Disclosed are macrocyclic compounds of formulae I-V, which are analogs of the pochonin resorcylic acid lactones, and processes for the preparation of the compounds. The compounds disclosed are useful as inhibitors of kinases and Heat Shock Protein 90 (HSP 90). Also disclosed are pharmaceutical compositions comprising an effective kinase-inhibiting amount or an effective HSP90-inhibiting amount of the compounds and methods for the treatment of disorders that are mediated by kinases and HSP90.

In the mid-1950's, it was discovered that phosphorylation can reversibly alter the function of enzymes by means of protein kinases which catalyze phosphorylation, or by protein phosphatases which are involved in the dephosphorylation step. These reactions play an essential role in regulating many cellular processes, especially signaling transduction pathways. In the late 1970's, the Rous sarcoma virus (v-Src)'s transforming factor was discovered to be a protein kinase, and also tumor-promoting phorbol esters were found to be potent activators of protein kinase C, revealing the first known connection between disease and abnormal protein phosphorylation. Since then transduction mechanistic defects have been found to cause numerous oncogenic processes and to have a role in diabetes, inflammatory disorders, and cardiovascular diseases. (T. Hunter, Cell, 100:113-127 (2000); P. Cohen, Nat. Rev. Drug Discov., 1:309 (2002)). Thus selective kinase and phosphatase inhibitors have emerged as important drug targets, and inhibition of kinase phosphorylation activity is one of the most promising strategies for chemotherapy. Three kinase inhibitor drugs are already approved: Gleevec, which inhibits Abl, and Iressa and Tarceva, which both inhibit EGFR.
Gleevec (imatinib) - STI 571inhibitor of the Abelson kinase;approved for chronic myelogenous leukemia Tarceva (erlotinib) - OSI774R1 = CCH; R2 = H; R3 = R4 = CH2OCH3 Iressa (gefitinib) - ZD1839R1 = Cl; R2 = F; R3 = H; R4 =  inhibitors of epidermal growth factorreceptor (EGFR); approved for lung cancer
Modulation of protein activity by kinase-mediated phosphorylation or phosphatase-mediated dephosphorylation of a serine, threonine or tyrosine residue is at the center of most signal transduction mechanisms. (T. Hunter, Cell, 100:113 (2000)). Small molecule inhibitors such as 6-dimethylaminopurine and staurosporine were instrumental in elucidating the importance of such phosphorylation mechanisms and shed light on the biological function of kinases. Kinases bind to ATP with a Km of 0.1-10 μM, and transfer the γ-phosphate group selectively to a specific residue of a given protein. The core domain of kinases, consisting of the ATP-binding site with the residues involved in phosphotransfer reaction, are highly conserved throughout the kinome. (G. Manning et al., Science, 298:1912 (2002)). This led to the speculation that inhibitors targeting this highly conserved ATP-binding pocket would not only have to compete with ATP present at high concentration (mM) but would necessarily lack selectivity. The discovery that modified purines such as (R)-roscovitine were potent and fairly selective inhibitors (L. Meijer and E. Raymond, Acc. Chem. Res., 36:417 (2003)) refuted that notion and inspired the synthesis of combinatorial libraries around the purine scaffold (Y. T. Chang et al., Chem. Biol., 6:361 (1999); S. Ding et al., J. Am. Chem. Soc., 124:1594 (2002)), yielding important leads. (N. S. Gray et al., Science, 281:533 (1998); M. Knockaert et al., Chem. Biol., 7:411 (2000)).

Macrocyclic resorcylic acid lactones have also been investigated in this respect. The archetypes of this class of compounds are radicicol and the related pochonins, which are a structurally related group of secondary metabolites isolated from cultures of the clavicipitaceous hyphomycete Pochonia genus, such as Pochonia chlamydosporia var. catenulate strain P0297. See, e.g., V. Hellwig et al., J. Natural Prod., 66(6):829-837 (2003). Halohydrin and oxime derivatives of radicicol were prepared and evaluated for their v-src tyrosine kinase inhibitory, antiproliferative, and antitumor in vitro activity (T. Agatsuma et al., Bioorg. & Med. Chem., 10(11):3445-3454 (2002).
Like kinases, heat shock proteins (HSPs) interact with ATP and are important targets for controlling disease, however they have a different mechanistic effect. Immediately after exposure to a stress such as heat, hypoxia or acidosis, cells in most tissues rapidly escalate production rate of the HSPs. It is now believed that heat HSPs are molecular chaperones, i.e., they prevent improper associations and assist in the correct folding of other cellular proteins collectively termed clients and substrates. HSP's are also found in association with tumors and other pathophysiological conditions. In fact, chaperone proteins facilitate the survival of tumor cells in stressful environments by facilitating tolerance of alterations inside the cell. HSPs are ubiquitous, highly conserved among the species, and usually classified by molecular weight to the following major families: HSP100, HSP90, HSP70, HSP60 and small HSPs. These families have structural and functional differences, but work cooperatively at different stages of protein folding. HSP90 has attracted particular attention due to its association with many types of signaling molecules such as v-Src and Raf that play a critical role in malignant transformation and metastasis development. Thus, HSP90 inhibitors are desired for designing chemotherapies, and also for elucidating the interplay in complex signaling networks.
Heat Shock Protein 90's (Hsp90s) are ubiquitous chaperone proteins that maintain the proper conformation of many "client" proteins (see Kamal et. al. Trends Mol. Med. 2004, 10, 283-290; Dymock et. al. Expert Opin. Ther. Patents 2004, 14, 837-847; Isaacs et. al. Cancer Cell, 2003, 3, 213; Maloney et. al. Expert Opin. Biol. Ther. 2002, 2, 3-24 and Richter et. al. J. Cell. Physiol. 2001, 188, 281-290), and are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. Researchers have reported that HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner, TIBS, 1999, 24, 136-141; Stepanova et. al., Genes Dev. 1996, 10, 1491-502; Dai et. al., J. Biol. Chem. 1996, 271, 22030-4). Studies further indicate that certain co-chaperones, e.g., Hsp70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 in its function (see for example Caplan, Trends in Cell Biol., 1999, 9, 262-268). Inhibition of Hsp90 causes these client proteins to adopt aberrant conformations, and these abnormally folded proteins are rapidly eliminated by the cell via ubiquitinylation and proteasome degradation. Interestingly, the list of Hsp90 client proteins includes a series of notorious oncogenes. Four of them are clinically validated cancer targets: HER-2/neu (Herceptin® (trastuzumab)), Bcr-Abl (Gleevec® (imatinib mesylate)), the estrogen receptor (tamoxifen), and the androgen receptor (Casodex® (bicalutamide)), while the others play a critical role in the development of cancer. Some of the most sensitive Hsp90 clients are involved in growth signalling (Raf-1, Akt, cdk4, Src, Bcr-Abl, etc). In contrast, few tumor suppressor genes, if any, seem to be clients of Hsp90 (for lists of client proteins see Pratt et. al. Exp. Biol. Med. 2003, 228, 111-133; Workman et. al. Cancer Lett. 2004, 206, 149-157 and Zhang et. al. J. Mol. Med. 2004, 82, 488-499.), and consequently, inhibition of Hsp90 has an overall anti-proliferative effect. In addition, some client proteins are involved in other fundamental processes of tumorigenesis, namely apoptosis evasion (e.g. Apaf-1, RIP, Akt), immortality (e.g. hTert), angiogenesis (e.g. VEGFR, Flt-3, FAK, HIF-1), and metastasis (c-Met).
However medicinal HSP inhibitors must be selective because HSPs also play a constructive role. Under non-stressed conditions, HSP90 is one of the most abundant proteins present in the eukaryotic cells, representing between 1-2% of the total cellular protein content and increasing only about two-fold when cells are stressed. Upon binding with the native client HSP90 is an essential housekeeper, e.g., for folding of nascent polypeptides, transporting proteins across membranes, and for normal protein turnover. Moreover, HSP90 plays a crucial role in post-translational regulation of signaling molecules, leading to their activation. HSP90 rarely functions alone but instead works with chaperone HSP70, with co-chaperones (HSP40, CDC37/p50, AHAL, p23), and with accessory proteins.
The numerous client proteins of HSP90 play a crucial role in growth control, cell survival and development processes, and those clients are known to include receptor tyrosine kinases, serine/threonine kinases, steroid hormone receptors, transcription factors and telomerase. Oncogenic mutants of clients are also clients themselves but have higher requirements for HSP90 function, for instance the mutant v-SRC tyrosine kinase requires more protein-folding capability from HSP90's cooperative assembly of proteins (Y. Xu et al., Proc. Natl. Acad. Sci. U.S.A., 96:109 (1999); H. Oppermann et al., Ibid., 78:1067 (1981); L. Whitesell et al., Ibid., 91:8324 (1994). Likewise, mutations of the tumor-suppressor protein p53 lead to the most common molecular genetic defect found in human cancers, and most p53 mutants show extended interactions with HSP90 (probably because of aberrant conformations), preventing their usual ubiquitylation and subsequent degradation by the proteasome (M. V. Blagoskionny et al., Ibid., 93:8379 (1996). However despite its ubiquitous participation, HSP90's clients are mostly pro-growth signaling proteins, and its chaperoning function is subverted during oncogenesis, leading to development of malignant transformation and the maintenance of transformed phenotypes.
In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating ischemia, and agents useful in treating neurodegenerative diseases and in promoting nerve regeneration (see M. Waza et al, Nature Med. 11:1088 (2005); Rosen et al., WO 02/09696; PCT/US01/23640; Degranco et al., WO 99/51223; PCT/US99/07242; Gold, U.S. Pat. No. 6,210,974 B1). There are reports in the literature that fibrogenetic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis may be treatable. (Strehlow, WO 02/02123; PCT/US01/20578).
Ansamycins and other HSP90 inhibitors thus hold great promise for the treatment and/or prevention of many types of disorders. However, many of the natural-product derived Hsp90 inhibitors exhibit pharmaceutical deficiencies; their relative insolubility makes them difficult to formulate and administer, and they are not easily synthesized and currently must, at least in part, be generated through fermentation. Further, the dose limiting toxicity of ansamyins is hepatic. For example, the semi-synthetic inhibitor 17-allylamino,17-desmethoxy-geldanamycin (17-AAG), currently in phase II clinical trials, is expensive to manufacture, difficult to formulate (the NCI clinical protocol consists of injecting a DMSO solution of 17-AAG) and at present administered only parenterally. Although the 17-dimethylaminoethylamino analog (17-DMAG) is more soluble, it exhibits all of the side effects of 17-AAG as well as gastrointestinal hemorrhaging in preclinical toxicity studies (Glaze et. al. Proc. Am. Assoc. Cancer. Res. 2003, 44, 162-162 and Eiseman et. al. Cancer Chemother. Pharmacol. 2005, 55, 21-32). Radicicol (RC), another natural product Hsp90 inhibitor, is poorly water-soluble and is inactive in tumor xenograft models. Semi-synthetic oxime derivatives of radicicol provide better solubility and substantially improved the pharmacological profile in murine models, but are still limited to intravenous administration (Ikuina et. al. J. Med. Chem. 2003, 46, 2534-2541. Furthermore, radicicol and its oximes contain an oxirane ring which has been viewed as a liability for stability and toxicity, prompting the synthesis of cycloproparadicicol: Yang et. al. J. Am. Chem. Soc. 2004, 126, 7881 and 2003, 125, 9602-9603.) Despite the potential of ansamycins, alternative HSP90 inhibitors are therefore needed.
Fully synthetic, orally active inhibitors of Hsp90 have been sought in order to provide more flexible dosing schedule options, and to possibly avoid the side-effects of the natural product inhibitors. Chiosis et al. described the design and synthesis of purine analogs that mimic geldanamycin and other ansamycins in their ability to bind the ATP binding pocket of, and thus inhibit, HSP90. See International Patent Application PCT/US01/46303 (WO 02/36075; Chemistry & Biology 8:289-299 (2001). The specific compounds that Chiosis et al. described included a trimethoxybenzyl entity substituted at positions 3, 4, and 5. Using gel-binding assays, these were shown to bind HSP90 approximately 20-fold less avidly than 17-AAG.
More recently, other novel non-natural product Hsp90 inhibitors have been reported (e.g. PU3 and CCT018159; see Chiosis et. al. Bioorg. Med. Chem. Lett. 2002, 10, 3555-3564; Vilenchik et. al. Chem. Biol. 2004, 11, 787-797; Chiosis et. al. WO 0236075, 2002; Drysdale et. al. WO 03/055860 A1, 2003; Wright et. al. Chem. Biol. 2004, 11, 775-785; Dymock et. al. Bioorg. Med. Chem. Lett. 2004, 14, 325-328; Dymock et. al. J. Med. Chem. 2005, 48, 4212-4215. Structure of Hsp90 in complex with PU3 pdb code 1UY6, and with PU24FCl: pdb code 1UYF and Clevenger et. al. Org. Lett. 2004, 6, 4459-4462). The structures of these inhibitors were designed using the crystal structures of Hsp90 in complex with ATP, geldanamycin, or radicicol. The 8-benzyladenines such as PU3 were designed to adopt the same C-shaped conformation as geldanamycin (Chiosis et. al. Current Cancer Drug Targets, 2003, 3, 371-376) with the adenine ring pointing to the adenine-binding site (hinge region), and the trimethoxybenzene ring emulating the H-bond accepting nature of the quinone ring of geldanamycin. (The benzene ring of PU3 was not designed to have exactly the same orientation as the quinone ring of geldanamycin. Rather, the trimethoxybenzene moiety was designed to point in the same general direction and form a hydrogen bond with Lys112, an amino acid which forms a hydrogen bond with the quinone ring of geldanamycin.) The recently obtained crystal structure of Hsp90 in complex with PU3 confirmed that the purine ring occupies the position normally occupied by ADP/ATP, but the benzene ring points in a direction opposite to the predicted one, to form a r-stacking interaction with Phe138. Nevertheless, PU3 inhibits Hsp90 (HER-2 degradation assay, HER-2 IC50=40 μM) and afforded a valuable starting point for further optimization. Structure-activity studies based on PU3 led to the more active PU24FCl (HER-2 IC50=1.7 μM) which was subsequently also co-crystallized with Hsp90. When PU24FCl was formulated in DMSO/EtOH/phosphate-buffered saline 1:1:1 and administered intraperitoneally to mice bearing MCF-7 xenograft tumors, it induced at 100-300 mg/kg down-regulation of HER-2 and Raf-1, a pharmacodynamic response consistent with Hsp90 inhibition, and at 200 mg/kg it significantly repressed tumor growth. Very high doses (500-1000 mg/kg) of PU24FCl were required to observe a similar pharmacodynamic response upon oral administration, and no 8-benzyladenine has been reported to inhibit tumor growth by the oral route. In our hands, PU24FCl proved to be too insoluble to be effectively formulated and delivered orally. So far, despite extensive SAR studies to improve potency and pharmaceutics properties, Hsp90 inhibitors have not demonstrated activity in animal models of human cancer (xenografts) when administered orally.
The discovery of the 8-benzyladenines led to the design of 8-sulfanyladenines (Kasibhatla et. al. WO 3037860, 2003 and Llauger et. al. J. Med. Chem. 2005, 48, 2892-2905), exemplified by 8-(2-iodo-5-methoxy-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine, which exhibited excellent potency in several cell-based assays, but was poorly soluble in water and did not have sufficient oral bioavailability in clinically acceptable formulations.
When HSP90 is inhibited, its clients are degraded, i.e., the unfolded protein is ubiquitinated, followed by proteasome-mediated hydrolysis. Most of the inhibitors reported so far bind to the N-terminal domain (vide infra), but some are reported to interact with the C-terminal domain; HSP90 has binding sites for ATP in both locations. The function of HSP90's C terminus is not entirely clear, but compounds interacting in this domain clearly impair HSP90 function and have anti-cancer effects. Some resorcylic acid lactones have been found to inhibit HSP90, thus natural products radicicol and geldanamycin (P. Delmotte and J. Delmotte-Plaquee, Nature (London), 171:344 (1953); and C. DeBoer et al., J Antibiot (Tokyo), 23:442 (1970), respectively) were shown to suppress the transformed phenotype of cell expressing activated Src (H. J. Kwon et al., Cancer Research, 52:6926 (1992); Y. Uehara et al., Virology, 164:294 (1988)). Related compounds such as herbimycin have been reported to have similar effects (S. Omura et al., J Antibiot (Tokyo), 32:255 (1979).

Other resorcylic acid lactones (RALs) studied in this respect include 17-allylamino-17-demethoxygeldanamycin (17AAG) (D. B. Solit et al., Clin. Cancer Res., 8:986 (2002); L. R. Kelland et al., J. Natl. Cancer Inst., 91:1940 (1999)); 17DMAG (J. L. Eiseman et al., Cancer Chemother. Pharmacol., 55:21-32 (2005)); IPI-504 (J. Ge et al., J. Med. Chem., 49:4606 (2006); oxime derivatives such as KF25706 (S. Soga, et al., Cancer Res., 59:2931 (1999)) and KF55823 (S. Soga et al., Cancer Chemotherapy and Pharmacology, 48:435 (2001)); and Danishefsky et al.'s cycloproparadicicol (A. Rivkin et al., Ibid., 44:2838 (2005)). Structurally related variants include chimeric inhibitors having radicicol's carboxyresorcinol and the geldanamycin's benzoquinone (R. C. Clevenger and B. S. Blagg, Org. Lett., 6:4459 (2004); G. Shen and B. S. Blagg, Ibid., 7:2157 (2004); G. Shen et al., J. Org. Chem., 71:7618 (2006)).

Macrocyclic compounds useful as inhibitors of kinases and HSP90

Le Centre National de la Recherche Scientifique


A tilting pad bearing for a rotatable surface includes a plurality of circumferentially-arranged tilting pads, each of the tilting pads having a working surface and a trailing surface. A lubrication device for lubricating fluid is detachably affixed to the tilt pad leading surface or is formed integral with the tilting pad. The lubrication device has a fluid conduit and a cavity that provide the cool lubricating fluid to those portions of the rotating collar which need the most cooling. The conduit has a ninety degree turn so that the cooling fluid has a velocity vector normal to the boundary layer of the hot carryover fluid. The outlet of the conduit is positioned, and the cavity is designed, to provide the greatest amount of cooling fluid where the rotating surface is the hottest. The lubrication device also has a wiper to wipe hot carryover fluid off of the rotating surface. The amount of lubricating fluid and bearing power losses are substantially reduced. In the thrust embodiment, the bearing has a smaller axial height because loads imposed by the rotating surface are borne by the bearing elements, not by the bearing retainer. A hydraulically actuated feed piston closes the gap between the pad and retainer to convey lubricating fluid to the pad working surface. Equalizing link contact stresses are reduced by using conformal cylindrical surfaces and line versus point contact.

This invention relates to hydrodynamic tilt pad bearings for use in rotating machinery such as generators and turbines. More particularly, this invention relates to the lubrication and cooling of tilt pad thrust and journal bearings and to the manner in which axial loads are handled in tilt pad thrust bearings.
Tilting pad journal and thrust bearings are known for use with high speed rotating shafts and rotating collars. The tilting pads pivot to uniformly distribute the load imposed upon them by the rotating collar. Each of the tilt pads typically has a working surface made of babbitt metal that is lubricated by a fluid film.
One major concern with such bearings is that the pad working surfaces be kept below a predetermined temperature to prevent the rotating surface from wiping and to maximize the performance of the machinery. The typical way in which the bearing temperature is controlled is by using an excessive volume of cool lubricating fluid. In some prior art bearings, the pad working surfaces are substantially flooded with the lubricating fluid. A disadvantage of such so-called "flooded" bearings is that the amount of oil provided to each tilting pad cannot be controlled. This is a significant disadvantage in the case of journal bearings since the loads applied to the tilt pads in a journal bearing are typically unequal. Therefore, it is desirable to apply varying amounts of lubricating fluid to the tilt pads, based upon their respective loads.
Another disadvantage of flooded bearings is that they require a great deal of lubricating fluid, and corresponding apparatus for circulating substantial amounts of lubricating fluid. Another disadvantage of flooded bearings is that the lubricating fluid must find its way to the drain holes, without being directed towards the drain holes. Yet another disadvantage with flooded bearings is that bearing power losses increase due to the additional oil shear in the oil path to the pad.
Tilt pad thrust bearings are known in which the flow of the lubricating fluid is directed by a stationary lubricant director, as an alternative to simply allowing the fluid to find the exit. For example, U.S. Pat. No. 5,271,676 issued Dec. 21, 1993 discloses a combination journal/thrust bearing having lubricant directors between adjacent thrust tilt pads to direct the flow of lubricating fluid to a succeeding bearing pad in a direction of shaft rotation and to dispose of lubricating fluid from a preceding pad to an oil sump.
In a typical prior art thrust bearing, the lubricating fluid is introduced into the bearing housing, and then proceeds in an axial direction toward the rotating collar before it flows onto the tilting pads. Unfortunately, this path for the fluid causes the lubricating fluid to pick up heat as the fluid moves in the axial direction. The fluid also mixes with the hot carryover fluid from the preceding, adjacent pad. As a result, the temperature of the fluid when it reaches the leading surface of a tilting pad is substantially greater than the temperature of the fluid when the fluid entered the bearing housing. The resulting higher pad temperatures reduce the load carrying ability and the safety margin of the bearing assembly.
In typical equalized tilting pad thrust bearings, the tilting pads are supported by upper equalizing links which in turn are supported by lower equalizing links. The lower links are supported by a retainer. The tilting pad-link assembly is kept together by the retainer, which has an inner retainer ring and an outer retainer ring. Axial loads imposed upon the tilting pads are transferred through the upper and lower links to the retainer, which in turn is disposed within the bearing housing. The tilting pads typically have a spherical lower surface that makes point contact with an upper link so that the tilting pads may pivot in both the radial and the circumferential directions. Each upper link typically contacts two adjacent lower links on two spaced flat surfaces. The lower links in turn transfer the axial loads to the retainer.
There are several disadvantages to the prior art equalized bearing described above. First, the tilting pads tend to thermally and elastically deflect in the axial direction about their respective pivots under high axial loads, thereby reducing the effective bearing surfaces of the tilting pads. The load carrying ability and the bearing safety margin are reduced.
A second disadvantage of such prior art equalized tilting pad bearings is that the bearing has a high axial profile because of the number of components that are stacked onto each other. The tilting pads are stacked on the upper links, which in turn are stacked on the lower links. The lower links rest on the retainer, which in turn is enclosed by the bearing housing. The height of a typical equalized thrust bearing (with a 10.5" O.D.) is about 3.38 inches.

Tilt pad hydrodynamic bearing for rotating machinery


When transesophageal echocardiography is used to obtain a transgastric short axis view of the left ventricle of the heart, the best place to position the transducer is in the fundus of the stomach, aimed up through the left ventricle. The probes disclosed herein facilitate placement of the transducer in the optimum position within the fundus, despite wide variations in the distance between the lower esophageal sphincter and the fundus among different subjects. In one preferred embodiment, the ultrasound probe uses a bending section with a series of vertebrae and stiffening that is more flexible proximally and less flexible distally, which causes the probe to bend relatively sharply at the point where the probe exits the lower esophageal sphincter. The flexibility of the proximal-most portion of the bending section is preferably greater than or equal to the flexibility of the interface between the bending section and the shaft.

Transesophageal echocardiography (TEE) is an ultrasound imaging technique that provides images of the heart for diagnostic and/or monitoring purposes. One particularly beneficial use of TEE is for obtaining images of the transgastric short axis view (TGSAV) of the left ventricle. To obtain the best images of the TGSAV using TEE, the ultrasound transducer should ideally be positioned in the fundus of the stomach, with the ultrasound beam aimed through the left ventricle.
TEE probes for imaging the TGSAV typically contain mechanical articulation mechanisms to bend the distal end the probe into the desired position in the fundus. Since conventional TEE probes are relatively large (i.e., on the order of ½ inch in diameter), the articulation mechanisms can be relatively strong. As a result, when the probe is not perfectly aligned with the desired position, the probe can exert significant forces on the relevant anatomical structures to push the distal end of the probe into the desired location for obtaining the TGSAV. However, when smaller TEE probes are used (e.g., the 5 or 6 mm diameter probes described in U.S. patent application Ser. No. 10/996,816), the probe may not be able to exert enough force to push the distal end of the probe into the desired location.
U.S. application Ser. No. 10/996,816, incorporated herein by reference, discloses a TEE probe for use in adults that is preferably less than 7.5 mm in diameter, more preferably less than 6 mm in diameter, and most preferably about 5 mm in diameter. It also discloses a pediatric TEE probe that is preferably between about 2.5 and 4 mm in diameter.
To obtain the best images of the TGSAV, the ultrasound transducer (which is located in the distal end of the probe) should be positioned in the fundus of the stomach, pressed up against the mucosa. The optimal position of the transducer within the fundus depends on a number of parameters including the size of the heart and the position of the heart relative to the fundus. These parameters may vary, for example, with body size, body habitus, and/or anatomical relationships. The optimum position for the transducer within the fundus is referred to hereinafter as "OPF".
To get the transducer at or near the OPF to perform imaging, the distal end of the probe is inserted in its unbent position into the patient's nose or mouth, down through the patient's esophagus, and into the fundus of the stomach. After the tip of the probe has been inserted to the appropriate depth, the operator (e.g., a doctor) actuates an articulation mechanism to bend the distal end of the probe until it comes into contact with the mucosa lining the superior portion of the fundus, preferably positioning the distal end of the probe at an acceptable position or, most preferably, at the OPF. Once the distal end of the probe is at a position, ultrasound images can be obtained. If, based on the images, it is determined that the distal end is not at an acceptable position or the OPF, the position of the probe may be adjusted to improve the images.
The entrance from the esophagus to the stomach is called the lower esophageal sphincter. The lower esophageal sphincter is a relatively stable area because the esophagus itself has a thicker musculature at this point and because the area is supported where it passes through the diaphragm. If the distance from the lower esophageal sphincter to the OPF was the same in all patients, a probe could be designed with its bending joint located at a corresponding distance from the distal tip of the probe. In practice, however, the distance between the lower esophageal sphincter and the OPF (referred to hereinafter as "LOD") varies from patient to patient. For example, the LOD may typically be between 4-10 cm in adults, and 2-5 cm in children, depending upon body size, body habitus and the position of the heart relative to the diaphragm.
Conventional large TEE probes (e.g., ½ inch in diameter) have a bending point that is located at a fixed distance from the distal tip of the probe, and can exert significant forces on the relevant anatomical structures to push the distal end of the probe into a suitable location for obtaining the TGSAV. However, the operator of the device may not perceive the forces as being high due to the mechanical advantage provided by the articulation controls. The distal tip positioning of conventional probes is accomplished by deflecting the relatively compliant lower esophagus and upper stomach cavity with a stiff probe insertion tube and by a powerful bending section within the probe. However, when smaller TEE probes are used, the probe will often be unable to exert enough force to push the distal end of the probe into a suitable location. Examples of smaller TEE probes include TEE probes for adults that are less than 7.5 mm in diameter, and pediatric TEE probes that are preferably less than 4 mm in diameter (as described in U.S. application Ser. No. 10/996,816).

This patent is subject to a terminal disclaimer.


In implementations of resource-aware training for neural network, one or more computing devices of a system implement an architecture optimization module for monitoring parameter utilization while training a neural network. Dead neurons of the neural network are identified as having activation scales less than a threshold. Neurons with activation scales greater than or equal to the threshold are identified as survived neurons. The dead neurons are converted to reborn neurons by adding the dead neurons to layers of the neural network having the survived neurons. The reborn neurons are prevented from connecting to the survived neurons for training the reborn neurons.

Neural networks achieve state-of-the-art performance in many tasks, including visual tasks such as image recognition and object detection. However, conventionally-configured neural networks are inefficient in terms of computational resource utilization. This is because only a fraction of the computations the network performs are useful in accomplishing a particular task. In other words, neural networks are often over-parameterized, and as a result of these computational inefficiencies, neural networks have not been well-suited for use on devices that have limited computational resources such as mobile devices. This computer-based problem is not addressed by widely used optimization methods such as stochastic gradient descent. Further, it is not possible to know which parameters of a neural network will be necessary for the network to accomplish a task until the network is at least partially trained to accomplish the task.

Resource-aware training for neural networks


A computer based system for guiding golfers around a golf course enables the holes to be played in an order designated by the system according to the situation on the golf course when the players are ready to start playing a now hole. The holes are not necessarily played in the traditional numerical sequence. A player inserts a card into a port on a golf course and is instructed, for example, by instructions received on a video monitor, as to the hole which is most convenient for play to begin for his party. At the end of that hole, the card is inserted into a terminal adjacent to the green on which play has been completed, and instructions are provided as to the next hole to be played. The players in the party proceed to the designated tee, as instructed, and play the hole. The process is repeated to find the next hole to play, etc. The computer system keeps a record of holes played, so that each hole is played only once by the party. The system eliminates problems caused by different speeds of play by different parties.

It is a waste of time for many golfers to wait for slower golfers on the golf course to vacate a hole in order for the waiting golfers to be able to continue play. This occurs, for example, when groups on a golf course are heterogeneous in the number of players, their relative skill and other characteristics which affect skill. This situation is contrary to an ideal shared by all golfers, that golf matches should be composed of the same number of players, and that they play at the same speed so that each of the holes can be played in the same amount of time enabling the numerical sequence defined by the course to be followed. Unfortunately, this is the exception rather than the rule because on any golf course the golf groups are often heterogeneous in the number of players, their skill and/or other characteristics. Because of the heterogeneity, it is impossible for the groups to play at the same speed. Therefore, play is delayed.
Players may choose to resolve the problem of slower players is ultimately the decision of the players to pass or be passed or to skip holes occupied by slower players which can culminate in conflicts between groups since there is no automatic or organized way to solve the problem. Such problems take away from the fundamental goal of golf, namely to spend a few hours outdoors while playing the sport the best that one can.
The problem, which is caused by unequal speed of play, occurs on courses of all sizes. Even on a large course, with only two golf parties, the problem still exists. Sooner or later, the faster group will catch up with the slower group. The faster group will continue to play behind the slower one or ask for permission to pass. The group that is ahead makes the decision as to whether or not the following group can pass, which causes displeasure or approval of the former and makes the latter uneasy. The faster group may then choose to skip that hole and come back to it later when they have the opportunity.
As the number of groups increases, the problem becomes more acute and the number of situations, like those described above, increase. This produces chaos and displeasure among the players. If the numerical order of the holes is always adhered to, all of the groups are forced to play at the pace of the slower groups.
On some courses, usually the public courses, the management tries to homogenize the matches as much as possible by making all the groups equal in number. This may produce groups which are not harmonious and may be unpleasant for the players. This method, however, does not guarantee that the groups play at the same pace, nor that the problem sought to be corrected does not arise.
It is clear that a problem exists because of the variance in speed of each group that plays on a given course. This problem has been a part of golf for most of its existence, and despite its negative effects it is considered to be a natural consequence of playing golf.
Remedio et al., U.S. Pat. No. 4,910,677, describes a golf score recording system and network. The system provides automated score keeping operated from a golf cart or other mobile unit. Several golf courses may be connected into one system and player profiles may be generated and retrieved. There is no disclosure of a system for playing holes in a variable order.
The patent to Dudley, U.S. Pat. No. 5,044,634, describes a golf information system which automatically provides golfers with golf course location information including yardage from several locations to the nearest green. The informational tags recognized by the computer may be buried in the ground along paths traveled by a golf cart or in other non-obtrusive positions. The system could also carry information concerning speed of play and other messages, such as advertising messages.
The two patents to Matthews, U.S. Pat. Nos. 5,086,390 and 5,097,416, describe systems for monitoring play of golfers. U.S. Patent No. 5,086,390 describes a system for monitoring the speed of play of golfers for purposes of utilization of golf carts and golf holes and also for warning players who are habitually slow that their rate of play should be increased to avoid disruption to others. A mobile transmitter is described which sends location signals responsive to the position of a golfer. The signals may be received by a mobile receiver. U.S. Pat. No. 5,097,416 describes a related system in which a player is alerted when play at a hole has exceeded the designated time for playing that hole. The location of the player is monitored and means are described for determining the length of actual elapsed time for each hole compared with a predetermined playing time for the subject hole.
None of these patents suggest a system for controlling the order in which the holes of a golf course are played according to measured conditions of speed of play and/or convenience according to the situation of the course.

Intelligent golf parties guidance system


A content (an amount of ink to be suctioned, or the number of times ink is preliminarily ejected) of the maintenance process to be performed after the ink tank replacement is made different depending on the amount of ink so far consumed from a tank which is replaced. This makes it possible to check the color mixture which would otherwise occur after the new ink tank is attached to the printing apparatus, and to concurrently manage an amount of waste ink in order that ink should not be consumed more than necessary in a case where the color mixture is less likely to occur.

1. Field of the Invention
The present invention relates to an ink jet printing apparatus. Particularly, the present invention relates to a method of performing a process for maintaining a color ink jet printing head capable of making a print with multiple color inks for the purpose of keeping the color ink jet printing head capable of ejecting the inks stably.
2. Description of the Related Art
Ink jet printing apparatuses eject liquids such as inks to a printing medium from their ink jet printing heads depending on inputted image data, and thus print multiple dots on a printing medium, thereby forming the image thereon. A common practice for ink jet printing apparatuses each with such a configuration is that a maintenance process (hereinafter also referred to as a "recovery operation") is applied to their printing heads for the purpose of keeping their ink ejecting conditions adequate.
The maintenance process consists of a suction recovery process, a preliminary ejection process, a wiping process and the like. The suction recovery process is that which discharges inks from individual ejection openings forcedly by generating a negative pressure inside a cap by use of pumping means such as a tube pump and a piston pump while a face of a printing head, in which the ejection openings are arranged, is covered with the cap. This suction recovery process makes it possible to remove thickened inks and bubbles in printing head ink chambers, which adversely affect its ejection operation, from the interior of the head.
In the preliminary ejection process, an ejection operation is preliminarily carried out in order for inks to be stably ejected from the individual ejection openings. Particularly, in a case of a printing head which has just undergone the suction recovery process, it is likely that part of inks once discharged into the cap by the forced suction may flow back to the insides of the individual ejection openings. In other words, part of the thickened inks returns to the insides of the ink chamber and the nozzles in the printing head. In a case where the face in the printing head which ejects multiple color inks is configured to be covered with a single cap, ink mixed up by multiple color inks in the cap flows back into the insides of nozzles assigned for the respective color inks. With these problems taken into consideration, a common practice performed after carrying out the suction recovery process is to preliminarily eject multiple color inks from the individual ejection opening toward the inside of the cap while the inside of the cap is caused to communicates with the atmosphere for the purpose of discharging the thickened inks and the mixed ink. For example, the preliminary ejection is carried out approximately 20000 times with an ejection frequency of 10 kHz for each nozzle assigned for a corresponding one of the multiple color inks. It does not matter how many times the preliminary ejection should be carried out with what driving frequency, as long as the number of times and the frequency are enough for discharging the thickened inks and the mixed ink which flow back into the individual nozzles.
The wiping process is that to be carried out for the purpose of wiping inks, which adhere to the surface of the printing head in conjunction with the suction recovery process, the preliminary process and regular printing operations, off the surface by use of a wiping member.
As described above, as long as the suction recovery process, the preliminary ejection process and the wiping process are carried out at adequate timings before, during and after each printing operation, it is possible to keep the ejecting operation of the printing head in a stable condition.
Inks are consumed for the suction recovery process and the preliminary ejection process, which have been described above, regardless of actual printing operations. For the purpose of cutting back on running costs, it is desirable that amounts of inks consumed for these processes should be held as small as possible. In particular, large amounts of inks are often suctioned for the suction recovery process to be carried out when replacing old ink tanks with new ones from a viewpoint of stabilizing the ejecting operation. A key point for cutting back on running costs is to hold the amounts of suctioned inks and the amounts of preliminarily ejected inks as small as possible.
Japanese Patent Laid-Open No. 07-17058 (1995) discloses a method of making amounts of suctioned inks different between the suction recovery process to be carried out for ink tank replacement and the suction recovery process to be carried out for the purpose of doing things other than the ink tank replacement. In addition, Japanese Patent Laid-Open No. 2003-291368 discloses a process for avoiding carrying out the suctioning operation both before and after ink tank replacement. Furthermore, Japanese Patent Laid-Open No. 2005-306013 discloses a method of making an amount of suctioned ink different according to ink type (ink color) in an ink jet printing apparatus which simultaneously applies a suction recovery process to a printing head for ejecting multiple color inks by use of a single cap. Moreover, Japanese Patent Laid-Open No. 2004-98626 discloses an effective preliminary ejecting method to be carried out after a suction recovery process of an ink jet printing head which has a nozzle row for printing larger dots and a nozzle row for printing smaller dots for each type of ink.
After gradually decreasing inks in the respective ink tanks depending on use, the ink jet printing apparatus finally becomes capable of carrying out no printing operation. For the purpose of avoiding a situation in which a printing operation can be carried out no longer suddenly in the middle of making a print on a sheet of paper, many of ink jet printing apparatuses of a regular type include means for estimating amounts of remaining inks on a basis of how many times the printing head has ejected and been suctioned, and inform their users that an ink remains in a very small amount when the amount of the remaining ink becomes very small, thus urging the users to replace the old tank with a new one. However, the old ink tank is not necessarily replaced with the new one immediately when their users are informed that the amount of the remaining ink is very small. Even though the users are informed that the amount of the remaining ink is very small, they are likely to continue the printing operation for a while, in a case where the number of sheets of paper on which a print remains yet to be made is very small, or in a case where no new ink tank with which the old ink tank is replaced is on hand.
In this respect, let us discuss how the pressure inside an ink tank changes after the ink tank becomes nearly empty of its ink. First of all, in a case of an ink tank whose inside can communicate with the atmosphere, as the ink in the ink tank is discharged therefrom in conjunction with an ejection operation, the air is suctioned into the ink tank, and an air path is thus formed in the ink tank. In other words, the inside of the ink tank can maintain an atmospheric pressure equal to that of the external air. On the other hand, in a case of an air-tight ink tank whose inside can not communicate with the atmosphere, the negative pressure in the tank increases rapidly after an amount of ink remaining in the tank becomes very small. Subsequently, when the value representing the negative pressure goes beyond the meniscus pressure (that is, a pressure which ink in the vicinity of a nozzle in a printing head can withstand for forming a meniscus due to mutual attraction between the capillary force of the nozzle and the negative pressure in the ink tank), the ink starts to flow back. In recent years, not only atmosphere-communicating ink tanks each containing an ink in an absorber such as a sponge but also air-tight ink tanks each are capable of containing an ink in the form of a liquid are supplied in.
In the case of an air-tight ink tank, once inks flow back as described above when a suction recovery process is carried out, mixed ink, which has been present in the cap, flows into the individual nozzles, and is thus introduced to the insides of the common ink chamber and ink supplying ports in the printing head, and as far as to the insides of the ink tanks. Furthermore, if old ink tanks are replaced with new ones while the mixed ink remains in the insides of the common ink chamber, ink supplying ports and the like, it is likely that part of the mixed ink remaining in vicinities of the ink supplying ports with which to connect the printing head and the ink tank may likely enter the new ink tank with which the old ones are replaced.

Ink jet printing apparatus and method of performing a maintenance process


The invention provides a transition board apparatus for a passenger bridge and a spring leaf thereof. A transition board apparatus includes a transition board and a spring leaf, wherein the transition board comprises a hinged end, a free end and the transition portion between them. The hinged end hinges on the end of the first tunnel bottom plate. The spring leaf is provided with the holding portion, which is secured on the sidewall of the first tunnel, and the bearing portion, which is used to raise the transition board up. Thus, there is a clearance between the free end and the bottom plate ornament laid on the second tunnel bottom plate. Therefore, when the second tunnel is moving back and forth relative to the first tunnel, the friction between the transition board and the bottom ornament can be avoided in order to protect the bottom plate ornament.

In a passenger bridge apparatus, there are provided with movable tunnels comprising at least a first tunnel fixedly mounted and a second tunnel movable back and forth relative to the first tunnel. The first tunnel has a rear end hinged to a rotatable platform and a front end extending into and being coupled with the second tunnel via a nylon slider (roller) device so as to enable the second tunnel to move back and forth relative to the first tunnel, thereby realizing a telescopic motion of the tunnels. A transition board is provided in the first tunnel at a transition area between the first and second tunnel, in order to eliminate the effect of the height difference between the two tunnels and seal the clearance between them, thereby improving the aesthetics of its appearance.
A transition board apparatus for a passenger bridge in the prior art is shown in FIG. 1. A hinged end 131 of a transition board 13 is articulated to an end of a first tunnel bottom plate 11 via a hinge 14. The transition board 13 can rotate around the axis of the hinge 14. Provided that a free end 132 of the transition board 13 directly rests on a bottom plate ornament 121 arranged on a second tunnel bottom plate 12, when the second tunnel is moving back and forth relative to the first tunnel, a sliding friction will occur between the free end 132 of the transition board 13 and the bottom plate ornament 121, thus the bottom plate ornament 121 can be worn out. To avoid the above-mentioned occurrence, a pair of elastic support members 15 is soldered on the bottom surface of the first tunnel bottom plate 11. The support members 15 extend to the bottom of the transition board 13. An adjusting bolt 151 is arranged at the end of the support member 15 and used to raise the transition board 13 up, so that the free end 132 of the transition board 13 does not contact with the bottom plate ornament 121. The adjusting bolt 151 can be adjusted as required so as to adjust the distance between the free end 132 of the transition board and the bottom plate ornament 121. This structure can effectively avoid the friction between the free end 132 of the transition board and the bottom plate ornament 121. However, the support members 15 and the adjusting bolts 151, which are located under the transition board, make the adjustment inconvenient. Furthermore, the adjusting bolts 151 are prone to become loose and function less effectively. Therefore, it is necessary to provide an improved tunnel transition board apparatus to overcome the above deficiencies.

Transition board apparatus for a passenger bridge and a spring leaf thereof

China International Marine Containers (Group) Ltd.


Method of optimizing well placement in an unconventional reservoir, by obtaining a plurality of produced oil, produced water and produced gas samples from an unconventional reservoir over a period of time, and obtaining a plurality of rock samples from the reservoir. Each of those plurality of samples is chemically fingerprinted, as well as assigned time and location identifiers. This data is then used to generate a plurality of reservoir maps over time and those maps then used to optimizing well placement in the reservoir.

Geologic formations may contain large quantities of oil or gas, but can have a poor flow rate due to low permeability, or from damage or clogging of the formation during drilling. This is particularly true for tight sands, shales and coalbed methane formations. Hydraulic fracturing (aka fracking) requires the pumping of fluids under high pressure into reservoirs to create fractures in the rock, thus improving flow. Fracking thus stimulates wells drilled into such formations, making profitable what would otherwise be a prohibitively expensive process.
Indeed, the combination of hydraulic fracturing with horizontal drilling has opened up shale deposits across the country and brought large-scale natural gas drilling to new regions. Shale deposits in combination with other unconventional resources such as heavy oil using steam assisted gravity drainage (SAGD) as well as cyclic steam stimulation (CSS) techniques have allowed economic production of a variety of unique reservoirs. Oil reserves that previously were thought commercially unfeasible to access are now being developed, even in the far North and Artic regions. In fact US oil production reached a 47 year high in 2015 (the highest being 1970).
The optimal spacing of horizontal wells in unconventional field developments remains a major uncertainty because of the lack of information regarding the volume of rock being drained, sometimes referred to as drained rock volume (DRV). The drained rock volume is often less than the stimulated rock volume (SRV). If spacing in either the vertical or lateral dimension is too wide between horizontal wells, hydrocarbon resources are left behind, and if too close, wells compete for the same in-place resource. Economic value during unconventional field development may be significantly reduced by sub-optimal horizontal well spacing.
Various methodologies, such as micro-seismic monitoring during the hydraulic fracturing process and monitoring pressure and injected tracers during production, have been used to evaluate wellbore communication and fracture network connectivity. However, these measurements are only proxies for understanding reservoir drainage, but define the stimulated rock volume.
There are a number of proxy solutions aimed at understanding the SRV through utilization of injected tracers in frack fluids, microseismic event distributions, and production metrics and pressure data between wells. These solutions are based on assumptions that may or may not be well understood in the unconventional realm, and rely on rock behavior during completion and production processes. Most importantly, the SRV does not necessarily equate directly to an effective drainage volume due to a variety of factors including possibly inadequate proppant distribution, reservoir damage, reservoir heterogeneity and the like.
Injected tracers are useful for addressing which stages of the completion are contributing to hydraulic fluid flow, but have a limited utility life as the tracer is either absorbed to strata or their concentration depletes over time.
Microseismic event monitoring is a powerful method for determining fracture patterns and densities during hydraulic fracturing processes. These events provide an important glimpse into rock behavior and the spatial extent of fracturing. Unfortunately, there is no straight forward method of determining whether microseismic events equate to amount and degree of hydrocarbon fluid flow. As with injected tracers, microseismic monitoring only provides a snapshot of the initial subsurface environment prior to production.
Pressure monitoring before and during production can be very helpful for determination of connectivity between wells because pressure responses between wells are a measurement of compression wave responses through a porous medium through time. Therefore, pressure monitoring adds a time component to understanding fracture connectivity, but still remains a remote detection method that cannot provide critical information about drained volumes.
Mechanical flow meters or remote sensing derived flow rate or volume are sometimes used to determine which parts of a well are contributing to production; however, neither method actually provides information on how far vertical or lateral from the well bore the fluid flow drainage is being derived. Ultimately, these technologies offer a wealth of information about the SRV and subsurface rock responses to completion and production, but do not directly address effective drainage volume (DRV) per well.
In 2013, Baskin, et al. described the first known application of geochemical fingerprinting technology to a shale-oil reservoir. He studied 18 oil samples produced from wells in South Texas, with the goal to determine if some of the oil produced from horizontal wells completed in one formation contained oil from another nearby reservoir because of the natural or induced fractures that extended therebetween.
This first required Baskin to determine if: (1) oil fingerprinting could differentiate oils produced from different reservoirs; (2) compositional differences could be employed as natural tracers to evaluate vertical communication between the reservoirs; and (3) the amount (if any) of contribution of oil produced in one of the wells from the other reservoir.
His results demonstrated that compositional differences did exist, and he concluded that about 9% of the oil produced from a horizontal well completed in the reservoir was actually from the second play.
What is needed in the art are better methods to quickly, accurately, and inexpensively determine the effective vertical and lateral drained rock volume over time from horizontal wells in an unconventional reservoir. This could then be used to determine production allocation, which can be used in reservoir modeling, to optimize well placement and thereby production of oil and recovery factors.

Time-series geochemistry in unconventional plays


An article of furniture can include an upper beam member, a first side member, a second side member, and a plurality of attachment bracket members connecting the first side member to the upper beam member adjacent a first side of the upper beam member and also connecting the second side member to the upper beam member adjacent a second side of the upper beam member. Each attachment bracket members can have a body and a plurality of arms extending from the body. The arms can include a first and second top arms, first and second intermediate arms, and first and second bottom arms. The arms can be positioned to define channels.

Examples of articles of furniture can be appreciated from U.S. Patent Application Publication Nos. 2019/0365089, 2013/0204438 and 2012/0126072 and U.S. Pat. Nos. 10,413,063, 10,390,611, 9,585,468, 9,265,340, 9,185,973, 8,667,909, 8,256,359, 8,056,489, 6,546,880, 6,536,357, 6,389,988, 6,029,587, 5,941,182, 5,881,979, 5,715,761, 5,706,739, 5,598,789, 5,562,052, 5,224,429, 5,408,940, and 4,604,955. Examples of other types of articles of furniture can be appreciated from U.S. Pat. Nos. 9,920,520, 8,365,798, 7,789,025, 7,310,918, 6,896,028, 6,367,213, 6,002,613, 6,000,180, 5,966,879, 5,675,946, 5,680,893, 5,287,909, 4,325,597, 4,248,325, and 2,821,450, U.S. Design Patent Nos. D800,459, D796,216, D653,862, D458,040, D457,359, and D427,783 and U.S. Patent Application Publication Nos. 2017/0226749 and 2012/0304441.
Examples of furniture systems that can be used in organizing or decorating interior spaces of buildings such as offices or homes can be appreciated from U.S. Pat. Nos. 9,730,513, 8,347,796, 8,132,371, 6,167,664, 6,067,762, 5,943,966, 5,906,420, 5,328,260, 5,309,686, 5,086,597, 4,567,698, 4,546,889, 4,382,642, 4,325,597, and 2,821,450.

Article of furniture and method of installing same


Methods of treating a subject having a cardiovascular disease, selecting a therapy for a subject having a cardiovascular disease, identifying a subject having a cardiovascular disease that will benefit or not benefit from exercise therapy, determining whether a subject having a cardiovascular disease should begin, continue, not begin, discontinue, or avoid exercise therapy, determining whether a subject having a cardiovascular disease should continue, discontinue, or avoid exercise therapy, reducing the risk of an adverse outcome (e.g., death) in a subject having a cardiovascular disease, and predicting the efficacy of exercise therapy in a subject having a cardiovascular disease. These methods include determining a level of soluble ST2 in a subject.

Circulating biomarkers play a critical role in the diagnosis and management of patients with chronic heart failure (Braunwald, N. Engl. J. Med. 358:2148-2159, 2008). Natriuretic peptides, such as brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), have been demonstrated to be powerful tools for the diagnosis, risk stratification, and management of patients with heart failure (Felker et al., Canadian Med. Assoc. J. 175:611-617, 2006). In addition to being useful for clinical management, biomarkers can provide insights into the mechanisms underlying important physiologic relationships. Exercise intolerance, typically manifested as exertional dyspnea, is a major morbidity of chronic heart failure. Both maximal (e.g., as measured by peak oxygen uptake [peak VO2]) (Aaronson et al., Circulation 95:2660-2667, 1997; Mancini et al., Circulation 83:778-786, 1991) and submaximal exercise capacity (e.g., as measured by distance in the 6-minute walk test) (Bittner et al., JAMA 270:1702-1707, 1993) have been demonstrated to be of substantial prognostic importance in chronic heart failure.
A variety of therapies can be used to treat patients diagnosed with a cardiovascular disease. For example, exercise therapy is commonly used to treat patients diagnosed with a cardiovascular disease (see, for example, Korhonen et al., J. Womens Health 20:1051-1064, 2011).

Methods of treating a subject having heart failure


A flexible composite surfacing film for providing a substrate with desired surface characteristics is disclosed. The film comprises a flexible temporary carrier film and a flexible transparent outer polymer clear coat layer releasably bonded to the temporary carrier film, the flexible outer polymer layer comprising an extruded thermoplastic polymer having a M.sub.w /M.sub.n ratio of 4 or lower. A pigmented base coat layer is adhered to said outer clear coat layer and is visible therethrough, and a thermoformable backing layer is adhered to the pigmented base coat layer. The film is produced by extruding a molten transparent thermoplastic polymer and applying the polymer to a flexible temporary carrier thereby forming a continuous thin transparent film. A pigmented thermoplastic polymer in a volatile liquid vehicle is applied to the exposed surface of the transparent film while the film is bonded to the flexible temporary carrier, thus forming thereon a coating of the pigmented thermoplastic polymer overlying the transparent thermoplastic polymer film. The thus formed composite may then be heated while the transparent thermoplastic polymer film is bonded to the flexible temporary carrier to evaporate the volatile liquid vehicle and form a pigmented polymer layer. The heating step also molecularly relaxes the underlying film of transparent thermoplastic polymer to relieve any molecular orientation caused by the extrusion.

It is often desirable to enhance certain surface characteristics of substrates such as, for example, exterior and interior body parts of automobiles. In particular, with regard to exterior automobile body parts, base coat/clear coat painted finishes have become quite popular. These finishes are conventionally applied by first painting a base coat, which may include metallic pigments, onto the body part and then painting a clear coat over the base coat. Both the base coat and the clear coat are typically applied by spraying. The base coat/clear coat painted finish thus can provide a "wet look" finish, with or without a metallic appearance, and can be used to produce a very high quality finish. In addition, because the clear coat protects the base coat, greater latitude can be used in pigment selection and loading in the base coat without the weatherability of the finish being unacceptably decreased.
Base coat/clear coat finishes, however, and particularly conventionally painted metallic finishes, pose significant pollution control problems arising from the evaporation of volatile paint solvents. Moreover, they are difficult to provide on plastic automobile body panels which are becoming a more popular mode of construction in the industry.
Accordingly, decorative composite surfacing films have been developed which can be applied to a substrate, such as an automobile body part, to impart the appearance of base coat/clear coat painted finishes. Exemplary films and methods for making and applying the same to automobile body parts are disclosed in U.S. Pat. Nos. 4,810,540; 4,931,324; 4,943,680; and 5,342,666 which are all incorporated by reference herein. These patents disclose composite surfacing films having a clear coat layer and an underlying base coat layer adhered thereto. After the films have been formed, they may be bonded to a plastic film or sheet and thermoformed into the final part; thermoformed into an insert for placement in a mold for resin injection to make the part; or placed directly into a mold, without preforming, for resin injection to make the part. The composite surfacing films thus provide a high quality decorative finish simulating that of a base coat/clear coat painted finish and substantially reduce or eliminate the emission control problems previously faced by manufacturers who wished to produce automobiles with base coat/clear coat finishes.
Another method of producing film materials of this type is disclosed in PCT International Application No. WO 94/03337 to Duhme et al. Duhme et al. discloses forming a clear coat layer by extrusion and then laminating the extruded clear coat layer to a PET carrier. A color layer may be cast onto a different carrier and then, after drying and removal of the carrier, laminated to the clear coat layer.
Extruded polymers typically take on a molecular orientation as a result of the extrusion process. During extrusion, the molecular chains become generally oriented in the machine direction as a result of the physical forces acting on the polymer as it is forced through the extrusion die. Molecular orientation, however, can have a deleterious effect on the resultant properties of the flexible surfacing film because various properties of the clear coat layer will become anisotropic. For example, the tensile strength of the clear coat layer will typically be greater in the machine direction (i.e., the direction of molecular orientation) than in the cross machine direction. The same may also be true of physical shrinkage when the surfacing film is later subjected to prolonged high temperatures, as in the thermoforming process. Dimensional instability is particularly troublesome with surfacing films as it may cause visual distortion or, in severe cases, delamination of the film or even debonding of the film from the substrate.

Flexible composite surfacing film and method for producing same


A keyboard cover of the present invention includes a cover holder removably mounted to one side of a keyboard. A flat plate is mounted on the cover holder and selectively rotatable toward the top of the keyboard for covering it or toward the bottom of the keyboard for covering it. A connecting device is rotatably connected to the cover holder at one end and rotatably connected to the plate at the other end for connecting the cover holder and plate. With this configuration, the keyboard cover is capable of selectively playing the role of a cover, a keyboard angle adjusting device or, when the keyboard is not used, a bookrest or a mouse table, as desired.

The present invention relates to a cover for a keyboard connectable to a data terminal as a data input unit and, more particularly, to a keyboard cover usable as a keyboard angle adjusting device or as, when a keyboard is not operated, a bookrest or a mouse tables, as desired.
A keyboard for a personal computer, work station or similar data terminal occupies a substantial area on a desk or similar base and noticeably effects the efficiency of work to be performed on the table. Particularly, in parallel with the trend toward space saving in, e.g., offices, there is an increasing demand for a decrease in the area to be occupied by the keyboard. By reducing an area to be occupied by the keyboard, it is possible to allocate a greater area to work to be performed in parallel with the input on the keyboard on the same desk and to improve the work environment. The above work includes the manipulation of a mouse and the handling of a book or similar document.
In light of the above, a cover/bookrest is taught in, e.g., Japanese Patent Laid-Open Publication No. 61-213908. The cover/bookrest includes a tray-like cover mounted on one side of the body of, e.g., a personal computer or on a keyboard table. The cover is rotatable about a vertical axis and a horizontal axis perpendicular to the vertical axis. Further, the cover is tiltable relative to a horizontal plane. When a keyboard is not used, the cover is used as a dust cover covering the top of the keyboard. When the keyboard is used, the cover may be used as an upright bookrest for supporting a document.
However, the above cover/bookrest has some problems left unsolved, as follows. The cover/bookrest is no more than a conventional bookrest except that it is mounted to a keyboard so as to play the role of a keyboard cover, as needed, so that it cannot reduce the space to be occupied by a keyboard. Moreover, when the cover/bookrest is used as a bookrest, it is raised away from the keyboard and positioned at, e.g., one side of the keyboard, occupying an additional space. In addition, when the cover/bookrest is used as a cover for covering the keyboard, it cannot be used as a bookrest, i.e., the keyboard occupies a substantial space on a desk even when it is not operated.
Furthermore, a structure for allowing the tray-like cover of the cover/bookrest to rotate about a vertical axis and a horizontal axis and to tilt relative to a horizontal plane is complicated and bulky.
Technologies relating to the present invention are also disclosed in, e.g., Japanese Utility Model Laid-Open Publication No. 60-71943 and Japanese Patent Laid-Open Publication Nos. 3-132815 and 4-188214.


An electromagnetic brake/clutch device includes a drive shaft supported by at least one bearing for transmitting torque, a housing, affixed to prevent its rotation, surrounding the drive shaft, and an electromagnetically activated device within the housing to selectively prevent and allow rotation of the drive shaft. The electromagnetically activated device includes a plurality of cammed rollers acting to prevent clockwise rotation of the drive shaft and a plurality of cammed rollers to prevent counter-clockwise rotation of the drive shaft. The drive shaft includes a circumferential disk and the housing includes a reaction ring for engagement with the plurality of cammed rollers. The plurality of cammed rollers are released from engagement with the circumferential disk and the reaction ring by a plurality of tripping mechanisms within the housing. The tripping action uses the locking force to act as a release force merely by changing the boundary conditions of the roller interface angles. The tripping mechanisms include trippers for disengaging the plurality of cammed rollers and an anvil shaped portion for providing lateral movement of the trippers. The plurality of cammed rollers is preloaded to engagement with the circumferential disk and reaction ring by a spring, and is located with respect to an adjacent tripping mechanism with another spring.

Electromagnetic brakes that depend upon friction for their holding power are commonly used with electric motors and other drives. Some of these devices use hydraulic forces to generate high holding torques. Another commonly used device is a magnetic particle clutch/brake. These type of devices use a magnetic field to align magnetic particles in a gap between rotating members and thus create frictional forces which bind the two members together. The magnetic particles can be steel or iron in a powder form and can be suspended in a liquid.
Prior art electromagnetic friction-hold brakes lack sufficient holding force for many applications. Hydraulic friction-hold brakes have the required holding force, but require a hydraulic system with its associated space, weight, complexity, and potential leaks. Magnetic particle brakes are stronger than standard electromagnetic friction-hold brakes, but are limited in holding strength to around 20 psi. In addition, the particles tend to wear out if the brake is allowed to slip, and they require seals to hold the particles in place and do not fail safe (i.e., locked). A permanent magnet system must be added to the magnetic circuit to obtain a fail safe feature.

The United States of America as represented by the Administrator of the National Aeronautics and Space Administration


Repeater apparatus for conveying a radio-frequency (RF) signal into an environment closed-off to the RF signal, including a master transceiver unit having a master port which receives the RF signal, a local oscillator (LO), which generates a LO signal at a LO frequency, and a frequency divider which divides the LO frequency of the LO signal by an integer to produce a divided LO signal. The master transceiver unit also includes a master mixer coupled to the master port and the divider which generates an intermediate-frequency (IF) signal responsive to the RF signal and the LO signal. The apparatus includes one or more slave transceiver units, each unit positioned within the environment closed-off to the RF signal and including a frequency multiplier which generates a recovered LO signal at the LO frequency by multiplying the frequency of the divided LO signal by the integer, a slave mixer coupled to the multiplier which generates a recovered RF signal responsive to the recovered LO signal and the IF signal, and a slave port coupled to the slave mixer which receives the recovered RF signal therefrom and transmits the recovered RF signal into the closed-off environment. The apparatus further includes one or more cables coupled between the master transceiver unit and the one or more slave transceiver units which convey the IF signal and the divided LO signal between the master transceiver unit and the one or more slave transceiver units.

I. Field of the Invention
The present invention relates generally to cellular communication systems, and specifically to cellular communication systems for areas where radio-frequency signals have difficulty entering.
II. Description of the Related Art
In cellular communications systems there are typically regions where the coverage is difficult or incomplete, for example, within metal-framed structures and underground. One of the reasons for the difficult coverage is Faraday-cage type shielding, wherein radio frequency (RF) signals have difficulty penetrating an effectively closed conducting structure. Another reason is Rayleigh fading, which is generated by a signal traversing multiple paths between a transmitter and a receiver. Typically the multiple paths are caused by reflections and/or refractions of the signal by objects between the transmitter and the receiver. The multiple paths followed by the signal generate interference effects at the receiver, which effects manifest themselves as differences in measured signal strength at the receiver, the measured signal strength being a function of the different paths followed by the signal. Methods for improving the coverage in regions where Faraday-cage type shielding and Rayleigh fading occur are known in the art.
U.S. Pat. No. 5,404,570, to Charas et al, whose disclosure is incorporated herein by reference, describes a repeater system used between a base transceiver station (BTS) which is able to receive signals and a closed environment such as a tunnel, wherein the environment is closed off to transmissions from the BTS. The system down-converts a high radio-frequency (RF) signal from the BTS to an intermediate-frequency (IF) signal, which is then radiated by a cable and an antenna in the closed environment to a receiver therein. The receiver up-converts the IF signal to the original RF signal. Systems described in the disclosure include a vehicle moving in a tunnel, so that passengers in the vehicle who would otherwise be cut off from the BTS are able to receive signals.
U.S. Pat. No. 5,603,080 to Kallandar et al., whose disclosure is incorporated herein by reference, describes a plurality of repeater systems used between a plurality of BTSs and a closed environment, wherein the environment is closed off to transmissions from the BTSs. Each system down-converts an RF signal from its respective BTS to an IF signal, which is then transferred by a cable in the closed environment to one or more respective receivers therein. Each receiver up-converts the IF signal to the original RF signal. Systems described in the disclosure include a vehicle moving between overlapping regions in a tunnel, each region covered by one of the BTSs via its repeater system. Thus passengers in the vehicle who would otherwise be cut off from one or more of the BTSs are able to receive signals from at least one of the BTSs throughout the tunnel.
U.S. Pat. No. 5,765,099, to Georges et al., whose disclosure is incorporated herein by reference, describes a system and method for transferring an RF signal between two or more regions using a low bandwidth medium such as twisted pair cabling. In a first region the RF signal is mixed with a first local oscillator to produce a down-converted IF signal. The IF signal is transferred to a second region via the low bandwidth medium, wherein the signal is up-converted to the original RF signal using a second local oscillator. The local oscillators are each locked by a phase locked loop (PLL) in each region to generate the same frequency, the locking being performed in each loop by comparing the local oscillator frequency with a single low frequency stable reference signal generated in one region. The reference signal is transferred between the regions via the low bandwidth medium.
One of the methods for overcoming Rayleigh fading, is to use a plurality of spatially-diverse receiving antennas, relying on the fact that statistically the chance of destructive interference occurring at all the antennas for a given signal is small. Using a plurality of antennas (in many cases two antennas are sufficient) enables a corresponding diversity of received signals to be analyzed, and typically the strongest signal is chosen. In the case of two antennas, the received signals are referred to as main and diversity signals.
U.S. Pat. No. 5,513,176, to Dean et al., whose disclosure is incorporated herein by reference, describes a distributed antenna array within a region where reception is difficult. The performance of the antenna array is enhanced by utilizing the signal diversity which is generated by the antennas being spatially distributed. Each antenna has a differential time delay applied to signals received by the antennas, so that the diverse signals are also separated in time. The differentially-delayed signals are preferably down-converted to an intermediate frequency and are combined, and the combined signal is then transferred out of the region via a cable.
It is an object of some aspects of the present invention to provide methods and apparatus for improved coverage in regions where cellular communication is inherently difficult.
In preferred embodiments of the present invention, repeater apparatus for use in a cellular communications system comprises a master transceiver unit, which communicates, preferably over the air or alternatively via a cable, with a base transceiver station using master radio-frequency (RF) signals. The master transceiver unit is coupled by one or more cables to one or more slave transceiver units, which are situated in an environment substantially closed off electromagnetically from the environment wherein the base transceiver station is situated. The slave units comprise respective slave antennas, by means of which the slave units communicate with mobile cellular transceivers using slave RF signals. Most preferably, the slave units are located in a region where the master RF signals are not able to penetrate, such as within a building. Signals between the master unit and the slave units are transferred at intermediate frequencies (IF) via the cables.
In both master and slave units, the IF signals are generated by down-converting the respective RF signals, and the RF signals are recovered by up-converting the IF signals. The up-conversion and down-conversion are performed using the same local oscillator (LO) frequency in the master and the slave units. In order to generate the same LO frequency in all units, one local oscillator in the master unit generates the LO frequency, and the generated LO frequency is divided by an integer in the master unit. The divided LO signal is transferred by the cable to the slave units, wherein the divided LO signal is multiplied by the same integer to recover the LO frequency.
Transferring an integer-divided LO frequency throughout the system, for use as a reference, enables recovery of the undivided LO frequency by multiplying by the same integer. Furthermore, the integer-divided LO signal can be distributed with low loss over conventional, inexpensive cable. Thus, one local oscillator supplies the entire system with the same LO frequency, so that problems which might be caused by LO frequency differences within the system are obviated.
In some preferred embodiments of the present invention, the RF signals comprise code division multiple access (CDMA) signals, which include one or more pilot signals associated with cellular channels over which the mobile transceivers are to communicate. The slave units comprise respective transmission delay elements which add a differential time delay to signals transmitted from the master unit to the respective slave units. The differential time delay effectively adds diversity to the signals received by the slave units, so that reception of pilot tone signals transmitted by the master unit is improved. In some preferred embodiments of the present invention, the slave units comprise respective receive delay elements, which add a differential time delay to signals received by the master unit from the respective slave units, so that reception of signals from the slave units is improved.
In some preferred embodiments of the present invention, the local oscillator generating the particular LO frequency is not necessarily a high-stability oscillator, since any variations in the LO frequency are transferred throughout the system.
In some preferred embodiments of the present invention, a plurality of master units communicate with a respective plurality of groupings of one or more slave units, each master and slave grouping operating substantially as described hereinabove. Preferably, the plurality of master units (and their respective slave units) utilize the same LO frequency to generate the IF frequencies used for master-slave communication. Alternatively, each master unit and its respective slave units utilize different LO frequencies. By dividing the slave units among the master units, an overall noise figure of the system is reduced. Most preferably, at least some of the slave units provide signals which are used as diverse receive signals, so that overall reception by the slave units is improved.
In some preferred embodiments of the present invention, the system operates as a channelized repeater system transferring channelized signals between the master and slave units. Most preferably, one or more filters are placed within the one or more slave units or one or more master units for the purpose of filtering out unwanted signals, for example signals outside specific channels which are designated to be transferred between the master and slave units.
There is therefore provided, in accordance with a preferred embodiment of the present invention, repeater apparatus for conveying a radio-frequency (RF) signal into an environment closed-off to the RF signal, including:
a master transceiver unit, including:
a master port which receives the RF signal;
a local oscillator (LO), which generates a LO signal at a LO frequency;
a frequency divider which divides the LO frequency of the LO signal by an integer to produce a divided LO signal; and
a master mixer coupled to the master port and the divider which generates an intermediate-frequency (IF) signal responsive to the RF signal and the LO signal;
one or more slave transceiver units, each unit positioned within the environment closed-off to the RF signal and including:
a frequency recovery circuit, preferably a frequency multiplier, which generates a recovered LO signal at the LO frequency by multiplying the frequency of the divided LO signal by the integer;
a slave mixer coupled to the multiplier which generates a recovered RF signal responsive to the recovered LO signal and the IF signal; and
a slave port coupled to the slave mixer which receives the recovered RF signal therefrom and transmits the recovered RF signal into the closed-off environment; and
one or more cables coupled between the master transceiver unit and the one or more slave transceiver units which convey the IF signal and the divided LO signal between the master transceiver unit and the one or more slave transceiver units.
Preferably, the master port is a two-way port, and each slave port is a two-way port through which the respective slave transceiver unit receives an RF slave signal from the closed-off environment and mixes the RF slave signal with the recovered LO signal to produce a slave IF signal which is conveyed by the one or more cables to the master transceiver unit, wherein a recovered slave RF signal is generated and is conveyed to the master port for transmission therefrom.
Preferably, each slave transceiver unit includes a respective IF signal reverse path wherein the reverse path comprises a delay element which delays the IF signal in the reverse path by a predetermined time.
Preferably, the master transceiver unit includes an antenna which receives the RF signal from a base transceiver station and transfers the received RF signal to the master port.
Preferably, the master port receives the RF signal via a cable coupled to a base transceiver station.
Further preferably, each slave unit includes one or more antennas coupled to the respective slave port which transmit the recovered RF signal into the closed-off environment.
Preferably, the master unit transceiver includes a DC power supply which generates a DC level that is conveyed over the one or more cables to power the one or more slave transceiver units.
Preferably, the master unit transceiver includes a controller which controls the operation of the master transceiver unit and the one or more slave transceiver units.
Further preferably, the repeater apparatus includes a remote control unit which transfers control signals between the controller and an operator of the apparatus.
Further preferably, the controller generates modulated control signals which are conveyed by the one or more cables between the master transceiver unit and the one or more slave transceiver units.
Preferably, the apparatus operates in a cellular communications network at frequencies substantially in the range 800 MHz to 1900 MHz.
Preferably, the IF signal corresponds to one or more predetermined channels of a multiple-access communications network.
Preferably, the one or more slave transceiver units include a plurality of slave transceiver units coupled to the master transceiver unit in one or more daisy-chain topologies.
Further preferably, the one or more slave transceiver units include a plurality of slave transceiver units coupled to the master transceiver unit in one or more star topologies.
Preferably, the one or more slave transceiver units include a plurality of slave transceiver units coupled to the master transceiver unit in one or more hybrid star-daisy-chain topologies.
Preferably, each slave transceiver unit includes a respective IF signal forward path, wherein the forward path includes a delay element which delays the IF signal in the forward path by a predetermined time.
There is further provided, in accordance with a preferred embodiment of the present invention, a method for conveying a radio-frequency (RF) signal into an environment closed-off to the RF signal, including:
receiving the RF signal at a master port;
providing a local oscillator (LO) signal operating at a LO frequency in a vicinity of the master port;
dividing the LO frequency of the LO signal by an integer to produce a divided LO signal;
generating an intermediate frequency (IF) signal responsive to the RF signal and the LO signal;
conveying the IF signal and the divided LO signal to the closed-off environment;
multiplying the frequency of the divided LO signal by the integer to generate a recovered LO signal having the LO frequency;
mixing the recovered LO signal and the IF signal to generate a recovered RF signal;
coupling the recovered RF signal to a slave port; and
transmitting the recovered RF signal into the closed-off environment from the slave port.
Preferably, the method includes:
receiving a slave RF signal from the closed-off environment at the slave port;
mixing the slave RF signal and the LO signal to produce a slave IF signal;
recovering the slave RF signal by mixing the slave IF signal with the LO signal; and
transmitting the slave RF signal from the master port.
Preferably, receiving the RF signal includes receiving a cellular communications transmission at a frequency in the range 800 MHz to 1900 MHz.
Preferably, generating the IF signal includes producing an IF signal having a frequency substantially less than the frequency of the RF signal.
Further preferably, generating the IF signal includes producing an IF signal having a frequency substantially less than the LO frequency.
Further preferably, generating the IF signal includes producing an IF signal to correspond to one or more predetermined channels of a multiple-access communications network.
Preferably, conveying the IF signal to the closed-off environment includes delaying the IF signal by a predetermined time.
Preferably, mixing the slave RF signal and the LO signal to produce a slave IF signal includes delaying the slave IF signal by a predetermined time.
There is further provided, in accordance with a preferred embodiment of the present invention a communications repeater system that includes a plurality of slave units, which receive a main radio frequency (RF) signal and a diversity RF signal transmitted by one or more mobile communication units in a vicinity of the slave units and which generate, responsive to the received RF signals, a respective main intermediate frequency (IF) signal and diversity IF signal, apparatus for converting the IF signals to respective recovered main and recovered diversity radio-frequency (RF) signals, including:
a main master unit, including:
a main IF port which receives the main IF signal;
a local oscillator which generates a local oscillator (LO) signal;
a reference signal generator, coupled to the local oscillator, which generates a reference signal responsive to the LO signal;
a main mixer coupled to the main IF port and the local oscillator which generates the recovered main RF signal responsive to the main IF signal and the LO signal; and
a main RF port coupled to the main mixer which transmits the recovered main RF signal; and
a diversity master unit, including:
a diversity intermediate frequency (IF) port which receives the diversity IF signal;
a receiver which generates a recovered LO signal from the reference signal received from the main master unit;
a diversity mixer coupled to the diversity IF port and the receiver which generates a recovered diversity RF signal responsive to the diversity IF signal and the recovered LO signal; and
a diversity RF port coupled to the diversity mixer which transmits the recovered diversity RF signal.
Preferably, the reference signal generator includes a frequency divider, which divides a frequency of the LO signal by an integer to produce a divided LO signal, and the receiver includes a multiplier which multiplies the divided LO signal by the integer to generate the recovered LO signal.
Preferably, the reference signal includes the LO signal, and the receiver includes a splitter which receives the LO signal and splits the LO signal to generate the recovered LO signal.
Preferably, each slave unit includes a respective IF signal forward path, wherein the forward path includes a delay element which delays the IF signal in the forward path by a predetermined time.
Further preferably, each slave unit includes a respective IF signal reverse path, wherein the reverse path includes a delay element which delays the IF signal in the reverse path by a predetermined time.
Preferably, the plurality of slave units includes:
one or more main slave units coupled to the main IF port which receive the main RF signal and generate the main IF signal responsive to the LO signal and the main RF signal; and
one or more diversity slave units coupled to the diversity RF port which receive the diversity IF signal and generate the diversity IF signal responsive to the LO signal and the diversity RF signal.
Preferably, the one or more main slave units are separated sufficiently in position from the one or more diversity slave units so that the main RF signal received by the one or more main slave units and the diversity RF signal received by the one or more diversity slave units are distinguishable from each other by the one or more main slave units and the one or more diversity slave units.
Preferably, the system includes an antenna coupled to the main RF port and the diversity RF port which radiates the main recovered RF signal and the diversity recovered RF signal.
Further preferably, the system includes a cable coupled to the main RF port and the diversity RF port which conveys the main recovered RF signal and the diversity recovered RF signal to a base transceiver station.
There is further provided, in accordance with a preferred embodiment of the present invention, a communications repeater system that includes a plurality of slave units, which receive a main radio frequency (RF) signal and a diversity RF signal transmitted by one or more mobile communication units in a vicinity of the slave units and which generate, responsive to the received RF signals, a respective main intermediate frequency (IF) signal, and diversity IF signal, a method for converting the main and diversity IF signals to respective recovered main and recovered diversity radio-frequency (RF) signals, including:
receiving the main IF signal generated responsive to the main RF signal in a main IF port;
generating a local oscillator (LO) signal;
mixing the main IF signal and the LO signal to generate a recovered main RF signal;
transmitting the recovered main RF signal from a main RF port;
receiving the diversity IF signal generated responsive to the diversity RF signal at a diversity IF port;
generating a reference responsive to the LO signal;
receiving the reference to generate a recovered LO signal;
mixing the diversity IF signal and the recovered LO signal to generate a recovered diversity RF signal; and
radiating the recovered diversity RF signal from a diversity RF port.
Preferably, generating the reference includes dividing a frequency of the LO signal by an integer to produce a divided LO signal, and receiving the reference includes multiplying the frequency of the divided LO signal by the integer.
There is further provided, in accordance with a preferred embodiment of the present invention, repeater apparatus, including:
first and second master units, which communicate with respective first and second wireless communication networks operating on respective first and second frequency bands;
a combiner, in wired communication with the first and second master units, so as to receive therefrom and convey thereto communication signals that are transmitted over the first and second networks; and
a plurality of slave units, coupled to the combiner, and located at a plurality of different, respective locations within a generally closed environment, so as to communicate with mobile wireless units operating on the first and second frequency bands.
Preferably, the first frequency band includes frequencies substantially in a range 800 MHz to 900 MHz and the second frequency band includes frequencies substantially in a range 1800 MHz to 1900 MHz.
Preferably, the plurality of slave units includes at least one slave unit operating on the first frequency band and at least one slave unit operating on the second frequency band.
Preferably, the repeater apparatus includes one or more antennas coupled at least to the first or the second master unit via which the respective master unit communicates with the respective wireless communication network.
Further preferably, the repeater apparatus includes a cable coupled to at least the first or the second master unit via which the respective master unit communicates with the respective wireless communication network.
Preferably, the first wireless communication network includes a cellular network, and the second wireless communication network includes a Personal Communication Services (PCS) network.
The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings, in which: