009158404, WO 2010123975, WO 2011054843, WO 2011054844, WO 2011054845, WO 2011054846, WO 2011054848, WO 2011143651, WO 2011143660, WO 2011143669, WO 2011161031, WO 2012075383, WO 2012116170, WO 2012151512, WO 2012174487, WO 2013024104, WO 2013027168, WO 2013030150, WO 2013033268, and WO 2013097601.
Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling (Taylor, B. S. et al., Cancer Cell 18:11-22 (2010); Chen, C. D. et al., Nat Med 10:33-39 (2004); Visakorpi, T. et al., Nat Genet 9:401-406 (1995)). Despite the success of recently approved therapies targeting AR signaling such as abiraterone (Stein, M. N., Goodin, S. and Dipaola, R. S., Clin Cancer Res 18:1848-1854 (2012); Reid, A. H. et al. J Clin Oncol 28: 1489-1495 (2010); de Bono, J. S. et al., N Engl J Med 364: 1995-2005 (2011)) and second generation anti-androgens MDV3100 (enzalutamide) (Mukherji, D. et al. Expert Opin Investig Drugs 21:227-233 (2012); Scher, H. I. et al., N Engl J Med 367:1187-1197 (2012)), durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies (Lockwood, W. W. et al., Proc Natl Acad Sci USA 109:19 408-19413 (2012); Dawson, M. A. et al., Nature 478: 529-533 (2011); Delmore, J. E. et al. Cell 146: 904-917 (2011); Puissant, A. et al. Cancer Discov 3:308-323 (2013)). BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (Delmore, J. E. et al. Cell 146: 904-917 (2011); Puissant, A. et al. Cancer Discov 3:308-323 (2013); Filippakopoulos, P. et al. Nature 468:1067-1073 (2010)).
The identification and therapeutic targeting of co-activators or mediators of AR transcriptional signaling should be considered as alternate strategies to treat CRPC (Attard, G. et al., Clin Cancer Res 17:1649-1657 (2011)). BRD4 is a conserved member of the bromodomain and extraterminal (BET) family of chromatin readers that include BRD2/3 and BRDT. BRD4 plays a critical role in transcription by RNA PolII, by facilitating recruitment of the positive transcription elongation factor P-TEFb (Jang, M. K. et al., Mol Cell 19:523-534 (2005); Yang, Z. et al., Mol Cell 19: 535-545 (2005). Similar to other BET-family proteins, BRD4 contains two conserved bromodomains, BD1 and BD2. Competitive binding of JQ1 or I-BET to the bromodomain pocket results in the displacement BRD4 from active chromatin and subsequent removal of RNA PolII from target genes (Dawson, M. A. et al., Nature 478: 529-533 (2011); Delmore, J. E. et al., Cell 146: 904-917 (2011); Puissant, A. et al., Cancer Discov 3:308-323 (2013); Filippakopoulos, P. et al., Nature 468:1067-1073 (2010); Loven, J. et al., 153:320-334 (2013)) Although most cancer cells express BET-family proteins, it is not clear why only a subset of cell lines from diverse cancers respond to BET-inhibitors (Lockwood, W. W. et al. Proc Natl Acad Sci USA 109:19408-19413 (2012); Mertz, J. A. et al., Proc Natl Acad Sci USA 108:16669-16674 (2011)). Recently, BRD4 was shown to interact with sequence-specific DNA-binding transcription factors in a gene-specific manner (Wu, S. Y. et al., Mol Cell 49:843-857 (2013)). As the genetic and epigenetic landscape differs between tumor types, it is possible that distinct transcriptional regulators that associate with BRD4 might influence the action of BET-inhibitors.
Breast cancer accounts for more than 20% of all cancers in women worldwide. The expression of androgen receptor (AR) is widespread both in ER (estrogen receptor)-positive and ER-negative breast cancers. In ER positive breast cancer adjuvant therapy with ER antagonist tamoxifen or aromatase inhibitors (AIs)—which block conversion of androgen to estrogens, has shown to be effective in inhibiting disease progression. Moreover, direct AR antagonist Enzalutamide (MDV3100) has recently been proposed as a therapeutic modality for AR positive breast cancers.
Despite research directed to BET bromodomains and BET bromodomain inhibitors, the design of potent, non-peptide inhibitors of BET bromodomains remains a significant challenge in modern drug discovery. Accordingly, a need still exists in the art for BET bromodomain inhibitors having physical and pharmacological properties that permit use of the inhibitors in therapeutic applications, especially in humans. The present disclosure provides compounds that bind to BET bromodomains and inhibit BET bromodomain activity.

9H-pyrimido[4,5-B]indoles and related analogs as BET bromodomain inhibitors

Abstract: and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R1a, A, B1, B2, G, X1, Y1, Y2, and Y3 are as defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a condition or disorder responsive to inhibition of BET bromodomains. Compounds of the present disclosure are especially useful for treating cancer.

THE REGENTS OF THE UNIVERSITY OF MICHIGAN


A connection device for injecting a laser beam into an optical fiber is provided. The device includes two half grips for receiving one end of the optical fiber in a gripped position, a connector body for receiving the grips and for holding them in an optical fiber gripped position, and a conduction cooling mechanism for cooling the two half grips.

1. Field of the Invention
This invention relates to the field of optical fiber connectors that permit introduction of a laser beam into an optical fiber.
2. Brief Description of Related Prior Art
A functional diagram of a device for injecting a laser beam into an optical fiber is shown in FIG. 1. As shown in this diagram, the device is made up of:
a convergent optical system 2 for allowing an incident laser beam 4 to be focused onto the input surface 6 of a fiber 8, PA1 an adjustable mechanical coupling 10 (an interface collar) between the optical system 2 and the fiber connector 12, that permits adjustments for centering the focused beam on the input surface of the fiber, PA1 and finally an optical fiber connector 12, which has a first fliction of creating a link between an optical component (the end at the optical fiber) and the mechanical coupling 10. PA1 the energy per pulse (for example from 1 to 140 J), PA1 the duration of the pulse (for example from 0.5 to 20 ms), PA1 the repetition frequency (for example from 1 to 500 Hz) PA1 the mean power (W) (energy per pulse).times.(repetition frequency), PA1 the energy per pulse (J), PA1 the peak power (kW) (energy per pulse)/(duration of the pulse). PA1 mean power: 900 W, PA1 energy per pulse : 90 J PA1 peak power: 18 kW. PA1 the laser energy parameters which slowly damage the input surface of the fiber, PA1 the possible deposition of dust on the input surface of the fiber, creating local hot spots, PA1 a slight axial defocusing of the beam on the input surface of the fiber, which results in heating of the periphery of the fiber, PA1 a slight transverse defocusing of the beam on the input surface of the fiber, which results in an asymmetrical temperature rise on one edge of the fiber, PA1 residual micro scratches, arising from previous polishing, which reduce the life of the input surface, PA1 residual traces of solvent, arising from previous cleaning, which reduce life of the input surface of the fiber. PA1 two half grips for receiving one end of the optical fiber in a gripped position, PA1 a connector body for receiving the two half grips and for holding them in an optical fiber gripped position PA1 cooling means for cooling the two half grips.
Document U.S. Pat. No. 5,291,570 describes a fiber connector for a continuous high energy laser shown diagrammatically in FIG. 2. A laser beam 14 passes into an optical fiber 16 through one of its ends. The external part of the connector is made up of a body 18. The end of the fiber is chamfered and protected by a sleeve 20. The sleeve is made of a material that is transparent to the wavelength of laser beam 14. Reference number 22 designates the area of contact of the sleeve with the end of the fiber.
Beyond this contact area 22, the fiber 16 and the sleeve 20 are separated by an air gap 24. The fraction of the beam 14 that does not pass into the interior of the fiber passes through the transparent sleeve 20. This parasitic beam is reflected by component 26 towards the body 18. This body is built of a material that is a good conductor of heat.
Document DE-40 28305 describes a fiber connector for a high energy laser. This device has the objective of automatically centering the end of the fiber with respect to the incident beam. A special bimetallic grip, with three branches, exerts a radial force on the end of the fiber when one of the branches receives a greater fraction of the beam. Hence the centering of the beam is automatic.
Although satisfactory in certain respects, these two devices nevertheless pose problems, particularly when high energy lasers are used, for example, a pulsed YAG laser. The YAG laser emits a beam with a wavelength of 1.06 .mu.m, which wavelength can be transported by an optical fiber. The diameter of the fibers used is, in general, 1 mm for a YAG 1 kW pulsed laser.
Compared with a continuous YAG laser, the mean power of the industrial YAG pulsed laser is actually less (1 to 2 kW). Even so, the quality of its beam is not so good.
The YAG pulsed laser is characterised by three parameters which control the laser pulse:
The different "energy values" characterizing the pulsed YAG laser beam are:
The technology of the YAG pulsed laser is particularly interesting since it is possible to modulate and optimize the pulse parameters for each application case and to attain good performance for scribing, welding, surface treatment and drilling.
For example, if the beam is transmitted via optical fiber (of 1 mm diameter), it is possible to cut a 30 mm stainless steel plate, when assisted by an oxygen jet, if the beam has the following parameters:
Energy parameters even higher than those shown above are envisaged in the field of dismantling nuclear installations by YAG pulsed laser.
For example, with direct firings (that is to say, without transport of the beam by an optical fiber), at 1300 W mean power, 130 J per pulse and 22 kW of peak power, it is possible to achieve a cut thickness of 50 mm (304 L stainless steel), with good cutting quality.
On the other hand, continuous progress in the technology of the industrial YAG laser has allowed the achievement today of mean powers of 2000 W and energies per pulse of 200 J. Three thousand W prototypes are in the process of being developed.
If a pulsed YAG laser beam, having increased energy parameters, is used in combination with an optical fiber, the end of which is held in a connector of the type described in the prior art, then the life of the fiber input surface is very short. Hence for a mean power of 900 W, an energy per pulse of 90 J and a peak power of 18 kW, the life of the input face of the fiber is about 5 minutes. Heating of the fiber to its softening temperature is also observed, and the input surface of the fiber sublimes little by little until its complete destruction occurs. It is therefore necessary to provide an optical fiber connector that allows resolution of this problem.
Furthermore, a maintenance problem is also posed for the input surface of the fiber which, even if it is not destroyed needs to be checked, and even repolished. The reasons why repeat polishing of the input surface is necessary are manifold. They are, for example:
These different phenomena necessitating repolishing the input surface of the fiber are, in practice, more or less cumulative and difficult to identify, especially when the input surface of the fiber is really damaged.
Consequently, the fiber must be capable of being dismantled from its connector before being repolished, and then reassembled with its connector after polishing. During this operation, it is necessary to avoid as much as possible, any risk of damaging the input surface of the fiber, e.g. chipping of the fiber that can arise if the input surface comes into contact with another element of the optical device.

Device for injecting high energy laser beam into optical fiber


A glove-like device, which may be fabricated in the form a glove, mitten or mitt, for actively exercising the muscles of the fingers, hand, wrist and forearm. A glove fabricated from a flexible non-extensible material having a plurality of elongated tube shaped inflatable elastomeric bladders contained within pockets of like material attached to the upper outer surface of the glove from the tips of the fingers and thumb extending behind the knuckles. The bladders are attached to and pressurized through a manifold attached to the top surface of the glove behind the knuckles. The manifold is pressurized through a valve containing inlet/outlet tube the amount of pressure being indicated by a pressure gauge connected to the rear of the manifold. Additionally a bladder is contained within a pocket located on the palm of the glove which inflates into a flexible ball-like structure.

1. Field of Invention
The present invention relates to an athletic therapeutic glove operated actively by the user and intended to strengthen the musculature of the fingers, hand, wrist and forearm by exercise.
2. Discussion of Related Art
A variety of therapeutic hand exercising devices have been perfected in order to provide for passive exercise of the hands and fingers whose function has been impaired by disease or injury. They vary in their complexity and are operated either by fluid or by mechanical means.
Takahashi et al., U.S. Pat. No. 4,596,240 have devised a ballonet with finger engaging members on its outer surface. Intermittent pressurization and depressurization allows both extension and fanning motions of the fingers exercising the carpel joint, hand and fingers. Hasegawa, U.S. Pat. No. 4,522,197 has perfected a complicated glove shaped body with sacs disposed between the fingers and on the palm of the glove. The fingers and carpel joints of a hand placed inside of the glove are passively exercised by the charge and discharge of compressed air into and out of the glove. In U.S. Pat. No. 4,274,399 Mummert describes a mitt with an array of attached bladders which when successively pressurized and depressurized by a fluid results in a passive flexing of the finger joints. Bartholome, U.S. Pat. No. 3,937,215 has devised a therapeutic hand exerciser which provides a cyclic flexing motion to exercise the fingers. As air pressure inflates a splint-like upper member the fingers are straightened and upon deflation of the splint-like member and inflation of a wrist pouch a flap is tightened pulling the fingertips down and curling the fingers towards the palm. A complicated air pressurizing system is required to operate the device. U.S. Pat. No. 3,457,912 to Clark et al. describes a complex pneumatically actuated system for extending and closing the fingers which uses inflation to extend the fingers but depends upon driven cords to close the fingers. The device passively exercises the fingers with both flexing and extension motion. Viau in Canadian Patent No. 735,700 describes a therapeutic glove intended to extend the fingers of hands afflicted with paralysis. The glove has an inflatable bladder attached to the palmar side with extensions under the fingers and thumb. A hand is placed in the glove on top of the bladder and under the top side of the glove. The glove is inflated through a valve molded into the bladder by use of a rubber bulb causing the fingers to be straightened. The device is simple to use but in contrast to the more complicated devices described does not provide for a continuous cyclic exercising motion.
U.S. Pat. No. 4,576,148 of Koerner et al. and U.S. Pat. No. 3,756,222 of Ketchum describe rather complicated mechanically driven devices which provide a flexing motion for passively exercising the fingers and carpel joints.
All of the above mentioned appliances are designed to provide passive exercise to the afflicted members. The fluid operated devices variously require air pumps, manifolds, valves and timers; the mechanically operated devices require motors, complex driving mechanisms and microprocessor controls. With the exception of Viau's Therapeutic Glove these exercisers are expensive to manufacture and their use is restricted to physical therapy facilities as their operation is rather complicated and necessitate exacting adjustments.


The present invention relates to an optical pickup apparatus enabling to reproduce/record data of different kinds of disks in different thicknesses, using one single optical pickup. The optical pickup apparatus includes two objective lens, in which one objective lens has an incident plane and an outgoing plant formed of a flat plane at a designated radius domain from an optical axis, thereby preventing spherical aberration caused by the difference of the thickness between different kinds of disks.

1. Field of the Invention
The present invention relates to an optical pickup apparatus. In particular, the present invention relates to an optical pickup apparatus, which enables to reproduce/record data for different kinds of discs with different thicknesses, using an optical pickup.
2. Description of the Related Art
To keep abreast of a recent trend in data digitalization and high capacity data storage, a recording medium also has been changed from a magnetic tape to a disc. Now, the storage capacity of the disc is even enlarged by increasing recording density for recording data in the disk.
As a result of long, untiring efforts for increasing the recording capacity, a digital video disk (hereinafter, it is abbreviated to DVD) having high recording capacity was first developed from the existing compact disk (hereinafter, it is abbreviated to CD). Before long, a high density (hereinafter, it is abbreviated to HD) disk was introduced. Amazingly, the HD disk could record and reproduce the data at a very high density (i.e., twice of CD), using the existing CD. The emitting wavelength from a laser diode light source is also different for each disk. For example, in case of the CD, the wavelength is equal to 780 nm, and in case of the DVD and the HD, the wavelengths are equal to 650 nm and 405 nm, respectively.
The numerical aperture (NA) of a typically used objective lens in an optical pickup apparatus for reproducing HD is equal to 0.85 and the thickness of its disk is equal to 0.1t. Meanwhile, the numerical aperture of the objective lens in an optical pickup apparatus for reproducing DVD is equal to 0.6 and the thickness of its disk is 0.6t.
As aforementioned, the numerical aperture of the HD use objective lens is 0.85, which is larger than the numerical aperture of the DVD use objective lens, 0.6. Therefore, when the HD use optical pickup apparatus is employed, one realizes that one objective lens is not just sufficient to satisfy the numerical aperture requirement. For this reason, two objective lenses are used instead of one, as shown in FIG. 1, to make the numerical aperture 0.85.
FIG. 1 is a schematic diagram showing a configuration of a HD use optical system in the prior art. As depicted in the drawing, the HD use optical system includes a first objective lens 110, whose incident plane 112 and outgoing plane 114 are aspheric, and a second objective lens 120, whose incident plane 122 is spherical but the outgoing plane 124 is flat. Alternatively, the optical system can be configured by making the incident plane 112 and the outgoing plane 114 of the first objective lens 110, and the incident plane 122 of the second objective lens 120 all aspheric, while making the outgoing plane 124 of the second objective lens 120 flat.
Still as another option, the optical system can be configured by making the incident plane 112 of the first objective lens 110 and the incident plane 122 of the second objective lens 120 aspheric, and making the outgoing plane 114 of the first objective lens 110 and the outgoing plane of the second objective lens 120 flat. Here, the reference numeral 130 can be either HD or DVD.
In short, the HD use optical system can have a variety of configurations by alternating the shape of the first objective lens 110 and the second objective lens 120.
However, if one intends to reproduce DVD using two objective lenses appropriate for the HD use optical system, the difference in thickness between HD and DVD, that is, 0.1 t for HD and 0.6 t for DVD, causes spherical aberration, and as the result thereof, signal degradation occurs.


A tie system and method for forming a wall from a hardenable building material over an existing concrete wall. In one embodiment, the tie system includes multiple wall ties configured to be directly interconnected to form a wall tie stack such that multiple wall tie stacks can be positioned over the existing concrete wall in a spaced apart, vertically extending arrangement. The multiple wall tie stacks are configured to extend substantially perpendicular between substantially parallel panel structures. The tie system may be secured with the parallel panel structures to extend vertically as forms for a concrete wall and, if desired, transversely as forms for a concrete roof structure over, for example, a roof truss system, joined together with forms for forming a concrete eave portion. In this manner, the tie system may be employed to form a concrete building structure extending as the walls and roof of the structure.

Many residential and light commercial structures are built on concrete foundation walls which are formed by pouring concrete into a system of forms that have been erected on a previously poured concrete footing. After the concrete has cured sufficiently, the forms are stripped from the concrete and in most cases soil is back filled on the exterior side of the concrete wall. Typically, the base of each foundation wall is supported on a concrete footing, which is wider than the thickness of the wall itself. Ideally, the centerline of the wall is aligned with the centerline of the footing. The footing spreads the load of the structure over a greater area and prevents uneven loading of the foundation wall.
As set forth, once the footing is in place and hardened, a system of forms are constructed over the footing. Such system of forms have typically been constructed using expensive and reusable forms. These forms are typically made of metal and are, thus, very heavy and extremely labor-intensive to assemble and remove after pouring the concrete. Further, due to the significant investment of reusable metal forms, concrete laborers will typically pass the cost on to others for their services. As a result, various other concrete form systems for cement walls have been proposed as alternatives to the heavy metal forms.
One recent development in this field is the use of expanded polystyrene panels, known as insulated concrete forms. These newer form systems utilize pairs of horizontally extending foam panels which are connected in parallel with a series of rigid plastic ties. Complete wall form systems are typically created by vertically stacking these horizontally extending paired foam panels into larger arrays. Concrete is then poured between the panels of the completed foam wall form system. The thickness of the poured concrete walls can be adjusted by the selection and utilization of form ties of appropriate size. Subsequent to concrete hardening these foam panels are left in place to serve as insulation.
Although such insulated concrete forms are lighter than the conventional metal form systems, the forms are bulky and, therefore, the cost for shipping such forms can be expensive. Further, due to the bulky and cumbersome nature of these forms, they are highly susceptible to the inherent risk of damage during transportation and even during installation. Another problem with the insulated concrete forms is the requirement for numerous different types of parts to fit the variations of the footprint of both residential and commercial construction. Due to these numerous different parts and sizes, the insulated concrete forms are high in cost to manufacture and therefore, such high cost is past on to the consumers and builders. Furthermore, the numerous different types of parts in the insulated concrete forms are complicated to construct and require skilled laborers who understand the complexities for such construction. In addition, another inherent problem with the insulated concrete forms is the difficulty to match such forms to the predetermined required lengths along the footing usually evident at corners and ends, in which shortening the forms by cutting and then adhesively repairing the forms is required, often leaving the forms in a damaged state with reduced structural integrity. Such problem further increases the complexity and time required to build the forms in preparation to pour the concrete.
Another problem with prior art systems, particularly conventional metal forms, involves the installation of rebar, wire mesh, or other reinforcing members between the parallel panels that are to be embedded within the finished foundation wall. The techniques employed typically involve various means and methods for suspending rebar haphazardly between the panels with wire ties. Although such wire ties have been used for years, inaccurate placement of the rebar is common, often resulting in unsatisfactory reinforcement of the foundation walls. Further, such wire tying techniques are labor intensive, time consuming and a tedious process.
Further, often it is desired to have walls with a radius; however, conventional metal or steel forms are not made to provide a wall with a constant radius. Rather, the best the conventional metal or steel forms can implement is segmenting a wall with multiple flat faced portions at different orientations at the dimension of the form itself. There are specialized aluminum forms that are specifically made to form curved walls, but such specialized aluminum forms are extremely expensive and are limited by the fixed radial dimensions of the form itself.
Based on the foregoing, it would be advantageous to provide a concrete form system that is low in cost for builders and, thus, the home owner, minimizes the waste of form materials, provides a non-complicated system with less part types and that inherently can be adjusted to any required lengths for ends and corners or overall footprints required for the foundation walls. Further, it would be advantageous to provide a concrete form system that is less labor intensive, light weight and compact and, further, provides for ready and precise assembly of reinforcing rebar materials to be placed in concrete forms. Even further, it would be advantageous to provide a concrete form system that readily facilitates forming walls with a radius that is low in cost and is not limited by the dimension of the forms.


A method for strengthening a housing comprises the following steps: providing a housing being made of colored glaze and having an initial temperature of about 480° C. to about 550° C.; and spraying the surface of the housing using a spray solution containing potassium nitrate, potassium silicate, diatomite, and water to create an exterior layer on the surface. The exterior layer contains K+ ions, and the concentration of the K+ ions gradually decreases from a maximum value in the area of the outside surface of the exterior layer to zero in the area of the inside of the housing.

1. Technical Field
The present disclosure relates to a method for strengthening housings and housings made by the method.
2. Description of Related Art
Many housings of portable electronic devices are made of metal or plastic, which cannot present a novel and attractive appearance.
Colored glaze is a kind of glass containing lead dioxide, and is aesthetically appealing. However, the colored glaze is brittle and can break easily. Accordingly, a housing made of colored glaze usually has a poor strength.
Therefore, there is room for improvement within the art.

Method for strengthening housing and housing made by same

SHENZHEN FUTAIHONG PRECISION INDUSTRY CO., LTD.


In an image processing apparatus, a controller infers a color space of image data that is to be processed, and performs a prescribed processing to the image data on the basis of information indicating the inferred color space.

1. Field of Invention
The present invention relates to an image processing apparatus, method and program which perform prescribed color-related processing on a color image.
2. Description of Related Art
Various methods for expressing color image data are available. For example, in a method using the RGB color space, the color of each pixel constituting image data is represented by luminance information of the three primary colors of red, green, and blue. In another method, the color of each pixel is represented by the ink primary colors of cyan (C), magenta (M), yellow (Y), and black (K). In such color representation methods that are generally device-dependent, colors having the same RGB values are seen as different colors according to the human visual sense depending on the color coordinates of primary colors used, the white point definition, etc. For example, the standard known as adobeRGB has a wider color range than the standard known as sRGB, which was established to serve as an HDTV color standard, and therefore colors having the same RGB values are seen differently according to these two standards. Similarly, a color according to the print color samples of "JapanColor" and a color according to those of "SWOP", which is a U.S. print standard, are seen (appear) differently even if they have the same CMYK values.
In recent years, to eliminate the above-described non-coincidence in color representation, image data formats have been developed in which image data contains information (color space identification information) indicating a color space that is used for expressing the image data. Specifically, a data format called "ICC (International Color Consortium) profile" and that includes color information is known.
However, the present situation is such that much of the conventional image data that are generated and used in many devices do not contain such color space identification information. For this reason, a method of using a pre-assumed color space and a method of causing a user to input color space identification information of image data are widely used when it is necessary to identify a color space to, for example, change color spaces.
However, in the method of using a pre-assumed color space, a desired processing result is not obtained if a color space actually employed is different from the assumed one. The method of causing a user to input color space identification information has a problem in that it is less convenient because the user needs to check a color space.
Further, even if image data contains color space identification information, there is a possibility that it is in error. Thus, there is a need for a method for checking the legitimacy of color space identification information contained in image data.

Image processing apparatus, method and program able to infer the color space of image data


Compounds, compositions and methods are provided for the prophylaxis and treatment of infections caused by viruses of the Pneumovirinae subfamily of Paramyxoviridae and diseases associated with such infections.

The present invention relates to compounds, compositions and methods for preventing and treating viral infections, and the diseases associated therewith, particularly those viral infections and associated diseases caused by viruses of the Pneumovirinae subfamily of the Paramyxoviridae.
The Pneumovirinae subfamily of the Paramyxoviridae family consists of pneumoviruses that cause significant disease in humans and a number of animal species including cattle, goats, sheep, mice and in avian species.
Human respiratory syncytial virus (RSV), the prototypic member of the pneumovirus group, is the major pediatric viral respiratory tract pathogen, causing pneumonia and bronchiolitis in infants and young children. RSV disease is seasonal, with outbreaks in the U.S. typically beginning in November and continuing through April. During these yearly epidemics, approximately 250,000 infants contract RSV pneumonia, and up to 35% are hospitalized. Of those hospitalized, mortality rates of up to 5% have been reported. Children with underlying conditions such as prematurity, congenital heart disease, bronchopulmonary dysplasia and various congenital or acquired immunodeficiency syndromes are at greatest risk of serious RSV morbidity and mortality. In adults, RSV usually causes upper respiratory tract manifestations but can also cause lower respiratory tract disease, especially in the elderly and in immunocompromised persons. Infection in elderly and immunocompromised persons can be associated with high death rates. Natural infection with RSV fails to provide full protective immunity. Consequently, RSV causes repeated symptomatic infections throughout life.
The pneumoviruses of animals and avian species are similar to the human virus antigenically, in polypeptide composition and in disease causation.
Attempts to develop vaccines for RSV are ongoing, but none have yet been demonstrated to be safe and efficacious. Vaccine development has been shadowed by adverse reactions exhibited by the initial formalin-inactivated RSV vaccine introduced in the late 1960s. Immunized children showed an increased incidence of RSV lower respiratory tract disease and developed abnormally severe illnesses, including death.
Chemotherapy with ribavirin [1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide], an antiviral nucleoside which is the only pharmaceutical approved by the U.S. Food and Drug Administration (FDA) for treatment of RSV disease, is considered only for certain RSV patients (e.g., those at high risk for severe complications or who are seriously ill with this infection). However, its efficacy and value are controversial. Recent studies have reported a failure to demonstrate either clinical or economic benefit to patients of ribavirin treatment. Moreover, ribavirin has certain toxic side-effects and, in order to minimize these, must be administred by inhalation as an aerosol in an enclosed environment.
A human intravenous immune globulin (IVIG) preparation is licensed for prophylactic use in certain patients at high-risk for RSV disease. Administration of this drug requires intravenous infusion of a large volume over a 2 to 4 hour period in children who have limited venous access due to prior intensive therapy, as well as compromised cardiopulmonary function. Moreover, intravenous infusion necessitates monthly hospital visits during the RSV season, which in turn places children at risk of nosocomial infections.
Thus, a need exists for new anti-viral agents and treatments for RSV infection that overcome the shortcomings of existing pharmaceutical preparations.
In one aspect, the invention provides a compound of the formula:
wherein Het represents an unsubstituted or substituted five to seven membered heterocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen or sulfur, said heterocyclic ring substituents being at least one selected from those consisting of hydrogen, alkyl, amino, monoalkylamino or dialkylamino;
R1 represents a radical selected from the group consisting of hydrogen; halogen; perfluoroalkyl; alkoxyalkyl; amino; alkylamino; dialkylamino; amido; alkylaminoalkyl; an unsubstituted or substituted, saturated or unsaturated, straight- or branched-chain alkyl radical, said alkyl chain substituent being at least one hydroxy group; carboxy; an unsubstituted or substituted phenyl radical (C6H5), said phenyl radical substituent being at least one selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamide, amidino, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, or alkoxy monosubstituted with a substituent selected from the group consisting of carboxy, amino, alkylamino or dialkylamino; a cycloalkyl radical; or a heterocyclic radical selected from the group consisting of pyridine, thiophene, oxazole, oxadiazole, thiadiazole, pyrazole, tetrazole, furan, pyrrole, isoxazole, imidazole, triazole and thiazole, including all positional isomers of said heterocyclic radicals;
R2 represents a radical selected from the group consisting of hydrogen, hydroxy, thio, alkoxy, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, carboxamide, carboxamidoalkyl, sulfonamide acetamido;
X represents a valence bond or a divalent linking moiety selected from the group consisting of xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94or xe2x80x94Nxe2x95x90Nxe2x80x94, n being an integer from 1 to 8;
Z represents a substituent selected from the group consisting of hydrogen, formyl, hydroxy or xe2x80x94Xxe2x80x94Het, wherein X and Het are as previously defined; the isomeric forms of said compound and the pharmaceutically acceptable salts of said compound.
Particularly preferred are compounds having the formula:
wherein X is a divalent linking moiety selected from the group of xe2x80x94Nxe2x95x90Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94; R is a radical selected from the group of hydrogen, hydroxy, alkoxy, alkyl, halogen, nitro or alkoxy monosubstituted with a substituent selected from carboxy, amino, monoalkylamino, dialkylamino or acetamido; R2 is hydroxy; and R3 is a heterocylic radical selected from the group consisting of 1-pyrazolyl radicals, 1-triazolyl radicals (including the 1,2,3-;1,2,4-; or 1,3,4-isomers thereof), 4-triazolyl radicals, 1-tetrazolyl radicals or 2-tetrazolyl radicals (including the isomers thereof) and the amino- and alkyl-derivatives of such radicals, including, without limitation, 5-amino-1H-tetrazolyl, 3-amino-4H-1,2,4 triazolyl, 5-amino-1H-1,2,4 triazolyl, 5-amino-2H-tetrazolyl and 5-methyl-1H-tetrazolyl radicals.
In accordance with another aspect, the present invention provides a class of novel intermediates that are useful in preparing the anti-viral agents described herein. These intermediates have the general formula:
wherein Q represents a reactive group selected from those consisting of 5,5-dimethyl-1,3-dioxan and formyl; R5 is a radical selected from those consisting of hydrogen and hydroxy; R6 is a radical selected from those consisting of hydroxy, alkoxy, aryloxy and aralkoxy and R7 is a radical selected from those consisting of hydrogen, hydroxy, alkoxy, alkoxyalkyl, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamide, amidino, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, or alkoxy monosubstituted with a substituent selected from the group consisting of carboxy, amino, alkylamino or dialkylamino.
The present invention also provides new synthetic methods for preparation of the compounds described herein. One method comprises causing a 3-halogen substituted-4-alkoxy-substituted benzaldehyde, in which the aldehyde moiety is protected with a protecting group, to undergo reaction with an alkylated alkali metal to effect a halogen-alkali metal exchange; adding to the reaction mixture an alkyl ester of an R-substituted benzoic acid under conditions yielding a dialkoxy-R-substituted triphenylcarbinol derivative including said protecting group; deprotecting and reducing the dialkoxy-R-substituted triphenylcarbinol derivative to restore the aldehyde functional groups and convert the triphenylcarbinol moiety to a triphenylmethane moiety; dealkylating any alkoxy substituents to hydroxy substituents; and reacting the aldehyde functional groups with an amine-substituted heterocyclic reactant to produce the desired product. The R substituents on the benzoic acid ester are selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, hydroxy, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamide, amidino, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, or alkoxy monosubstituted with a substituent selected from the group consisting of carboxy, amino, alkylamino or dialkylamino.
Another method for preparing compounds of this invention comprises reacting a 4,4xe2x80x2-dihydroxy-3,3xe2x80x2-(4-R-substituted phenyl)methylenebisbenzaldehyde, in which the hydroxy groups are etherified, with the anion of a methyl-substituted heterocyclic reactant to yield a heterocyclic hydroxyalkyl derivative of etherified, R-substituted triphenylmethane as an intermediate product; and subjecting the intermediate product to dehydration and deetherification to produce the desired product.
According to still another aspect, the present invention provides pharmaceutical compositions comprising one or more of the above-described compounds in combination with a pharmaceutically acceptable carrier medium.
In accordance with a further aspect, the present invention provides a method for preventing and treating pneumovirus infection and for preventing and treating diseases associated with pneumovirus infection in living hosts, by administering to a living host susceptible to pneumovirus infection a therapeutically effective amount of a compound of the above structures and/or the isomers and pharmaceutically acceptable salts of said compounds, or pharmaceutical compositions containing same.
The compounds of the invention can be conveniently prepared from known starting materials according to one of the synthetic scheme illustrated below, wherein R and Het are as previously defined.
Synthetic scheme A involves protection of the aldehyde moiety of a bromobenzaldehyde followed by halogen-metal exchange and reaction of two equivalents of the desired aryl lithium species with an ester group to provide a triaryl methanol. Reduction and regeneration of the aldehyde can be achieved with formic acid. Liberation of the phenolic groups with boron tribromide (or pyridine hydrochloride) and condensation of the aldehyde groups with the appropriate heterocyclic amine provides the compounds of the invention.
Synthetic scheme B involves the reaction of a bis aldehyde, prepared as described in Scheme A, above, with the anion of a methyl heterocycle generated from n-butyl lithium to give a heterocyclic hydroxyalkyl derivative of an etherified, R-substituted triphenylmethane, as an intermediate product. Dehydration of the intermediate with methane sulfonyl chloride provides the unsaturated compound which is deetherified with boron tribromide to give the desired compound.
The term xe2x80x9calkylxe2x80x9d, as used herein, refers to aliphatic hydrocarbon radicals of one to six carbon atoms in length. Similarly, the term xe2x80x9calkylxe2x80x9d, or any variation thereof, used in combination form to name substituents, such as alkoxy (xe2x80x94O-alkyl), alkylthio (xe2x80x94S-alkyl), alkylamino (xe2x80x94NH-alkyl), alkylsulfonyl (xe2x80x94S(O)2-alkyl), carboxyalkyl (-alkyl-COOH), or the like, also refers to aliphatic hydrocarbon radicals of one to six carbon atoms in length, and preferably of one to four carbon atoms in length.
The designation xe2x80x9cHetxe2x80x9d, as used herein, refers to an unsubstituted or substituted 5-7 membered heterocyclic ring substituent on the compounds of the invention, which substituent contains 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, in which the heterocyclic ring substituent is at least one selected from the group of hydrogen, alkyl, amino, alkylamino or dialkylamino. Representative examples of such heterocyclic rings include, without limitation, those derived from pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, imidazole, oxazole, thiazole, isoxazole, pyridine, pyrimidine, triazine, morpholine, piperidine, piperazine, 1,2,4-diazepine or the like.
The term xe2x80x9camidoxe2x80x9d, as used herein, refers to a radical or substituent of the formula xe2x80x94NRxe2x80x3C(xe2x95x90O)Rxe2x80x2xe2x80x3, wherein Rxe2x80x3 and Rxe2x80x2xe2x80x3 represent hydrogen or alkyl.
The term xe2x80x9ccarboxamidexe2x80x9d, as used herein, refers to a radical or substituent of the formula xe2x80x94C(xe2x95x90O)xe2x80x94NRxe2x80x3Rxe2x80x2xe2x80x3, wherein Rxe2x80x3 and Rxe2x80x2xe2x80x3 are as previously defined.
The term xe2x80x9csulfonamidexe2x80x9d, as used herein, refers to a radical or substituent of the formula xe2x80x94SO2NRxe2x80x3Rxe2x80x2xe2x80x3 or xe2x80x94NRxe2x80x3SO2Rxe2x80x2xe2x80x3, wherein Rxe2x80x3 and Rxe2x80x2xe2x80x3 are as previously defined.
The term xe2x80x9ccarbalkoxyxe2x80x9d, as used herein, refers to a radical or substituent xe2x80x94C(xe2x95x90O)xe2x80x94ORxe2x80x3, wherein Rxe2x80x3 is a previously defined.
Preparation of specific embodiments of anti-pneumovirus compounds within the scope of the invention are exemplified below.
In vitro studies have been performed demonstrating the usefulness of compounds described herein as antiviral agents against pneumoviruses. Antiviral activity was measured on the basis of activity against RSV in a cell culture assay.
All possible isomers of the compounds described herein are within the scope of the present invention. Representative examples of such isomers include, without limitation, cis and trans isomers.
The compounds described herein, their isomers and pharmaceutically acceptable salts exhibit antiviral activity against pneumoviruses and are within the scope of the present invention.
The compounds of the invention can form useful salts with inorganic and organic acids, including, for example, hydrochloric acid, hydrobromic acid, methanesulfonic acid salts, or the like, as well as with inorganic bases, such as sodium or potassium salts.
The pharmaceutically acceptable salts of the compounds of the invention are prepared following procedures which are familiar to those skilled in the art.
The antiviral pharmaceutical compositions of the present invention comprise one or more of the above-described compounds or precursors thereof, as the primary active ingredient in combination with a pharmaceutically acceptable carrier medium and, optionally one or more supplemental active agents.
The composition may be prepared in various forms for administration, including tablets, caplets, pills or dragees, or can be filled in suitable containers, such as capsules, or, in the case of suspensions, filled into bottles. As used herein, xe2x80x9cpharmaceutically acceptable carrier mediumxe2x80x9d includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington""s Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the antiviral compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
The compounds of the invention, any precursors thereof and their isomers and pharmaceutically acceptable salts are also useful in treating and preventing pneumovirus infections and diseases when used in combination with supplemental active agents, which may be optionally incorporated into the pharmaceutical composition of the invention, or otherwise administered during a course of therapy. These include, without limitation, interferons, ribavirin, and immunomodulators, immunoglobulins, anti-flammatory agents, antibiotics, anti-virals, anti-infectives, and the like, the combination of which with one or more compounds of the invention offers additive or synergistic therapeutic benefit.
In the pharmaceutical compositions of the invention, the active agent may be present in any therapeutically effective amount, which is typically at least 0.1% and generally not more than 90% by weight, based on the total weight of the composition, including carrier medium and/or supplemental active agent(s), if any. Preferably, the proportion of active agent varies between 1-50% by weight of the composition.
Pharmaceutical organic or inorganic solid or liquid carrier media suitable for enteral or parenteral administration can be used to make up the composition. Gelatine, lactose, starch, magnesium, stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers or excipients for medicaments may all be suitable as carrier media.
Compounds of the invention are usefull in treating and preventing pneumovirus infections (and diseases) in humans, as well as in livestock, and may be used to treat cattle, swine and sheep, or to treat avian species such as turkeys, or for other animals susceptible to pneumovirus infection. Thus, the term xe2x80x9cpatientxe2x80x9d as used herein includes, without limitation, all of the foregoing.
Compounds described herein are also useful in preventing or resolving pneumoviral infections in cell cultures, tissue cultures and organ cultures, as well as other in vitro applications. For example, inclusion of compounds of the invention as a supplement in cell or tissue culture growth media and cell or tissue culture components will prevent pneunoviral infections of cultures not previously infected with pneumoviruses. Compounds described above may also be used to eliminate pneumoviruses from cultures or other materials infected or contaminated with pneumoviruses, after a suitable treatment period, under any number of treatment conditions as determined by the skilled artisan.
The compounds of the invention may be administered using any amount and any route of administration effective for attenuating infectivity of the pneumovirus. Thus, the expression xe2x80x9camount effective to attenuate infectivity of pneumovirusxe2x80x9d, as used herein, refers to a nontoxic but sufficient amount of the antiviral agent to provide the desired treatment of viral infection. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular antiviral agent and its mode of administration, and the like.
The anti-pneumovirus compounds are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to a physically discrete unit of antiviral agent appropriate for the patient to be treated. Each dosage should contain the quantity of active material calculated to produce the desired therapeutic effect either as such, or in association with the selected pharmaceutical carrier medium. Typically, the antiviral compounds of the invention will be administered in dosage units containing from about 0.1 xcexcg to about 50 mg of the antiviral agent, with a range of about 0.001 mg to about 25 mg being preferred.
The compounds of the invention, including their isomers and pharmaceutically acceptable salts, may be administered as such, or in the form of a precursor from which the active agent can be derived, such as a prodrug. A prodrug is a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo. Prodrugs of the compounds of the invention may include, but are not limited to mono-, di- or tri-esters of simple or functionalized aliphatic carboxylic acids; esters of carbamic acids (Raxe2x80x94(Oxe2x80x94COxe2x80x94NRbRc)n); esters of amino acids (Raxe2x80x94(Oxe2x80x94COxe2x80x94CH(NH2)Rb)n); esters of unsubstituted or substituted aromatic acids (Raxe2x80x94(Oxe2x80x94COxe2x80x94aryl)n), wherein the aryl ring may be substituted with hydroxy, carboxy, lower alkyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phosphoric acid, amino, alkylamido and halogen groups; esters of derivatized phosphoric acids; (acyloxy)methyl or acyloxy(ethyl)ethers (Raxe2x80x94(Oxe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Rb)n or Raxe2x80x94(Oxe2x80x94CH(CH3)xe2x80x94Oxe2x80x94COxe2x80x94Rb)n); (alkoxycarbonyloxy)methyl or (alkoxycarbonyloxy)ethyl ethers (Raxe2x80x94(Oxe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rb)n); and O-glycosides, wherein Ra is a residue of a compound of the invention, Rb and Rc are aliphatic radicals (C1-C10) and n=1-3. Such prodrugs may be prepared according to procedures well known in the field of medicinal chemistry and pharmaceutical formulation science and are within the scope of the present invention.
The compounds of the invention may be administered orally, parenterally, such as by intramuscular injection, intraperitoneal injection, intravenous infusion or the like, or by inhalation, such as by aerosol, in the form of a solution or a dry powder, or the like, or by intubation, depending on the nature and severity of the infection being treated. The compounds of the invention may be administered orally, parenterally, or by inhalation or intubation at dosage levels of about 106 mg to about 1000 mg/kg, one or more times a day, to obtain the desired therapeutic effect.
The compounds of the invention will typically be administered from 1 to 4 times a day so as to deliver the above-mentioned daily dosage. However, the exact regimen for administration of the compounds and compositions described herein will necessarily be dependent on the needs of the individual host being treated, the type of treatment administered and the judgment of the attending physician, veterinarian or medical specialist.
In view of the inhibitory effect on pneumovirus replication in cell culture produced by the compounds used in the method of the invention, it is anticipated that these compounds will be useful not only for therapeutic treatment of pneumovirus infection, but for pneumovirus prophylaxis, as well. The dosages will be essentially the same, whether for treatment or prophylaxis of pneumovirus infection.
The following examples are provided to describe the invention in further detail. These examples, which set forth the preferred mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention.
Examples 1-14 illustrate the chemical synthesis of representative compounds of the invention.

Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases


A portion measuring device of the type having a first, flexible, reservoir having an inlet, and a second, portion measuring, reservoir in fluid communication with said first reservoir. The first, flexible, reservoir is of a larger volume than that heretofore known, and may have a handle to aid in holding. The second, portion measuring, reservoir has a rotatable closure with a pouring spout or opening therein. A configured periphery is provided on the closure to aid in turning the same.

1. Field of the Invention
The present invention relates to a portion measuring device for fluids. More particularly, the present invention relates to a portion measuring device of a known type having a first reservoir in fluid communication with a second reservoir having indicia thereon indicating, for example, ounces and milliliters.
2. Description of the Prior Art
Portion measuring devices of the type having a first, flexible, reservoir and a second, portion measuring, reservoir are generally known. The first reservoir is generally made of a flexible material, such as a high density polyethylene, and has indications thereon of ounces, milliliters and dilution measurements. The second reservoir is generally cylindrical in nature, and made of a rigid material.
Portion measuring devices are commonly used to produce mixtures of liquids. A cleaning solution may require three ounces of a solution to be mixed with a gallon of water. The outer flexible walls of a first reservoir of a known portion measuring device containing a solution are caused to be squeezed together. The cleaning solution therein is forced upwardly of a tube, through an inlet, into a second reservoir. The second reservoir is closed by a cap. When the liquid forced up through the tube contacts the cap or closure means, it is directed downwardly into the generally cup-shaped second reservoir to the extent desired by the user, for example, three ounces. The entire device is then rotated until the pouring opening in the cap is in a convenient pouring position, and the three ounces of solution is poured into the gallon of water.
Problems have developed in the use of these known portion measuring devices. The first reservoirs had to be small enough to place in the palm of the hand of the user, and thus, have been limited in size. Any attempt to increase the size of the first reservoir has made that portion heavy and extremely fatiguing in use. The constant need to rotate the entire device to align the pouring opening has also been extremely inconvenient. Thus, those in the field of portion measuring devices have continued searching for a larger, yet convenient, measuring device.