The present invention relates to cardiac hypertrophy. More particularly, the present invention defines the molecular events linking calcium stimulation to cardiac hypertrophy. More specifically, the present invention shows that Ca2+ stimulation of the hypertrophic response is mediated through an HDAC 4 and 5 interaction with MEF2, and that phosphorylation of HDACs results in loss of HDAC-mediated repression of MEF2 hypertrophic action. Thus, the present invention provides methods and compositions of treating cardiac hypertrophy, as well as methods and compositions for identifying subjects at risk for cardiac hypertrophy. Further provided are methods for the detection of compounds having therapeutic activity toward cardiac hypertrophy.

This application is a continuation of U.S. patent application Ser. No. 09/643,206 filed on Aug. 21, 2000, now U S. Pat. No. 6,632,628, which claims priority to U.S. Provisional Application No. 60/150,048 filed on Aug. 20, 1999, the entire contents of each which are incorporated herein by reference. Additionally, all patents, published patent applications, and other references cited throughout this specification are hereby incorporated by reference in their entireties.
1. Field of the Invention
The present invention relates generally to the field of molecular biology. More particularly, it concerns the discovery of a central mediator of cardiac hypertrophy.
2. Description of Related Art
Cardiac hypertrophy is an adaptive response of the heart to virtually all forms of cardiac disease, including those arising from hypertension, mechanical load, myocardial infarction, cardiac arrythmias, endocrine disorders and genetic mutations in cardiac contractile protein genes. While the hypertrophic response is initially a compensatory mechanism that augments cardiac output, sustained hypertrophy can lead to dilated cardiomyopathy, heart failure, and sudden death. In the United States, approximately half a million individuals are diagnosed with heart failure each year, with a mortality rate approaching 50%.
Despite the diverse stimuli that lead to cardiac hypertrophy, there is a prototypical molecular response of cardiomyocytes to hypertrophic signals that involves an increase in cell size and protein synthesis, enhanced sarcomeric organization, upregulation of fetal cardiac genes, and induction of genes such as c-ƒos and c-myc (reviewed in Chien et al., 1993; Sadoshima and Izumo, 1997). The causes and effects of cardiac hypertrophy have been documented extensively, but the underlying molecular mechanisms that couple hypertrophic signals, initiated at the cell membrane to reprogram cardiomyocyte gene expression remain poorly understood. Elucidation of these mechanisms is a central issue in cardiovascular biology and is critical in the design of new strategies for prevention or treatment of cardiac hypertrophy and heart failure.
Numerous studies have implicated intracellular Ca2+ as a signal for cardiac hypertrophy. In response to myocyte stretch or increased loads on working heart preparations, intracellular Ca2+ concentrations increase (Marban et al., 1987; Bustamante et al., 1991; Hongo et al., 1995). This is consistent with a role of Ca2+ in coordinating physiologic responses with enhanced cardiac output. A variety of humoral factors, including angiotensin II (AngII), phenylephrine (PE) and endothelin-1 (ET-1), which induce the hypertrophic response in cardiomyocytes (Karliner et al., 1990; Sadoshima and Izumo, 1993a, 1993b; Leite et al., 1994), also share the ability to elevate intracellular Ca2+ concentrations.
Hypertrophic stimuli result in reprogramming of gene expression in the adult myocardium such that genes encoding fetal protein isoforms like β-myosin heavy chain (MHC) and α-skeletal actin are upregulated, whereas the corresponding adult isoforms, α-MHC and α-cardiac actin, are downregulated. The natriuretic peptides, atrial natriuretic factor (ANF) and β-type natriuretic peptide (BNP), which decrease blood pressure by vasodilation and natriuresis, also are rapidly upregulated in the heart in response to hypertrophic signals (reviewed in Komuro and Yazaki, 1993). The mechanisms involved in coordinately regulating these cardiac genes during hypertrophy are unknown, although binding sites for several transcription factors, including serum response factor (SRF), TEF-1, AP-1, and SpI are important for activation of fetal cardiac genes in response to hypertrophy (Sadoshima and Izumo, 1993a; 1993b; Kariya et al., 1994; Karns et al., 1995; Kovacic-Milivojevic et al., 1996). Most recently, the cardiac-restricted zinc finger transcription factor GATA4 also has been shown to be required for transcriptional activation of the genes for Ang II type 1α receptor and β-MHC during hypertrophy (Herzig et al., 1997; Hasegawa et al., 1997; reviewed in Molkentin and Olson, 1997).
The potential roles of the myocyte enhancer factor-2 (MEF2) family of transcription factors in cardiac development and hypertrophy are also considered. There are four members of the MEF2 family, referred to as MEF2A, -B, -C, and -D, in vertebrates (reviewed in Olson et al., 1995). These transcription factors share homology in an N-terminal MADS-box and an adjacent motif known as the MEF2 domain. Together, these regions mediate DNA binding, homo- and heterodimerization, and interaction with various cofactors, such as the myogenic bHLH proteins in skeletal muscle. MEF2 binding sites, CT(A/T)4TAG/A, are found in the control regions of the majority of skeletal, cardiac, and smooth muscle genes. The C-termini of the MEF2 factors function as transcription activation domains and are subject to complex patterns of alternative splicing.
During mouse embryogenesis, the MEF2 genes are expressed in precursors of cardiac, skeletal and smooth muscle lineages and their expression is maintained in differentiated muscle cells (Edmondson et al. 1994). The MEF2 factors also are expressed at lower levels in a variety of nonmuscle cell types. Targeted inactivation of MEF2C has been shown to result in embryonic death at about E9.5 due to heart failure (Lin et al., 1997). In the heart tubes of MEF2C mutant mice, several cardiac genes fail to be expressed, including α-MHC, ANF, and α-cardiac actin, whereas several other cardiac contractile protein genes are expressed normally, despite the fact that they contain essential MEF2 binding sites in their control regions. These results have demonstrated the essential role of MEF2C for cardiac development and suggest that other members of the MEF2 family may have overlapping functions that can support the expression of a subset of muscle genes in the absence of MEF2C. In Drosophila, there is only a single MEF2 gene, called D-MEF2. In embryos lacking D-MEF2, no muscle structural genes are activated in any myogenic lineage, demonstrating that MEF2 is an essential component of the differentiation programs of all muscle cell types (Lilly et al., 1995; Bour et al., 1995).
Although MEF2 factors are required for activation of muscle structural genes, they are not sufficient to activate these genes alone. Instead, biochemical and genetic studies have shown that MEF2 factors act combinatorially with other transcription factors to activate specific programs of gene expression. In skeletal muscle, MEF2 establishes a combinatorial code through interaction with members of the MyoD family to activate muscle gene transcription (Molkentin et al., 1995; Molkentin and Olson, 1996). The specific partners for MEF2 in cardiac and smooth muscle cells or in nonmuscle cells in which MEF2 proteins have been shown to regulate a variety of genes, remain to be defined.
As discussed below, there are four lines of evidence that suggest an important role for MEF2 in the control of cardiac hypertrophy. 1) MEF2 regulates many of the fetal cardiac genes that are up-regulated during hypertrophy. 2) MEF2 transcriptional activity is induced by the same signal transduction pathways that control hypertrophy. 3) MEF2C is upregulated in the hearts of human patients with congestive heart failure. 4) MEF2 synergizes with the thyroid hormone receptor to regulate transcription of the α-MHC gene (Lee et al., 1997) and thyroid hormone is a potent inducer of hypertrophy.
Transcriptional activation of the orphan steroid receptor Nur77 gene (NGFI-B) in T cells in response to T cell receptor activation is mediated by a CsA-sensitive, calcium-dependent signaling pathway (Woronicz et al., 1995). This signaling pathway is directed at two MEF2 binding sites in the NGFI-B promoter. There is no change in DNA binding activity of MEF2 in the presence or absence of calcium signals in that system, whereas transcriptional activity of MEF2 is dramatically increased by calcium signaling. This implies that calcium signals must enhance MEF2 activity by inducing a cofactor or a posttranslational modification of MEF2 that stimulates transcriptional activity.
In addition, transcription of the calcium-dependent lytic cycle switch gene BZLF1, which is required for induction of the lyric cycle of Epstein-Barr virus (EBV), is inhibited by CsA and FK506, indicating that a calcineurin-dependent pathway mediates activation of this gene (Liu et al, 1997). CsA-sensitivity of BZLF1 transcription maps to three MEF2 sites in the BZLF1 promoter. CsA-sensitive inducibility was shown to be reconstituted using an artificial promoter containing multiple copies of the MEF2 site in conjunction with a CREB/AP-1 site. NFAT did not bind the BZLF1 promoter, but CsA-sensitive induction of this promoter was shown to be calcineurin- and NFAT-dependent. CaMKIV was also shown to be a potent inducer of MEF2 activity (Liu et al., 1997). The mechanism whereby MEF2 confers responsiveness to the calcineurin/NFAT signaling system remains to be elucidated, however.
The MAP kinase signaling pathway also has been shown to lead to enhanced transcriptional activity of MEF2 factors in a variety of cell types (Han et al., 1997; Coso et al., 1997; Kato et al., 1997; Clarke et al., 1998). This enhancement has been shown for MEF2C to be mediated by phosphorylation of three amino acids, Thr293, Thr300, and Ser387, in the C-terminal activation domain by the MAP kinase family member p38. Whether these same residues are phosphorylated by hypertrophic signaling in the heart remains to be determined.
It is clear that the cardiac hypertrophic response is somehow initiated through a Ca2+ dependent pathway. However, the precise identification of the gene(s) which mediate(s) the hypertrophic response remains elusive. The present invention is directed toward the elucidation of the exact point in the hypertrophic pathway which may be manipulated to achieve beneficial effects on cardiac hypertrophy. In order to develop pharmacologic strategies for treatment of cardiac hypertrophy in humans, it will be important to establish experimental models which accurately reflect the pathological profile of the disease and to identify compositions which regulate or inhibit hypertrophic growth.

Methods and compositions relating to HDAC 4 and 5 regulation of cardiac gene expression

Board of Regents, The University of Texas System


Methods and systems herein provide for color conversion. Such color conversion includes gamut mapping by determining a color gamut of an imaging device and receiving color data having color values external to the color gamut of the imaging device. The gamut mapping proceeds by determining a color region external to the color gamut and mapping the color values within the color region to the color gamut. Thereafter, the area of the color region is increased and the color values within the increased color region are mapped to the color gamut.

1. Field of the Invention
The invention relates to the field of printing systems, and in particular, to methods and systems for color conversions.
2. Statement of the Problem
In color printing, displaying, and reproduction, the term gamut represents the set of colors that a color-reproduction device is physically able to generate. Every device that displays or reproduces an image, such as a printer, monitor, scanner, or digital camera, may have its own unique color gamut. When an image is transferred from one device to another, the color gamut of each device is examined.
The color gamut generally has two components that are considered when performing a color conversion. Those components include the gamut boundary and the number of colors that are realizable within the gamut boundary. The gamut boundary of a device represents the outermost extent of the device's capabilities in a reference color space. Because of quantization in color reproduction systems, such as those of color halftone printers, not all colors within a device's boundary are realizable. Moreover, the shape of the boundaries can vary dramatically.
When an input color space is larger than the gamut of an output color device, gamut mapping algorithms are applied. The gamut mapping process transforms a point in the source gamut to a realizable color inside the gamut of the output device. The form of this transformation can dramatically impact the quality of the reproduced images. As such, care is taken in the design and implementation of gamut mapping transformations.
Certain current gamut mapping algorithms map all out-of-gamut points directly to the destination gamut. For example, clipping algorithms clip out-of-gamut points to the destination gamut boundary. Scaling algorithms, on the other hand, scale an input color gamut to an output color gamut such that some of the out-of-gamut points are mapped inside the destination gamut while others are mapped to the boundary of the destination gamut.
The large variability in past color gamut mapping studies suggests that ideal gamut mapping depends on image content, preservation of perceived hue throughout color space and the extent of the gamut mismatch in various regions of color space. Thus, image dependent and regional-dependent gamut mappings have been preferred. One such gamut mapping includes a linear conversion function that interpolates color space source data to printer specific color space data by subdividing the source data into a plurality of subsets and interpolating the data for each subset using one or more linear conversion functions. A problem, however, exists with the linear conversion function as it does not generate an optimum interpolation for each subset. To compensate for sub-optimal interpolations of subsets, one or more of a plurality of conversion functions may be selected for each subset, optimizing the interpolation for each subset. The converted subsets, however, still do not optimally combine to form a target data set.
Perceptual gamut mapping is also used in color reproduction. Perceptual gamut mapping modifies both in-gamut and out-of-gamut colors from their colorimetric representation in order to provide a pleasing or perceptual appearance. The results of the perceptual gamut mapping normally depend on the input color range and the device color gamut. However, if the input color range is much larger than the actual output color range, as is normally the case, the reproduced colors have lower chroma and are less vivid. Accordingly, there exists a need to map colors from the gamut of one device to the gamut of another device while ensuring that the colors remain aesthetically pleasing and vivid.

Gamut mapping based on numerical and perceptual models


A method for forming three-dimensional (3D) integrated circuits includes providing a first wafer comprising a silicon layer on a top surface of the first wafer, providing a second wafer comprising a silicon oxide layer on a top surface of the second wafer, bonding the first and the second wafers by placing a top surface of the silicon oxide layer against a top surface of the silicon layer and applying a pressure, and forming vias electrically interconnecting integrated circuits in the first and second wafers. The bonding is preferably preformed using a low pressure. A CMP and a plasma treatment are preferably performed to substantially flatten the surface of the silicon oxide layer before bonding.

Since the invention of the integrated circuit, the semiconductor industry has experienced a constant rapid growth due to continuous improvements in the integration density of various electronic components (i.e., transistors, diodes, resistors, capacitors, etc.). For the most part, this improvement in integration density has come from repeated reductions in minimum feature size, which allows more components to be integrated into a given area.
These integration improvements are essentially two-dimensional (2D) in nature, in that the volume occupied by the integrated components is essentially on the surface of the semiconductor wafer. Although dramatic improvement in lithography has resulted in considerable improvement in 2D integrated circuit formation, there are physical limits to the density that can be achieved in two dimensions. One of these limits is the minimum size needed to make these components. Also, when more devices are put into one chip, more complex designs are required.
An additional limit comes from the significant increase in the number and length of interconnections between devices as the number of devices increases. When the number and length of interconnections increase, both circuit RC delay and power consumption increase.
Three-dimensional (3D) integrated circuits (ICs) are therefore created to resolve the above-discussed limitations. In a typical 3D integrated circuit formation process, two wafers, each including an integrated circuit, are formed. The wafers are then bonded with the devices aligned. Deep vias are then formed to interconnect devices on the first and second substrates.
Much higher device density has been achieved using 3D IC technology, and up to six layers of wafers have been bonded. As a result, the total wire length is significantly reduced. The number of vias is also reduced. Accordingly, 3D technology has the potential of being the mainstream technology of the next generation.
Conventional methods for bonding two wafers include adhesive bonding, direct copper bonding and direct oxide bonding. Adhesive bonding is performed by bonding two wafers with an adhesive. This approach is relatively easy and the cost is low. A main problem of this approach is the low thermal stability and extendibility. When a third wafer is bonded to the two already bonded wafers, the existing adhesive between the first and the second wafers may contract under the thermal conditions, and the potentially uneven contraction generates stresses. Therefore, it is difficult to bond three or more wafers together.
In direct copper bonding, each of the two wafers have copper pads exposed on the surfaces of the wafers, and the two wafers are bonded by applying a high pressure, which is typically about 80 pounds per square inch (psi) to about 100 psi. Under such a high pressure, low-k dielectric materials on the wafers are densified, and the respective k values are increased, undesirably.
In direct oxide bonding, the two wafers have oxide layers on the respective surfaces of the wafers, and are bonded oxide-to-oxide. Vias are then formed through the oxide layers to connect the wafers. Direct oxide bonding typically requires a temperature as high as 900° C., or a temperature of about 400° C. to about 500° C. plus a pressure of about 40 psi to about 50 psi. The high temperature and/or high pressure also cause the k values of the low-k dielectric materials to increase.
The conventional adhesive bonding, direct copper bonding and direct oxide bonding are suitable for forming 3D integrated circuits with relatively high-k dielectric materials, for example, dielectric materials having k values greater than about 3.5. However, these methods either cause an increase in k values of porous low-k materials or have an extendibility problem. As such, the existing technologies are not suitable for 3D integrated circuits with low-k dielectric materials, and thus a novel method is needed.

Method for forming a 3D interconnect and resulting structures

Taiwan Semiconductor Manufacturing Company, Ltd.


A system and method for unified password processing is provided. According to an aspect, a device can receive a unified passcode. The unified passcode can be a passcode for unlocking access to the device, or can be the basis for generating additional passwords or both. The unified passcode can also be used for generating additional passcodes for unlocking additional features of the device. The generated passcodes can also be used for unlocking modules that are connected to a device such as a universal integrated circuit card (UICC). In cases where a generated passcode can be used to unlock a UICC, the generated passcode is converted to a personal identification number (PIN). The mobile interface to the UICC can be extended to include alphanumeric passwords, in addition to PINs.

Operating a device can require multiple passwords or other security prompts to be entered to access its features. For example, at device startup a code for unlocking the device, and/or a code for registering the device on a network can be required. Additional passwords may also be needed to access additional features of the device such as work related functionality. Moreover, entering the wrong password multiple times can lead to a wiped device.

System and method for unified passcode processing


A sheet member and a method for constructing the sheet member. The sheet member includes a plurality of elongated, enclosed channels formed by electrodeposition.

Various approaches have been developed in the past for providing an article having elongated enclosed channels. Such channels are useful, such as for the circulation of fluids. Articles have been assembled having a plurality of discrete tubes bonded together, or to a common support structure. Additionally, holes may be machined into a solid block of material to form passageway. However, such constructions have been expensive to manufacture and have been difficult to construct with extremely small, and/or closely spared elongated passageways.
Electrodeposition of materials on patterns known as mandrels to construct articles having a desired shape has been known in the past. It is also recognized that electrodeposition on to a mandrel containing recesses or grooves may result in the formation of enclosed voids. That is, due to localized variations in the potential gradient during the electrodeposition process, the deposited material will form at a faster rate adjacent corners, projections or other sharp changes in the geometry of the mandrel. If allowed to accumulate at the tops of recesses of a mandrel, the material on each side of the recess will meet or "bridge" at an intermediate point over the recess, shielding the interior of the recess from the accumulation of further material. An enclosed void is thus formed, generally recognized prior to the present invention as a defect in the article produced.

Sheet-member containing a plurality of elongated enclosed electrodeposited channels and method

Minnesota Mining and Manufacturing Company


A reverse implement option for a tractor or mowing vehicle is activated by moving the reverse foot pedal to an intermediate position. An arm linked to the reverse foot pedal pivots in response to movement of the reverse foot pedal to the intermediate position to actuate a reverse sensing switch. The reverse sensing switch is actuated before a transmission control rod, which links the reverse foot pedal to a hydrostatic transmission swash plate, enables reverse travel of the tractor or vehicle. The PTO operates during reverse travel of the tractor if both the hand operated bypass switch and the reverse sensing switch are actuated.

Vehicles such as lawn and garden tractors with PTO driven attachments, or mowing vehicles, may include an interlock circuit with several functions including the prevention of PTO operation when the tractor or vehicle travels in reverse. Under certain conditions, operation of the PTO or mowing blade(s) while the tractor or vehicle travels in reverse is necessary or desired. This may be referred to as a reverse implement option. Various override or bypass systems have been proposed for this purpose. Some of the override or bypass systems may also be referred to as latch circuits, which typically require the operator or driver to actuate one or more switches. For example, U.S. Pat. No. 5,994,857 assigned to Deere and Company of Moline, Ill., relates to an interlock circuit having several relays and a hand operated PTO switch provided with a momentary on (or override) position to allow operation of the PTO while the tractor or vehicle travels in reverse. U.S. Pat. No. 6,316,891, also assigned to Deere and Company, describes an interlock circuit having only a single relay, and an override or bypass system that does not require the operator to continuously push or hold the hand operated PTO switch to permit PTO operation while traveling in reverse.
Override or bypass systems may include a reverse sensing switch, in addition to a hand operated PTO switch. For example, the override or bypass system may allow PTO operation if a hand operated PTO switch is moved to a momentary on (or override) position, and the reverse sensing switch is closed or actuated, indicating the vehicle is in reverse. In vehicles having hydrostatic transmissions, the reverse sensing switch may be on the transmission or hydrostatic control rod.
After the operator actuates a hand operated PTO switch, the PTO override system may allow PTO operation to begin when the operator depresses the reverse foot pedal sufficiently for the reverse sensing switch to detect the tractor or vehicle is in reverse. The reverse sensing switch may detect the tractor or vehicle is in reverse beginning at a speed of zero mph. However, when the operator steps on the reverse pedal, the reverse sensing switch may not detect the tractor or vehicle is in reverse until after it has begun traveling in reverse. The reverse sensing switch may not be actuated at the same speed for all tractors or vehicles and/or operating conditions. For example, some machines or operating conditions may not detect the vehicle is in reverse and allow PTO operation until it reaches a speed of 0.75 mph in reverse. The override or bypass system also may unlatch at different speeds, depending on the tractor or vehicle condition and the operating conditions.
There is a need for a reverse implement option for a lawn and garden tractor or mowing vehicle that will provide a more predictable start of PTO operation when the tractor or vehicle begins travel in reverse. There is a need for more consistent PTO operation for traveling in reverse across different tractors or vehicles, and for different operating conditions.

Reverse implement option using reverse pedal


Provided are various aqueous formulations of the neonatal Fc receptor (FcRn) antagonist ARGX-113, including formulations useful as pharmaceutical compositions, methods for their preparation, devices comprising the various formulations, and uses thereof. In certain embodiments the formulations are suitable and useful for administration of ARGX-113 to a human subject. In certain embodiments the formulations are suitable and useful for subcutaneous administration of ARGX-113 to a human subject. The formulations can be used in the treatment of any condition that would benefit from inhibition of FcRn-mediated antibody recycling. Such conditions can include any one or more of various antibody-mediated autoimmune diseases, including, for example and without limitation, myasthenia gravis (MG) and immune thrombocytopenia (ITP).

Immunoglobulin gamma (IgG) antibodies play a key role in the pathology of many disorders, such as autoimmune diseases, inflammatory diseases, and disorders in which the pathology is characterized by over-expression of IgG antibodies (e.g., hypergammaglobulinemia) (see e.g. Junghans, Immunol Res. 16 (1):29 (1997)).
The half-life of IgG in the serum is prolonged relative to the serum half-life of other plasma proteins (Roopenian et al., J Immunol. 170:3528 (2003); Junghans and Anderson, Proc. Natl. Acad. Sci. USA 93:5512 (1996)). This long half-life is due, in part, to the binding of the Fc region of IgG to the neonatal Fc receptor (FcRn). Although FcRn was originally characterized as a neonatal transport receptor for maternal IgG, it also functions in adults to protect IgG from degradation. FcRn binds to pinocytosed IgG and protects the IgG from transport to degradative lysosomes by recycling it back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG/FcRn interaction is stronger at acidic endosomal pH than at extracellular physiological pH.
When the serum concentration of IgG reaches a level that exceeds available FcRn molecules, unbound IgG is not protected from degradative mechanisms and will consequently have a reduced serum half-life. Thus, inhibition of IgG binding to FcRn reduces the serum half-life of IgG by preventing IgG endosomal recycling of IgG. Accordingly, agents that antagonize the binding of IgG to FcRn may be useful for regulating, treating or preventing antibody-mediated disorders, such as autoimmune diseases, inflammatory diseases, etc. Certain of these diseases are currently treated, at least in part, by intravenous infusion of pooled IgG (IVIg) from human donors. As many of these autoimmune diseases are chronic, afflicted individuals may require repeated administrations of IVIg and/or other suitable therapies in order to manage their disease.
In another approach, blocking antibodies to FcRn have been developed to inhibit IgG Fc binding to FcRn (see e.g. WO 2002/043658). Peptides have also been identified that bind to and antagonize FcRn function (see e.g. U.S. Pat. Nos. 6,212,022 and 8,101,186). In addition, full-length IgG antibodies comprising variant Fc receptors with enhanced FcRn binding and decreased pH dependence have also been identified that antagonize FcRn binding to IgG (see e.g. U.S. Pat. No. 8,163,881 and Vaccaro et al., Nat Biotechnol. 23(10): 1283-1288 (2005)).
Recently, another FcRn inhibitor, a modified version of human IgG1 Fc fragment, named efgartigimod (also known as ARGX-113), has been developed. See WO 2015/100299, the entire contents of which are incorporated herein by reference. ARGX-113 is currently undergoing clinical trials in a number of autoimmune diseases, including myasthenia gravis (MG) and immune thrombocytopenia (ITP).
A need still exists for improved formulations and methods of administration of FcRn inhibitors for use in the treatment of autoimmune diseases.

Pharmaceutical formulations of FcRn inhibitors suitable for subcutaneous administration


A method for washing the interior surfaces of tanks with a washing head is provided with a nozzle (28) which ejects a liquid beam and which is rotatable about a first (11) and a second (34) axis whereby the nozzle is allowed to cover a two-dimensional solid angle. The washing head is controlled in such a manner that for an entire revolution about the first axis, the nozzle performs a small rotation about the second axis, and that over a number of revolutions about the first axis the nozzle follows a path which covers the entire a solid angle. The drive mechanism for rotating the washing head is arranged externally of the conduits carrying washing liquid in order to avoid loss of washing pressure and wear of the drive mechanism. According to the invention the movement of the nozzle along the defined path is monitored and the result of the monitoring is utilised to control the energy density of the beam in order that it is reduced when the beam is directed at the zones which do not require the maximum energy.

1. Field of the Invention
The present invention relates to a method and an apparatus for washing the interior surfaces of tanks and containers. In particular, the invention relates to the cleaning of containers wherein a jet or a beam of cleaning fluid is ejected under high pressure and at a high velocity, which beam impinges the surfaces to be treated, and wherein the beams are controlled in particular with respect to their orientations with a view to cleaning or the like of predetermined surfaces interiorly of the container.
The cleaning by washing may be obtained through different effects, such as the dissolving effect of the washing fluid on impurities, loosening of dirt by the impact of the washing liquid or possibly of the cleaning particles slurried therein, or by heating of the impurities to render them more fluent or easier to dissolve through the influence of hot washing fluid.
In general, it is the object of the washing fluid to loosen adhering impurities and to transport them out of the tank, following which they may be processed, separated and/or disposed of in a controlled manner. Typical washing fluids include water with or without chemicals, oil products, solvents and/or mixtures thereof.
2. The Prior Art
U.S. Pat. No. 5,591,272 incorporated herein by reference discloses a method by which washing fluid is sampled from the usual contents of the tank, the washing medium optionally being roughly purified and heated to make it less viscous prior to its utilisation in the washing procedure.
Various washing heads are known on the market which are provided with nozzles and adapted to be installed in a fixed position and pivoted automatically to make the washing beam cover a specified solid angle during the washing process (corresponding to a surface section on a spherical surface) thereby ensuring that any point within this angle is covered with a guaranteed minimum intensity, and said units controlling the nozzles in accordance with various preprogrammed patterns so as to ensure that the distribution of the washing intensities in different directions are known. It is necessary for the nozzles to have degrees of freedom to pivot in two dimensions, i.e. in practice they should be allowed to pivot about two orthogonal axes. However, if the drive wheels for pivoting about the two axes are to be constructed in a mechanically uncomplicated manner, i.e. with simple mechanical gears, it is not readily feasible to provide uniform washing intensities in all directions in space seen from the nozzle's position. Thus, it is necessary to tolerate that usually some areas are more intensely washed than need be, if it is a priority to maintain a minimum intensity in certain other areas.
During cleaning of tanks the impurities to be cleaned out need not necessarily be uniformly distributed across the surfaces. In many instances a sedimentation has occurred which means that the tank floor may be covered with a thick layer of material which is difficult to remove. Another area where there may be a propensity to form solid deposits is the zone on the tank wall slightly above a liquid surface which has prevailed for an extended period of time in the tank where there may be a propensity to cake formation over time. In this case it is desired to direct a particularly high cleaning intensity towards the surfaces where the impurities have a particular tendency to stick or perhaps are particularly difficult to remove whereas other areas need not be subjected to an equally intense cleaning procedure.
In general, the tank geometry and the distribution of impurities relative to the positions in which the pivotable nozzles may be installed makes it difficult to match the beam pattern of the washing heads, and therefore general purpose washing heads with broad-sweeping beam patterns capable of covering all the directions to be reached, and washing for such extended period of time and with such intensity that in reality a substantial excess consumption of washing liquid occurs over a large portion of the tank are often resorted to. This excess consumption of washing liquid represents a poor exploitation of time, an increased energy cost, possibly an undesired wear on the tank interior, and it involves an increased cost of purifying the waste liquid which is discharged in larger quantities than desired.
U.S. Pat. 3,874,594 describes a washing unit including a nozzle arranged to be pivoted 360.degree. about a vertical axis and an angle about a horizontal axis to allow the washing beam pattern to cover a spherical surface, a rotatable head being driven by a shaft rotating centrally in a vertical support pipe, the rotatable head housing a worm gear arrangement causing a reduced speed rotation of the nozzle about the horizontal axis. The worm is free to slide axially a short distance equivalent to one half of the pitch of the worm in order that the nozzle may describe a helical pattern upon several revolution of the shaft, and upon reversing the direction of rotation, a non-coincident helical pattern during reversed rotation. The rotation of the shaft is driven by a turbine equipped with a gear box with changeable gears for reversal of the rotation. A lead screw mechanism in the gear box is connected to a cam mechanism associated with a lever adapted to control the pitch angle of the blades in the turbine.
The whole set-up looks exceedingly complicated comprising a great number of parts which must be matched very accurately and which indeed make it questionable whether this apparatus could be implemented in a practical version capable of actually operating as intended. The great number of parts, bearings and seals in contact with the washing medium represents a substantial complication, bearing in mind that the washing medium might include corrosive or aggressive ingredients and bearing in mind that any leakage in the area outside the tank are unacceptable in case oil or other inflammable liquids are used for washing medium. The rotatable nozzle head seems to be effectively suspended in the drive shaft representing a considerably complication in the manufacturing as well as in the maintenance work on the unit. The turbine and the presence of the shaft together with the various bearings inside the flow conduit are bound to cause a pressure drop in the washing liquid representing an energy cost for the pumping and a loss of washing effectiveness. Variations in the pressure in the washing liquid fed to the apparatus will influence the speed of rotation and the range of speed variations possible by controlling the blade pitch angle in the tubine will be narrow.
Patent application GB 2 096 455 discloses a tank washing apparatus with a washing head arranged to be pivoted 360.degree. about a vertical axis and an angle about a horizontal axis in order to allow the beam pattern to cover a spherical surface wherein the washing head is rotated about the vertical axis driven by a shaft arranged centrally inside the support pipe and wherein the rotatable washing unit includes means for causing the nozzle to pivot in a small increment about the horizontal axis by each revolution about the vertical axis.
The rotation is driven by means of a turbine rotated by the washing medium, the turbine driving a hydraulic pump connected by hydraulic connection lines to a hydraulic motor geared to drive the shaft. A lead screw mechanism is driven by the shaft and fitted with nuts which operate a hydraulic reversal valve in order to ensure the automatic reversal of the rotation.
This apparatus is quite complicated in including numerous small parts, bearings and seals, many of which are in contact with the washing medium and many of which will give rise to a pressure drop in the washing medium.
With a mechanism of a type wherein the orientation of the nozzle describes a helical movement pattern with parallel tracks disposed at completely identical intervals as seen on a spherical shell and wherein the speed of rotation about the vertical axis is constant, the beam ejection intensities are not identical in all directions. The nozzle allocates equal periods of time to angular paths of equal angular extent relative to the vertical axis. However, these angular paths correspond to solid angles of different sizes extending from small circles about the polar directions and to an expanded band around the equatorial plane. This heterogeneity may also be expressed in the angular velocity of the nozzle movement which approaches the angular velocity of the movement about the horizontal axis when close to the polar directions, whereas in the equatorial plane it is a vector sum of this velocity plus the angular velocity in the movement about the vertical axis. Therefore, a mechanism of this kind rotating at constant speed about the vertical axis will produce a beam pattern which is symmetrical about the vertical axis and wherein the intensity is higher in the axial directions than in the directions perpendicular to the axis.
In addition to being decisive for the intensity with which a given stretch or surface is swept, the angular velocity is of particular importance to the operational range obtainable with a washing nozzle. The liquid molecules which are ejected from the nozzles at a suitably high velocity will be slowed down when they strike on stagnant air. Thus, the ejection length obtained with a nozzle is most far reaching when the nozzle is set in a fixed direction thereby providing a liquid beam which continuously accelerates the air in an area around the beam path whereas the operational range of the beam drops if the nozzle is swept during washing because the liquid molecules in the front side of the beam will be slowed due to the air resistance.
It is considered realistic to obtain an effective cleaning effect at a distance of e.g. 25-30 meters from the nozzle outlet at an operational nozzle pressure of a magnitude of 12 bar and with the use of a suitably large nozzle, where the throughput amounts to 50-100 m.sup.3 per hour. However, this presupposes that the nozzle does not move or pivots only very slowly, the maximum allowable velocity being empirically expressed by a maximum travelling velocity of the beam's impingement area on a value comprised within the interval of 0.5-1.5 meter per second. If the velocity increases substantially beyond this limit, the beam loses its momentum by the slowing effect of the air, and it is scattered without obtaining said operational range. Although it is conceivable that the beam's impulse may be enhanced to increase the operational range by applying a higher operational pressure, increased volume throughput, etc., it will be understood that in case of ejection lengths of a magnitude of 25 meters, the air resistance will in any case severely restrict the sweep velocity of the beam.
Practice has established the need for cleaning tanks of particular configurations and with particular cleaning needs wherein the most desirable beam pattern is very different from the one which may be produced with the known washing heads. This applies to e.g. tanks where the roof is displaced vertically, e.g. the socalled floating-roof tanks where the roof floats on top of an enclosed amount of liquid during the normal use of the tank, and where the roof drops to a bottom position when the tank is emptied with a view to cleaning. In the bottom position, the roof is supported by supporting legs which serve to keep it in such a position that it is possible for the service personnel to enter the tank.
This constructive principle is employed e.g. in cylindrical tanks for the storage of oil where the tank diameter may be from 40 to 50 meters, occasionally as wide as 80 meters. In the empty tank the internal height above floor is typically from 1.8 to 2.3 meters. If the tank has a diameter of 50 meters it will be possible to sweep the entire tank floor where the most heavy impurities are located from a position at the tank centre provided that a washing nozzle having an operational range of 25 meters is employed.
Of course the nozzle will have to be arranged below the tank roof and the nozzle will have to be pivoted within a solid angle corresponding largely to a semisphere or a semispace below the nozzle whereby the entire floor area is covered. However, the intensity should not be the same in all directions from the nozzle within this semispace. On the exemplary assumption that the floor is to be cleaned by means of a nozzle located at a height of 1.5 meters above the tank floor, it may be calculated that within a nozzle angle of from 0 to 30.degree. from the vertical line, a subtending circle having a radius of about 0.9 meters and an area of 2.4 m.sup.2 would be covered, from 30 to 60.degree. a subtending circular belt towards a radius of 2.6 meters would be covered, the belt area being 18.6 m.sup.2, and from 60 to 90.degree. angle (it is assumed here that at 90.degree. the beam only just deflects and impinges the floor 25 meters from the nozzle), a subtending circular belt extending to a radius of 25 meters would be covered where the belt area is about 2,000 m.sup.2.
An apparatus producing a helical pattern and sweeping with constant speed about the vertical axis and with a constant speed about the horizontal axis will distribute even amounts of washing intensity to each of said three areas. If washing time is selected to produce the required dose of treatment in the outermost areas, it is estimated that the treatment dosage will be in the order of 100 times greater in the intermediate area and in the order of 1,000 times greater in the innermost area.

Method for washing the interior surfaces of tanks and containers


A computer implemented method for controlling camera exposure to augment a wiper system of a sensor enclosure. The computer implemented method can detect a presence of a wiper in one or more images captured by one or more cameras. An exposure time of the one or more cameras can be adjusted. Wiper speed can be adjusted such that wipers move in and out of one or more field of views of the one or more cameras while the one or more cameras are capturing images.

In general, autonomous vehicles rely on myriad of information obtained from sensors to determine operations to be taken next (e.g., turning, accelerating, breaking, etc.). Such sensors can include light detection and ranging sensors (LiDARs), cameras, and radars, to name some examples. Often, these sensors are mounted exteriorly to an autonomous vehicle. Such a configuration can be undesirable because it exposes the sensors to harsh environmental conditions (e.g., temperature swing, radiation, oxidation, etc.), and thereby may prematurely shorten a sensor's lifetime. Furthermore, mounting the sensors exteriorly to the autonomous vehicle can subject the sensors to an increased risk of impact or damage from road debris. To alleviate these and other problems, a sensor enclosure may be utilized such that sensors can be encased in the sensor enclosure. The sensor enclosure can offer additional protection against environmental elements and road debris while still allowing the encased sensors to function or operate. However, encasing sensors in a sensor enclosure can create other challenges. For example, while driving in rain or snow, an outer surface (e.g., a cover) of the sensor enclosure may collect moisture (e.g., rainwater, snow, etc.). The moisture can accumulate on the outer surface and may interfere with operations of sensors.
Under traditional approaches, a system comprising one or more moving wipers can be utilized to remove the moisture accumulated on the outer surface of the sensor enclosure. However, under such approaches, the wipers may interfere with sensor operations. For example, the wipers may be present in field of views of cameras while the cameras are actively capturing image data. To overcome this issue, a wiper system can be designed such that wiper rotations are synchronous with sensor operations so the wipers do not interfere with sensor operations. However, such a solution can overstress the wiper system. An alternative approach is discussed herein.

Method for controlling camera exposure to augment a wiper system of a sensor enclosure


A method for quality testing asphalt includes: directing light from a light source to at least one surface of asphalt; detecting light reflected or refracted from the at least one surface of the asphalt using a light detector; and assigning a number indicating the quality of the asphalt in response to detecting light reflected or refracted from the at least one surface of the asphalt.

During asphalt or bituminous mixture design, one of the primary concerns is the adhesion strength (quality) between the asphalt binder and the aggregate. If these components have poor adhesion strength, the mixture is likely to perform poorly when placed on an asphalt pavement. Many tests have been developed over the years to determine the adhesion strength between the asphalt binder and aggregate. One of these tests is the asphalt mixture boil test, as described in ASTM D3625. The boil test is used by highway agencies and material testing labs to quickly determine adhesion or compatibility of the mixture by visually observing a change in color of asphalt. The test procedure involves boiling an approximately 250 g sample of mixture in distilled water for 10 minutes or more and then estimating the amount of binder that is stripped from the aggregate based on visual observation. If the asphalt binder and aggregate have low quality, the asphalt binder will tend to debond from the aggregate and the aggregate will be exposed, which is quantified as percentage of stripped area or percent loss. The challenge with visual quantification of the compatibility is that each person evaluates and quantifies the loss differently. The current invention produces a quantitative and reproducible number representative of the percent stripped.

Systems and methods for quality testing of asphalt by predicting an indirect tensile strength ratio of the asphalt sample based on the binder loss value


A method of minimizing localized heating of, or minimizing signal losses across a source of loss in, an optical fiber used in transmission of a high power optical signal at an operating wavelength. These methods include the steps of: providing an optical fiber which comprises either (i) a coating characterized by an absorbance of less than about 4.5 dB/cm at the operating wavelength or (ii) a refractive index lower than the refractive index of a cladding layer of the optical fiber by more than about 3×10−3 at the operating wavelength, or (iii) both (i) and (ii); and transmitting a optical signal having a power greater than about 250 mW through the optical fiber, wherein the coating, cladding layer, or combination thereof are selected to minimize localized heating of the optical fiber or to result in a signal loss across a source of loss that is less than about 250 mW at the operating wavelength.

In the last several years high optical power reliability in optical fiber and photonic components has become a major concern. This is due to the increasing output power of optical amplifiers in wavelength-division multiplexing systems and the advent of Raman amplification. Though today's C-band amplifiers are capable of launching more than 200 mW of C-band signal, the greatest concern now is in the area of Raman amplification where pump laser systems typically operate in the range of 1-2 W at about 1400 nm to about 1480 nm. When power this high is launched into transmission systems, it can cause long-term degradation of materials that can sometimes lead to catastrophic failure of a component, module, or the fiber itself.
A photothermal heating problem was recently discovered in a fiber re-coat material used to re-coat stripped regions at fusion splice joints of specialty dispersion compensating fibers used in a dispersion compensation module. In particular, a Raman-pumped module was constructed using a dispersion compensating fiber that was fusion spliced to a CS980 fiber (available from Corning Incorporated), and then re-coated with a standard ultraviolet curable urethane acrylate coating (Desolite 950-200, available from DSM Desotech Inc.). Due to the nature of the fiber, high splice losses of approximately 0.5-1.0 dB are common. These splice losses result in power being dumped into the cladding and then ultimately into the fiber re-coat material, where localized heating takes place. In the above-described Raman-pumped module, the module is expected to operate at 1.6 W at 1430-1480 nm, which means that even with the best splice losses achievable today as much as 180-330 mW of radiation can get dumped into the coating material and cause significant heating. In recent laboratory tests it was found that the Desolite 950-200 re-coated fiber splices can heat up to as much as 120-200° C. at 1.6 W of 1480 nm radiation. These temperatures will certainly cause long-term reliability problems with the coating and ultimately the fiber, if not short-term failure.
A similar problem of localized heating was also observed for coated optical fibers designed for high power applications of the type described above, but where the fibers were employed in environments requiring tight bends of the fiber (e.g., present in amplifier modules).
Though components in high power environments were the focus several years ago, today there is growing concern around the fiber and more particularly the fiber coating. It is known that organic materials can absorb radiation in the region of 1400-1620 nm due to vibrational overtones of the C—H, O—H, or N—H bonds commonly found in organic polymeric materials. As these bonds absorb energy, they heat and can cause thermal degradation of the coating. And if the coating integrity becomes compromised, the fiber will fail mechanically. From the foregoing, it should be appreciated that a need exists for optical fibers that can operate in high power applications without long-term or short-term failure caused by localized heating of the fiber coating.
The present invention is directed to overcoming these and other deficiencies in the art.

Method of preventing optical fiber failure in high power application


The present invention intends to provide a novel peptide and use thereof. More particularly, the present invention provides a novel peptide and a DNA encoding the same, a drug comprising the peptide or DNA, a screening method/screening kit for a compound or its salt that promotes or inhibits the activity of the peptide, a compound or its salt obtained by the screening, a drug comprising the compound or its salt, etc.

Important biological functions including maintenance of homeostasis in the living body, reproduction, development of individuals, metabolism, growth, control of the nervous, circulatory, immune, digestive or metabolic system, sensory adaptation, etc. are regulated by cells that receive endogenous factors such as various hormones and neurotransmitters or sensory stimulation such as light or odor, via specific receptors present on cell membranes reserved for these factors or stimulation and interact with them. Many of these receptors for hormones or neurotransmitters by such functional regulation are coupled to guanine nucleotide-binding proteins (hereinafter, sometimes merely referred to as G proteins), and are characterized by developing a variety of functions through intracellular signal transduction via activation of the G proteins. In addition, these receptor proteins possess common seven transmembrane domains. For the reasons above, these receptors are therefore collectively referred to as G protein-coupled receptors or seven transmembrane receptors. As stated above, it is known that various hormones or neurotransmitters and their receptor proteins are present and interact with each other to play important roles for regulating the biological functions. However, it is even now poorly understood if any other unknown substances (hormones, neurotransmitters, etc.) and receptors to these substances are present.
In recent years, the human gene has been clarified at an accelerating pace by accumulated sequence information through sequencing of human genomic DNA or various human tissue-derived cDNA at random and rapid progress in gene analysis technology. Based on the foregoing, it is manifested that there are many genes supposed to encode proteins with unknown functions. G protein-coupled receptors not only have seven transmembrane domains but many common sequences are present in their nucleic acids or amino acids, and can thus be clearly identified to be G protein-coupled receptors in such proteins. On the other hand, such G protein-coupled receptor genes are obtained by polymerase chain reaction (hereinafter abbreviated as PCR) utilizing such a similarity in structure (Nature Cell Biology, 2, 703-708 (2000)). In these G protein-coupled receptors thus obtained so far, ligands to some receptors that are subtypes having high homology in structure to known receptors may be readily predictable but in most cases, their endogenous ligands are unpredictable so that no ligands corresponding to these receptors are found. For this reason, these receptors are called orphan receptors. It is likely that unidentified endogenous ligands to such orphan receptors would take part in the biological phenomena poorly analyzed, because the ligands were unknown. And when such ligands are associated with important physiological effects or pathologic conditions, it is expected that development of these receptor agonists or antagonists will result in breakthrough of new drugs (Stadel, J. et al., TiPS, 18, 430-437, 1997; Marchese, A. et al., TiPS, 20, 370-375, 1999; Civelli, O. et al., Brain Res., 848, 63-65, 1999). Until now, however, there are few examples to actually identify ligands to orphan G protein-coupled receptors.
Recently, some groups attempted to investigate ligands to these orphan receptors and reported isolation of ligands, which are novel physiologically active peptides, and determination of their structures. Reinsheid et al. and Meunier et al. independently introduced cDNA encoding orphan G protein-coupled receptor LC132 or ORL1 into animal cells to express a receptor, isolated a novel peptide from porcine brain or rat brain extract using response of the receptor as an indicator, which was named orphanin FQ or nociceptin with reference to its response, and determined its sequence (Reinsheid, R. K. et al., Science, 270, 792-794, 1995; Meunier, J.-C. et al., Nature, 377, 532-535, 1995). This peptide was reported to be associated with a sense of pain. Further investigations on the receptor in knockout mouse revealed that the peptide was involved in memory (Manabe, T. et al., Nature, 394, 577-581, 1998).
Subsequently, novel peptides including PrRP (prolactin releasing peptide), orexin, apelin, ghrelin and GALP (galanin-like peptide), etc. were isolated as ligands to orphan G protein-coupled receptors (Hinuma, S. et al., Nature, 393, 272-276, 1998; Sakurai, T. et al., Cell, 92, 573-585, 1998; Tatemoto, K. et al., Bichem. Biophys. Res. Commun., 251, 471-476, 1998; Kojima, M. et al., Nature, 402, 656-660, 1999; Ohtaki, T. et al., J. Biol. Chem., 274, 37041-37045, 1999).
On the other hand, some receptors to physiologically active peptides hitherto unknown are unraveled by similar methods. It was unraveled that a receptor to motilin associated with contraction of intestinal tracts was GPR38 (Feighner, S. D. et al., Science, 284, 2184-2188, 1999). In addition, SLC-1 was identified to be a receptor to melanin-concentrating hormone (MCH) (Chambers, J. et al., Nature, 400, 261-265, 1999; Saito, Y. et al., Nature, 400, 265-269, 1999; Shimomura, Y. et al., Biochem. Biophys. Res. Commun., 261, 622-626, 1999; Lembo, P. M. C. et al., Nature Cell Biol., 1, 267-271, 1999; Bachner, D. et al., FEBS Lett., 457, 522-524, 1999). Also, GPR14 (SENR) was reported to be a receptor to urotensin II (Ames, R. S. et al., Nature, 401, 282-286, 1999; Mori, M. et al., Biochem. Biophys. Res. Commun., 265, 123-129, 1999; Nothacker, H.-P. et al., Nature Cell Biol., 1, 383-385, 1999, Liu, Q. et al., Biochem. Biophys. Res. Commun., 266, 174-178, 1999). It was shown that MCH took part in obesity since its knockout mice showed hypophagic and lean phenotype (Shimada, M. et al., Nature, 396, 670-674, 1998), and because its receptor was unraveled, it became possible to explore a receptor antagonist likely to be useful as an anti-obesity agent. It is further reported that urotensin II shows a potent action on the cardiocirculatory system, since it induces heart ischemia by intravenous injection to monkey (Ames, R. S. et al., Nature, 401, 282-286, 1999).
As described above, orphan receptors and ligands thereto are often engaged in a new physiological activity, elucidation of which will lead to development of novel drugs. However, investigations of ligands to orphan receptors are accompanied by many difficulties. While the presence of many orphan receptors was unraveled to date, only a very few ligands were discovered for these receptors.
The present inventors found a novel receptor ZAQ, which is an orphan G protein-coupled receptor (a protein containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1 of the specification: hereinafter sometimes simply referred to as ZAQ in the specification). However, it was heretofore unknown what the ligand was.
It has been the problem to find a ligand to the orphan receptor protein ZAQ and establish a method of screening a compound characterized by using ZAQ and a ligand thereto.

Isolated physiologically active peptide and use thereof

Abstract: The peptide of the invention and the DNA encoding the same are usable, e.g., for the diagnosis, treatment, prevention, etc. of digestive diseases, etc. Moreover, the peptide of the invention is useful as a reagent for screening a compound or its salt that promotes or inhibits the activity of the protein of the invention.


The input and/or output device for process data exhibits a subrack (1) and at least one assembly (2) mounted on the subrack (1) and a process connector (4) which can be frictionally introduced into the at least one assembly at the front. The at least one assembly (2) exhibits a circuit board (17) arranged in a housing and a connector strip (18) which is frictionally connected to the process connector (4). This device is to be of simple and appropriate design and, at the same time, loading of the circuit board (17) with large mechanical forces is to be avoided. This is achieved by the fact that the connector strip (18) is mechanically rigidly connected to the housing and contains elastically deformable terminal pins (21) on which the circuit board (17) is supported.

1. Field of the Invention
The invention is based on an input and/or output device such input and/or output devices exhibit assemblies mounted on a subrack and connected via process connectors and cables to a device for executing a process, which communicate with one another via a system bus. The assemblies contain in each case at least one circuit board arranged in a housing and accept signals from signal transmitters of the process execution device, process the signals, if necessary by taking into consideration signals which are emitted by other assemblies, and/or supply signals to signal receivers of the process execution device. Depending on requirement, an assembly can fulfill input, output, input and output and/or processing functions.
2. Discussion of Background
An input and/or output device is known, for example, from EP-A-165434. In this device, the process connectors are in each case provided with a pivoting hinge which is adapted to a connector strip which is mechanically and electrically permanently connected to the circuit board. Thus transverse forces caused by operation, wiring and/or vibrations and acting on the process connectors arranged at the front are transferred from each process connector via the connector strip to the circuit board permanently Joined to it which, in turn, delivers the forces via the housing to a subrack fixing the assembly.

I/O device including circuit board non-rigidly supported by elastically deformable terminal pins extending from a connector strip


Medication management is facilitated at least by accessing at least a portion of data, the data may identify medication sets to be taken by a user according to a schedule including time periods. Each of the plurality of medication sets may be associated in the data with identification codes and at least one of the time periods. A medication message may be output identifying a particular medication set of the medication sets to be taken at a particular time period of the time periods. An input identification code may be received, and it may be determined whether the input identification code corresponds to the particular medication set. A warning message may be output in response to it being determined that the input identification code does not correspond to the particular medication set.

Digital systems and devices which provide services to elderly clients are available from a number of companies. For example, Independa™, of San Diego, Calif., provides services to enable organizations and individuals to cost-effectively help the elderly remain independent longer by providing social engagement, medication and appointment reminders, and wireless health and safety monitoring. These features may be provided using a system which includes a TV or tablet computer located in the elder person's home. Aspects of this system are described in U.S. Patent Application Publication 2012/0179485 "Systems and Methods for Integrated Care Management" to Saneii.
A tablet computer, such as an Apple™ iPad™, is a one-piece mobile computer which uses a touch screen as the primary means of control. Tablet computers typically connect to the Internet using wireless communications technologies, such as WiFi or cellular data communications. Tablet computers can use "apps" to provide many different functions. For example, the RxmindMe™ Prescription/Medicine Reminder and Pill Tracker of Walgreens Co., 200 Wilmot Road Deerfield, Ill. 60015, is a prescription reminder that uses multitasking to alert the user when they need to take a prescription. It allows the user to enter all their prescriptions, setup reminders, and track when they have taken them.
In order to track whether users are taking their medication, a pillbox can be wired with sensors to create a "smart pillbox", as described in the article, "ORCATECH Living Laboratory", AARP Bulletin, pp. 16-17 (April 2012).
It is known to provide portable registration devices to assist in remote health care, as described in EP 2219515 "Method and System for Providing Remote Healthcare".
It is known to use RFID technology to identify storage containers, as described in U.S. Pat. No. 8,258,961 "RFID Reader Enclosure and Man-O-War RFID Reader System".
However, there remains a need in the art for improvements in the above-discussed technologies.

This patent is subject to a terminal disclaimer.


A product display unit for displaying products includes a track defining a non-linear path and a pusher that moves along the non-linear path. The pusher is configured to move the products along the non-linear path.

The following U.S. Patents are incorporated herein by reference in entirety.
U.S. Pat. No. 9,392,882 discloses a merchandising system for displaying a plurality of products. The system comprises a base and a pusher member. The base includes a product-supporting surface and a track disposed beneath the product-supporting surface. The base defines a longitudinal axis. The pusher member is disposed in mechanical cooperation with the base and is configured to slide longitudinally with respect to the base. The pusher member includes a base-contacting surface and a plurality of legs downwardly depending from the base-contacting surface. Each of the plurality of legs is configured to mechanically engage the track. The track includes a discontinuity to enable the legs of the pusher member to selectively mechanically engage the track.
U.S. Pat. No. 9,949,577 discloses a product display unit that includes a width extension with a first lateral sidewall, a second lateral sidewall, and a track. The first lateral sidewall is configured to releasably engage a sidewall of a product display member. The second lateral sidewall includes a first segment, a second segment, and a third segment. The second segment is parallel to the first lateral sidewall. The first segment is disposed at an angle with respect to the second segment. The third segment is disposed at an angle with respect to the second segment. The track is disposed between the first lateral sidewall and the second lateral sidewall. The track is configured to support products thereon.
U.S. Pat. No. 10,045,637 discloses a product display unit that includes a first track and a second track. The first track defines a longitudinal axis and is configured to support products thereon. The first track is configured to guide the products along the longitudinal axis. The second track is configured to support products thereon. A first portion of the second track is configured to guide the products in a first direction that is disposed at an angle with respect to the longitudinal axis. A second portion of the second track is configured to guide the products in a second direction that is parallel to the longitudinal axis.


Systems, computer-implemented methods, and computer-readable media are provided to target internet-based services on a geographic location relating to a plurality of candidate geographic locations. A targeted geographic location may be provided based on usefulness, to a user probabilistically located among the plurality of candidates, of internet-based services being targeted thereon. From a first server, a plurality of candidate geographic locations may be obtained, each of which may be associated with a client IP address and a plurality of candidate confidence levels. A plurality of route-utility factors for each respective candidate geographic location, a plurality of probabilistic utility scores for each respective candidate geographic location, and an aggregate probabilistic utility score may be determined for each candidate geographic location. Further, a geographic location having an aggregate probabilistic utility score satisfying preselected criteria may be selected and transmitted to a second server so that geographically-targeted internet-based services can be provided.

1. Technical Field
The invention disclosed herein generally relates to internet-based services, and it more particularly relates to providing internet-based services according to a potential geographic location of a user.
2. Description of the Related Art
The Internet is a global system of interconnected computer networks serving billions of users worldwide. It is a network of networks that consists of millions of different networks of local and global scope (e.g., including private, public, academic, business, and government networks), which are linked by a broad array of electronic networking technologies including wired (e.g., copper cable, fiber optic, etc.) and wireless (e.g., radio-frequency, optical, etc.) technologies, using the standard Internet Protocol Suite (TCP/IP). Data transmitted (e.g., carried) over the Internet relates to a vast range of information resources and services, such as the inter-linked hypertext documents (e.g., web pages) of the World Wide Web (WWW). Services available on the Internet (or connected to the Internet) to provide or process information are referred to herein as "internet-based services," and human beings interacting with or otherwise using internet-based services are referred to herein as "users."
Various internet-based services may relate to the physical world of users, including, for example, internet-search services (e.g., provided by search engines), social-networking services (e.g., provided by social networks), electronic-commerce services (e.g., provided by online retailers), publishing services (e.g., provided by online publishers), electronic mail services, and so on. One way in which internet-search services may relate to the physical world of users, for example, is that users may intend to interact with resources in the physical world relating to the results of internet search (e.g., a user may desire to visit restaurants that appear in the search results for an internet search directed to "restaurants").
Some internet-based services provided with specific relevance to a geographic location can be said to be "targeted" on a particular geographic location (a "targeted geographic location"). Various attempts in the art have been made to identify a targeted geographic location that is the likely geographic location of a user. In some circumstances, providers of internet-based services can be informed of the geographic location of a user by receiving an unambiguous indication of the user's geographic location. For example, a subscriber to an internet-based service can create a profile for the internet-based service, which can specify the user's geographic location in various degrees of detail (e.g., time zone, country, state/province, county, city, postal code, dialing code, etc.). By way of further example, a subscriber to an internet-based service may create a profile indicating that the subscriber is in Palo Alto, Calif.; and the internet-based service provider deliver advertisements to the subscriber targeting the Palo Alto, Calif. market. Many providers of internet-based services, however, do not or cannot always receive such an unambiguous indication of the user's geographic location. As a result, internet-based services may be not targeted, or internet-based services may be mistakenly targeted.
So-called geolocation services are known to estimate or ascertain one or more geographic location of a computer device (e.g., a time zone, country, state/province, county, city, postal code, dialing code, etc.). So-called IP-geolocation services are known to do the same based on an internet address (e.g., an IP address) of the computing device. For example, a user accessing the internet from a computer on a university computer network in Palo Alto, Calif. may use an IP address relating to the geographic locations "Palo Alto" [city] or "94305" [postal code]; and search services targeted on either of those geographic locations may to yield search results related to (e.g., located in or near) the city of Palo Alto or, more particularly, the postal code 94305.
One particular disadvantage of IP-geolocation services is that internet addresses can relate to more than one geographic location, some of which may be geographically remote (e.g., San Francisco, Calif. and Los Angeles, Calif.) or geographically broad (e.g., California). Conventional geolocation services relating an internet address to more than one geographic location can provide confidence levels associated therewith. Accordingly, for any one internet address, IP-geolocation services may return a plurality of "candidate geographic locations," and a confidence level for each, e.g., a plurality of candidate geographic location confidence levels or, simply, "candidate confidence levels." In some examples of the prior art, candidate confidence levels can reflect probability values that a user (who is associated with an internet address) is physically located in or near a particular candidate geographic location. Further, in some examples of the prior art, a candidate confidence level for a particular candidate geographic location can reflect a relative probability that the user is physically located in or near the particular candidate geographic location, over all other candidate geographic locations of the plurality of candidate geographic locations. In certain examples in the prior art, internet-based services have been targeted on a candidate geographic location that is most likely (e.g., according to a relative probability) to be that which the user is located in or near ("probabilistic locality").

Systems, computer-implemented methods, and computer-readable media to target internet-based services on a geographic location


An implantable cardioverter-defibrillator (ICD) provides a tiered therapy designed to automatically terminate tachyarrhythmias using the least aggressive therapy possible while reducing the "time-to-therapy." The tiered therapy first applies a first tier of therapy (e.g., antitachycardia). If unsuccessful, the tiered therapy next applies a second tier of therapy (e.g., cardioversion pulse with a pulse of moderate energy). If unsuccessful, the tiered therapy finally applies a third tier of therapy (e.g., a high energy pulse). So that more aggressive (higher energy) tiered therapies may be applied as early as possible following the failure of a less aggressive (lower energy) therapy, the ICD begins charging one or more high voltage capacitors of the ICD in parallel with the application of the less aggressive therapy, and/or in parallel with the verification interval immediately following a prior therapy attempt during which the ICD attempts to verify the successful termination of the tachyarrhythmia.

It is known in the ICD art to provide a "tiered" therapy with regard to the termination of sensed tachyarrhythmias. The term "tiered" therapy has been used typically to describe the different tachyarrhythmia rate zones, such as low rate ventricular tachycardia (VT Low), high rate tachycardia (VT High), and ventricular fibrillation (VF). The term "tiered therapy" also has been used to describe the increasing degree of aggressiveness within each rate zone. For example, within each zone the physician may program the number of stimulation pulses, the interval between stimulation pulses, the energy level of the stimulation, and the number of attempts, etc. Thus, based upon the detected rate of the arrhythmia, the ICD will continue to increase the level of aggressiveness until such arrhythmia is terminated.
For example, upon sensing a low rate ventricular tachycardia, an ICD may attempt to terminate such tachycardia by first applying a prescribed type of antitachycardia ("antitach") pacing. Such antitach pacing typically includes burst pacing, ramp pacing, and/or scanning pacing, as is known in the art. See, e.g., U.S. Pat. Nos. 4,427,011 and 4,541,430 (burst pacing); 4,398,536 (ramp pacing); and 5,103,822 (scanning pacing); which patents are incorporated herein by reference. If the antitach pacing is unsuccessful, the ICD may be programmed to apply a low energy, cardioversion energy shock in an attempt to cardiovert the heart. If the low energy cardioversion shock is unsuccessful, the ICD may apply a higher energy shock in an attempt to cardiovert the heart. If the tachycardia accelerates to ventricular fibrillation, the system will then apply a high energy defibrillation shock with starting values typically on the order of 10 joules and increasing up to 40 joules.
It should be noted that the basic difference between cardioversion and defibrillation is the type of arrhythmia being detected. That is, the term "cardiovert" or "cardioversion" refers to the application of energy shock treatment to a heart in response to a sensed ventricular tachycardia in an attempt to terminate the tachycardia. The term "defibrillate" or "defibrillation," on the other hand, refers to the application of energy shock treatment to a heart in response to a sensed ventricular fibrillation in an attempt to terminate the fibrillation. Cardioversion is often thought of as being "low energy" since the heart has been known to successfully convert the arrhythmia with electrical shocks in the range of 0.1 to 10 joules. However, it is still classified as cardioversion if the arrhythmia is a ventricular tachycardia even if the energy required to convert the arrhythmia goes up to the maximum value (e.g., 40 joules). Defibrillation, on the other hand, is often thought of as being "high energy" since the heart has been successfully defibrillated with energy shocks in the range of 10 to 40 joules. In contrast, the pacing pulses that are applied to a heart during normal or antitach pacing are typically of much lower energy (e.g., between 50 and 200 micro joules). The principal difference between the types of therapy provided by an ICD supporting tiered therapy is that of arrhythmia detection and the programmed level of aggressiveness with the therapy typically starting by applying the lowest energy stimulation for that detected arrhythmia and working its way up to high energy shock therapy, as required.
The energy shock, whether cardioversion or defibrillation, is delivered to the heart via what is commonly referred to as "defib leads," "defibrillation lead or electrode," or "patch electrodes." However, it is recognized that the electrode system could also be epicardial electrodes (attached to the external surface of the heart) or endocardial (attached to the internal surface of the heart) or any combination of patch, epicardial or endocardial. Such electrodes are well known in the art. See, for example, U.S. Pat. No. 4,662,377 (Heilman et al.), issued May 5, 1987, entitled "Cardioverting Method and Apparatus Utilizing Catheters and Patch Electrodes"; U.S. Pat. No. 4,481,953 (Gold et al.), issued Nov. 13, 1984, entitled "Endocardial Lead Having Helically Wound Ribbon Electrode"; and U.S. Pat. No. 4,010,758 (Rockland et al.), issued Mar. 8, 1977, entitled "Bipolar Body Tissue Electrode," which patents are hereby incorporated herein by reference. Hereinafter, the electrodes (whether patch, epicardial, or endocardial, etc.) will be referred to as simply "shocking electrodes."
In order to apply an electrical pulse to the heart (whether of low, moderate or high energy), it is first necessary to charge one or more output capacitors of the ICD device with an electrical charge of the desired energy. Typically, one set of low voltage output capacitors (which may be a single capacitor) is charged to provide the requisite energy for normal or antitach pacing. The normal pacing lead(s) is then A.C. coupled to such set of low voltage capacitors through an appropriate output switch. Another set of capacitors, which is generally a set of high voltage capacitors, is charged to provide the requisite energy for cardioversion or defibrillation. Appropriate shocking electrodes are then coupled to such set of high voltage capacitors through an appropriate high voltage output switch. When an electrical stimulation pulse is to be applied to the heart, the appropriate output switch is closed to connect the low or high voltage output capacitor(s) to the cardiac tissue through either the pacing or shocking electrodes, thereby effectively "dumping" the charge stored in the low or high voltage output capacitor(s) across the cardiac tissue.
All tiered therapy ICD's known to applicants begin to charge their output capacitor(s) following verification of the failure of the previous less aggressive therapy. For example, as soon as the ICD sensing and logic circuits determine that the first tier of therapy (e.g., antitach therapy) has not successfully terminated the tachyarrhythmia, the high voltage output capacitors are charged to the appropriate energy for a second tier of therapy (e.g., cardioversion in the case of ventricular tachycardia; or defibrillation in the case of ventricular fibrillation). As soon as the ICD sensing and logic circuits determine that the second tier of therapy has not successfully terminated the tachyarrhythmia, the high voltage output capacitors are charged to a higher energy level. Unfortunately, it may take 3-4 seconds to charge the high voltage output capacitors to a moderate energy level to (1 to 10 joules), and 7-15 seconds to charge such capacitors to a high energy level (11 to 40). Disadvantageously, these charging times represent a significant period of time, or "time-to-therapy," during which the tachyarrhythmia continues without the benefit of having the ICD apply any therapy. Furthermore, as the duration of the tachyarrhythmia lengthens, it becomes increasingly more difficult to terminate the arrhythmia with an electrical stimulus. Thus, what is needed is an ICD device wherein the time-to-therapy is reduced, thereby reducing the exposure of the patient to the tachyarrhythmia, and thereby increasing the probability of success of the cardioversion-defibrillation attempt.

Implantable cardioverter-defibrillator having early charging capability


A radiation image detection apparatus comprising a scintillator, which is configured to include columnar crystals and converts radiation into light when the radiation is irradiated thereon, and an optical detector, which converts the light, emitted from the scintillator into an electrical signal, the scintillator and the optical detector being arranged on a support such that the radiation is incident on the optical detector and the scintillator in this order, wherein a columnar crystal area is present at a radiation-incident side of the scintillator, and a non-columnar crystal area is present at a side of the scintillator opposite to the radiation-incident side; and a method for manufacturing the radiation image detection apparatus are provided.

1. Field of the Invention
The present invention relates to a radiation image detection apparatus, which is used in an X-ray imaging apparatus for medical use or the like, and a manufacturing method of the same.
2. Description of the Related Art
In recent years, a radiation image detection apparatus, such as a Flat Panel Detector (FPD), capable of directly converting radiation into digital data, has been put to practical use. The radiation image detection apparatus is being rapidly distributed since it has an advantage of being able to immediately verify an image compared to conventional image plates.
Various types of such radiation image detection apparatuses were proposed. For example, an indirect type converts radiation into light in a single operation using a scintillator of, for example, CsI:Tl, GOS (Gd2O2S:Tb), or the like, converts the converted light into electric charges through a semiconductor layer, and then stores the electric charges.
It is preferred to decrease the amount of radiation emitted when the radiation image detection apparatus is used, for example, in living bodies. In the field of optical detectors, the scintillator, which emits a great amount of light and has high sensitivity, is preferable. From that point of view, several radiation image detection apparatuses were proposed (e.g., Japanese Patent No. 3333278 and Japanese Patent Application Laid-Open (JP-A) No. 2001-330677). Such a radiation image detection apparatus is constructed by attaching a scintillator, made of crystals of CsI or the like, to an insulating substrate, and emits radiation from an optical detector side.
In the scintillator, which is configured to include such crystals, it is known in theory that sensitivity rises as according to the thickness of the crystals. In practice, however, if the thickness of the crystals is increased up to a certain value, light is attenuated or scattered while it is passing through the scintillator. This causes problems such as being unable to obtain sufficient sensitivity or blurring of an image. Therefore, additional improvement in sensitivity is required.
For the purpose of improving sensitivity, a radiation image detection apparatus was proposed, in which a scintillator layer is constructed with an assembly of columnar crystals, and which ensures that the density of an activator has a slope (e.g., JP-A No. 2008-51793). However, there is possibility that the scintillator may decrease the yield of an article due to the need for precision in process control during the manufacturing. In addition, neither sensitivity nor the resolution of a produced image is satisfactory, and improvement is still demanded.

Radiation image detection apparatus and manufacturing method of the same


A high frequency semiconductor apparatus is provided which prevents characteristics of a high frequency semiconductor element from being deteriorated so that the high frequency semiconductor element can be made to operate stably. The high frequency semiconductor apparatus is so configured that heat generated by a high frequency semiconductor element is sequentially conducted through a grounding via hole to a first ground layer, a first via hole, a first ground sublayer, a bonding material layer, a second ground layer, a second via hole, and a third ground layer.

1. Field of the Invention
The present invention relates to a high frequency semiconductor apparatus, transmitting apparatus and receiving apparatus, and an art applied to, for instance, an antenna-integrated wireless communication apparatus for microwave communication having an antenna function.
2. Description of the Related Art
In recent years, as the processing speed of a data processing apparatus and the resolution of an image processing apparatus have increased, a high-speed and large-capacity personal communication using a high frequency wave such as a microwave has attracted public attention. Since there is higher power loss at a connecting portion of an antenna and a high frequency circuit especially in a millimeter-wave band, it has been attempted to develop an antenna-integrated wireless communication apparatus having the antenna and the high frequency circuit integrated (for instance, refer to Japanese Unexamined Patent Publication JP-A 8-250913 (1996) (page 5, FIG. 10)).
FIG. 9 is a cross sectional view showing a conventional high frequency semiconductor apparatus. The antenna-integrated wireless communication apparatus comprises a base 4 having dielectric layers 1 and 2 and a ground layer 3 which is sandwiched between the dielectric layers 1 and 2. The ground layer 3 is provided with a slot portion 4a. A planar antenna 6 is formed on one surface of a package 5 facing outside. A feeding microstrip line 7 is formed on one surface of the dielectric layer 1 facing an internal space of the package. The feeding microstrip lines 7 are electrically connected to an output terminal 9 and input terminal 10 of a monolithic microwave integrated circuit 8 (abbreviated to MMIC) with a bonding wire 11.
A conventional high frequency transmission line as typified by a microstrip has a width of only several hundred of micrometers (μm) since characteristic impedance of the conventional high frequency transmission line is 50 Ω. In the above-described antenna-integrated wireless communication apparatus, heat generated by the MMIC must be radiated by the feeding microstrip line 7 which is narrow in width and connected to the MMIC. Therefore, it is not possible to sufficiently radiate the heat generated by a high frequency semiconductor element such as the MMIC, and the heat is confined to a space closed by a lid 12. As a result, the high frequency semiconductor element operates in a high temperature caused by the heat generated by the high frequency semiconductor element itself, which leads a bungle or deterioration of characteristics.

High frequency semiconductor apparatus, transmitting apparatus and receiving apparatus


An information recording mechanism for recording information onto a film surface from the front side of the film provides a light emitter for emitting, as light, the information to be recorded on the film; a light emitter mounting substrate for mounting the light emitter thereon; an optical stop for narrowing the light emitted from the light emitter; and an optical member for causing the light narrowed by the optical stop to become incident on the film surface. The optical stop is integrally formed with the camera body part, while the light emitter mounting substrate and the optical member are directly attached to the camera body part without substantially generating positional shifts, thereby improving operability for assembling the camera.

1. Field of the Invention
The present invention relates to an information recording mechanism for a camera and, in particular, to such mechanism for recording information such as date onto a film surface.
2. Related Background Art
Conventionally, in order to record information such as date onto a film surface, an information recording mechanism is disposed on the back cover side of the camera, i.e., on the back side of the film, so as to record such information onto the film surface from the back side thereof.
In order to reduce the thickness of the camera itself, however, recently has been employed is a system in which an information recording mechanism is disposed on the front side of the film so as to record information such as date from the front side of the film.
As shown in FIG. 4, this information recording mechanism comprises pieces of light emitters 50 corresponding to the number of dots in a row required when characters for a date or the like to be recorded on the film are indicated in terms of dots; an optical stop 52 for narrowing the light emitted from the light emitters 50; and an optical member 56 for causing the light narrowed by the optical stop 52 to become incident on a surface of a film 54. While this information recording mechanism is used, the light emitters 50 are turned on and off in response to the feeding of the film, whereby the date or the like is recorded onto the film surface.
In this information recording mechanism, an exit opening 58 for guiding the light emitted from the optical member 56 onto the film surface is formed in a camera body 60. On the other hand, the optical member 56 and a stop member 62 including the optical stop 52 is attached to the camera body 60 from thereabove (from the upper side of the drawing). Also, a light emitter holding member 64 having the light emitters 50 is attached to the camera body 60. Accordingly, when each of the light emitters 50, optical member 56, and stop member 62 is being attached to the camera body 60, a shift in attachment may occur, thereby tilting or obscuring the characters, or lowering the quantity of light such that the characters cannot be recorded.
Also, since the optical member 56 and the stop member 62 are disposed at the bottom of a deep hole, it is difficult for them to be accurately attached there, thus deteriorating operability.

Information recording mechanism for camera