Novel small molecular biaryl compounds as inhibitors of endothelin converting enzyme are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, myocardial ischemia, cerebral vasospasm, cerebral ischemia, cerebral infarction, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, stroke, benign prosthatic hyperplasia (BPH), and diabetes.

This application claims the benefit of U.S. Provisional application Ser. No. 60/028,803 filed Oct. 29, 1996.
The present invention relates to novel biaryl inhibitors of endothelin converting enzyme useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention are inhibitors of endothelin converting enzyme useful in treating elevated levels of endothelin and in controlling hypertension, myocardial infarction and ischemia, metabolic, endocrinological, and neurological disorders, congestive heart failure, endotoxic and hemorrhagic shock, septic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute and chronic renal failure, cyclosporin-A induced nephrotoxicity, angina, gastric mucosal damage, ischemic bowel disease, cancer, pulmonary hypertension, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, cerebral ischemia and vasospasm, and diabetes.
Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs). The unique bicyclic structure and corresponding arrangement of the disulfide bridges of ET-1, which are the same for the endothelins, VIC, and the sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure to receptor binding and functional activity. ET-1 analogs with incorrect disulfide pairings exhibit at least 100-fold less vasoconstrictor activity.
Endothelin-1 is generated from a 203 amino acid peptide known as preproendothelin by an unknown dibasic endopeptidase. This enzyme cleaves the prepropeptide to a 38 (human) or 39 (porcine) amino acid peptide known as big endothelin or proendothelin. Big ET is then cleaved by an enzyme, known as endothelin converting enzyme or ECE, to afford the biologically active molecule ET-1. Big ET is only 1% as potent as ET-1 in inducing contractile activity in vascular strips but it is equally potent in vivo at raising blood pressure, presumably by rapid conversion to ET-1 (Kimura S, Kasuya Y, Sawamura T, et al., "Conversion of big endothelin-1 to 21-residue endothelin-1 is essential for expression of full vasoconstrictor activity: Structure-activity relationship of big endothelin-1," J Cardiovasc Pharmacol 1989;13:S5).
Endothelin converting enzyme (ECE) is a metalloprotease that was recently cloned by Yanagisawa, et al., (Cell 1994; (78):473-485). The ECE-1 enzyme has two isoforms which differ only in their N-terminus and their cellular location. In vitro both enzymes display, within experimental error, identicle activities (FEBS Letters 1995; (371) 140-144). The ECE gene has more recently been expressed in human tissues (Biochem Biophys Res Comm 1995; (211):249-253). A review article summarizes the molecular pharmacology of the ECE enzymes (Biochem Pharm 1996; (51):91-102).
Micromolar concentrations of phosphoramidon have been shown to block the pressor response of big ET both in vitro and in vivo (Takada J, supra; Fukuroda T, Noguchi K, Tsuchida S, et al., "Inhibition of biological actions of big endothelin-1 by phosphoramidon," Biochem Biophys Res Commun 1990;172:390; Matsumura Y, Hisaki K, Takaoka M, Morimoto S, "Phosphoramidon, a metalloproteinase inhibitor, suppresses the hypertensive effect of big endothelin-1," Eur J Pharmacol 1990;185:103; McMahon E G, Palomo M A, Moore W M, et al., "Phosphoramidon blocks the pressor activity of porcine big endothelin-1-(1-39) in vivo and conversion of big endothelin-1-(1-39) to endothelin-1-(1-21) in vitro," Proc Natl Acad Sci USA 1991;88:703). It has recently been reported that phosphoramidon is able to inhibit vasoconstrictor effects evoked by intravenous injections of big ET-1 in anaesthetized pigs, but did not have any effect on the plasma ET-1 level (Modin A, Pernow J, Lundberg J M, "Phosphoramidon inhibits the vasoconstrictor effects evoked by big endothelin-1 but not the elevation of plasma endothelin-1 in vivo," Life Sci 1991;49:1619). It should be noted that phosphoramidon is a rather general metalloproteinase inhibitor and clearly the discovery of specific ECE inhibitors such as those described in the present invention is important.
The importance of ECE inhibitors is supported further by more recent reports. Several studies demonstrating the inhibition of ECE by metalloprotease inhibitors like phosphoramidon in vitro have been published (Doherty A. D., Endothelin: A New Challenge. J Med Chem 1992;35:1493; Simonson J. S., Endothelins: Multifunctional Renal Peptides. Physiological Reviews, 1993;73:375; Opgenorth T. J.; Wu-Wong J. R.; Shiosaki K. Endothelin Converting Enzymes, FASEB J 1992;6:2653-2659; Pollock D. M.; Opgenorth T. J. Evidence for metalloprotease involvement in the in vivo effects of big endothelin-1 Am J Physiol 1991;261:257-263). These studies have also been followed up by in vivo studies where the effects of ET in physiological conditions have been blocked by ECE inhibitors. For example, several reports have demonstrated that phosphoramidon (IC.sub.50 =.about.1 .mu.M) inhibits ECE in vitro. These results were supported by in vivo studies where phosphoramidon blocked the vasoconstrictive effects of ET. In ganglion-blocked anesthetized rats the pressor response of big ET-1 was blocked by phosphoramidon in a dose-dependent manner (McMahon E. G.; Palomo M. A.; Moore W. M. Phosphoramidon blocks the pressor activity of big endothelin (1-39) and lowers blood pressure in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1991;17(Suppl. 17):S29-S33; McMahon E. G.; Palomo M. A.; Moore W. M.; McDonald J. F.; Stern M. K. Phosphoramidon blocks the pressor activity of porcine big endothelin-1-(1-39) in vivo and conversion of big endothelin-1-(1-39) to endothelin-1-(1-21) in vitro Proc Natl Acad Sci (USA) 1991;88:703-707). Phosphoramidon was also shown to inhibit the effects of big ET-1 in the microvasculature of anesthetized hamsters and has also been used to suppress the lethality induced by the intravenous infusion of big ET-1 (Lawerence E.; Brain S. D. Big endothelin-1 and big endothelin-3 are constrictor agents in the microvasculature: evidence for the local phosphoramidon-sensitive conversion of big endothelin-1. Eur J Pharmacol 1993;233:243-250). In all cases it was shown that phosphoramidon inhibited the effects of big ET-1 and not ET-1 indicating that it was not behaving as a receptor antagonist. Intracisternal administration of big ET-1 in anesthetized dogs decreased the caliber of the basilar artery on the angiogram and systemic arterial pressure was also elevated. These effects were blocked by phosphoramidon (Shinyama H; Uchida T; Kido H; Hayashi K; Watanabe M; Matsumura Y; Ikegawa R; Takaoka M; Morimoto S. Phosphoramidon inhibits the conversion of intracisternally administered big endothelin-1 to endothelin-1. Biochem Biophys Res Commun 1991;178:24-30). Similar enzyme inhibitory activity has been reported in the studies involving phosphoramidon sensitive inhibition of hemodynamic actions of big ET-1 in rat brain (Hashim M. A.; Tadepalli. Functional evidence for the presence of a phosphoramidon-sensitive enzyme in rat brain that converts big endothelin-1 to endothelin-1. Life Sci 1991;49:207-211).
The blockade of ECE with phosphoramidon has further been shown to reduce elevated pulmonary vascular resistance after cardiopulmonary bypass in young piglets, a model for pulmonary hypertension (Surgery, 1995;118:440-445).
A peptide derivative containing a D-Val residue, D-Val.sup.22 !Big ET-1{16-38}, has been reported that inhibits ECE (FEBS Lett 1994;353:84-88). This analog was shown to inhibit the ET-1 induced release of dopamine from the stratum of rats. A dose of 0.33 pmol caused a 50% reduction of response.
A series of amino acid derivatives containing a phosphonic acid group have been reported as ECE and neutral endopeptidase (NEP) inhibitors (Biochem Biophys Res Comm 1994;204:407-412). One of these analogs, CGS 26303, was shown to be effective at lowering the antihypertensive responses in the SHR after an IV infusion.
A series of phosphinic acid derivatives have been reported as inhibitors of ECE (Bioorgan Med Chem Lett 1996;6:1257-1260). These analogs were shown to be selective for ECE over the closely related enzyme NEP.
Endothelin is involved in many human disease states.
Several in vivo studies with ET antibodies have been reported in disease models. Left coronary artery ligation and reperfusion to induce myocardial infarction in the rat heart, caused a four- to seven-fold increase in endogenous endothelin levels. Administration of ET antibody was reported to reduce the size of the infarction in a dose-dependent manner (Watanabe T, et al., "Endothelin in Myocardial Infarction," Nature (Lond.) 1990;344:114). Thus, ET may be involved in the pathogenesis of congestive heart failure and myocardial ischemia (Margulies K B, et al., "Increased Endothelin in Experimental Heart Failure," Circulation 1990;82:2226).
Studies by Kon and colleagues using anti-ET antibodies in an ischemic kidney model, to deactivate endogenous ET, indicated the peptide's involvement in acute renal ischemic injury (Kon V, et al., "Glomerular Actions of Endothelin In vivo," J Clin Invest 1989;83:1762). In isolated kidneys, preexposed to specific antiendothelin antibody and then challenged with cyclosporine, the renal perfusate flow and glomerular filtration rate increased, while renal resistance decreased as compared with isolated kidneys pre-exposed to a nonimmunized rabbit serum. The effectiveness and specificity of the anti-ET antibody were confirmed by its capacity to prevent renal deterioration caused by a single bolus dose (150 pmol) of synthetic ET, but not by infusion of angiotensin II, norepinephrine, or the thromboxane A.sub.2 mimetic U-46619 in isolated kidneys (Perico N, et al., "Endothelin Mediates the Renal Vasoconstriction Induced by Cyclosporine in the Rat," J Am Soc Nephrol 1990;1:76).
Others have reported inhibition of ET-1 or ET-2-induced vasoconstriction in rat isolated thoracic aorta using a monoclonal antibody to ET-1 (Koshi T, et al., "Inhibition of Endothelin (ET)-1 and ET-2-Induced Vasoconstriction by Anti-ET-1 Monoclonal Antibody," Chem Pharm Bull 1991;39:1295).
Combined administration of ET-1 and ET-1 antibody to rabbits showed significant inhibition of the blood pressure and renal blood flow responses (Miyamori I, et al., Systemic and Regional Effects of Endothelin in Rabbits: Effects of Endothelin Antibody," Clin Exp Pharmacol Physiol 1990;17:691).
Other investigators have reported that infusion of ET-specific antibodies into spontaneously hypertensive rats (SHR) decreased mean arterial pressure (MAP), and increased glomerular filtration rate and renal blood flow. In the control study with normotensive Wistar-Kyoto rats (WKY), there were no significant changes in these parameters (Ohno A, "Effects of Endothelin-Specific Antibodies and Endothelin in Spontaneously Hypertensive Rats," J Tokyo Women's Med Coll 1991;61:951).
Burnett and co-workers recently demonstrated that exogenous infusion of ET (2.5 ng/kg/mL) to anesthetized dogs, producing a doubling of the circulating concentration, did have biological actions (Lerman A, et al., "Endothelin Has Biological Actions at Pathophysiological Concentrations," Circulation 25 1991;83:1808). Thus heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis. These studies support a role for endothelin in the regulation of cardiovascular, renal, and endocrine function.
In the anesthetized dog with congestive heart failure, a significant two- to three-fold elevation of circulating ET levels has been reported (Cavero PG, et al., "Endothelin in Experimental Congestive Heart Failure in the Anesthetized Dog," Am J Physiol 1990;259:F312), and studies in humans have shown similar increases (Rodeheffer R J, et al., "Circulating Plasma Endothelin Correlates With the Severity of Congestive Heart Failure in Humans," Am J Hypertension 1991;4:9A). When ET was chronically infused into male rats, to determine whether a long-term increase in circulating ET levels would cause a sustained elevation in mean arterial blood pressure, significant, sustained, and dose-dependent increases in mean arterial blood pressure were observed. Similar results were observed with ET-3 although larger doses were required (Mortenson L H, et al., "Chronic Hypertension Produced by Infusion of Endothelin in Rats," Hypertension 1990;15:729). Recently the nonpeptide endothelin antagonist RO 46-2005 has been reported to be effective in models of acute renal ischemia and subarachnoid hemorrhage in rats (3rd International Conference on Endothelin, Houston, Tex., February 1993). In addition, the ET.sub.A antagonist BQ-153 has also been shown to prevent early cerebral vasospasm following subarachnoid hemorrhage after intracisternal injection (Clozel M., et al., Life Sciences 1993;52:825); to prevent blood pressure increases in stroke-prone spontaneously hypertensive rats (Nishikibe M, et al., Life Sciences 1993;52:717); and to attenuate the renal vascular effects of ET-1 in anaesthetized pigs (Cirino M, et al., J Pharm Pharmacol 1992;44:782).
Plasma endothelin-1 levels were dramatically increased in a patient with malignant hemangio-endothelioma (Nakagawa K, et al., Nippon Hifuka Gakkai Zasshi 1990;100:1453).
The ET receptor antagonist BQ-123 has been shown to block ET-1-induced bronchoconstriction and tracheal smooth muscle contraction in allergic sheep providing evidence for expected efficacy in bronchopulmonary diseases such as asthma (Noguchi, et al., Am Rev Respir Dis 1992;145(4 Part 2):A858).
Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations indicate a role for ET in renal constriction in preeclampsia (Clark B A, et al., Am J Obstet Gynecol 1992;166:962).
Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlate with the degree of illness and depression of cardiac output (Pittett J, et al., Ann Surg 1991;213(3):261).
In addition, the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic shock. This ET.sub.A antagonist significantly increased the survival rate in this model (Toshiaki M, et al., 20.12.90. EP 0 436 189 A1).
Endothelin is a potent agonist in the liver eliciting both sustained vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output (Gandhi C B, et al., J Biol Chem 1990;265(29):17432). In streptozotocin-diabetic rats, there is an increased sensitivity to endothelin-1 (Tammesild P J, et al., Clin Exp Pharmacol Physiol 1992;19(4):261). In addition, increased levels of plasma ET-1 have been observed in microalbuminuric insulin-dependent diabetes mellitus patients indicating a role for ET in endocrine disorders such as diabetes (Collier A, et al., Diabetes Care 1992;15(8):1038).
ET.sub.A antagonist receptor blockade has been found to produce an antihypertensive effect in normal to low renin models of hypertension with a time course similar to the inhibition of ET-1 pressor responses (Basil M K, et al., J Hypertension 1992;10(Suppl 4):S49). The endothelins have been shown to be arrhythmogenic, and to have positive chronotropic and inotropic effects, thus ET receptor blockade would be expected to be useful in arrhythmia and other cardiovascular disorders (Han S-P, et al., Life Sci 1990;46:767).
The widespread localization of the endothelins and their receptors in the central nervous system and cerebrovascular circulation has been described (Nikolov R K, et al., Drugs of Today 1992;28(5):303). Intracerebroventricular administration of ET-1 in rats has been shown to evoke behavioral effects. These factors strongly suggest a role for the ETs in neurological disorders. The potent vasoconstrictor action of ETs on isolated cerebral arterioles suggests the importance of these peptides in the regulation of cerebrovascular tone. Increased ET levels have been reported in some CNS disorders, i.e., in the CSF of patients with subarachnoid hemorrhage and in the plasma of women with preeclampsia. Stimulation with ET-3 under conditions of hypoglycemia have been shown to accelerate the development of striatal damage as a result of an influx of extracellular calcium. Circulating or locally produced ET has been suggested to contribute to regulation of brain fluid balance through effects on the choroid plexus and CSF production. ET-1-induced lesion development in a new model of local ischemia in the brain has been described.
Circulating and tissue endothelin immunoreactivity is increased more than twofold in patients with advanced atherosclerosis (Lerman A., et al., New England J Med 1991;325:997). Increased endothelin immunoreactivity has also been associated with Buerger's disease (Kanno K, et al., J Amer Med Assoc 1990;264 2868) and Raynaud's phenomenon (Zamora M R, et al., Lancet 1990;336:1144). Likewise, increased endothelin concentrations were observed in hyper-cholesterolemic rats (Horio T, et al., Atherosclerosis 1991;89:239).
An increase of circulating endothelin levels was observed in patients that underwent percutaneous transluminal coronary angioplasty (PTCA) (Tahara A, et al., Metab Clin Exp 1991;40:1235; Sanjay K, et al., Circulation 1991;84(Suppl. 4):726).
Increased plasma levels of endothelin have been measured in rats (Stelzner T J, et al., Am J Physiol 1992;262:L614) and humans (Miyauchi T, et al., Jpn J Pharmacol 1992;58:279P; Stewart D J, et al., Ann Internal Medicine 1991;114:464) with pulmonary hypertension.
Elevated levels of endothelin have also been measured in patients suffering form ischemic heart disease (Yasuda M, et al., Amer Heart J 1990;119:801; Ray S G, et al., Br Heart J 1992;67:383) and either stable or unstable angina (Stewart J T, et al., Br Heart J 1991;66:7).
Infusion of an endothelin antibody 1 hour prior to and 1 hour after a 60-minute period of renal ischemia resulting in changes in renal function versus control. In addition, an increase in glomerular platelet-activating factor was attributed to endothelin (Lopez-Farre A, et al., J Physiology 1991;444:513). In patients with chronic renal failure as well as in patients on regular hemodialysis treatment mean plasma endothelin levels were significantly increased (Stockenhuber F, et al., Clin Sci (Lond.) 1992;82:255). In addition, it has been suggested that the proliferative effect of endothelin on mesangial cells may be a contributing factor in chronic renal failure (Schultz P J, J Lab Clin Med 1992;119:448).
Also, Haleen, S., et al., FASEB J April 1994, demonstrated efficacy of an ET.sub.A /ET.sub.B antagonist, PD 145065, which essentially also blocks all ET function (similar to an ECE inhibitor) in a severe model of acute renal failure.
The effects of endothelin receptor blockade on ischemia-induced acute renal failure and mortality were assessed in rats undergoing unilateral nephrectomy and global ischemia in the remaining kidney. Sprague Dawley male rats (300-400 g) were housed in metabolic cages for 2 days before and 7 days after renal injury; urine output and plasma creatinine levels were monitored daily. On the day of renal injury, rats were anesthetized with sodium pentobarbital (50 mg/kg, IP), heparinized (50 units, IV), and instrumented with a tail vein canulae for drug or vehicle infusion. Both kidneys were exposed via a flank incision and the right kidney was removed. The left renal artery was clamped for 60 minutes and released. PD 145065 was infused 60 minutes prior to and following the ischemic period. Renal injury was evident 1 and 2 days following ischemia from a tenfold increase in plasma creatinine levels and significant decreases in urine output. Mortality occurred primarily between the second and third days postinjury. However, mortality was significantly less (52%, N=23) in rats treated with PD 145065 compared to vehicle rats (83%, N=23). In addition, urine output on the second day following renal injury was significantly different between treatment groups on either the first or second days postinjury. Thus blockade of endothelin receptors with PD 145065 significantly decreases mortality in rats subjected to ischemia-induced renal failure.
Local intra-arterial administration of endothelin has been shown to induce small intestinal mucosal damage in rats in a dose-dependent manner (Mirua S, et al., Digestion 1991;48:163). Administration of endothelin-1 in the range of 50 to 500 pmol/kg into the left gastric artery increased the tissue type plasminogen activator release and platelet activating formation and induced gastric mucosal hemorrhagic change in a dose-dependent manner (Kurose I, et al., Gut 1992;33:868). Furthermore, it has been shown that an anti-ET-1 antibody reduced ethanol-induced vasoconstriction in a concentration-dependent manner (Masuda E, et al., Am J Physiol 1992;262:G785). Elevated endothelin levels have been observed in patients suffering from Crohn's disease and ulcerative colitis (Murch S R, et al., Lancet 1992;339:381).
Additionally, there is a correlation between the inhibition of ECE in an in vitro assay, as used and described for the quinazolines of the present invention, and demonstration of in vivo activity in various pathophysiological conditions. For example, Grover G. J., et al., J Pharmacol Exp Ther 1992;263:1074-1082, tested the effect of phosphoramidon, an ECE inhibitor, in a rat model of ischemia. Thus, Grover G. J., et al. determined the effect of endothelin-1 (ET-1) and big ET-1 on coronary flow and contractile function in isolated nonischemic and ischemic rat hearts. Both ET-1 (IC.sub.50 =12 pMol) and big ET-1 (IC.sub.50 =2 nMol) reduced coronary flow in a concentration-dependent manner. Both 30 pMol ET-1 and 10 nMol big ET-1 pretreatment significantly reduced the time to contracture in globally ischemic rat hearts,suggesting a preischemic effect. Phosphoramidon (IC.sub.50 =100 .mu.M) and BQ-123 (0.3 .mu.M, ET.sub.A receptor antagonist) abolished the preischemic increase in coronary perfusion pressure induced by big ET-1 as well as its preischemic effect. Phosphoramidon was also given IV to rats subjected to coronary occlusion and reperfusion and was found to significantly reduce infarct size 24 hour postischemia. Phosphoramidon has been disclosed to be an effective inhibitor of ECE, IC.sub.50 =1 .mu.M, (European Published Patent Application EP 0518299 A2 and International Published Patent Application WO 92/13944).
Two natural product isolates, WS75624A and WS75624B, have been identified and published J Antibiotics 1995;48(10):1066 and J Antibiotics 1995;48(10):1073. ##STR1##
These derivatives as well as two additional natural product isolates of undetermined structure, have been disclosed as inhibitors of endothelin converting enzyme, GB 2272435A.

Small molecule biaryl compounds as inhibitors of endothelin converting enzyme


A heat exchange apparatus is provided with an indirect evaporative heat exchange section. The indirect evaporative heat exchange section includes a series of serpentine tubes, and an evaporative liquid is passed downwardly onto the indirect heat exchange section. The evaporative liquid is collected in a sump and then pumped upwardly to be distributed again across the indirect heat exchange section. An improved heat exchange apparatus is provided with a top and a bottom indirect evaporative heat exchange section including a series of serpentine tubes A secondary system to distribute evaporative liquid below the first indirect heat exchange section and a direct heat exchange section may be provided between the two indirect heat exchangers.

The present invention relates generally to an improved heat exchange apparatus such as a dosed circuit fluid cooler, fluid heater, condenser, evaporator, thermal storage system, air cooler or air heater. More specifically, the present invention relates to a combination or combinations of separate indirect and direct evaporative heat exchange sections or components arranged to achieve improved capacity and performance.
The invention includes the use of a coil type heat exchanger as an indirect heat exchange section. Such indirect heat exchange section can be combined with a direct heat exchange section, which usually is comprised of a fill section over which an evaporative liquid such as water is transferred, usually in a downwardly flowing operation. Such combined indirect heat exchange section and direct heat exchange section together provide improved performance as an overall heat exchange apparatus such as a closed circuit fluid cooler, fluid heater, condenser, evaporator, air cooler or air heater.
Part of the improved performance of the indirect heat exchange section comprising a coil type heat exchanger is the capability of the indirect heat exchange section to provide both sensible and latent heat exchange with the evaporative liquid which is streamed or otherwise transported downwardly over and through the indirect heat exchange section. Such indirect heat exchangers are usually comprised of a series of serpentine tube runs with each tube run providing a circuit of a coil. Improved performance of such indirect heat exchangers is achieved by opening the spacing between the generally horizontal tube runs in one or more of the serpentine coil return bends. Such opened spacing in the serpentine coil return bends creates a more efficient cooling zone for the evaporative liquid flowing downwardly over the serpentine coils.
Various combinations of the heat exchange arrangements are possible in accordance with the present invention. Such arrangements could include an arrangement having an indirect heat exchange section with increased vertical spacing in the series of serpentine tube runs formed by increased height return bends. In such an arrangement, an evaporative liquid flows downwardly onto and through the indirect heat exchange section with such evaporative liquid, which is usually water, then exiting the indirect section to be collected in a sump and then pumped upwardly to again be distributed downwardly over the indirect heat exchange section. In this counterflow arrangement, embodiments work more efficiently with generally lower spray flow rates, in the order of 2-4 GPM/sq. ft. In other arrangements presented, the design spray flow rates may be higher.
In another arrangement, a combined heat exchange apparatus is provided with an indirect heat exchange section comprised of serpentine tube runs over which and evaporative liquid is distributed downwardly onto and through the indirect heat exchange section. Such indirect heat exchange section is comprised of serpentine tube runs having an increased spacing between one or more return bends of increased height. Further, a direct heat exchange section comprised of fill can be located in one or more of the areas of increased vertical spacing formed by the return bends of the serpentine coil. In this arrangement, the embodiments work more efficiently with generally lower spray flow rates, in the order of 2-4 GPM/sq. ft. So not only are the embodiments presented within more efficient providing increased heat rejection but they also do it with less energy requirement for the spray water pump. In other arrangements presented, the design spray flow rates may be higher.
Further, it is also part of the present invention to provide a second, intermediate spray water distribution arrangement whereby the evaporative liquid is distributed downwardly over the indirect and, if present, the direct heat exchange sections, at a point below the top of the indirect heat exchange section For this arrangement, there are several different modes of operation which further improve the heat transfer capabilities and customer benefits. In one mode of operation, both the top and intermediate spray sections are active and spray water onto the indirect and direct sections is present. In another mode of operation, the intermediate spray section is not active and the top spray arrangement provides the evaporative liquid to the entire assembly. In yet another mode of operation, the top spray section is not active and the intermediate spray section is active which can provide evaporative cooling for the lower coil section while providing dry sensible cooling for the dry upper coil section. In yet another mode of operation, the top spray section is not active, the intermediate spray section is active, there is selectively no heat transfer from the lower coil section beneath the intermediate spray section allowing the upwardly flowing air to become adiabatically saturated through the direct section if present before transferring sensible heat with the top portion of the coil above the intermediate spray section. This last mode of operation further reduces the amount of water use while providing lower temperature air to provide sensible cooling to the top portion of the coil above the intermediate spray arrangement.
The heat exchanger apparatus or fluid cooler of the present invention could be operated wherein both air and an evaporative liquid such as water are drawn or supplied across both the indirect and direct heat exchange section if present. It may be desirable to operate the heat exchanger without a supply of the evaporative liquid, wherein air only would be drawn across the indirect heat exchange section and across a direct section if present. It is also possible to operate a combined heat exchanger in accordance with the present invention wherein only evaporative liquid would be supplied across or downwardly through the indirect heat exchange section and the direct heat exchange section if present, and wherein air would not be drawn by typical means such as a fan.
In the operation of an indirect heat exchange section, a fluid stream passing through the serpentine coils is cooled, heated, condensed, or evaporated in either or both a sensible heat exchange operation and a latent heat exchange operation by passing an evaporative liquid such as water together with air over the serpentine coils of the indirect heat exchange section. Such combined heat exchange results in a more efficient operation of the indirect heat exchange section, as does the presence of the increased spacing formed in one or more of the return bends of the serpentine tube runs of the indirect heat exchange section. Further efficiency in operation can also be achieved by the provision of a second or intermediate spray distribution system for providing evaporative liquid to flow downwardly onto and through the serpentine coils of the indirect heat exchange section. The evaporative liquid, which again is usually water, which passes generally downwardly through the indirect heat exchange section and generally downwardly through the direct heat exchange section which is typically a fill assembly, if such a direct heat exchange section is provided in the increased vertical spacing in one or more of the increased height return bends of the serpentine coils of the indirect heat exchange section. Heat in the evaporative liquid is passed to air which is drawn generally passing downwardly or upwardly through the indirect heat exchange section and outwardly from the closed circuit fluid cooler or heat exchanger assembly by an air moving system such as a fan. The evaporative liquid draining from the indirect or direct heat exchange section is typically collected in a sump and then pumped upwardly for redistribution across the indirect or direct evaporative heat exchange section.
The type of fan system whether induced or forced draft, belt drive, gear drive or direct drive can be used with all embodiments presented. The type of fan whether axial, centrifugal or other can be used with all embodiments presented. The type of tubes, material of tubes, tube diameters, tube shape, whether finned or un-finned, the number of tube passes, number of return bends, number of increased vertical spaces, can be used with all embodiments presented. Further, the coil may consist of tubes or may be a plate fin type or may be any type of plates in any material which can be used with all embodiments presented within. The type of fill, whether efficient counterflow fill, contaminated water application fills or any material fill can be used with all embodiments presented.
Accordingly, it is an object of the present invention to provide an improved heat exchange apparatus, which could be a closed circuit fluid cooler, fluid heater, condenser, evaporator, air cooler or air heater, which includes an indirect heat exchange section with increased spacing formed in one or more return bends of the serpentine tube forming the indirect heat exchange section.
It is another object of the present invention to provide an improved heat exchange apparatus such as a closed circuit fluid cooler, fluid heater, condenser, evaporator, air cooler or air heater, including an indirect heat exchange section that comprises a series of serpentine tube runs with increased vertical spacing between one or more of the tube runs and with a direct heat exchange located in one or more of the areas of increased vertical spacing.
It is another object of the invention to provide an improved heat exchange apparatus comprising an indirect heat exchange section comprised of serpentine coils with both a primary evaporative liquid distribution system at or near the top of the serpentine coils and a secondary evaporative liquid distribution system located below the top of the serpentine coils. Further the primary and secondary evaporative liquid distribution systems may be selectively operated such that water may be preserved.
It is another object of the present invention to provide an improved evaporative heat exchange apparatus such as a closed circuit fluid cooler, fluid heater, condenser, evaporator, air cooler or air heater, including at least two indirect heat exchange sections that comprise a series of serpentine tube runs with increased vertical spacing between one or more tube runs and with a direct heat exchange located in one or more of the areas of increased vertical spacing between tube runs.
It is another object of the present invention to provide an improved evaporative heat exchange apparatus such as a closed circuit fluid cooler, fluid heater, condenser, evaporator, air cooler or air heater, including at least two indirect heat exchange sections separated by an increased vertical spacing with an optional direct heat exchange located in the increased vertical space between indirect heat exchange sections.
It is another object of the present invention to provide an improved evaporative heat exchange apparatus such as a closed circuit fluid cooler, fluid heater, condenser, evaporator, air cooler or air heater, where direct heat exchange sections located in one or more of the areas of increased vertical spacing between tube runs or alternatively located between increased vertical space between indirect heat exchange sections are easily accessible and replaceable for serviceability.

Cooling tower with indirect heat exchanger


To provide a wheel support bearing assembly designed to avoid an ingress of foreign matter from an area, where a sensor is fitted, into the inside of the bearing assembly. The wheel support bearing assembly includes an outer member (1) adapted to be secured to a vehicle body structure, an inner member (2) adapted to support a vehicle wheel, and circular rows of rolling elements (3) interposed between the outer and inner members (1,2). A sensor cap (13) is provided for closing an inboard end of the outer member (1) and has an insert nut (15) embedded therein. The sensor cap (13) is also provided with a reduced diameter hole (23), in which an elastic sealing member (25) is interposed under interference fit between it and a deep end face of the insert nut (15).

1. Field of the Invention
The present invention generally relates to a rolling bearing assembly for rotatably supporting a vehicle wheel and, more particularly, to the wheel support bearing assembly incorporating a rotation sensor mounted on a sensor cap closing one open end of the bearing, for detecting the number of revolutions of the vehicle wheel.
2. Description of the Prior Art
Some of the vehicle wheel bearing assemblies are known, in which a rotation detecting device for detecting the number of revolutions of vehicle wheels is incorporated for the purpose of performing various controls, for example, for controlling an automobile anti-skid control system, also known as an anti-lock brake system (ABS), and a traction control system (TCS). This rotation detecting device includes a pulsar ring fitted to a rotatable member of the bearing assembly for rotation together therewith and a sensor fitted to a stationary member of the same bearing assembly. In the case of a vehicle driven wheel having the sensor incorporated on an inboard side, the sensor is generally installed in a sensor cap used to close one of opposite open ends of an annular bearing space delimited between the rotatable and stationary members. See, for example, the Japanese Laid-open Utility Model Publication No. 7-31539, the Japanese Laid-open Patent Publication No. 9-61443 and the Japanese Patent No. 3440800.
The wheel support bearing assembly, in which the sensor is installed in the sensor cap, is illustrated in FIGS. 3 and 4. The wheel support bearing assembly shown therein is of a structure designed to rotatably support a vehicle driven wheel and includes an outer member 31 rigid with a vehicle body structure, and an inner member 32 having a vehicle wheel secured thereto for rotation together therewith, and a plurality of, for example, two, rows of rolling elements 3 accommodated within an annular bearing space delimited between the inner and outer members 31 and 32 and spaced a distance axially from each other. The inner member 32 is made up of an hub axle and an inner race forming segment 35 fixedly mounted on an inboard end of the hub axle as shown in FIG. 3. A pulsar ring 39 is secured to the inner race forming segment 35 and, on the other hand, a sensor cap 43 made of a synthetic resin is secured to the outer member 31 so as to close an inboard open end of the annular bearing space between the outer and inner members 31 and 32.
The sensor cap 43 is provided with the sensor 40 therewith and arranged so as to confront the pulsar ring 39 in a direction axially of the bearing assembly, and the sensor 40 cooperates with the pulsar ring 39 to define a rotation sensor unit 38. A portion of FIG. 3 indicated by the phantom circle IV is shown on an enlarged scale in FIG. 4. As shown therein, the sensor 40 is fitted to a sensor support member 49 and is fixedly inserted into a sensor insertion hole 46 defined in the sensor cap 43 with the sensor support member 49 arranged on an outer surface of the sensor cap 43. When the sensor support member 49 is firmly fastened to the sensor cap 43 by means of at least one sensor fastening bolt 52, the sensor 40 can be firmly locked to the sensor cap 43. This fastening of the sensor support member 49 with the sensor fastening bolt 52 is carried out by threading the sensor fastening bolt 52 into an insert nut 45 embedded in the sensor cap 43.
It has, however, been found that the foregoing construction has the following problem associated with an undesirable ingress of foreign matter into the bearing assembly. Specifically, foreign matter such as, for example, muddy water may ingress through slight gaps between the internal threads of the insert nut 45 and the sensor fastening bolt 52 and surfaces of contact between the sensor fastening bolt 52, the sensor support member 49 and the sensor cap 43 and then into the interior of the bearing assembly, and particularly the annular bearing space, through an axial bottom hole 42 defined in the sensor cap 43. The foreign matter such as, for example, muddy water may also ingress through surfaces of contact between the insert nut 45 and a portion of the sensor cap 43 made of the synthetic resin. Once such ingress of the foreign matter into the interior of the bearing assembly occurs, not only will the lifetime of the bearing assembly be lowered, but also the pulsar ring may possibly be deteriorated.


A gas cylinder actuator with a safety device for controlled ejection of the piston stem, which has, on the side of the region for fixing the head portion to the jacket, a region in low relief on the inner face of the jacket, designed to interrupt the seal provided selectively either by the gasket elements associated with the piston or by the gasket elements associated with the head portion, and normally operating against the inner face of the jacket, in case of separation of the head portion with an outward movement of the piston.

Gas cylinder actuators in general are formed by a tubular jacket for gas containment that is sealed hermetically at one end by a bottom provided with a gas filling valve, and at the opposite end by a head portion, which is provided with a hole for the passage of a stem with a piston, which performs a translational motion inside the jacket; the jacket, the bottom and the head portion form the stroke chamber for the piston, while the piston itself, with the jacket and the bottom, forms the gas compression and expansion chamber.
Such gas cylinder actuators are used typically, but not exclusively, also in situations, such as molds, molding presses and the like, in which they can be subjected to such operational conditions that they might be damaged; such damage can render the gas cylinder actuator itself unusable, with the need to replace it and interrupt the work of the machine or plant in which it is arranged to work, but it can also injure an operator who is in the vicinity, as in the case of an explosion caused by overpressure, or in the case of ejection of the stem due to breaking of the piston, caused by an unexpected and uncontrolled rising thrust caused by the pressurized gas.
Experience shows that the most critical condition is observed in the case in which a mold, on which a gas cylinder actuator operates, jams with the actuators in the compression configuration, and then the same mold is suddenly released, causing an unexpected return thrust of the piston stem, such as to break, as a consequence of an impact, either the head portion that retains the piston stem in the jacket or the piston stem.
In both cases, there is the great risk that the stem might be ejected with force, with great danger to any personnel that may be in the vicinity.
In order to obviate this drawback various means and devices for avoiding the uncontrolled ejection of the stem are currently known.
A first type of such devices is provided with an auxiliary safety shoulder, formed on the stem proximately to the piston, so that if there is a fracture between the piston and the stem in the junction region, the stem is retained inside the jacket thanks to the abutment of its auxiliary shoulder against a corresponding extraction-preventing shoulder provided on the head portion of the gas cylinder actuator.
In a second type of safety device for preventing the ejection of the stem, a predetermined part of the piston or of the stem is separated as a consequence of an impact of predefined strength, and this part damages the sealing gasket of the piston or of the stem, allowing the external discharge of the pressurized gas and preventing the violent and uncontrolled ejection of the stem.
Both of these types work to retain the stem inside the jacket.
Events could occur, however, for which the predefined breakages in the types mentioned above are not sufficient to ensure a discharge of the pressurized gas that is fast enough to prevent the gas cylinder actuator from yielding in other points in addition to the ones provided, or to prevent the piston stem from being ejected.

Gas cylinder actuator with safety system for controlled ejection of the piston stem


A fastening arrangement for attaching a handgrip knob assembly to a vehicle gearshift lever rod. The knob has a through cavity comprising an upper cavity portion, an intermediate cavity portion supporting a metal insert, and a lower upwardly tapered cavity portion. The insert upper surface defining a bottom wall clamping surface of the upper cavity portion bottom wall. An internally threaded insert through bore is divided from a lower counterbored portion by an internal stop shoulder. The shift lever rod has an upper threaded stem connected by a cylindrical shank portion to an upwardly tapered rod section while the stem portion terminates in a frustoconical pilot end. A rod external stop shoulder divides the stem and shank sections. A spring steel drive washer, having a central aperture intermeshed with an upper crown portion of a locknut, is initially press-fitted in the upper cavity until its outer edge frictionally engages a serrated portion of the upper cavity. Assembly begins with the installer releasing the knob assembly above the rod stem such that the knob's lead-in cavity slidably receives the rod stem in a gravity induced torque ready manner. Initial torquing of the locknut results in self-threading of the stem through the insert and into the locknut bore causing the stop shoulders to clamp in a first anti-rotational lock. Continued torquing releases the frictionally retained drive washer from the serrated portion thereby clamping the locknut undersurface against the cavity bottom wall providing a second anti-rotational lock.

This invention relates generally to vehicle transmission gearshift levers and more particularly to an improved gearshift lever handgrip knob attaching arrangement.
An example of one form of prior art gearshift knob is shown in U.S. Pat. No. 4,991,461 issued Feb. 12, 1991 to Sennett et al. comprises a cap, a gripping section having an axial bore through it and gear teeth about one end of the bore, and an annular anti-rotation member having an axial bore therethrough and gear teeth about each end of the bore. When assembled, a stem of the cap passes through the axial bores of the gripping section and of the anti-rotation member. The gear teeth of the gripping section mesh with the gear teeth of the anti-rotation member and prevent the member from rotating with respect to the gripping section. A base has an axial bore through it and gear teeth about one end of the bore. The bore has inwardly projecting ribs between which, when the knob is assembled, a spline of the stem of the cap fits at substantially all rotational portions of the spline relative to the base. The gear teeth of the anti-rotation member mesh with the gear teeth of the base and prevent the anti-rotation member from rotating with respect to the base.
The U.S. Pat. No. 4,991,535 issued Feb. 12, 1991 to Kobayashi et al. entitled Shift lever Unit For Automotive Automatic Transmission discloses an arrangement for mounting a control knob on top of a shift lever. The knob has a bore formed therethrough, which bore includes a smaller diameter elongate lower part, a middle diameter intermediate part, and a larger diameter upper part wherein a metal core tightly received in the lower part. The metal core has a longitudinally extending bore which includes a smaller diameter upper part and a larger diameter lower part. The shift lever has a hollow bolt at its upper end while a nut is screwed about the bolt to tightly connect the knob to the shift lever.


A miniature stacked glass lens module is disclosed. The miniature stacked glass lens module includes at least one stacked optical glass lens element, a lens holder and other optical element. The stacked optical glass lens element is formed by cutting along alignment notches on a glued and stacked optical glass lens array. Then the stacked optical glass lens element and other optical element are mounted into the lens holder to form a miniature stacked glass lens module. Thereby the precise alignment of the optical axis of the lens in the lens module can be achieved. The manufacturing processes of the lens module can be simplified dramatically and the manufacturing cost is reduced significantly.

The present invention relates to a miniature stacked glass lens module, especially to a stacked glass lens module applied to small-size optical lenses of cameras of mobile phones, notebooks, personal digital assistant (PDA) and etc. The stacked optical glass lens is produced by cutting alignment notches of stacked and glued optical glass lens array.
Glass precision molding technology has been widely applied to manufacture aspherical molded glass lens with high resolution, good stability and low cost such as lens revealed in US2006/0107695, US2007/0043463, TW095101830, TW095133807, and JP63-295448 etc. A glass preform (or glass material) is set into a mold having an upper mold and a lower mold to be heated and softening. Then the upper mold and the lower mold are clamped correspondingly and apply pressure on the upper mold and the lower mold so as to make the soft glass perform have the same optical surfaces as that of the upper mold and the lower mold. After cooling, a molded glass lens with molding surfaces of the upper mold and the lower mold is produced. In order to reduce manufacturing cost, prior arts JP63-304201 and US2005/041215 provided a lens array formed by glass molding. As to a single lens-called a lens element hereunder, JP02-044033 revealed that a lens blank having a plurality of lenses is manufactured by movement of glass materials and multiple molding procedures. Then the lens array is cut into a plurality of lens elements.
The optical lens formed by glass molding is widely applied to assembled lenses of LED light sources, lenses of solar energy conversion systems, and optical lenses of mobile phone cameras. The assembled lens or optical lens is formed by a plurality of optical lenses with different lens power arranged with a certain spacing on the optical axis between one another on the optical axis. Thus while assembling, an optical axis of each optical lens must be aligned precisely so as to avoid the reduction of resolution. Moreover, the distance between two adjacent optical lenses (spacing on the optical axis) is fixed. Thus the assembling requires a complicated process and precise alignment process. Therefore, the yield rate is unable to increase and the cost down is difficult. Since that, the optical resolution (example as MTF effect) will be affected when the assembly having disalignment from optical axis. Thus lens alignment of the optical lens array is more complicated and important. As to the manufacturing of the optical lens array, JP2001194508 disclosed a manufacturing method of plastic optical lens array. Taiwanese patent No. M343166 reveals a manufacturing method of glass optical lens array. After being produced, the optical lens array can be cut to form a single optical lens element so as to be assembled in a lens module. Or the optical lens array is assembled with other optical elements to form a lens submodule array that is then cut to form a lens submodule. The lens submodule is assembled with lens holder, image sensors or other optical elements to form a lens module.
In manufacturing of lens module array, wafer level lens modules are revealed in U.S. Pat. No. 7,183,643, US2007/0070511, WO2008011003 and so on. Refer to FIG. 1, a lens module array generally includes an aperture 711, a cover glass 712, a plurality of optical lenses and an infrared (IR) cut lens 717. As shown in figure, a plurality of optical lenses form a three piece type optical lens set. The optical lens set includes a first optical lens 714, a second optical lens 715 and a third optical lens 716. Two adjacent optical lenses are separated by a spacer 713. After being assembled, a lens module array is formed and then is cut into a plurality of lens modules. Moreover, as shown in FIG. 2, a lens module disclosed in WO2008/063528 is formed by a stacking way. An aperture 711, a first optical lens 714, a spacer 713, a second optical lens 715, a spacer 713, a third optical lens 716, an image sensor 717 and a circuit board 718 are packaged in an encapsulant 719 to a lens module.
In a lens module array, while assembling a lens array with plurality of optical lenses, the alignment of the lens array has effects on resolution of the lens module. In US2006/0249859, imaging techniques are used to determine if stacked wafers are in proper alignment. Fiducial marks that were previously patterned on each wafer of the stack are exposed in an image produced by the infrared ray. In assembling of plastic optical lens arrays, JP2000-321526 and JP2000-227505 revealed bi-convex type optical lens arrays formed by combination of heights with crevices. As to U.S. Pat. No. 7,187,501, cone-shaped projections are provided on a periphery of a resin lens. A plastic resin lens array is formed by stacking the resin lens plates one over another through fitting these projections and holes to each other. However, in the conventional assembling way of projections and holes to form plastic optical lens array, material shrinkage after the plastic injection molding will lead to size change of the projections and the holes. Thus the location precision is affected and the alignment of the optical axis is difficult. Therefore, the applications of the plastic optical lens array is limited, especially during manufacturing of small-size lens module, the complicated processes cause cost increase. The molded glass lens has higher refractive index than the plastic lens and also with better thermostability so that the molded glass has been applied to various optical systems. Moreover, the optical lens array made from molded glass exhibit less shrinkage.
Thus there is a need to develop an optical glass lens array with simple structure and high precision so as to produce lens modules that meet requirement of compact design and mass production.


A vaccine includes at least one bacterial antigen capable of producing an immune response in a host when the vaccine is administered at a dose that is sufficient for preventing or treating Q fever in the host. The vaccine composition confers immunity against Q fever without the reactogenic side effects observed in prior art vaccines.

This section provides background information to facilitate a better understanding of the various aspects of the disclosure. It should be understood that the statements in this section of this document are to be read in this light, and not as admissions of prior art.
Coxiella burnetii infection of humans causes Q fever, a flu-like illness whose symptoms typically include fever, headache, and myalgia. In some cases, pneumonia and/or hepatitis can be present. Most patients resolve the infection and are immune to future C. burnetii infections. However, a minority of patients are unable to clear the bacteria and develop a chronic infection that most often presents as culture-negative endocarditis. C. burnetii is a Gram-negative bacterium that is typically transmitted by inhalation of aerosols that contain the bacteria. Once the organism is in the lungs, cells of the monocyte/macrophage lineage are infected. Infections can be initiated with small numbers of organisms, and the bacteria are slow growing in vivo. Humans therefore have a dose-dependent incubation period of 1 to 3 weeks before the onset of symptoms. At the time of symptom onset, C. burnetii organisms are often detectable in blood and serum.
Antibody responses develop 7 to 14 days after the onset of symptoms, with IgG antibody appearing shortly after IgM. Once IgG antibodies are present, C. burnetii quickly becomes undetectable in the blood. The mechanism by which C. burnetii is cleared from the blood is not known, but the timing correlates well with the development of immune responses. Although recent reports have suggested that C. burnetii DNA and antigen can be detected years after an acute infection, viable organisms are thought to be eliminated more quickly. However, the time required for complete clearance of viable C. burnetii in humans is not known. Cellular immune responses are thought to be initiated in humans with kinetics similar to those of the antibody response. However, this aspect has not been studied extensively.
Mouse models of Coxiella burnetii infection have been used to demonstrate that both CD4 and CD8 T cells are needed for clearance of the agent, with B cells playing a supporting role. Both serum and splenocytes from immune mice can transfer significant protection against C. burnetii to nave mice, but only transfer of immune splenocytes can confer protection on SCID mice. These studies have suggested that both T and B cell responses play a significant role in protective immunity in humans.
The only currently commercially available human vaccine against Q fever is Q-Vax®. Q-Vax® is a whole-cell formalin-inactivated preparation of the phase 1 Henzerling strain of C. burnetii. This vaccine is licensed for use only in Australia, where it is given primarily to farmers, abattoir workers, and laboratory personnel. The vaccine has been demonstrated to be highly effective and has a strong safety record. The vaccine cannot be given to persons already immune to C. burnetii, as this can cause a severe adverse reaction at the injection site. Because of this, potential vaccine recipients have to be carefully screened both for anti-Coxiella antibodies and by a skin test to identify potentially adverse responses. Both of these tests need to be negative before vaccination is advised.
The longevity of the protective immune response against C. burnetii provided by either natural infection or vaccination has not been well defined. The most common approach to evaluate immunity has been the measurement of the levels of serum antibody against C. burnetii. A study from the Netherlands that followed serology in a large group of naturally infected persons observed during that country's 2007-2011 Q fever epidemic found that IgG phase 2 serum antibody peaked at a mean of 53 days after symptom onset and then declined slowly, with the half-life of the antibody decay rate being 318 days. Thus, greater than 20% of acute Q fever patients could become seronegative 3 to 4 years after having the disease. Indeed, an analysis of Q fever patients in Australia 6 years after an outbreak found that 7/38 (18.4%) had become seronegative. A study of antibody responses in people vaccinated against Q fever found that only 60% had positive titers 20 months after vaccination, whereas 90% had detectable cellular immune responses. These results suggest that measurement of cellular immunity should be considered an indicator of previous exposure to C. burnetii. However, detection of cellular immunity in vaccinated subjects has also been reported as variable.
Due to the fact that that there is no commercially available human vaccine against Q fever available in the United States, coupled with the potential health risks that can arise with the administration of a whole cell preparation of C. burnetii, it would be advantageous to have a vaccine that showed efficacy in immunizing subjects against Q fever, while at the same time posing less of a health risk to the vaccine recipient. Embodiments of the invention described herein present a solution to this existing problem.

Vaccine for immunization against Q-fever


A system automatically adaptively modifies a fail-over configuration priority list of back-up devices of a group (cluster) of processing devices to improve availability and reduce risks and costs associated with manual configuration. A system is used by individual processing devices of a group of networked processing devices, for managing operational failure occurrences in devices of the group. The system includes an interface processor for maintaining transition information identifying a second processing device for taking over execution of tasks of a first processing device in response to an operational failure of the first processing device and for updating the transition information in response to a change in transition information occurring in another processing device of the group. An operation detector detects an operational failure of the first processing device. Also, a failure controller initiates execution, by the second processing device, of tasks designated to be performed by the first processing device in response to detection of an operational failure of the first processing device.

Computing platforms are used in various industries (telecommunication, healthcare, finance, etc.) to provide high availability online network accessed services to customers. The operational time (uptime) of these services is important and affects customer acceptance, customer satisfaction, and ongoing customer relationships. Typically a service level agreements (SLA) which is a contract between a network service provider and a service customer, defines a guaranteed percentage of time the service is available (availability). The service is considered to be unavailable if the end-user is not able to perform defined functionality at a provided user interface. Existing computing network implementations employ failover cluster architectures that designate a back-up processing device to assume functions of a first processing device in the event of an operational failure of the first processing device in a cluster (group) of devices. Known failover cluster architectures typically employ a static list (protected peer nodes list) of processing devices (nodes of a network) designating back-up processing devices for assuming functions of processing devices that experience operational failure. A list is pre-configured to determine a priority of back-up nodes for individual active nodes in a cluster. In the event of a failure of an active node, a cluster typically attempts to fail over to a first available node with highest priority on the list.
One problem of such known systems is that multiple nodes may fail to the same back-up node causing further failure because of over-burdened computer resources. Further, for a multiple node cluster, existing methods require a substantial configuration effort to manually configure a back-up processing device. In the event that two active nodes fail in a multiple node cluster configured with the same available back-up node as highest priority in their failover list, both nodes failover to this sarne back-up node. This requires higher computer resource capacity for the back-up node and increases the cost of the failover configuration. In existing systems, this multiple node failure situation may possibly be prevented by user manual reconfiguration of failover configuration priority lists following a single node failure. However, such manual reconfiguration of an operational node cluster is not straightforward and involves a risk of causing failure of another active node leading to further service disruption. Further, in existing systems a node is typically dedicated as a master server and other nodes are slave servers. A cluster may be further separated into smaller cluster groups. Consequently, if a disk or memory shared by master and slave or separate groups in a cluster fails, the cluster may no longer be operational. Also, load balancing operations are commonly employed in existing systems to share operational burden in devices in a cluster and this comprises a dynamic and complex application that increases risk. A system according to invention principles provides a processing device failure management system addressing the identified problems and deficiencies.

System for managing operational failure occurrences in processing devices

Siemens Medical Solutions Health Services Corporation


A method for forming a metal electrode of a system in package of a system in package including a multilayer semiconductor device having semiconductor devices stacked in a plurality of layers. The method may include forming a through hole extending through the plurality of layers, forming a combustible material layer having high viscosity at a lower portion of the through hole in order to seal the lower portion thereof, and forming a through electrode by filling copper in the through hole. There is an effect of efficiently forming a through electrode having a large depth corresponding to the height of stacked semiconductor devices in the system in package. Filling copper in a through hole having a large depth-to-width ratio may be efficiently done by OSP coating, electrolysis copper plating, and electro Cu plating processes.

Along the trend of multifunction and miniaturization of various electronic devices, a semiconductor device such as an integrated circuit device having a multilayer structure may be provided in an electronic device. Such a multilayer semiconductor device may have a plurality of circuit devices and structured having a small size with an increased integration density of a semiconductor device is increasing. For example, there are proposed a high-integration semiconductor device having a structure of stacking and fixing LSI chips having a through electrode over a plurality of layers and a three-dimensional (3D) semiconductor device having a structure of stacking a plurality of semiconductor substrates having integrated circuits.
As one of key technologies for realizing compact, light and thin electronic equipment, various packaging technologies have been developed in the semiconductor devices to realize high density mounting of semiconductor chips. As a technology related to a package structure of semiconductor devices for reducing an area required for mounting the semiconductor devices on a mother board, there have been developed a pin insertion-type package such as a dual inline package (DIP), a surface mount package such as a small outline package (SOP) by a peripheral lead, and a package having external output terminals in a grid shape on the lower surface of the package such as a ball grid array (BGA). Furthermore, as a technology for realizing high density mounting by reducing an area ratio of a package to semiconductor chips, the pitch of the external output terminals becomes small and the reduction in the size of the package become promoted according to miniaturization of lines of the substrate.
A technology of a multichip package for mounting a plurality of semiconductor chips in a single package has been developed. In the multichip package, a technology of a chip stacked package for stacking a plurality of semiconductor chips has been developed in order to realize higher density mounting. Furthermore, a multichip package systematized by sealing a plurality of semiconductor chips having different functions in a single package is referred to as a system-in-package (SIP) and the development of the SIP has been conducted.
Meanwhile, a separate method from high-density packaging and mounting of semiconductor chips has been given attention as a method for realizing compact, light and thin electronic equipment. The separate method employs a system-on-chip (SOC) such that memory, logic and analog circuits and the like, which are different semiconductor chips, are mixedly loaded to integrate system functions in a single chip.
However, in a case of integrating memory, logic circuits and the like in a single chip, it is difficult to obtain a low-voltage memory circuit, and thus, necessary to control noise generated in the logic circuit. Further, in a case of mixedly loading a bipolar analog circuit, it is difficult to manufacture the analog circuit in a CMOS circuit equal to memory and logic circuits. Accordingly, instead of the SOC, an SIP capable of being developed for a short period of time at low cost to have the same functions as the system on chip has been given attention.
As a technology required to manufacture 3D multilayer LSI and SIP, there is a technology for forming a through electrode in a semiconductor substrate. A current process for forming a through electrode in a silicon (Si) wafer still has many process steps. Moreover, there is difficulty in forming a through electrode having a large depth. A through electrode capable of connecting devices should be formed to package various devices into one body. In order to form the through electrode, metal is filled in the through hole formed by etching in the previous step to form a conductor through which electricity flows. The SIP includes a multilayer semiconductor device having semiconductor devices stacked in a plurality of layers. As a total thickness of the multilayer semiconductor device having a plurality of layers, the through hole has a very large depth compared to an opening area. Accordingly, there is a problem that it is difficult to closely form a through electrode by filling tungsten in a through hole by a general chemical vapor deposition (CVD) process.

Method of forming metal electrode of system in package


An integrated circuit is partitioned into two or more sub-circuits, each sub-circuit including two supply terminals across which to receive supply voltage. The sub-circuits are connected in series with the first sub-circuit receiving input voltage at its first supply terminal, and the voltage level output at the second supply terminal of the first sub-circuit being used as input voltage level in a second sub-circuit. Further, a control-circuit is configured to balance voltage drops across the sub-circuits and to maintain constant voltage-drops over the sub-circuits. The control-circuit includes two buffer capacitors, each coupled in parallel over one of the two sub-circuits respectively. The control-circuit also includes at least one bucket capacitor alternately coupled in parallel over the first and the second buffer capacitor through a switching system controlled by a toggling signal.

Starting with the 0.35 μm generation, CMOS scaling has changed from a constant-voltage regime with a nominal supply voltage of 5V to a constant-field regime where the supply voltage is being reduced in concert with geometric dimensions with each process generation. We are thus likely to see more and more CMOS circuits in the future that must operate with a supply voltage below that of the usual sources of electrical energy. As an example, consider a 1.2V battery cell that feeds a low-power low-voltage circuit operating at a mere 0.6V. The most obvious solution is to use a voltage converter in down mode. While this is possible, the converter is costly, space consuming, and also has its own power dissipation. Partitioning the overall IC into two or more sub-circuits and connecting them in series does away with the down converter because the IC can so be powered from a supply with a higher voltage than what is suitable for an individual sub-circuit. U.S. Pat. No. 6,479,974 further proposes to adjust the voltages across the various sub-circuits with the aid of controllable current sources that bleed off excess voltage. The invention improves on the energy-efficiency and on the simplicity of series-connected power schemes by doing the voltage balancing with capacitor switching instead.
According to U.S. Pat. No. 6,479,974, the circuit on the IC is partitioned into power-consuming sub-circuits each of which is to be fed with its own supply voltage and the sub-circuits are then connected in series. This effectively cuts the supply voltage for each sub-circuit. In this way it becomes possible to use a battery cell with a high voltage to feed a low voltage circuit without the need to provide the usual down converter. As voltage drops across the individual sub-circuits will tend to distribute unevenly because current drains in the various workload sub-circuits are never quite the same, U.S. Pat. No. 6,479,974 proposes to compensate for this undesirable effect by connecting a regulator in parallel with each sub-circuit. A controlled current source in each regulator adjusts its current drain such as to maintain a fixed voltage across its own terminals and, hence, across the power-consuming sub-circuit as well. An extra central unit is utilized to coordinate the various regulators such that at least one of them draws zero current thereby minimizing the collective current drain from the power supply.
An alternative embodiment of U.S. Pat. No. 6,479,974 proposes to adjust switching activities in the workload sub-circuits at run time such as to balance their supply currents and, hence, also the voltage drops across them. The patent even suggests the duplication of logic circuitry to provide for sufficient headroom for activity adjustments.


The invention relates to a method of reading a machine-readable barcode including a pre-determined number of code elements, in particular bars and spaces, with a respective picture being taken by means of optical imaging of at least two adjacent and/or mutually overlapping part sections of the bar code, with the individual part sections each including a code element and the part sections including in sum all the code elements of the barcode, with the pictures being stored in a data store, and with the stored pictures or parts thereof being put together for the reconstruction of the information encoded by the barcode. The invention further relates to a corresponding apparatus.

Methods and apparatuses for the machine reading of a barcode printed, for example, on a package are generally known. Generally, a barcode can be read using a contact pen or a laser scanner. It is furthermore also known to read a barcode by means of a matrix camera which, unlike scanners, has no moving parts, but photo-sensitive CCD elements, with a picture of the barcode being able to be generated by optical imaging.
It is, however, a disadvantage with such a matrix camera that it has a limited image field. This has the consequence that only those barcodes can be read by a matrix camera which completely fit into the image field of the matrix camera. In contrast, barcodes which project beyond the image field of the matrix camera due to their size cannot be read completely and can thus not be decoded. A conventional size of the image field of a matrix camera amounts, for example, to 30 mm×40 mm.

Method and an apparatus to read a barcode


The present invention provides movable visual communication systems, more specifically movable electronic whiteboard systems. The invention provides an electronic whiteboard having at least one positioning member and a guide element adapted to receive the positioning member, wherein the electronic whiteboard and the positioning member are movable along the guide element. The guide element can house an extendable or retractable line that maintains connectivity with the electronic whiteboard at any point along the guide element.

1. Field of the Invention
This invention relates generally to the field of visual communication systems, and more particularly to electronic whiteboards and movable interactive electronic whiteboard systems.
2. Description of Related Art
Electronic whiteboards provide many benefits to users during lectures, meetings, and presentations. During meetings and presentations, not only do electronic whiteboards allow users to present electronic presentations, electronic whiteboards also permit handwritten notes on the whiteboard to be saved electronically for future reference.
In the classroom setting, electronic whiteboards are advantageous as they provide educators with a modern and user-friendly teaching tool. Educators prefer electronic whiteboards because of their versatility. Electronic whiteboards allow educators to project virtually any text and images onto the whiteboard as well as write along side of any projected image and markup projected images with electronic ink.
Although electronic whiteboards are increasing in popularity, using electronic whiteboards in existing settings is problematic because of existing visual aids and limited wall space in the front of classrooms. For example, classrooms typically have visual aid devices such as charts, markerboards, maps, and information placed on a wall in the front of the class. Thus, in some existing classrooms and auditoriums, additional visual communication devices such as electronic whiteboards may not have sufficient space to be installed. Installing an electronic whiteboard may require removal of an existing visual aid. Rather than remove existing visual communication devices, a user may desire to combine the use of electronic whiteboards with existing visual aid devices including stationary dry-erase whiteboards, chalkboards, or tackboards.
Current methods of solving this problem include mobile electronic whiteboards, wherein the electronic whiteboards are free-standing and not secured to a wall. Thus, these mobile electronic whiteboards have their own stands and power cords, which are safety hazards because people can easily trip over the cords and the stands. Also, these electronic whiteboards are inconvenient because a larger amount of space is needed to store these mobile units.
Thus, there is a need for movable electronic whiteboard systems.
There is further need for positionable electronic whiteboard systems that are compatible with existing room structures.
There is still another need for track systems for movable electronic whiteboard systems.


The disclosure extends to methods, systems, and computer program products for migrating automatic financial services from one institution to another institution with minimum user input required.

Automatic payments and deposits have been facilitated by financial institutions, entities, payees, and employers for the convenience of all involved. Another benefit for financial service providers is that by facilitating automatic payments and deposits they increase the number of interactions with their customers. The increased interaction between the financial institution and its customers creates a dependent relationship, at least in part, because setting up automatic payments and automatic deposits is time consuming and difficult to change. Accordingly, many customers and patrons are deterred from changing financial institutions because of the difficulty in changing automated services, such as direct deposit or bill payments. Additionally, financial institutions that provide superior customer service or the like may experience difficulty in attracting new customers because many of the customers already have existing automatic services, such as direct deposit or bill payments, with financial institutions that may provide inferior customer service or the like.
The disclosure relates generally to automatic financial services and relates more particularly, but not necessarily entirely, to a system for automating the switching of automatic financial services from a first institution to a second institution with minimal user input.
The features and advantages of the disclosure will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the disclosure without undue experimentation. The features and advantages of the disclosure may be realized and obtained by means of computing systems, networks, and combinations of firmware, software and hardware, particularly disclosed and enumerated in the appended claims.


An imaging lens includes first to fifth lens elements arranged from an object side to an image side in the given order. Through designs of surfaces of the lens elements and relevant optical parameters, a short system length of the imaging lens may be achieved while maintaining good optical performance.

1. Field of the Invention
The present invention relates to an imaging lens and an electronic apparatus including the same.
2. Description of the Related Art
In recent years, as use of portable electronic devices (e.g., mobile phones and digital cameras) becomes ubiquitous, much effort has been put into reducing dimensions of portable electronic devices. Moreover, as dimensions of charged coupled device (CCD) and complementary metal-oxide semiconductor (CMOS) based optical sensors are reduced, dimensions of imaging lenses for use with the optical sensors must be correspondingly reduced without significantly compromising optical performance.
Each of U.S. patent application publication nos. 20110316969, 20100254029, 20130107376, 20130057967, U.S. Pat. Nos. 8,345,323, 7,911,712, 7,746,572, and Japanese patent publication no. 2008-281760 discloses a conventional imaging lens that includes five lens elements, and that has a system length of over 10 mm. Particularly, the imaging lens disclosed in U.S. patent application publication no. 20110316969 has a system length of over 14 mm, which disfavors reducing thickness of portable electronic devices, such as mobile phones and digital cameras.
Reducing the system length of the imaging lens while maintaining satisfactory optical performance is always a goal in the industry.

Imaging lens, and electronic apparatus including the same


The invention may comprise circuit for programmable control of a discharge deactivation signal when interfacing local bitlines to a global bitline or other circuit. The invention may also comprise a method for programmable ground circuit control for control of a discharge signal deactivation when interfacing local bitlines to a global bitline via a bitline evaluation discharge device comprising: providing input logic states to inputs of a controller circuit; outputting an adjustable ground value from the controller circuit; and controlling the bitline evaluation discharge device with the adjustable ground value.

FIGS. 1A and 1B illustrate a high performance, low power domino SRAM design including multiple local cell groups such as that shown in U.S. Pat. No. 6,657,886, the entire contents of which are incorporated herein by reference. As shown in FIG. 1A, each cell group includes multiple SRAM cells 1–N and local true and complement bitlines LBLT and LBLC. Each SRAM cell includes a pair of inverters that operate together in a loop to store true and complement (T and C) data. The local true bitline LBLT and the local complement bitline LBLC are connected to each SRAM cell by a pair of wordline N-channel field effect transistors (NFETs) to respective true and complement sides of the inverters. A WORDLINE provides the gate input to wordline NFETs. A particular WORDLINE is activated, turning on respective wordline NFETs to perform a read or write operation.
For arrays of sufficient size, as shown in FIG. 1B, the prior art domino SRAM includes multiple local cell groups 1–M. Associated with each local cell group are precharge true and complement circuits coupled to the respective local true and complement bitlines LBLT and LBLC, write true and write complement circuits, and a local evaluate circuit. Each of the local evaluate circuits is coupled to a global bitline labeled 2ND STAGE EVAL and a second stage inverter that provides output data or is coupled to more stages. A write predriver circuit receiving input data and a write enable signal provides write true WRITE T and write complement WRITE C signals to the write true and write complement circuits of each local cell group.
A read occurs when a wordline is activated. Since true and complement (T and C) data is stored in the SRAM memory cell, either the precharged high true local bitline LBLT will be discharged if a zero was stored on the true side or the precharged high complement bitline LBLC will be discharged if a zero was stored on the complement side. The local bitline, LBLT or LBLC connected to the one side will remain in its high precharged state. If the true local bitline LBLT was discharged then the zero will propagate through one or more series of domino stages eventually to the output of the SRAM array. If the true local bitline was not discharged then no switching through the domino stages will occur and the precharged value will remain at the SRAM output.

Programmable analog control of a bitline evaluation circuit

International Business Machines Corporation


Lithographic imaging of 50 nm (or less) half-pitch features in chemically amplified resists (commonly used in the manufacture of integrated circuits) is enabled by the use of reduced temperature post-exposure processing and low activation energy chemically amplified resists. The post-exposure processing preferably involves ambient to moderately elevated temperature and the presence of a deprotection reaction-dependent co-reactant (e.g., water).

The microelectronics industry strives toward fabricating high density circuitry by decreasing the minimum feature size of the components on the chip. This requires high-resolution lithography, the principal technique used in patterning microelectronics circuitry. Over approximately the last 20 years, the industry has migrated to shorter wavelength photolithography as the primary means of scaling the resolution to sustain the progressive demand for smaller features. The wavelength of photolithography has migrated from mid-ultraviolet (MUV) wavelengths (350450 nm) to deep-UV (DUV) radiation (190–300 nm) and vacuum UV (VUV, 125–160 nm). Likewise the photosensitive materials used in photolithography, photoresists, have evolved. MUV lithography employed diazonaphthoquinone (DNQ) and novolak-based resists. These materials offered high performance but were not extendible to DUV and VUV wavelengths due to their opacity at these shorter wavelengths. In addition, these resists were not of sufficient sensitivity to afford high throughput manufacturing.
In response to the need for new, lower opacity, higher sensitivity materials for DUV imaging, Ito et al. disclosed (U.S. Pat. No. 4,491,628) the development of chemically amplified resists (CARs) based on the photochemically-generated-acid (from a photosensitive acid generator) catalyzed deprotection of acid-labile polymer. That is, for positive tone CARs, labile moieties of the polymer are cleaved by acid catalyzed thermolysis reaction that renders the deprotected form of the polymer soluble in a subsequently applied developer, such as aqueous base. Thus, an image of the projected patternwise radiation is formed in the resist film after development, which can then serve as an etch-resistant mask for subsequent pattern transfer steps. The resolution obtained is dependent on quality of aerial image and ability of resist to maintain that image.
CARs have been developed for 248, 193, and 157 nm lithography. The theoretical dimensional limit of equal-sized half-pitch features is one quarter of the wavelength, Î>>(k1=0.25) when NA=1, as the dose applied to the resist is equal to the square of the intensity, and thus the resolution cannot be modulated by any more than Î>>/4, or a pitch of Î>>/2. The resolution attainable with each advancing generation of materials has been extended toward these limits through the use of low k1 techniques and high numerical aperture tools. For the latest VUV wavelength being developed for manufacturing, 157 nm, with a very high but potentially manufacturable NA of 0.95, Î>>/4 equals ˜40 nm. To obtain images below this feature size, either an extension of NA to >1, such as is afforded with immersion lithography or with a non-diffraction limited, non-optical lithography system, such the so-called next generation lithography (NGL) options. The most promising of these NGLs are extreme ultraviolet (EUV, sometimes referred to as soft x-ray) or electron beam lithography (EBL).
One barrier to imaging in the sub-50 nm half-pitch regime is a phenomenon known as image blur diminishes the integrity of the pattern (Hinsberg et al., Proc. SPIE, 2000, 3999, 148 and Houle et al., J. Vac. Sci. Technol B, 2000, 18, 1874). Image blur can be defined as the deviation of the developable image from that of projected aerial image which is transferred into the film as the concentration of photochemically generated acid. While accelerating the rate of the deprotection reaction, the application of thermal energy diminishes the fidelity of the aerial image of acid formed during the patternwise exposure. Image blur can be divided into two contributing factors: gradient-driven acid diffusion and reaction propagation. Both factors contribute to blur, but to different degrees and with different temperature dependence.
The first factor contributing to image blur is often referred to as acid diffusion and can be described by Fickian diffusion models for solids (Hinsberg, 2000). Choice of the photoacid being generated from photoacid generator (PAG) and the mobility in the chosen polymer matrix dictate this factor. The mobility in the polymer matrix is dependent on the comprising chemical functionality of the polymer, the free volume of the matrix, the glass transition temperature (Tg) of the polymer and the temperature and time of baking steps encountered during the resist processing.
A second contributing factor to image blur is sometimes described as reaction propagation (Hinsberg, 2000; Houle, 2000) and is best described by Arhenius behavior. Activation energy (enthalpy), volatility of products (entropy), and the availability and concentration of deprotection-reaction-dependent co-reactants such as moisture dictate the degree to which the reaction propagates away from the original acid profile.
In order to achieve high resolution, high sensitivity and high degree of process latitude, both image blur factors must be eliminated or minimized. Both of these contributing factors can be tempered by the addition of acid-quenchers, or bases, which have been shown to reduce image blur. Additionally it has been recognized that image blur is temperature dependent. Breyta et al. disclose that appropriate baking conditions can optimize the resolution attainable with CARs in U.S. Pat. No. 6,227,546. However, since the extent of thermally induced image blur has been estimated to be on the order of 10–50 nm with conventional resist processing schemes by various researchers (Hinsberg 2000; Houle 2000; Krasnaperova et al., J. Vac. Sci. Technol. B, 1994, 12, 3900; Lin et al, Science 2002, 297, 372), processing that reduces this phenomenon further are desirable and necessary to reach the sub-50 nm half-pitch regime of imaging.
Thus, remains a need for reliable methods of performing sub-50 nm half-pitch imaging.

Process for forming features of 50 nm or less half-pitch with chemically amplified resist imaging


Triglycerides, having at least two long chain polyunsaturated fatty acids L.sub.1 and L.sub.2, from which at least one is present for more than 20 wt %, while the weight ratio L.sub.1 :L.sub.2 is at least 2 and which triglycerides also contain at least 15 wt % of saturated fatty acids with 14 or more carbon atoms and have a weight ratio saturated C.sub.18 :saturated C.sub.16 fatty acid residue of >2, while at least 5 wt % of the saturated fatty acid residues with at least 14 C-atoms is bonded on a triglyceride molecule, wherein also L.sub.1 and/or L.sub.2 is present, display a number of beneficial properties (good oxidative stability healthier, less off-flavor, lower caloric, better digestibility, and in particular better structuring properties).

According to EP 265 699 fats with a superior digestibility and absorptivity are obtained, when these fats are composed of triglycerides having a specific amount of C.sub.8 to C.sub.14 fatty acid residues at the 2-position, while residues with C.sub.18 or higher fatty acids are bonded at the 1.3-positions. Typical examples of the C.sub.18 and higher fatty acids are polyunsaturated fatty acids, such as arachidonic acid, eicosapentenoic acid and dodecahexenoic acid. However nothing is disclosed about fat compositions that combine in the fat saturated fatty acid residues and at least two different long chain polyunsaturated fatty acid residues and that have structering properties. In WO 90/04012 it is disclosed that triglycerides that contain saturated C.sub.8 /C.sub.10 fatty acid residues in 1.3 and simultaneously a polyunsaturated fatty acid residue (in particular DHA) in the 2-position, have beneficial nutritional properties, in particular for enteral or parenteral purposes. However again, nothing is disclosed about fat compositions that contain in the fat specific amounts of saturated and two different polyunsaturated fatty acid residues and that have structering properties.
From WO 94/00044 it is known that fatblends that contain unhardened fish oil have significant health benefits. Fish oil often contains appreciable amounts of two different polyunsaturated fatty acids, e.g. DHA and EPA. However it is also known that fish oil has a number of draw backs. A particular disadvantage of fish oils being that they do not have structuring properties, which makes it difficult to apply them in fat compositions wherein a structuring agent is required in order to give the fat composition a performance, that is desired to make the fat applicable in foodproducts.
Toyoshima c. s. disclosed in Journ. of the Japan Oil chem Soc 42 (11), 1993, pages 30-35 a transesterification process, applying Mucor miehei as enzyme of a fish oil, such as sardine oil, EPA concentrated oil or DHA concentrated oil with polyunsaturated fatty acids. This resulted in triglycerides with about 62% of PUFA in it. It is further disclosed that EPA was incorporated more easily than DHA. Therefore triglycerides high in DHA were made by an additional transesterification in the fish oil/PUFA system. This document therefore does not disclose triglycerides rich in a first LCPUFA and containing a second LCPUFA in a weight ratio of >2, which triglycerides further contain saturated C.sub.14+ fatty acids.
Endo in Bioscience Biotechn Biochem 57 (12) 1993, pages 2202-2204 discloses that sardine oil can be stabilized by interesterification with saturated or mono-unsaturated fatty acids. However, the effects with stearic acid are very low. As a result of the enzymic interesterification the total amount of LCPUFA in sardine oil (was 20%) decreased to 17.5 wt % if stearic acid groups were introduced. Therefore, this document does not teach triglycerides rich in a first LCPUFA and also containing a second LCPUFA in a ratio of >2, while also at least 15 wt % C.sub.14+ saturated fatty acids were present in the triglycerides.
From U.S. Pat. No. 5,151,291 can be concluded that triglycerides, rich in EPA with good properties to make them suitable for margarine applications can be obtained by a process wherein EPA-ester is converted with a "higher fatty acid" triglyceride. Higher fatty acid triglycerides are defined as saturated or unsaturated C.sub.14+ fatty acid triglyceride.
They include palmitic, stearic but also oleic, linoleic, EPA and DHA. However, this method will never result in triglycerides containing two different LCPUFA's in a ratio of >2, while simultaneously saturated C.sub.14+ fatty acid will be present. Moreover this document does not disclose the impact of the C.sub.18:0 /C.sub.16:0 -ratio in the products on the structurering properties of the fats.
EP 271,909 discloses triglycerides, wherein simultaneously three different fatty acid residues are present. These residues are selected from C.sub.20 -C.sub.22 saturated or (poly)unsaturated fatty acids; C.sub.14 -C.sub.18 saturated or unsaturated fatty acids and C.sub.6 -C.sub.12 saturated or unsaturated fatty acids. The products never comprise two different LCPUFA's in a ratio of >2 in combination with >15 wt % saturated C.sub.14+ fatty acid.

Triglycerides rich in polyunsaturated fatty acids