Disclosed herein is a gray cast iron having high strength and reduced casting defects. The high-strength gray cast iron may include: an amount of about 3.10 to 3.50 wt % of carbon (C), an amount of about 2.10 to 2.40 wt % of silicon (Si), an amount of about 0.50 to 0.80 wt % of manganese (Mn), an amount less than or equal to about 0.10 wt % (not including 0%) of phosphorus (P), an amount less than or equal to about 0.10 wt % (not including 0%) of sulfur (S), an amount of about 0.25 to 0.45 wt % of chromium (Cr), an amount of about 1.00 to 1.40 wt % of copper (Cu), an amount less than or equal to about 0.20 wt % (not including 0%) of nickel (Ni), and a balance of iron (Fe), all the wt % are based on the total weight of the gray cast iron. In particular, the gray cast iron may include a carbon equivalent (CEQ) of about 3.95 to 4.1% calculated by the Equation 1.

Gray cast iron is a material that is widely used for components of vehicle internal combustion engines since it is relatively inexpensive and has high performance. The gray cast iron is used in combination with various elements at an appropriate ratio due to the interrelation between physical properties such as tensile strength and fatigue strength, costs, and productivity such as machinability of materials in use.
Since FC250, conventional 250 MPa general-purpose gray cast iron, has a relatively high carbon equivalent to cause excessive growth of graphite, it is difficult to have high strength.
Accordingly, there has been proposed and used a high-strength gray cast iron having enhanced strength by reducing the carbon equivalent of the gray cast iron to refine graphite and adding an alloying element such as Cu to the gray cast iron to refine pearlite, in recent years. However, this gray cast iron is rapidly solidified after casting due to a low carbon equivalent, and for this reason, there is a problem in that many casting defects occur due to poor discharge of gas.
In addition, in general-purpose gray cast iron such as CGI400, the reinforced high strength of the gray cast iron is achieved through spheroidizing of some graphite. However, this gray cast iron is problematic in that machinability is deteriorated due to an increase in ferrite structure and a heat transfer rate is lowered due to spheroidizing of some graphite, resulting in a reduction in heat fatigue life.


Systems and methods for a multichannel power supply are disclosed. The multichannel power supply includes a front end circuit configured to receive an input voltage and to provide a regulated front end direct current (DC) voltage. A multichannel source circuit is coupled to the front-end circuit. The multichannel source circuit includes a controller, a reference voltage circuit, and a plurality of source circuits. Each source circuit in the plurality of source circuits represents a distinct output channel of the multichannel power supply. The multichannel source circuit is configured to generate a constant current output for each source circuit in the plurality of source circuits. Each load in a plurality of loads is connected to a corresponding source circuit in the plurality of source circuits and is configured to receive the corresponding constant current output via the corresponding source circuit.

Multiple output channel (a.k.a. multiple channel or multichannel) power supplies used in the United States are typically subject to the UL1310 Class 2 safety standard. The UL1310 standard limits the voltage, current, and power of each output of a power supply classified as a Class 2 power supply. These limits must be met even under single component fault conditions. The power limit on a UL1310 Class 2 power supply, for example, is currently 100 Watts per output channel. Thus, while a single channel power supply may be limited to driving electronic devices at 100 Watts per output channel, a multichannel power supply may combine multiple 100 Watt channels to drive much higher power devices without exceeding the limits enforced by the standard. Thus, typical multichannel power supplies often employ a shunt resistor and differential amplifier on each channel to control output, wherein the feedback and control loop tolerances are kept as low as possible by using low tolerance components.


An apparatus comprises a detection indicator, a housing, and an exoskeleton in which the housing nests. The detection indicator is configured to furnish a visual indication upon contact with a fluid responsive to a characteristic of the fluid. The housing comprises an interior chamber configured to receive the fluid and to provide contact between the fluid and the detection indicator. The housing is configured to removably engage a conduit coupled to a source of a fluid sample, which may be a lumen inserted into a patient to receive fluid therefrom. In methods for use with the apparatus, a sample is collected, a characteristic is measured by the apparatus, and the apparatus is disconnected so as to avoid leakage of the sample and exposure of personnel.

In medical practice, it is common to obtain a sample of a fluid for evaluation of various characteristics to aid in evaluation of a patient's health. Examples of such fluids include blood, urine, and stomach contents, which may be taken for analysis. Characteristics of the fluids that may be measured include pH and the presence or levels of various chemicals or medication. Fluids may be taken as a diagnostic aid and also to aid in placement of medical devices such as medical tubing for feeding, breathing, medication, and other uses.
There are many different clinical situations in which it is beneficial to know the gastric pH of a patient, or other chemical properties associated with the patient. Currently to determine the pH, a practitioner aspirates the stomach contents from a lumen (e.g., nasogastric tube, feeding tube, gastric tube) that is in communication with the stomach into a syringe. The contents are then expelled from the syringe and placed in a test tube and sent to a lab for a gastric pH analysis. It is also possible to place a pH probe down the lumen to attain a reading of the stomach contents. However these methods take a considerable amount of time and both can be costly. Another method is to aspirate the stomach contents into the syringe and then expel the contents of the syringe onto litmus paper or other pH indicating paper. This method is also timely and forces the practitioner to handle bodily fluids in the open. This can be both messy and inaccurate.
The pH is measured for multiple reasons. The most common reason being to monitor an intubated or critically ill patient's gastric pH. This is often measured because these critically ill patients develop gastric ulcers due to a lower gastric pH. These ulcers can bleed rapidly and are a cause for significant morbidity and mortality. These often require emergent endoscopy and cauterization to stop the bleeding.
Patients that are critically ill are often on medications that raise the gastric pH. However, dosages needed to adequately raise the pH of the stomach in critically ill patients may vary for each patient and are difficult to determine without measuring the gastric pH. This is often not done because it can be timely and costly to do so. Deviation in gastric pH from a relatively narrow preferred range has been associated with higher risk for certain types of pneumonia, ulcers, gastric bleeding, and other complications.
Detection of the desired characteristic is typically shown using a visual indicator, such as a colorimetric medium that changes from a first color to a second color upon sufficient contact with the fluid. For example, determining the pH for a sample of stomach contents can be performed with a litmus paper which turns red or blue upon contact with acids or bases, respectively. However, some media produce a range of colors responsive to a range of pH values, which both enables the acquisition of a pH reading, and creates challenges for medical personnel in correctly performing, interpreting, and recording the measurement. In addition, the fact that the response of the colorimetric medium can vary from manufacturer to manufacturer, manufacturing lot to manufacturing lot, and other conditions, makes the reliable acquisition of an accurate reading even more challenging.
Determination of the characteristics is often performed by a practitioner (e.g., nurse or doctor) who views the colorimetric medium for the change to occur. However, with many indicator mediums, the initial color change may happen quickly and include a range of colors. For example, a pH paper may be designed to change colors between a range of blue, green, and brown or between red, orange, and yellow to indicate specific levels of pH. The practitioner must then compare the colors of the pH paper with a known reference color to estimate the pH value. Reference colors are often provided on a separate chart for comparison with the visual indicator. Determination of the characteristics generally must be performed without delay, as the sample pH may change when the sample is exposed to air, and the response of the colorimetric medium may be stable and accurate for only a limited time after the medium is exposed to the sample.
A further challenge in a clinical setting is avoidance of personnel exposure to gastric aspirate and other bodily fluids.


The present invention relates to a coating composition which contains. A) 100 parts by weight of a water-soluble polyether component having an average hydroxyl functionality of least 2.5 and an average OH number of 100 to 600 and containing at least one polyether polyol, PA0 B) 40 to 240 parts by weight of a water-soluble or water-dispersible polyisocyanate component containing at least one nonionically/hydrophilically modified organic polyisocyanate having (cyclo)aliphatically bound isocyanate groups, PA0 C) 10 to 50 parts by weight magnesium oxide and/or hydroxide in finely dispersed form and PA0 D) 50 to 150 parts by weight water.. The present invention also relates to mineral substrates coated with this coating composition.

1. Field of the Invention
The present invention relates to a new aqueous coating composition based on organic polyhydroxyl compounds and organic polyisocyanates containing free isocyanate groups and to the use of this coating composition for coating mineral substrates.
2. Background of the Invention
Reducing the organic solvent content of lacquers and coating compositions is a current problem for ecological and industrial hygiene reasons. Accordingly, the replacement of organic solvents by water is of considerable importance in modern coating technology.
Known aqueous two-component polyurethane lacquers contain blocked polyisocyanates because it has previously been assumed that polyisocyanates containing free isocyanate groups would not be useable in lacquer systems of the type in question because it would be expected that the polyisocyanates would react with the large excess of water and would not selectively react with the organic polyhydroxyl compounds that are always present as the main binder component of such coating compositions.
Aqueous lacquers based on blocked polyisocyanates are described, for example, in DE-OS 2,507,842 or 2,507,884. The systems according to DE-OS 3,829,587 are an exception to the rule mentioned. The aqueous lacquers described in this publication are in fact lacquers which, in addition to organic polyhydroxyl compounds, contain polyisocyanates containing free isocyanate groups. The selective reaction of the polyisocyanates with the organic polyhydroxyl compounds in the presence of a large excess of water is attributable to the very special nature of these polyhydroxyl compounds.
A completely new aqueous coating composition based on organic polyisocyanates and organic polyhydroxyl compounds has now surprisingly been found, containing water-soluble polyether polyols, nonionically hydrophilically modified polyisocyanates and magnesium oxide or hydroxide as its principal binder components. The coating composition according to the invention, which is described in more detail hereinafter, is particularly suitable for coating mineral substrates, such as masonry, concrete, gypsum and the like.

Aqueous coating composition and its use for coating mineral substrates


A reference pattern for creating a defect recognition level comprises a blank region formed on a transparent substrate and a grating region formed adjacent to the blank region, wherein the grating region includes a plurality of parallel trench lines.

1. Technical Field
The present disclosure relates to a photomask used in a process for manufacturing semiconductor devices, and more particularly, to a photomask having a reference pattern for creating a defect recognition level.
2. Discussion of Related Art
A photomask is a high precision plate containing patterns, i.e., microscopic images of electronic circuits. The photomask is used in wafer fabrication, mostly to make Integrated Circuits (ICs). Photolithography involves projecting photomask patterns onto a wafer. A defect is any flaw affecting the patterns on the photomask. Generally, defects on the photomask create errors to the ICs. The errors to the ICs may cause failures of a semiconductor device. Therefore, there exists a need to inspect the defects of the photomask during manufacturing semiconductor devices.
Conventionally, when inspecting for defects, a pattern being inspected is compared to a pattern on a database. With this inspection method, an image seen through a known inspecting device is compared to a digitalized image on the database. In other words, inspection results, obtained by detecting light-shielding patterns on the photomask, are compared to a reference data on the database. Another conventional inspection method is to compare two identical patterns after forming the two identical patterns on one photomask to determine if there is any discrepancy. The inspection results are also used to compare the two identical patterns. In the conventional inspecting methods, it is known that a defect recognition level is used to obtain the inspection results.
FIG. 1A is a plain view showing a reference pattern for creating a conventional defect recognition level. FIG. 1B is a cross-sectional view taken along the line I-I shown in FIG. 1A. Referring to FIGS. 1A and 1B, a conventional reference pattern includes a blank region A in which a transparent substrate 10 is exposed, and a light-shielding region B in which a light-shielding layer 20 is formed on the transparent substrate 10. The light-shielding region B is formed adjacent to the blank region A.
FIG. 1C is a graph showing a defect recognition level obtained by using the conventional reference pattern. Referring to FIG. 1C, light (not shown) is irradiated on an area including the blank region A and the light-shielding region B shown in FIG. 1A. Then, intensities of light transmitted to the blank region A and the light-shielding region B are measured by a known device. Most of the light is transmitted through the blank region A. The intensity of the light transmitted to the light-shielding region B is lower than the intensity of light transmitted to the blank region A because most of light irradiated on the light-shielding region B is blocked by the light-shielding layer 20.
Then, as shown in the graph of FIG. 1C, the intensity of the light transmitted to the blank region A, and the intensity of the light transmitted to the light-shielding region B can be indicated by normalized intensity values, respectively. For example, the intensity of the light transmitted to the blank region A is determined as a standard intensity value "1". The intensity of the light transmitted to the light-shielding region B can be represented as a relative value to the standard intensity value "1". A middle value between the standard intensity value "1" and the normalized intensity value of the light transmitted to the light shielding region B is determined as a defect recognition level 30.
After the defect recognition level 30 is determined, light is irradiated on an inspection pattern (for example, a pattern shown in FIG. 1D) of a photomask which is to be inspected. Then, intensities of light transmitted to the inspection pattern are measured by a known device. If a normalized intensity value of the light transmitted to the inspection pattern is lower than the defect recognition level 30, it is recognized that a light-shielding pattern exists on the transparent substrate.
FIG. 1D is a cross-sectional view of an inspection pattern of an alternating phase shift photomask under a defect inspection. Referring to FIG. 1D, the alternating phase shift photomask 400 includes a phase 0 degree region 21, a light-shielding region 23, and a phase shift region 25. A transparent substrate 11 is exposed in the phase 0 degree region 21. The transparent substrate 11 is covered with a light-shielding layer 22 in the light-shielding region 23. The transparent substrate 11 is etched to form the phase shift region 25. The phase 0 degree region, the light-shielding region 23, and the phase shift region 25 can alternately be aligned. For example, in a Cr-less mask (CLM), the phase 0 degree region 21 and the phase shift region 25 are alternately aligned because the CLM does not include a light-shielding layer 23.
When the transparent substrate 11 is etched to form the phase shift region 25, a transparent defect 27 can be formed in the phase shift region 25. Generally, because the transparent defect 27 (which was a part of the transparent substrate) is formed of the same material as the transparent substrate 11, the transmittance of the transparent defect 27 is same as the transmittance of the transparent substrate 11.
FIG. 1E is a graph showing a relationship between the defect recognition level 30 and normalized intensity values of light transmitted to the inspection pattern of an alternating phase shift photomask 400 (shown in FIG. 1D). Referring to FIG. 1E, after determining the defect recognition level 30, light (not shown) is irradiated on the inspection pattern of the phase shift photomask 400 under the defect inspection. Then, intensities of the light transmitted to the inspection pattern are measured by a known device. When the normalized intensity value of light is close to "1", it is recognized that there is no light-shielding pattern (for example, the light shielding pattern 22 shown in FIG. 1D).
When the normalized intensity value of light is close to "0", it is recognized that there exists a light-shielding pattern. Because most of light can be transmitted through the transparent defect 27, the normalized intensity value of light transmitted to the transparent defect 27 is close to "1". However, the light transmitted to the phase shift region 25 and the light transmitted to the transparent defect 27 interfere with each other so that the normalized intensity value of light measured at a boundary of the transparent defect 27 and the phase shift region 25 is lower than "1".
The intensity of the light measured at the boundary of the transparent defect 27 and the phase shift region 25 varies depending on a phase angle of the light transmitted to the transparent defect 27. The intensity of the light provides various values of a defect distribution 35 depending on thickness of the transparent defect 27.
The lowest normalized intensity value of light in the defect distribution 35 can be obtained when the intensity of the light transmitted to the transparent defect 27 and the intensity of the light transmitted to the phase shift region 25 have 180 degrees of phase difference.
Even the lowest normalized intensity value in the defect distribution 35 can have a higher normalized intensity value than the normalized intensity value of the light measured at the light-shielding region 23 due to a limitation of a known inspection device. Because the intensity of light measured by the known inspection device is based on a given area, it is difficult to measure the intensity of light at the boundary of the transparent defect 27 and the phase shift region 25. As a result, when measuring the intensity of the light at the transparent defect 27 and the phase shift region 25, an intensity of light transmitted to adjacent areas can be included. Therefore, most of the values of the defect distribution 35 caused by the transparent defect 27 are located above the defect recognition level 30. As a result, most of the transparent defects 27 cannot be detected by the conventional defect recognition level 30.

Reference pattern for creating a defect recognition level, method of fabricating the same and method of inspecting defects using the same


Curcumin analogues and methods are provided for treatment of disease.

The transcription factor NF-κB is an established regulator of numerous genes important in the inflammatory response. More recently, activation of NF-κB has been shown to have a role in many aspects of oncogenesis including control of apoptosis as well as regulation of cell cycling and cell migration (Yamamoto et al., J. Clin. Invest. 2001, 107, 135; Baldwin, A. S. J. Clin. Invest. 2001, 107, 241). Activated NF-κB has been observed in many cancers and is especially important in metastasis (Andela et al., Clin. Orthop. Relat. Res. 2003, 415 (suppl), S75).
NF-κB is a collective name for dimeric transcription factors comprising members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κB is also commonly referred to as, for example, NFκB and NFkB, with the abbreviations being used interchangeable. Five members of the mammalian Rel family are known: RelA (p65), RelB, c-Rel, NF-κB1 (p50) and NF-κB2 (p52) (Baldwin, A. S., Annu. Rev. Immunol. 14, 649 (1996)). The five members to the NFκB family are distinguished by the presence of a Rel homology domain. Each NFκB member is retained in the cytosol as a complex, the most prevalent of which is a dimer consisting of the two subunits, p65 and p50. Any homo- and heterodimer is considered NF-κB, although the most commonly found in activated cells, RelA/NF-κB (p65/p50) heterodimer, is often referred to as "classic" NF-κB. All Rel proteins contain a Rel homology domain (RHD) that is responsible for dimer formation, nuclear translocation, sequence-specific DNA recognition, and interaction with I-κB proteins. RelA, RelB and c-Rel also contain transactivation domains required for the recruitment of transcriptional machinery, and thus represent transcriptionally active components of NF-κB. FIG. 1A provides a pictorial representation of the NF-κB activation cascade.
NF-κB activation is controlled by an interaction with a family of inhibitors proteins known as I-κB. The I-κB family includes I-κBα, I-κBβ, I-κBε, p100, p102, and Bcl-3 (Whiteside et al., Semin. Cancer Biol. 8, 75 (1997)). All I-κBs share three common structural features: an N-terminal regulatory domain, which is responsible for a signal-dependent I-κB proteolysis, a core domain composed of six or seven ankyrin (ANK) repeats mediating an interaction with Rel proteins, and a C-terminal domain containing a PEST motif implicated in basal I-κB turnover.
In unstimulated cells, NF-κB resides in the cytoplasm as an inactive NF-κB-I-κB complex. I-κB binding hinders recognition of the NF-κB nuclear localization signal by nuclear import machinery, thus retaining NF-κB in the cytoplasm. Stimulation of cells releases active NF-κB, which is now free to enter the nucleus and activate transcription. Release of NF-κB is generally mediated by the degradation of I-κB.
Phosphorylation of IκB by IκB kinase (IKK) in response to an array of signals leads to degradation of IκB and the release of NFκB. Free NFκB is translocated to the nucleus where it binds to promoter regions of DNA resulting in the activation of a battery of genes, including pro-inflammatory genes (cytokines IL1 and TNFα; chemokines; stress response genes; and pro-inflammatory enzymes including iNOS, COX-2 and MMP-9). Compounds inhibiting the activation of NFκB can be directed at IKK or at NFκB. IKK inhibitors will prevent phosphorylation of IκB whereas direct inhibitors of NFκB may block NFκB-DNA interactions. Karin et al., (2004) Nat Rev Drug Discov 3, 17-26. The inducible degradation of I-κB occurs through consecutive steps of phosphorylation, ubiquination, and proteosomal degradation. I-κB processing is controlled by three large multi-protein complexes: IKK or signalsome, I-κB ubiquitin ligase, and 26S proteosome (Makarov, S. S., Mol Med Today. 6, 441-8 (2000)). Whereas the I-κB ubiquin ligase and the 26S proteosome are constitutively active, IKK activity is induced upon stimulation. Various stimuli, including inflammatory cytokines, mitogens, viral proteins, and stress, can activate IKK, thereby inducing phosphorylation of two critical serine residues of I-κB. The phosphorylation of I-κB targets it for rapid ubiquination and proteosomal degradation.
There are two IKK's, designated IKKα and IKKβ, that exist in a complex called the IKK signalsome. Also included in the complex are the IKK-associated protein (IKAP) and NEMO (also called IKKγ). There are many upstream regulators of the IKK signalsome that have been identified and could be useful "targets" for suppression of IKK expression and, ultimately, NFκB expression. Thus, compounds that prevent the phosphorylation of IκB (and therefore prevent the activation of NFκB) may act directly on one or more members of the IKK signalsome or may inhibit upstream kinases, such as SFK or any other such family of kinases. This complicates structure-based design of potential drugs to prevent activation of NFκB, especially because crystal structures of members of the IKK signalsome are not available. It is noteworthy that there are also IKK-independent pathways for activation of NFκB.
Most available evidence suggests that IKKβ is the canonical pathway for NFκB activation and that IKKα functions in special circumstances. Karin et al., (2004) Nat Rev Drug Discov 3, 17-26. Whereas binding to IκBβ effectively sequesters NFκB in the cytoplasm, binding to IκBα does not preclude nuclear translocation. In fact, the NFκB-IκBα trimeric complexes shuttle between the cytoplasm and the nucleus. The source of this difference is that binding of IκBβ to a p50/p65 complex blocks NLS located on both NFκB subunits, whereas binding to IκBα blocks only the p65 NLS. Thus, NFκB-IκBα complexes contain both an exposed functional NLS and several nuclear export signals (NES) found in the N-terminal domain of IκBα and in the activation domain of p65. The functions of both NLS and NES result in this shuttling between the cytoplasm and the nucleus. However, multiple NES seem to dominate, resulting in a primarily cytoplasmic localization of NFκB-IκBα complexes. When nuclear export is blocked with leptomycin B (LMB), the complex accumulates in the nucleus. Since IκBα is the most prevalent IκB isoform, in most resting cells the majority of NFκB protein is located in the cytoplasm bound to IκBα. Inflammatory stimuli, such as IL-1 treatment, leads to activation of IKK activity, phosphorylation of IκBα on serine 32 and 36, recognition of IκBα by the E3 ubiquitin ligase, IκBα ubiquination, degradation of IκBα by the 26S proteasome, and release of NFκB. The two exposed NLS on NFκB subunits then cause nuclear translocation of the transcription complex. However, numerous studies have now documented states where NFκB activation occurs in the absence of IκBα degradation.
For many stimuli, including interleukin-1 (IL-1), and tumor necrosis factor α (TNF-α), I-κB degradation and NF-κB nuclear translocation are necessary, but not sufficient, for the induction of NF-κB dependent transcription. The ability of NF-κB to initiate transcription depends on interactions with different transcriptional co-activators (Schmitz et al., J. Biol. Chem. 270, 7219-7226 (1995). Although regulated independently, the pathways controlling I-κB degradation and NF-κB transcription function act in synergy with the activation of NF-κB mediated transcription.
NF-κB appears to play a pivotal role in both initiation and perpetuation of chronic inflammation. CD4+ T cells are a trigger of immune inflammation, and NF-κB appears to be an important mediator of antigen-induced T-cell activation. Secreted products of activated T cells and direct cell-cell contacts cause activation of macrophages, fibroblasts, and endothelial cells. Once established, autocrine/paracrine loops of inflammatory cytokines and growth factors are capable of maintaining the activation of non-immune cells within the lesion, thereby perpetuating the chronic inflammatory process. Persistent NF-κB activation has been found in many chronic inflammatory diseases, including rheumatoid arthritis, asthma, inflammatory bowel disease, ulcerative colitis, and atherosclerosis (Barnes et al., New Engl. J. Med. 336, 1066-1071 (1997).
Additionally, the evidence that links activation of NF-κB to oncogenesis is compelling. NF-κB is activated by a number of viral transforming proteins (Hiscott et al., J. Clin. Invest. 2001, 107, 143), and inhibition of NF-κB activation through expression of a dominant negative IKK can block cell transformation (Arsura et al., Mol. Cell Biol. 2000 20, 5381). NF-κB activation protects cells from apoptosis induced by cancer chemo-therapeutics and oncogenes (Barkett et al., Oncogene 1999, 18, 6910), and activation of NF-κB promotes expression of metastatic factors (Baldwin, A. S. J. Clin. Invest. 2001, 107, 241). NFκB activation results in up-regulation of cyclin D1, a cell cycle regulator that is up-regulated in many tumors. NFκB is constitutively expressed in many cancer cell lines. Additionally, a number of dietary chemopreventive compounds such as flavonoids, curcumin, and reserveratol block activation of NFκB. Further, the expression of interleukin 8 (IL-8) which has been identified as a key factor in both angiogenesis and metastasis is very dependent on NFκB activity.
NF-κB is active in many tumors, and expression of NF-κB-responsive genes provide cancer cells with distinct survival advantages that inhibit cancer treatment. NF-κB is constitutively activated in many cancer cells, and NF-κB may also be conditionally activated in both cancer cells and stromal cells by the tumor microenvironment. Normally, NF-κB activation is prevented by binding to inhibitor (IκB) proteins, the most prevalent being inhibitor of NF-κB alpha (I-κBα). In response to inflammatory cytokines, the release of NF-κB is triggered by phosphorylation of I-κBα on serines 32 and 36, resulting in ubiquination and degradation of I-κBα protein. However, in cancer cells subjected to environmental conditions such as hypoxia, nutrient starvation, or X-rays, NF-κB activation is caused by phosphorylation of I-κBα on a tyrosine residue (Tyr42) by Src family kinases (SFKs). Thus, NF-κB activation via IκBα Tyr42 phosphorylation is expected to occur in solid tumors due to constitutive activation of SFKs such as the Src oncogene in response to the hypoxic and nutrient poor nature of the tumor microenvironment, or due to radiation treatment of the tumor.
NFκB was first identified as the nuclear factor in mature B-lymphocytes that binds to an 11 bp element (GGGACTTTCC) within the κ-light chain gene enhancer, but it was soon realized that NFκB is not a B-cell-specific transcription factor. A wide variety of environmental stimuli and stresses lead to the formation of active NFκB complexes within almost every cell type, and NFκB activation mediates the transcription of over 180 target genes.
There are several NFκB crystal structures for use in structure-based drug design including a human NFκB-DNA structure. However, compounds that have been reported to inhibit activation of NFκB have generally been suggested to work at the level of IKK, rather than to interfere with NFκB-DNA interactions or with NFκB dimerization to prevent its interaction with DNA. Given the mechanisms of suppression and expression of NFκB, compounds inhibiting the activation of NFκB can be directed at IKK, SFK, or other kinases at NFκB-DNA interactions. Kinase inhibitors will prevent phosphorylation of IκB where direct inhibitors of NFκB may block NFκB-DNA interactions. For example, it has been shown recently that a new class of retinoid-related drug candidates inhibits IKK directly. Bavon et al., (2003) Mol Cell Biol 23, 1061-1074. By comparison, a synthetic derivative of the fungal metabolite jesterone, which blocks activation of NFκB, was shown to inhibit a kinase involved in phosphorylation and activation of IKK (β-subunit). Liang et al., (2003) Mol Pharmacol 64, 123-131. It appears, therefore, that inhibition of one or more of the kinases associated with the IKK signalsome may be a promising route to the development of new therapeutic agents that work through blocking the activation of NFκB. Further, because NFκB responsive genes can promote angiogenesis, cell motility and invasion, and block apoptotic cell death, this mechanism represents a considerable obstacle to cancer treatment. Therefore, there is a greatly felt need for development of small molecule inhibitors of NFκB expression. Particularly, but not exclusively, inhibitors of IκBα Tyr42 phosphorylation have vast potential to serve as adjuvant cancer therapeutics.
Activator Protein-1 (AP-1) is another protein transcription factor found in mammalian cells. AP-1 like NF-κB is a prosurvival and pro-inflammatory protein. AP-1 is an established regulator of numerous genes important in a variety of cellular processes including cell growth regulation, differentiation and proliferation (Angel et al., Cell 1987, 49, 729-739). Growth factors, hormones, tumor promoters and oncogenes regulate AP-1 binding to DNA (Bernstein et al., Science 1989, 244, 566-569). Activated AP-1 has been shown to play a role in apoptosis, angiogenesis and metastasis (Kang et al., Am. J. Pathol. 2005, 166(6), 1691-1699) and is also involved in many diseases including cancer, diabetes and Alzheimer's disease. AP-1 is also associated with the production of metalloproteinases. Collagenases, a class of metalloproteinases, are known to contain AP-1 response elements in their DNA promoters (Kang et al., Am. J. Pathol. 2005, 166(6), 1691-1699). The combination of these factors makes AP-1 crucial to many oncogenic processes.
AP-1 consists of 18 dimeric combinations of the families Jun (c-Jun, JunB and JunD) and Fos (c-Fos, FosB, Fra-1 and Fra-2) (Young et al., Trends Mol. Med. 9(1), 36-41 (2003)). Of the dimeric possibilities are Jun-Jun homodimers and Jun-Fos heterodimers. Jun dimers bind tightly to AP-1 DNA recognition elements (Angel et al., Cell 49, 729-739 (1987)). Fos-Fos homodimers are unstable and not readily formed but can bind to DNA by forming heterodimers with Jun proteins (Ziegler et al., J. Nutr. 2004, 134, 5-10). The most common dimer is a heterodimer consisting of c-Jun and c-Fos. Also associated with the Jun and Fos families are Jun dimerization partners and activating transcription factors (ATF's) (Angel et al., Biochim. Biophys. Acta 1072, 129-157 (1991)).
In normal tissues, the AP-1 component c-Fos is found only in small concentrations but cytosolic levels are rapidly increased when the cell is induced by mitogenic stimuli (Muller et al., Nature 1983, 304, 454-456). c-Jun, another AP-1 component, plays an important role in the regulation of cellular proliferation (Karin et al., Curr. Opin. Cell Biol. 1997, 9(2), 240-246). When c-Jun and c-Fos become unregulated in the body, abnormal cell proliferation occurs leading to cellular transformations. c-Jun is known to be essential in tumor promotion in several cell lines (Jochum et al., Oncogene 2001, 20(19), 2401-2412; Orlowski et al., Trends Mol. Med. 2002, 8, 385-389; Pain, Eur. J. Biochem. 1996, 236, 747-771; Karin et al., Nat. Rev. Cancer 2002, 2(4), 301-310; Dhar et al., Mol. Cell. Biochem. 2002, 234-235, 185-193). c-Fos is also involved in the conversion of cells from benign to malignant (Dong et al., Proc. Natl. Acad. Sci. USA 1994, 91, 609-613; Greenhalgh et al., Cell Growth Differ. 1995, 6, 579-586) and is essential in tumor progression (Saez et al., Cell 1995, 82(5), 721-732). In general, the activation of both NF-κB and AP-1 are required for tumor promotion and progression.
The AP-1 activation cascade can be induced by TNFα, okadaic acid, 12-O-tetradecanoylphorbol-13-acetate (TPA), UV light (Young et al., Trends Mol. Med. 9(1), 36-41 (2003)), cytokines, mitogens, phorbol esters, growth factors, environmental and occupational particles, toxic metals, intracellular stresses, bacterial toxins, viral products and ionizing radiation (Fontecave et al., FEBS Lett. 421, 277-279 (1998)). In general, AP-1 is activated primarily through mitogen-activated protein kinase (MAPK) cascades (Kundu et al., Mutat. Res. 2004, 555, 65-80). MAPK's are composed of MAPK itself and MAPK kinase, also called MAPK-extracellular signal regulated kinase (MEK) (Wilkinson et al., Genes Dev. 1998, 12, 1391-1397). MAPK's are activated by cytokines, hormones and stress-inducing agents (Blenis, Proc. Natl. Acad. Sci. USA 1993, 90(13), 5889-5892). In general, the same factors that stimulate NF-κB also stimulate AP-1.
MAPK or MEK can phosphorylate additional kinases including extracellular regulating kinases (ERK's), c-Jun N-terminal kinase (JNK) and p38 MAPK (Baker et al., Mol. Cell. Biol. 1992, 12(10), 4694-4705; Davis, J. Biol. Chem. 1993, 268(20), 14553-14556). JNK activates the c-Jun protein and ERK activates a protein called Elk-1 both by phosphorylation. c-Jun then binds to DNA along with an ATF to activate genes that produce more of the Jun family in a positive feedback loop (Thevenin et al., J. Biol. Chem. 1991, 266(15), 9363-9366). Elk-1 also binds to DNA with a serum response factor (SRF) to activate genes that produce the Fos family. The Jun and Fos protein families are then activated by JNK and c-Fos-regulating kinase (FRK) respectively. The activated families can now dimerize, bind to DNA and activate gene expression that adversely affects cellular processes. A pictorial representation of AP-1 activation is shown in FIG. 1B.
AP-1 proteins and their activating kinases are related to NF-κB. AP-1 proteins are known to interact with the p65 subunit of NF-κB (Li et al., Mol. Carcinog. 29(3), 159-169 (2000)). MAPK's are known to phosphorylate I-κB (Adler et al., EMBO J. 18, 1321-1334 (1999)). Because AP-1 and NF-κB responsive genes can promote angiogenesis, cell motility and invasion, and block apoptotic cell death, activation of these genes and their products may result in cancerous or precancerous growth. Moreover, AP-1 and NF-κB responsive genes can promote inflammation, activation of these genes and their products may result in greater inflammation in diabetics and others. Therefore, there is a greatly felt need for development of small molecule inhibitors of AP-1 or NF-κB activation.
Alzheimer's Disease
Alzheimer's disease (AD), the most common cause of dementia in elderly populations, currently afflicts almost 5 million people in the U.S., and this number is estimated to increase to 15 million by 2050. Hebert et al., (2003) Arch Neurol 60, 1119-1122. Most AD is sporadic with multiple risk factors, while some 10-15% is familial. It is well accepted that excessive production or diminished clearance of the Aβ peptide derived from the amyloid precursor protein (APP) is an essential factor in the etiology of AD. This is supported by studies of genetic mutations in APP in experimental animal models of AD as well as from studies of the genetics of familial AD. Selkoe et al., (2000) Annu Rev Genomics Hum Genet 3, 67-99.
There are two major neuropathological signatures of AD: extraneuronal amyloid plaques and neurofibrillary tangles. The plaques primarily consist of Aβ aggregates while the tangles consist of hyperphosphorylated tau protein. The exact mechanism by which these aggregates cause neuronal cell death remains to be established. However, considerable recent evidence points towards a major role for oligomeric forms of Aβ which are neurotoxic and can diffuse. Soluble Aβ is found in CSF of AD patients and correlates better with severity of disease than does the quantity of plaques. Kim et al., (2003) FASEB J 17, 118-120; McLean et al., (1999) Ann Neurol 46, 860-866.
There are other common features of AD including the presence of chronic inflammation. The inflammatory response in brain is directed by activated microglia and reactive astrocytes. In normal brain, microglia are not activated. Under these conditions, neither pro-inflammatory signals nor reactive oxygen/nitrogen species (ROS/RNS) are formed. McGeer et al., (2003) Prog Neuropsychopharmacol Biol Psychiatry 2, 741-749. However, when microglia become activated in response to various insults, there is up-regulation of a number of surface receptors that promote phagocytotic activity by microglia. In addition, pro-inflammatory signals are released including interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) as well as ROS/RNS, thus contributing to the oxidative stress associated with AD. Activated microglia also associate with amyloid plaques. Microglia isolated from AD brain can scavenge Aβ. Rogers et al., (2002) Glia 40, 260-269. The considerable literature on the role of microglia in AD suggests that activation of microglia may contribute initially to clearance of Aβ aggregates, but that the chronic activation of microglia observed in AD leads to the neuropathological changes in the AD brain. Griffin et al., (1998) Brain Pathol 8, 65-72. Activated microglia also contribute to hyperphosphorylation of tau with development of neurofibrillary tangles, as well as to recruitment of activated astrocytes into the Aβ plaques. Kitazawa et al., (2004) Ann NY Acad Sci 1035, 85-103.
It is now recognized that Aβ can increase the inflammatory response by activation of microglia and that the inflammatory response can contribute to Aβ deposition. Consequently there has been interest in hindering microglial activation as an approach to breaking this pathological cycle. Aisen (1997) Gerontology 43, 143-149. Since activation of microglial results in release of ROS/RNS, attention has focused on use of anti-oxidants such as vitamin E. There are conflicting reports of the effects of anti-oxidants on development of AD, some supporting a role for anti-oxidants (Engelhart et al., (2002) JAMA 287, 3223-3229) and others not supporting a role (Laurin et al, (2004) Am J Epidemiol 159, 959-967). Activation of microglia increases the oxidative burden in affected brain regions. However, how significant this increase is in contributing to neurodegeneration is not known. The field of anti-oxidant treatment of AD will need further controlled trials to assess this question.
Another area that has produced conflicting reports is the use of anti-inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDS), in treatment of AD. COX-2, the inducible form of cyclooxygenase found in neurons and other cells and the source of pro-inflammatory eicosenoids, is up-regulated in AD brains. Yasojima (1999) Brain Res 830, 226-236. Overexpression of human COX-2 in mice results in age-related cognitive decline as well as neuronal apoptosis and astrocyte activation. Andreasson et al., (2001) J Neurosci 21, 8198-8209. The epidemiology studies of use of COX inhibitors (i.e. NSAIDs) by AD patients suggest that NSAID therapy may be useful. McGeer et al., (2003) Prog Neuropsychopharmacol Biol Psychiatry 2, 741-749. However, controlled clinical trials have been disappointing. These conflicting results may reflect the fact that the epidemiology studies begin with normal subjects and then assess risk of developing disease and whether this risk correlates inversely with drug use, whereas the clinical trials begin with subjects who have AD and look for improvement upon treatment. Other studies suggest that only a limited group of NSAIDs are effective and that these NSAIDs influence multiple targets in addition to COX-2. Gasparini et al., (2005) Brain Res Rev 48, 400-408. Animal model studies suggest that the dosing level of NSAID that is clinically feasible may not be sufficient to produce a pharmacological dose at the sites of plaque formation in AD brains. Cole et al., (2004) Ann NY Acad Sci 1035, 68-84.
Another area of interest in AD drug development focuses on signaling pathways that regulate expression of pro-inflammatory genes. Aβ stimulation of microglia results in up-regulation of the expression of TNFα and IL1 that is at least partly NFκB-dependent. Combs et al., (2001) J. Neurosci. 21, 1179-1188. IL1 is known to affect the expression of over 90 genes including those for cytokines, cytokine receptors, tissue remodeling enzymes and adhesion molecules. O'Neill (1995) Biochim Biophys Acta 1266, 31-44. The mechanism for IL1 action involves activation of an IL1 receptor-mediated signal transduction pathway which leads to activation of NFκB. O'Neill et al., (1998) J Leukoc Biol 63, 650-657. Thus NFκB is involved both in up-regulation of IL1 and in expression of the multiple genes regulated by IL1. These observations make inhibition of NFκB an attractive target for control of IL1-responsive genes in brain inflammation.
Diabetes
In 1998, it was suggested that the innate immune system is activated in diabetes, leading to a chronic inflammatory state that contributes to the disease process (Pickup et al., 1998, Diabetologia 41:1241-1248). More recently, there has been considerable support not only for an inflammatory contribution to diabetes but also to diabetic complications (Navarro et al., 2005, Nephrol Dial Transplant 20:2601-2604; Pillarisetti et al., 2004, Expert Opin Ther Targets 8:401-408). Specifically, pro-inflammatory cytokines play a major role in microvascular complications. Endogenous production of TNF-α in vascular tissue is accelerated in diabetes where it contributes to increased vascular permeability in diabetic neuropathy (Satoh et al., 2003, Exp Diabesity Res 4:65-71). Both TNF-α and IL-1 expression are increased in diabetic retina where chronic low-grade inflammation appears to contribute to retinopathy (Joussen et al., 2002, FASEB J 16:438-440). Likewise, diabetic nephropathy is associated with expression of inflammation markers such as CRP, fibrinogen and IL-6, and with increased expression of adhesion molecules such as ICAM-1, which promote inflammation by increasing leukocyte adherence and infiltration (Dalla Vestra et al., 2005, J Am Soc Nephrol 16:S78-S82). The responses to these pro-inflammatory cytokines are especially prominent in endothelial cells (EC). Moreover, the response of EC to these cytokines commonly involves signaling through transcription factor NF-κB (Mohamed et al., 1999, BioFactors 10:157-167).
Oxidative stress has consistently been shown in experimental models of diabetes (Mohamed et al., 1999, BioFactors 10:157-167). Multiple mechanisms are involved that produce oxidative stress in EC in response to hyperglycemia, including: 1) protein glycosylation leading to AGE that trigger ROS production upon binding to the AGE receptor (RAGE) (Wautier et al., 2004, Circ Res 95:233-238); 2) glucose auto-oxidation (Ceriello, 1997, Diabet Med 14:S45-S49); 3) accelerated metabolism of glucose through the aldose reductase/polyol pathway which consumes NADPH (Srivastava et al., 2005, Endocrin Rev 26:380-392); 4) uncoupling of oxidative phosphorylation and of endothelial NO synthase (eNOS) (Satoh et al., 2005, Am J Physiol Renal Physiol 288:F1144-F1152); 5) activation of specific isoforms of PKC (Ahmed et al., 2005, Curr Drug Targets 6:487-494); 6) increased flux through the hexosamine pathway (Schleicher et al., 2000, Kidney Int Suppl 77:S13-S18); and 7) exposure to angiotensin II (Yamagishi et al., 2005, FEBS Letters 579:4265-4270). Activation of NF-κB is often observed in response to these stresses. For example, exposure of EC to AGE generates ROS through activation of NADPH oxidase which then activates NF-κB followed by up-regulation of NP-κB-dependent cytokines and adhesion molecules (Wautier et al., 2001, Am J Physiol Endocrinol Metab 280:E685-E694). Angiotensin II can augment this process through crosstalk with the AGE-RAGE system, again involving NF-κB (Yamagishi et al., 2005, FEBS Letters 579:4265-4270). High glucose can induce EC apoptosis through a PI-3-kinase-regulated expression of COX-2; this was shown to involve ROS and the NF-κB-regulated expression of COX-2 (Sheu et al., 2005, Arterioscler Thromb Vasc Biol 25:539-545). There has been considerable interest in a role for poly(ADP)-ribose polymerase (PARP) in EC dysfunction. PARP directly interacts with both the p50 and p65 subunits of NF-κB, suggesting that the role of PARP activation in diabetic complications is, at least in part, due to its interaction with NF-κB (Zheng et al., 2004, Diabetes 53:2960-2967). Glucose-induced activation of NF-κB in EC is prevented by inhibitors of PKC, suggesting that the role of PKC in triggering the expression of pro-inflammatory cytokines is through downstream activation of NF-κB (Pieper et al., 1997, J Cardiovasc Pharmacol 30:528-532). There has also been considerable interest in mitochondria-derived ROS (specifically superoxide) produced in response to hyperglycemia and the relationship between these ROS and enhanced flux through the polyol pathway and the hexosamine pathway, PKC activation, and intracellular generation of AGE, all of which can be prevented by inhibiting the formation of mitochondria-derived ROS (Nishikawa et al., 2000, Nature 404:787-790). The activation of these biochemical pathways appears to be due to ROS-induced activation of PARP, which results in inactivation of glyceraldehyde-3-phosphate dehydrogenase and subsequent accumulation of glycolytic intermediates that promote these pathways (Araujo et al., 2001, Mem Inst Oswaldo Cruz 96:723-728). It is noteworthy that inhibiting the production of mitochondria-derived ROS also prevents the activation of NF-κB (Du et al., 2003, J Clin Invest 112:1049-1057), which may be related to the activation status of PARP. Clearly, activation of NF-κB appears to be a general feature of EC that are stressed by factors related to diabetic complications, suggesting a central role for NF-κB in EC dysfunction, especially as the key regulator of pro-inflammatory cytokines, adhesion molecules and extracellular matrix components, all of which are major players in diabetic microvascular complications.
The signaling mechanisms involved in inflammation that contributes to diabetes are under investigation, and are described by Wellen et al. (Wellen et al., J. Clin. Invest., 115, 1111-1119). This research indicates that inflammatory signaling pathways can be activated by metabolic stress or extracellular signaling molecules, and that endoplasmic reticulum stress (ER stress) leads to the activation of inflammatory signaling pathways and thus contributes to insulin resistance. Ozcan et al., Science, 306, 457-461 (2004). For example, several serine/threonine kinases are activated by inflammatory or stressful stimuli that contribute to inhibition of insulin signaling, including c-Jun N-terminal kinase (JNK) and I-κB kinase (IKK). The three members of the JNK group of kinases (JNK-1, -2, and -3) belong to the MAPK family and regulate multiple activities, in part through their ability to control transcription by phosphorylating activator protein-1 (AP-1). Loss of JNK1 has been shown to prevent the development of insulin resistance and diabetes in both genetic and dietary models of obesity. Hirosumi et al., Nature, 420, 333-336 (2002).
A model of the overlapping metabolic and inflammatory signaling and sensing pathways in adipocytes and macrophages that influence diabetes and inflammation is provided by FIG. 2. As shown in FIG. 2, signals from various mediators converge on the inflammatory signaling pathways, including the kinases JNK and IKK. These pathways lead to the production of additional inflammatory mediators such as NF-κB and AP-1 through transcriptional regulation as well as to the direct inhibition of insulin signaling. Opposing the inflammatory pathways are transcriptional factors from the PPAR and LXR families, which promote nutrient transport and metabolism and antagonize inflammatory activity.
Glutathione S-Transferase
Glutathione S-transferases (GSTs) are a superfamily of enzymes classified into eight gene families. Many GSTs are also classified as phase II detoxification enzymes that catalyze the conjugation of glutathione to a wide variety of electrophiles as the first step in elimination of xenobiotics. However, GSTs also exhibit numerous family-specific functions, some but not all of which involve glutathione. For example, GSTP1-1, which is the main member of the "pi" family and is the most widely distributed GST, is important as both a detoxification enzyme and in signal regulation through its protein-protein interactions with c-Jun N-terminal kinase (JNK), a kinase that is important in the stress response and apoptosis. Thus, up-regulation of GSTP1-1 serves to protect cells from apoptosis-inducing stress by inhibiting JNK. Notably, the promoter for GSTP1-1 contains NFκB-binding sites. It is important to understand that oxidative stress leads to modification of critical cysteine residues in GSTP1-1, resulting in the release of JNK and initiation of apoptosis. Therefore, it is known that tumors that over-express GSTP1-1 are resistant to stress-induced apoptosis, and the presence of GSTP1-1 assists in the prevention of apoptosis.
Glutathione S-Transferase P1-1 (GSTP1-1) thus has two distinct functions which contribute to the survival of cancer cells. First, GSTP1-1 detoxifies xenobiotic electrophiles, including some cancer drugs, by catalyzing the conjugation of glutathione, thereby contributing to drug resistance. It is involved in eliminating toxic molecules from the cell including drugs that are supposed to be assisting the cell in fighting diseases, and has been implicated in the development of drug resistance in a variety of cancers. Elevated levels of GSTP1-1 are found in numerous cancer cell lines and tumors, including, among others, breast cancers, prostate cancers, and leukemias that are resistant to a range of anti-cancer drugs. It is known in the art that GSTP1-1 positive breast tumors are more aggressive than GSTP1-1 negative tumors and have a poorer prognosis. For example, the MCF7 breast cancer cell line, which is a GSTP1-1 expressing line, was shown to develop resistance to a number of drugs when the cells were transfected with GSTP1-1. It is also known in the art that ovarian cancer cell lines that over-express GSTP1-1 are resistant to taxol and doxorubicin. In fact, GSTP1-1 has also been used as a prognostic tool in invasive breast cancer. Over-expression of GSTP1-1 has been shown to be a marker of poor outcome in breast cancer and advanced non-Hodgkin's lymphoma. And second, because GSTP1-1 also inhibits the pro-apoptotic factor c-Jun N-terminal kinase (JNK), it promotes the pro-survival state.
A number of studies support the idea that inhibitors of GSTP1-1 may have therapeutic potential in the treatment of cancer. If GSTP1-1 can be inhibited, then known cancer therapeutics would not be eliminated from the cell. In one study, inhibition of GSTP1-1 by the glutathione conjugate of doxorubicin induces apoptosis in rat hepatoma cells. Also, ethacrynic acid, a broad-spectrum inhibitor of glutathione S-transferases, provides a therapeutic advantage when combined with other agents. Ethacrynic acid, however, is a potent diuretic; this along with its lack of GST isozyme selectivity precludes the development of ethacrynic acid as an anti-cancer therapeutic. A number of peptidomimetic inhibitors that are selective for GSTP1-1 are in various stages of development, including one in Phase III for non-small cell lung cancer and ovarian cancer.
Curcumin
Nontraditional or alternative medicine is becoming an increasingly attractive approach for the treatment of various inflammatory disorders. Among these alternative approaches is the use of food derivatives, which have the advantage of being relatively nontoxic. A number of dietary compounds such as flavonoids and curcumin block activation of NFkB (Yamamoto et al., J. Clin. Invest., 107, 135 (2001); Bharti et al., Blood 101, 1053 (2003)). Curcumin is a non-nutritive, non-toxic polyphenol natural product found in turmeric, a spice that has been used for centuries in India and elsewhere as an herbal medicinal treatment of wounds, jaundice, and rheumatoid arthritis (Ammon et al., Planta Med., 57, 1 (1991)). Curcumin is the major constituent of turmeric powder extracted from the rhizomes of the plant Curcuma longa L found in south and southeast tropical Asia (Govindaraja, V. S., Crit. Rev. Food Sci. Nutri. 12:199 (1980)). In the countries of its origin, turmeric has also been used for centuries as a traditional medicine to treat inflammatory disorders. Scientists have subsequently demonstrated the anti-inflammatory properties of curcumin (Ammon et al., Planta Med. 57:1 (1991). Curcumin also exhibits potent anti-oxidant activity, which depends upon the presence of phenolic groups in the aryl rings (Baldwin, A. S. J. Clin. Invest. 107:241 (2001)). In traditional Indian medicine, curcumin has been used to treat a host of ailments through topical, oral and inhalation administration, and has recently been found safe in six human trials at oral loads up to 8 grams/day for 6 months. Chainani-Wu (2003) J Ahern Complement Med 9, 161-168. Most of the clinical trials of curcumin pertain to its anti-tumor activity in colon, skin, stomach, duodenal, soft palate and breast cancers. However, the mechanism of action for curcumin is not well understood.
Curcumin derivatives have been shown to provide antitumor activity. For example, the antitumor activity of curcumin derivatives is described in U.S. patent application Ser. No. 11/057,636, entitled "Method and Compounds for Cancer Treatment Utilizing NFkB as a Direct or Ultimate Target for Small Molecule Inhibitors," filed Feb. 14, 2005, by Vander Jagt et al. and incorporated herein by reference, and U.S. patent application Ser. No. 11/373,444, entitled "Cancer Treatment Using Curcumin Derivatives," filed Mar. 10, 2006, also by Vander Jagt et al. and incorporated herein by reference.
Curcumin is a natural chemoprotective agent that elevates the activities of Phase 2 detoxification enzymes, while inhibiting procarcinogen activating Phase 1 enzymes. It decreases expression of several proto-oncogenes including c-jun, c-fos, and c-myc, and of particular interest, it suppresses the activation of NFκB. Related to this, curcumin has also been shown to induce apoptosis in several tumor cell lines. In addition to the down-regulation of uPA by dominant negative inhibitors of NFκB, numerous other factors, including VEGF, IL-8, and MMP-9 that contribute to angiogenesis, invasion, and metastasis are down-regulated by dominant negative inhibitors of NFκB. Likewise, curcumin inhibits angiogenesis in vivo. Curcumin can be viewed as a lead compound that inhibits metastasis and promotes apoptosis. Other antiangiogenic properties of curcumin are also known. Shim et al. have shown that curcumin causes the irreversible inhibition of CD13/aminopeptidase N, a membrane-bound, zinc-dependent metalloproteinase that plays a key role in tumor invasion and angiogenesis. Shim et al., "Irreversible inhibition of CD13/aminopeptidase N by the antigenic agent curcumin", Chem. Biol. 10(8): 695-704 (August 2003).
Curcumin is known to inhibit the formation of Jun-Fos heterodimers in TPA induced cells and curcumin analogs are known to be up to 90 times more potent than curcumin (Hahm et al., Cancer Lett. 184, 89-96 (2002). It is also known that besides curcumin (turmeric), several natural products including resveratrol (peanuts and grape skins) (Manna et al., J. Immunol. 164, 6509-6519 (2000)), silymarin (artichoke) (Manna et al., J. Immunol. 163(12), 6800-6809 (1999)), oleandrin (Manna et al., Cancer Res. 60, 3838-3847 (2000)) and several compounds isolated from both green and black tea leaves (Chung et al., Cancer Res. 59, 4610-4617 (1999)) inhibit the AP-1 activation cascade. It is possible that curcumin analogs exhibit their activities on JNK since it is known that both silymarin (Manna et al., J. Immunol., 163(12), 6800-6809 (1999)) and oleandrin (Manna et al., Cancer Res. 60, 3838-3847 (2000)) inhibit JNK activity.
In addition, curcumin exhibits anti-inflammatory activity and is a potent anti-oxidant and free radical scavenger. Leu et al., (2002) Curr Med Chem Anti-Canc Agents 2, 357-370. In APP-overexpressing transgenic mice, curcumin reduced levels of oxidized proteins and inflammatory cytokine IL1 (Lim et al., (2001) J Neurosci 2, 8370-8377), thus offering a potential therapy against microglial activation in patients with Alzheimer's disease. Curcumin has additional activities of interest: it limits the progression of renal lesions in the STZ-diabetic rat model (Suresh Babu et al., (1998) Mol Cell Biochem 181, 87-96), and ameliorates oxidative stress-induced renal injury in mice (Okada et al., (2001) J Nutr 131, 2090-2095). Consequently, there has been extensive interest in the anti-oxidant properties of curcumin and the possibility that many of its biological activities are derived from its anti-oxidant properties. Balasubramanyam et al., (2003) J Biosci 28, 715-721.
Curcumin also inhibits the activation of NFκB (Bharti et al., (2003) Blood 101, 1053-1062), which may explain its anti-inflammatory properties. Curcumin was shown to attenuate the plasma inflammatory cytokine surge and cardiomyocyte apoptosis following cardiac ischemia/reperfusion in experimental animals by inhibiting activation of NFκB. Yeh et al., (2005) J Surg Res 125, 109-110. Curcumin suppressed NOS induction in LPS-stimulated macrophages by inhibiting the activation of NFκB. Pan et al., (2000) Biochem Pharmacol 60, 1655-1676. Likewise, curcumin inhibited mitogen stimulation of lymphocyte proliferation by inhibiting activation of NFκB. Ranjan et al., (2004) J Surg Res 121, 171-177. Of particular interest is the report that curcumin inhibits the activation of NFκB in BV2 microglia cells (Kang et al, (2004) J Pharmacol Sci 94, 325-328). The limited bioavailability of curcumin (Garcea et al., (2004) Br J Cancer 90, 1011-1015) suggests that clinical use of this natural product will be limited and points to the need to develop curcumin analogs with improved properties including improved bioavailability.
It was reported that curcumin inhibits TNF-α-induced NF-κB activation in human myelomonoblastic leukemia cells and phorbol ester-induced c-Jun/AP-1 activation in mouse fibroblast cells (Singh et al., J. Biol. Chem. 270:24995 (1995); Huang et al., Proc. Natl. Acad. Sci. USA 88:5292 (1991). The molecular mechanism for NF-κB inhibition by curcumin was unclear, but involved inhibition of I-κB degradation (Kumar et al., Biochem. Pharmacol. 55:775 (1998). More recent work has demonstrated that curcumin blocks intestinal endothelial cell gene expression by inhibiting the signal leading to IKK activation without directly interfering with NIK or IKK, and that blockade of IKK activation causes inhibition of I-κB phosphorylation/degradation and NF-κB activation (Jobin et al., J. Immunol. 163, 3474-83 (1999)).
The anti-inflammatory properties of curcumin and its ability to inhibit the immune response upon exposure to a variety of external stimuli may, at least in part, result from inhibition of the activation of NF-κB by these external signals, since many of the genes that are implicated in the immune/inflammatory response are up-regulated by NFκB. For example, curcumin inhibits the LPS-induced production of IL-1β and TNFα (Chan, M. M. Biochem. Pharmacol. 49, 1551 (1995)) and the IL-1β-induced expression of IL-2 (Chaudhary, L. R.; Avioli, L. V. J. Biol. Chem. 271, 16591 (1996)), as well as the TNFα-induced expression of ICAM-1, VCAM-1 and E-selectin (Gupta, B.; Ghosh, B. Int. J. Immunopharmacol. 21, 745 (1999)). NF-κB is implicated in these signaling pathways (Wang et al., Cytokine 29, 245 (2005); Krunkosky et al., Free Radical Biol. Med. 35, 1158 (2003)). However, curcumin has also been shown to be a direct inhibitor of enzymes that are important in the inflammatory response, including lipoxygenase and cyclo-oxygenase (Skrzypczak-Jankun et al., J. Int. J. Mol. Med. 6, 521 (2000)).
Further, curcumin has been shown to have possible application in the treatment of cystic fibrosis defects caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR), particularly for A508 mutations. Egan, et al., "Curcumin, A Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects", Science, 304: 600-602 (23 Apr. 2004).
The large consumption of curcumin by the Indian population may help explain their relatively low (4 times less) incidence of Alzheimer's disease compared to the U.S. population. Chandra et al., (2001) Neurology 57, 985-989. Although no systematic trials have been preformed using curcumin in India, recent studies have provided valuable insights on curcumin's role in Alzheimer's disease. Yang et al., (2005) J Biol Chem 280, 5892-5901; Ono et al., (2004) J Neurosci Res 75, 742-750. Curcumin was shown to inhibit the formation of Aβ oligomers and fibrils in vitro and reduce Aβ amyloid burden in vivo. Specifically, Ono et al. have indicated that curcumin inhibits the accumulation of amyloid β-peptide (Aβ) and the formation of β-amyloid fibrils (fAβ) from Aβ and destabilizes preformed fAβ. Ono et al., "Curcumin Has Potent Anti-Amyloidogenic Effects for Alzheimer's β-Amyloid Fibrils In Vitro", J. Neuroscience Res., 75: 742-750 (2004). Importantly, curcumin administered by intravenous (i.v.) injection lowered Aβ deposition in aged APP(Swedish)-transgenic mice (Tg2576), clearly demonstrating its ability to cross the blood-brain barrier in sufficient quantities to reduce amyloid burden. Curcumin is structurally similar to other inhibitors of Aβ aggregation such as Congo Red and Chrysamine G.
Thus, NFκB and its upstream regulators, as well as AP-1 and GSTP1-1, present inviting targets for development of anti-inflammatory drugs, and curcumin represents a promising lead compound. Analogues of curcumin that function as small molecules inhibitors of NFκB, AP-1 and GSTP1-1 activation are highly desirable for the treatment of diseases with inflammatory symptoms or components such as Alzheimer's disease, diabetes, cystic fibrosis and cancer, and also as assistive or adjuvant agents in the chemotherapeutic treatment of cancer.


This invention provide an image display apparatus having an illumination optical system for effectively illuminating a plurality of areas on a single common plane uniformly by shortening optical paths of the optical system and a new projection optical system capable of reducing the overall size of the optical system and a production cost thereof. The illumination optical system has an ellipse mirror for collecting light beams generated from a light source, a first lens group for suppressing divergence of the light beams reflected from a light collecting area of the ellipse mirror, a plural color filters for separating the light beams into three color light beams and altering a path of each of the three color light beams, and a second lens group for illuminating objects disposed on the single common plane by focusing the separated three color light beams thereon.

1. Field of the Invention
This invention relates to optical systems for constituting image display apparatuses, particularly, relates to illumination optical systems and projection optical systems suitable for constructing an image display apparatus in which plural images having respective colors are formed on a single and common plane at every.
2. Description of the Related Arts
As an optical system in which plural images are formed on a single and common plane with respective colors, there is disclosed a tri-color separation optical system in Japanese Patent Laid-open Publication, 1-68190/1989, filed by the present Applicant.
This optical system is constructed as a tri-color separation system for an image sensing device as shown in FIG. 1. Description is simply given of a principle thereof.
FIG. 1 is a schematic view showing a tri-color separation optical system in the prior art. Referring to FIG. 1, an object "O"is focused on an image plane "F"by an image sensing lens "PL". A dichroic prism Dp is disposed in an optical path. In the dichroic prism Dp, a reference character BDM denotes a B-dichroic mirror surface for reflecting a blue color and transmitting green and red colors, and RDM an R-dichroic mirror surface for reflecting a red color and transmitting green and blue colors. Reference characters Mr and Mb denote total reflection mirrors, Pr an optical path compensating prism for the red color and Pb an optical path compensating prism for the blue color. The optical path compensating prisms Pr, Pb are respectively used for both a red color optical path and a blue color optical path to cause their optical path lengths from the image sensing lens PL to the image plane F to be equal to that of a green color which passes straight the dichroic prism Dp. Thus, the red, blue and green colors images are respectively focused on the common plane by the functions of the optical compensating prisms Pr, Pb.
A white light beam impinging on the image sensing lens PL from the object 0 further impinges on the dichroic prism Dp.
Among a white light beam impinging on the dichroic prism Dp, a green color component beam passes through the R-dicrhoic and B-dicrhoic mirror surfaces RDM, BDM, and is focused on the image plane F as a displayed image Ig.
Among the white light beam impinging on the dichroic prism Dp, a blue color component beam is reflected by the B-dicrhoic mirror surface BDM, and impinges on the optical compensating prism Pb. Then, the blue color component beam impinging on the B-optical compensating prism Pb is reflected by the total reflection mirror Mb, and is focused on the image plane F as a displayed image Ib.
Among the white light beam impinging on the dichroic prism Dp, a red color component beam is reflected by the R-dicrhoic mirror surface RDM, and impinges on the optical compensating prism Pr. Then, the red color component beam impinging on the R-optical compensating prism Pr is reflected by the total reflection mirror Mr, and is focused on the image plane F as a displayed image Ir.
As a result, the image of the objective O is obtained on the image plane F as three displayed images Ib, Ig, Ir by being separated into three colors, blue, green and red.
In this case, the description is given of the tri-color separation optical system for the image sensing device.
However, this principle is applicable to the tri-color separation optical system for the illumination optical system by substituting the object O with a light source. Thus, the three light source images are obtained on a common image plane with respective colors.
This principle is also applicable to a tri-color composition optical system by reversing these optical paths.
As an exemplary display device employing the optical system shown in FIG. 1, there is a color image display device disclosed in Japanese Patent Laid-open Publication, 3-288124/1991, filed by the present Applicant.
This color image display device is shown in FIG. 2.
FIG. 2 is a perspective view showing a color image display apparatus in the prior art.
The description is simply given of the principle of the color image display apparatus.
Referring to FIG. 2, when a light beam from a light source LAMP impinges on a polarizing beam splitter PBS, a light beam having a component mainly oscillating in a direction perpendicular to a plane of incidence defined by a normal line of a boundary surface and an incident ray is reflected by a boundary surface thereof in a direction of a tri-color separation optical system SCA having the same construction as one shown in FIG. 1. The light beam is separated into the three color RGB light beams in the tri-color separation optical system SCA in the same manner as mentioned in the foregoing, and each of them impinges on a reflection type spatial light modulation element SLMr. The three color RGB light beams are reflected by the reflection type spatial light modulation element (referred to as display element) SLMr, and back-track the optical path to the tri-color separation optical system SCA, and impinge on the polarizing beam splitter PBS. The polarizing beam splitter PBS causes the light beam having a component oscillating in a direction parallel to the plane of incidence to pass through the boundary surface thereof. Thus, these light beams are projected by a projection lens PL by being magnified.
However, when the prisms shown in FIG. 1 are applied to the tri-color separation optical system SCA shown in FIG. 2, effective light beams among the light beams incident on the optical system from the light source correspond to ones impinging on areas EA of the display element SLMr. In other words, effective apertures of the display element SLMr becomes smaller than those of the optical system. Thus, the availability factor of the, display element SLMr is decreased, resulting in a cost problem of the display element.
When three individual pieces of the display elements SLMr are disposed on a single plane, it requires the prisms having larger apertures than effective areas of the display element. This poses problems of a large size of the optical system and of a decrease of the availability factor of the light because of a long optical path.
In the color composition optical system, the same problem occurs. In order to effectively utilize the light beam reflected by the display element, it requires an objective lens having a larger aperture. Thus, the prism needs an aperture as large as that of the objective lens.
Further, when the tri-color separation optical system shown in FIG. 2 is constructed by using the prisms made of optical glass, a birefringence occurs due to the optical glass. This poses a problem of a decrease of a contrast ratio.
These problems occur not only in the case of the reflection type display element but also in the case of the transmission type display element.

Illumination optical system, projection optical system and display apparatus using the same


A method for browsing and replaying a selected picture by a multimedia player is disclosed. The method includes the steps of providing a display and an controlling interface, showing a plurality of subpictures corresponding to a plurality of fullscale pictures containing said selected picture on the display, selecting one of the subpictures corresponding to the selected picture by the controlling interface, and showing the selected picture on the display. The mutlimedia player includes a display, a pickup header for picking up an image data corresponding to the selected picture from a memory device, a servo connected to the pickup header for moving the pickup header to pick up the image data, a decoder electrically connected to the pickup header for decompressing the image data to generate a fullscale image, a zoom processor electrically connected to said decoder for converting said fullscale image to a subpicture, an image overlapping device electrically connected to the zoom processor for showing a plurality of the subpictures on the display, and a controlling interface for selecting one of the plurality of the subpictures corresponding to the selected picture to show the selected picture on the display. The user can easily distinguish the bookmark spots by a plurality of subpictures and correctly select a picture to replay.

The present invention is related to a method for browsing and replaying a selected picture by a multimedia player, and more particularly to a method for browsing and replaying a selected picture by a multimedia player with a bookmark function.
At the present time, a general VCD player has a special function of recording a picture in advance for being browsed or replayed. The function of the VCD player is named as bookmark and the recorded picture is called as a bookmark spot. When a user is watching a program, he can randomly set a bookmark spot as a starting point for being browsed or replayed. Then, he can select any one of the bookmark spots which he has set to be browsed or replayed by a VCD player.
The operation process of a general bookmark function includes the steps of:
1. Under a play mode, the user can turn it to a bookmark mode and the program will still be played at the same time;
2. When the program shows a picture which the user wants to mark, the user can press a memory key to memory the tune parameter of the bookmark spot in the VCD player; and
3. End the bookmark mode and return to the play mode.
The operation process of replaying a bookmark spot includes the steps of:
1. A browse-and-replay mode is selected under a stop mode, and then a list of bookmark numbers with corresponding time parameters will be shown on the display for a user to select; and
2. Operate the controlling interface such as a remote controller or a keyboard and press the number key of the controlling interface corresponding to the bookmark numbers to replay the selected picture.
The general way of showing a list of bookmark numbers with corresponding time parameters on the display is shown in FIG. 1. As shown in FIG. 1, there are three bookmark spots which have been recorded marked with bookmark numbers 1, 2, and 3 respectively. The other bookmark numbers 4, 5, 6, 7, 8, 9, and 10 have not been marked with any bookmark spot.
It is very inconvenient to replay a bookmark spot by the way of showing the time parameters to be selected, because too many sets of the time parameters will easily make the user confused. Moreover, the time parameters are not associated with the selected pictures so that the user can not easily remember the time parameters corresponding to the pictures which he wants to replay. The object of the present invention is to provide a method for improving the defects encountered by the prior arts and make selecting a bookmark spot to be replayed easier and simpler.
An object of the present invention is to provide a method for browsing and replaying a selected picture by a multimedia player. A display is provided for showing the pictures of the program and a controlling interface is provided for controlling the multimedia player. When the program shows a picture which the user wants to mark, the user can bookmark the picture as a bookmark spot by using the bookmark function of the multimedia player. Thereafter, when the user wants to replay the selected picture, the multimedia player will show a plurality of subpictures corresponding to a plurality of fullscale pictures containing the selected picture on the display for the user to select. The user can select by the controlling interface one of the subpictures corresponding to the selected picture to be replayed, and then the selected picture will be shown on the display. By the method of the present invention, the user can easily distinguish the bookmark spots with corresponding subpictures instead of the bookmark spots with corresponding time parameters, and can correctly select a picture to replay.
In accordance with one aspect of the present invention, the controlling interface is a remote controller or a keyboard. The storage device is a video compact disc (VCD) title, super video compact disc (SVCD) title, a china video disc (CVD) title or a digital versatile disc (DVD) title. The image data is a motion picture expert group (MPEG) image data.
Among these steps, the step of showing the subpictures on the display further includes steps of picking up an image data from a storage device, decompressing the image data to generate a fullscale image, converting the fullscale image to one of the subpictures, and showing the one subpicture on the display. Moreover, the step of showing one subpicture on the display further includes a step of marking the subpicture with a bookmark number by way of on screen display (OSD), wherein each of the subpictures is represented by the corresponding bookmark number. The bookmark number is provided for selecting one subpicture by the controlling interface. The maximum number of the subpictures contained in one page on the display is n. There is a second page for selecting the one subpicture by pageup/pagedown when a count of the subpictures is more than n.
The step of showing the selected picture on the display further includes steps of picking up an image data from a storage device according to a selected bookmark number, decompressing the image data, and scanning the decompressing data to show the selected picture on the display.
Another object of the present invention is to provide a multimedia player adapted to be used to browse and replay a selected picture. The multimedia player includes a display, a pickup header for picking tip an image data corresponding to the selected picture from a storage device, a servo connected to the pickup header for moving the pickup header to pick up the image data, a decoder electrically connected to the pickup header for decompressing the image data to generate a fullscale image, a zoom processor electrically connected to the decoder for converting the fullscale image to a subpicture, an image overlapping device electrically connected to the zoom processor for showing a plurality of the subpictures on the display, and a controlling interface for selecting one of the plurality of the subpictures corresponding to the selected picture to show the selected picture on the display. The decoder is a MPEG decoder.
The multimedia player further includes a memory electrically connected to the image overlapping device and decoder for recording a plurality of small-scale images, corresponding to the plurality of the subpictures, obtained from the image overlapping device in a first instance, and recording the fullscale image, corresponding to the selected picture, obtained from the decoder in a second instance.
The multimedia player further includes a video scanner electrically connected to the memory for converting the plurality of small-scale images to the plurality of the subpictures to be shown on the display in the first instance, and converting the fullscale image to the selected picture to be shown on the display in the second instance. The multimedia player further includes an on screen display controller for marking the plurality of the subpictures with a plurality of bookmark numbers respectively by way of on screen display.
The present invention may best be understood through the following description with reference to the accompanying drawings, in which:

Method for browsing and replaying a selected picture by a multimedia player


A plug assist drive assembly is provided for a thermoforming press. The plug assist drive assembly includes a drive platen, a plug assist platen, a first elongated gear rack, a second elongated gear rack, a drive gear, a driven gear, and a drive source. The first elongated gear rack and the second elongated gear rack are carried by the plug assist platen in longitudinally extending and substantially parallel, spaced apart relation with a plurality of rack teeth extending on each gear rack between proximal and distal ends. The drive gear is carried by the drive platen and is operably communicating with the first elongated gear rack. The driven gear is carried by the drive platen and is operably communicating with the second elongated gear rack and the drive gear. The drive source is operably communicating with the drive gear to drive the assist platen in linearly reciprocating motion relative to the drive platen. A thermoforming machine having the plug assist drive assembly is also provided. A method is also provided.

The use of a third platen on a thermoforming machine is known in order to more quickly advance an array of plugs into female mold cavities of a thermoforming machine. One machine uses a plurality of ball screws. Another machine uses a single roller screw shaft. Both machines provide a compromise between providing sufficient torque, or forming pressure, and providing a sufficiently fast stroke. Improvements are needed in order to provide both sufficient torque and sufficiently fast stroke in order to optimize article formation and surface finish.

Thermoforming machine, plug assist drive assembly and method


A method for automatically generating test programs includes receiving a description of a system under test, expressed in terms of variables associated with the system and conditional constraints including semantics applied to the variables, and receiving a definition of an event to be tested in the system. The method generates an ECondCSP over the variables responsively to the definition of the event and to the conditional constraints, such that at least some of the semantics of the conditional constraints are preserved in the ECondCSP when one or more of the variables to which the semantics are applied are inactive. The ECondCSP is solved to generate a test case for the system.

Many of the tasks that are addressed by decision-making systems and artificial intelligence can be represented as constraint satisfaction problems (CSPs). In this representation, the task is specified in terms of a set of variables, each of which can assume values in a given domain, and a set of constraints that the variables must simultaneously satisfy. The set of variables, domains and constraints is referred to as a CSP. Each constraint may be expressed as a relation, defined over some subset of the variables, denoting valid combinations of their values. A solution to a CSP is an assignment of a value to each variable from its domain that satisfies all of the constraints. Various techniques have been proposed for solving CSPs. A survey of common techniques can be found in a paper by Kumar entitled "Algorithms for Constraint Satisfaction Problems: A Survey," Artificial Intelligence Magazine, 13:1 (1992), pages 32-44, which is incorporated herein by reference.
Constraint satisfaction methods have been found useful in a variety of applications, including:                Artificial intelligence        Robotic control        Temporal reasoning        Natural language parsing        Spatial reasoning        Test-case generation for software and hardware systems        Machine vision        Medical diagnosis        Resource allocation        Crew scheduling        Time tabling        Frequency allocation        Graph coloring.
For example, Bin et al. describe a constraint satisfaction method for use in automated generation of test programs, in a paper entitled "Using a Constraint Satisfaction Formulation and Solution Techniques for Random Test Program Generation," IBM Systems Journal 41:3 (2002), pages 386-402, which is incorporated herein by reference. The authors show how random test program generation can be modeled as a CSP, and they describe a set of solution techniques that are used in practical test-case generation tools. Adir et al. in a paper entitled "Piparazzi: A Test Program Generator for Micro-architecture Flow Verification," Eighth IEEE International High-Level Design Validation and Test Workshop (Nov. 12-14, 2003), pages 23-28, which is incorporated herein by reference, describe a test generator that uses a dedicated CSP solver. The test generator converts user requests for micro-architectural events into test programs.
A number of other constraint satisfaction systems are described in the patent literature. For example, U.S. Pat. No. 5,636,328, whose disclosure is incorporated herein by reference, describes methods and apparatus for finding values that satisfy a set of constraints, applied particularly to control of a robotic arm. U.S. Pat. No. 5,617,510, whose disclosure is also incorporated herein by reference, describes a method, useful in computer-aided design, of identifying possible solutions to an over-constrained system having a collection of entities and constraints.
The concept of a CSP was generalized by Mittal et al. to cover more complex problems, in which variables may be active or inactive, in a paper entitled "Dynamic Constraint Satisfaction Problems," Proceedings of the Eighth National Conference on Artificial Intelligence (AAAI-90), Boston, Mass., July 1990, pages 25-32, which is incorporated herein by reference. To avoid ambiguity, this generalization is commonly referred to as "Conditional CSP," or CondCSP. A CondCSP comprises the following:                A set of variables V={v1, v2, . . . , vn}.        A set of domains D={D1, D2, . . . , Dn}, such that Di is the set of valid values for the variable vi.        A set of initial variables VI⊂V, VI≠φ.        A set of compatibility constraints CC.        A set of activity constraints CA.
In contrast to the traditional definition of CSP, a variable in a CondCSP can be either active or inactive. A variable is assigned a value only if it is active. A compatibility constraint specifies the set of allowed combinations of values for a set of variables. A compatibility constraint is active only if all its variables are active. An activity constraint has the form cact→v, in which c is defined in the same manner as a compatibility constraint, and v is a variable. Such an activity constraint states that if the left hand constraint c holds, then the variable v is active. Similarly, crn→v (wherein rn stands for "require not") states that the variable v is not active if constraint c holds.
A Solution to a CondCSP contains (a) a set of active variables that must include all initial variables, and (b) a value assignment to all the active variables, in which each variable is assigned a value from its domain, the assignment satisfying all the active compatibility constraints. The assignment and the set of active variables must satisfy all the activity constraints.

Automatic test program generation using extended conditional constraint satisfaction

Intranational Business Machines Corporation


An absorbent pad for use with meat and poultry products in retail sale packages has a laminated tissue absorbent mat sandwiched and sealed between upper and lower plastic sheets. The pad is perforated by penetration of perforating pins entirely through the pad to develop a series of holes for the passage of liquid from the meat package into the absorbent mat inside the pad. A myriad of outwardly projecting tufts of tissue material are developed along the underside of the pad by the perforating pins. These tufts develop a wicking effect which enhances the capillary action of the tissue layers inside the pad. Methods of fabrication of the individual pads and continuous linear absorbent sheet material are also disclosed.

1. Field of the Invention
This invention relates to absorbent pads and, more particularly, to such pads which are used in packaging of meat products for absorbing liquids leaking therefrom and to the method of fabricating such pads.
2. Description of the Related Art
Absorbent pads particularly designed for packaging with meats, poultry and fish food products are used in food markets, poultry processing plants and the like to reduce product display costs and to provide a cleaner, more attractive product. These pads are generally wrapped with the food product on the underside thereof to absorb liquids which may "bleed" from the product. In poultry products, for example, it is customary to place the poultry parts of a given package in a molded shallow tray of foamed plastic or the like. One of these absorbent pads is placed in the bottom of the tray and the poultry parts are placed thereon. The complete package is then wrapped with clear polyethylene or the like. U.S. Pat. Nos. 4,735,846 and 4,770,920 of Lionel M. Larsonneur, one of the inventors herein, disclose one such pad which is constructed of layers of highly absorbent cellulose tissue plus at least a polyethylene backing layer. The layers are bonded together by a plurality of pressure bonds and protected against delamination by the application of melted wax or the like to the areas surrounding the individual pressure bonded spots.
U.S. Pat. Nos. 4,275,811, 4,321,997, 4,382,507 and 4,410,578 of Alan H. Miller disclose receptacles for containing and displaying food products which tend to exude juices or liquids, which receptacle comprises a tray or bag and an absorbent pad associated therewith. The disclosed pad comprises a mat of liquid absorbent material, an upper liquid impermeable sheet overlying the absorbent mat, and a perforated bottom sheet underlying the absorbent mat. When a food product is positioned upon the upper sheet of the absorbent pad, any exuded liquids flow around the pad and enter the mat by capillary action through perforated openings of the bottom sheet.
Another set of patents of John C. Rhodes et al, U.S. Pat. Nos. 4,940,621, 5,022,945 and 5,055,332, discloses an absorbent pad for meat and poultry products. The disclosed pad includes upper and lower plastic film layers, at least one of which is perforated, and an intermediate absorbent layer disposed between the film layers. The intermediate absorbent layer includes a series of juxtaposed and overlapping material fibers with superabsorbent granules dispersed throughout the absorbent layer and supported by the absorbent material fibers within interstices thereof. The absorbent pads of Rhodes et al function substantially like the pads of the Miller patents listed above.
All of the poultry/meat pads which are known comprise a liquid absorbent mat or laminated tissue pad within a plastic envelope or supported on a plastic layer which is perforated or otherwise rendered permeable to liquid. The liquid must pass through the plastic layer in order to reach the absorbent mat or pad contained therein. Once past the plastic layer, the liquid spreads throughout the absorbent pad by capillary action. However, there are circumstances where the liquid does not readily pass through openings in the plastic layer, in which case it is not absorbed, such as, for example, when meat packages are "shingled", i.e., stacked on edge or in a canted display. What is needed is an improved arrangement in which the effectiveness of the capillary action within the absorbent pads in the interior of the plastic envelopes can be enhanced and extended to reach liquid outside the envelope

Perforated absorbent pad with tufts of tissue projecting from the underside