The present invention relates to compounds of general formula (I) and their preparation and use for the production of pharmaceuticals, and pharmaceuticals comprising these compounds.

The present invention relates to new multiheterocyclic compounds as integrin antagonists with a broad spectrum of action having, inter alia, antiosteoporotic, antirestenotic, anticarcinogenic and antiatherosclerotic activity. The present invention moreover relates to the preparation of these compounds and their use for the production of medicaments, and also medicaments comprising them.
Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single letter code for the amino acid sequence arginine-glycine-aspartate).
In general, integrins such as, for example, the vitronectin receptor, which is also called the xcex1vxcex23 receptor, or alternatively the xcex1vxcex25 receptor or the GpIIb/IIIa receptor play an important part in biological processes such as cell migration and cell-matrix adhesion and thus in diseases in which these processes are crucial steps. Cancer, osteoporosis, arteriosclerosis, restenosis (reoccurrence of stenosis after percutaneous transluminal angioplasty) and opthalmia may be.mentioned by way of example.
The xcex1vxcex23 receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. Thus the xcex1vxcex23 receptor plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial prerequisite for tumor growth and metastasis formation in carcinoses. Furthermore, it is also responsible for the interaction between osteoclasts, i.e. cells resorbing mineralized tissue, and the bone structure. The first step in the degradation of bone tissue consists in the adhesion of osteoclasts to the bone. This cell-matrix interaction takes place via the xcex1vxcex23 receptor, which is why the corresponding integrin plays an important part in this process. Osteolytic diseases such as osteoporosis are induced by an inequilibrium between bone formation and bone destruction, i.e. the resorption of bone material caused by accumulation of osteoclasts predominates.
It was possible to show that the blockage of the abovementioned receptors is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their appropriate integrin receptors, for example, by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Therefore angiogenesis does not occur, which leads to a cessation or resolution of the tumor growth (cf., for example, Brooks et al., Cell, Volume 79, 1157-1164, 1994).
Moreover, the invasive properties of tumor cells and thus their capability for metastasis formation are markedly decreased if their xcex1vxcex23 receptor is blocked by an antibody (Brooks et al., J. Clin. Invest., Volume 96, 1815, 1995).
The degradation of bone tissue can be suppressed by blockage of the xcex1vxcex23 receptors of the osteoclasts, since these are then unable to accumulate on the bone in order to absorb its substance (WO 98/18461, p. 1, 1.24 to p. 2, 1.13).
By means of the blockage of the xcex1vxcex23 receptor on cells of the smooth aorta vascular musculature with the aid of integrin receptor antagonists, the migration of these cells into the neointima and thus angioplasty leading to arteriosclerosis and restenosis can be suppressed (Brown et al., Cardiovascular Res., Volume 28, 1815, 1994).
In recent years, compounds have therefore been sought which act as antagonists of integrin receptors. For example WO 97/24119 discloses victronectin (xcex1vxcex23) receptor antagonist as antiosteoporosis agents which are structurally related to the compounds described here, but do not have a broad spectrum of action of this type.
It was the object of the present invention to develop compounds which exhibit a high activity as integrin antagonists and in particular against the xcex1vxcex23 and/or the xcex1vxcex25 receptor.
The compounds on which the present invention is based can be described by the following general formula (I):
where
R1 and R2 together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by halogen, nitro, cyano, trifluoromethyl, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, amino, carboxyl, phenoxy, (C6-C10)-aryl, (C1-C6)-alkylamino, (C1-C6)-alkylsulfone or a group of the formula xe2x80x94SO2NRaRb wherein Ra and Rb may independently represent hydrogen or (C1-C6)-alkyl, and
R3=H or (C1-C4)-alkyl, and
A=O, S, (CH2)n where n=1,2,3 or 4 or Nxe2x80x94R7 where R7=H or (C1-C4)-alkyl, or is absent and
X, Y, Z=O, S, N, Nxe2x80x94R8 where R8=H, (C1-C6)-alkyl or (C6-C10)-aryl, or Cxe2x80x94(R9)(R10) where R9, R10=H, (C1-C6)-alkyl or (C1-C10)-aryl, or Cxe2x80x94(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C1-C6)-alkyl or (C6-C10)-aryl, and
D=O, S, (CH2)n where n=1,2,3 or 4, or Nxe2x80x94R7 where R7=H or (C1-C4)-alkyl, or is absent and
E, G, L=H, halogen, nitro, cyano, trifluoromethyl, hydroxyl, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy or (C1-C6)-alkoxycarbonyl, where E, G and L can be identical or different and
R4=H, (C3-C8)-cycloalkyl, (C1-C6)-alkyl, which is optionally substituted by hydroxyl, (C1-C6)-alkoxy or phenyl, where the latter is optionally in turn substituted on the phenyl ring by halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, trifluoromethoxy or trifluoromethyl, and
R5=H or (C1-C4)-alkyl and
R6=H, (C1-C6)-alkyl or benzyl
and their salts.
Preferred compounds according to the general formula (I) are those where
R1 and R2 together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by (C1-C6)-alkoxy, nitro or amino, and
R3=H, and
A=O, S, (CH2)n where n=1,2,3 or 4 or Nxe2x80x94H, or is absent and
X, Y, Z=O, S, N, Nxe2x80x94R8 where R8=H, (C1-C6)-alkyl or (C6-C10)-aryl, or Cxe2x80x94(R9)(R10) where R9, R10=H, (C1-C6)-alkyl or (C6-C10)-aryl, or Cxe2x80x94(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C1-C6)-alkyl or (C6-C10)-aryl, and
D=O, S, (CH2)n where n=1, 2, 3 or 4, or Nxe2x80x94H, or is absent and
E, G, L=H, and
R4=H, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylethyl or (C1-C4)-alkyl, which is optionally substituted by hydroxyl or methoxy, and
R5=H, and
R6=H or methyl.
and their salts.
Particularly preferred compounds according to the general formula (I) are those where
R1 and R2 together with the formal double bond bridging them form a phenyl ring, which is optionally substituted by nitro. and
R3=H and
A=is absent and
X=N, Y=O and Z=N or X=N, Y=N and Z=O, S or X=CH2, Y=O, Z=N and
D=is absent and
E, G, L=H, and
R4=methyl, cyclopropyl or (C1-C4)-alkyl substituted by methoxy and
R5=H, and
R6=H or methyl
and their salts.
The compounds according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The present invention also includes ammonium compounds which can be prepared by conversion of the free amines by means of alkylation.
In the context of the present invention, the substituents in general have the following meaning:
(C1-C6)-alkyl in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl.
(C1-C6)-alkoxycarbonyl can be represented, for example, by the formula
Alkyl here represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. Lower alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety is preferred. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
(C3-C8)-cycloalkyl in general represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
(C6-C10)-aryl in general represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
(C1-C6)-alkoxy in general represents, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical bonded via an oxygen atom and having 1 to 6 carbon atoms. Lower alkoxy having 1 to 4 carbon atoms is preferred. An alkoxy radical having 1 to 3 carbon atoms is particularly preferred. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy.
(C1-C6)-alkylsulfone can be represented by the formula
wherein Alkyl represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms. Examples which may be mentioned are: methylsulfone, ethylsulfone, propylsulfone, isopropylsulfone.
Six-membered aromatic heterocycles in the context of the invention, depending on the abovementioned substituents, in general represent a 6-membered heterocycle which can contain up to 2 nitrogen atoms and which can optionally also be bonded via a nitrogen atom. Examples which may be mentioned are: pyridyl and pyrimidyl.
In general formula (I) the heterocyclic moiety
represents an aromatic or partially saturated heterocycle. Preferred examples for this moiety are:
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
The compounds of the general formula (I) according to the invention can be prepared in the following way using process variant (A) or (B):
(A) reaction of a component (a)
xe2x80x83with a component (b)
where (b) is first reacted in the presence of sulfonyl chloride, POCl3 or PCl5 to give the acid chloride and is then reacted with (a) in the presence of a base in an inert organic solvent, or a coupling of (a) with (b) is carried out by means of Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP) or carbodiimide reagents, followed by a cyclization reaction which can be effected by means of heat, acids, bases, dehydrating substances and by addition of generally nucleophilic reagents,
where, if appropriate, the COOR6 group is finally hydrolyzed and where Q in one of the two components (a) or (b) is oxygen and in the other components corresponds to Z, or
(B) reaction of a component (axe2x80x2)
xe2x80x83with a component (b)
where (b) is first reacted in the presence of sulfonyl chloride, POCl3 or PCl5 to give the acid chloride and then reacted with (axe2x80x2) in the presence of a base in an inert organic solvent, or a coupling of (axe2x80x2) with (b) is carried out by means of BOP or carbodiimide reagents, followed by a cyclization reaction which can be effected by means of heat, acids, bases, dehydrating substances and by addition of generally nucleophilic reagents,
where, if appropriate, the COOR6 group is finally hydrolyzed and where Q in one of the two components (axe2x80x2) or (b) is oxygen and in the other component corresponds to Z.
Preferably, in process variant (A), for component (a), Xxe2x95x90N, Yxe2x95x90O and Qxe2x95x90NH is employed and for component (b), Qxe2x95x90O is employed and in process variant (B), for component (axe2x80x2), Xxe2x95x90NH, Yxe2x95x90NH and Qxe2x95x90O is employed and, for component (bxe2x80x2), Qxe2x95x90O is employed.
Particularly preferably, it applies to both process variants that R1 and R2 together with the formal double bond bridging them form a phenyl radical,
R3, R5, E, G, L=H,
R4, R6 =methyl and
A, D=is absent.
The compounds of the formula (I) according to the invention have a surprisingly wide spectrum of pharmacological action.
The compounds according to the invention exhibit an antagonistic action against integrin inhibitors, in particular the xcex1vxcex23 receptor or the xcex1vxcex25 receptor.
They can be used as active compounds in medicaments for the reduction of changes to vascular walls and are employed for the treatment of arterial hypertension and atherosclerosis. Moreover, they can be employed for the treatment of coronary heart disorders, cardiac insufficiency, disorders of brain function, ischemic brain disorders, (peripheral) circulation disorders, microcirculation disorders and thromboses, functional disorders of the kidney and adrenal gland, bronchospastic and vascular system-related disorders of the airways, sodium retention and edemas as well as osteolytic disorders such as osteoporosis, cancer, carcinoses and ophthalmic diseases.
Furthermore, the proliferation and migration of smooth muscle cells plays a decisive part in the occlusion of vessels. The compounds according to the invention are suitable for inhibiting this proliferation and can therefore also be employed for the treatment of restenosis.
The novel active compounds are distinguished pharmacologically by good kinetic parameters. In particular, they have favorable properties with respect to clearance.
The novel active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents. In this case the therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, if water is used as a diluent organic solvents can optionally be used as auxiliary solvents.
Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.
In the case of parenteral administration, solutions of the active compound using suitable liquid carrier materials can be employed.
In general, it has proven advantageous in the case of intravenous administration to administer amounts from approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve effective results, and in the case of oral administration the dose is approximately 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg, of body weight.
In spite of this, if appropriate, it may be necessary to depart from the amounts mentioned, namely depending on the body weight or the type of application route, on individual behavior toward the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limits mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.
The present invention is illustrated in greater detail below by working examples.
Starting Compound I
0.877 g of methyl S-7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (Tetrahedron Letters 38, 3131-34, 1997) is stirred under reflux for 1 h with thionyl chloride (40 ml), concentrated and the residue is dissolved in 20 ml of chloroform. The solution obtained is added dropwise to a mixture of 0.53 g of benzimidazole-2-carboxamidoxime (J. Chem. Soc. C, 1967, 28) and chloroform (50 ml), pyridine (0.48 g) and triethylamine (0.30 g). It is stirred at room temperature for 2 h, then concentrated and the residue is taken up in ethyl acetate. After this, washing with water, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution and drying over magnesium sulfate takes place, after concentration an amorphous residue being obtained which is stirred with dichloromethane and filtered off with suction. Recrystallization is carried out from ethanol (0.41 g). The mother liquor is concentrated and chromatographically purified (CH2Cl2; CH2 Cl2/CH3OH=30/1). 0.6 g of the title compound is obtained from the mother liquor.

1,4-benzodiazepinone derivatives and their use as integrin antagonists


In accordance with this invention, a device is provided which is able to develop upper body strength, including doing exercising such as pull-ups, push-ups, tricep presses, tricep presses, dips, arm curls, flys, etc. Also with the device of the invention abdominal and leg muscles could be developed by such exercises as sit-ups, leg-lifts, leg extentions and back rests.. The exercise device preferably comprises a horizontal bar adapted for being selectively gripped by the hands of a user or supporting the user's legs. A means is included for adjusting the length of the bar. At least two sets of vertical support structures support the bar at at least two based locations. Each of the vertical supports structures includes means for adjusting the length of its structure whereby the elevation of said bar may be varied in accordance with a particular exercise program.. The device may be used for performing an exercise program by adjusting the horizontal bar to the desired length and adjusting the vertical support structures to the desired height. The horizontal bar is gripped by the user's hands. The user the moves his body towards the horizontal bar under the force from the user's and holds the body in place for a predetermined time. The body is then moved toward original position and the various steps are repeated until the exercise program is complete.. A similar exercise program may be performed by using additional parts with the device such as elastic bands or a slant board.

In today's society there is a growing need for new exercising devices. There is a need for a light-weight, portable exercising device that is good for the development of the arms, stomach, back and the legs. An ideal device must be adaptable for all different sizes of men, women and children.


A sequential iterative methodology is used to generate a solution space with different cost/availability values for multiple network architectures from which an optimal or near-optimal solution can be determined. A modeling module (10) provides a cost value for a network architecture under consideration and, once cost modeling is done, an availability analysis is performed for the architecture under analysis. If a relatively few connections prevent a model from acceptability, the availability analysis module (12) reveals the causing factors of the unsatisfactory availability for those few connections and suggests that the modeling perform further optimisations on those causing factors. This iterative process is repeated until an optimum or near-optimum acceptable solution is found; if no acceptable solution is found, the solutions generated in the availability analysis module are reviewed to find the best available solution.

1. Technical Field
This invention relates in general to communications networks and, more particularly, to optimization of a network design.
2. Description of the Related Art
In the design and modification of a network architecture, such as a local exchange network or a core (backbone) network, both capital expenditures and operational expenditures should be considered in evaluating the total cost of the network. Capital expenditures would include the cost of new equipment and, if necessary, additional lines (such as optical fiber lines). Operational expenditures include those expenses necessary to operate the network at the service provider's expectations. In determining the operational expenditures, the availability of the network should be considered are part of the cost, through maintenance and repair efforts.
The solution that provides the lowest capital expenditures may often not result in the lowest total cost. This would be true if the network with the lowest capital expenditures does not meet the service provider's requirements for availability or if additional operational expenses would be required to bring the network's availability to a reasonable level in an attempt to shorten the Mean Time To Repair (MTTR) by spending more on repair crew efforts.
With the large number of options available for a network configuration, such as parameters related to traffic grooming, express routes, network dimensioning, and so on, it is virtually impossible to find a solution that is a near optimum solution. Integrating similar constraints relating to availability, would increase the complexity of the problem which is already non-trivial to cope with. Moreover, the objectives of availability and cost are often conflicting. This means that when one of the objectives (e.g. cost or availability) improves, the other one (availability or cost) worsens. Service providers generally are satisfied to find a solution that works, without considering other options. This can lead to excessive present costs due to capital expenditures or excessive future costs due to ongoing operational expenditures.
With communications being a highly cost competitive field, it has become more necessary to reduce total costs.
Therefore, a need has arisen for finding a near-optimal solution for designing a network.

Availability aware cost modeling for optical core networks


A system and method for performing laser induced optical breakdown (LIOB) in corneal tissue of an eye requires calculating a pattern of focal spots. LIOB is then induced at a first focal spot, and is continued at a plurality of interim focal spots within a time period τ. Each focal spot has a diameter “d1” and generates a temporal cavitation bubble of diameter “d2”. It then collapses within time “τ” to a substantially stationary diameter “d3”, with (d1≦d3≦d2). Importantly, each focal spot is located more than “d2” from every other interim focal spot within the time period of “τ”. At the time “τ”, a second focal spot in the pattern can be generated at a distance “d3” from the first focal spot. This process is then continued with another plurality of interim focal spots being generated within another time period “τ”.

During an ophthalmic laser surgical procedure, wherein stromal tissue within the cornea is ablated, the ablation is caused by an effect known as Laser Induced Optical Breakdown (LIOB). Typically, LIOB in the stroma is accomplished using pulsed laser beams that may have pulse repetition rates as high as 10 KHz. In detail, the LIOB effect of successive individual laser pulses is cumulative. Each individual laser pulse, however, can be considered separately.
For an individual laser pulse, it happens during LIOB that the tissue being ablated may be subjected to several different phenomena. For one, tissue that is peripheral to the ablated tissue is subject to adverse side effects, such as tearing (mechanical damage) and scorching (thermal damage). It is known, however, that these particular adverse side effects can be avoided if the pulse energy density is minimized. On the other hand, the pulse energy density must be above the tissue threshold in order for LIOB to occur. With these countervailing considerations in mind, it has been determined that a laser pulse having the following characteristics can cause LIOB in stromal tissue, while avoiding adverse mechanical or thermal side effects on peripheral tissue.
Laser Pulse                Pulse Length (duration): 1-1000 femtoseconds        Energy Density: 1-10 J/cm2        Focal Spot Size: 1-10 μm diameter        Pulse Repetition Rate: multi KHz
Despite the adverse, but avoidable, side effects on peripheral tissue noted above, LIOB will still affect stromal tissue in at least three other different, identifiable ways. These are: 1) plasma formation; 2) shock wave generation; and 3) cavitation bubbles. Schematically, these three phenomena are shown in FIG. 1 of the drawings.
Referring for the moment to FIG. 1 in the drawings, the consequences of LIOB caused by a single laser pulse are illustrated in a spatial context. It is to be appreciated, however, these consequences also have a temporal context. First, a micro plasma is formed from tissue located within the focal spot of the laser pulse. Specifically, this plasma results from the evaporation of corneal tissue 10 in a tissue volume 12 that has a diameter "d1" in the range of around 1-10 microns (d1=1-10 μm). The formation of this plasma is then followed by a shock wave that radiates through the tissue 10. Typically, the shock wave extends from the center of volume 12 through a radius "r" that is approximately twenty microns (r≅20 μm). The shock wave, however, decays within a few nanoseconds. Nevertheless, despite its relatively short duration, the shockwave effect should be kept as small as possible by using pulse energies that are not too far above the threshold for LIOB.
Perhaps, the most pronounced adverse effect from LIOB at relatively low pulse energies is the creation of a cavitation bubble 14. Stated differently, at relatively low pulse energies there is typically no mechanical or thermal damage to peripheral tissue. Instead, a laser pulse having the parameters set forth above will induce LIOB that immediately results in a cavitation bubble 14 (see FIG. 1). There it will be seen that the bubble 14 has a diameter "d2" that will generally be greater than about twice the diameter "d1" of the tissue volume 12 (d2≧2d1). Although the cavitation bubble 14 will eventually decay, as generally indicated in FIG. 2, it has a time dependence that should be accounted for (N.B. FIG. 2 is only exemplary). In particular, FIG. 2 indicates the temporal influence of a cavitation bubble 14 may be considered as continuing through two decay periods. Specifically, the decay of the bubble 14 experiences a first relaxation rate of approximately 10 microns per second (10 μm/sec) during a first decay period, of time "τ". During "τ" the bubble 14 decays to a diameter "d3" which is less than "d2" but greater than "d1" (d1<d2>d3, with d3>d1). Typically, the period "τ" is in the range of about 1-1000 μs and depends on a number of factors including pulse energy density. Thereafter, during a second decay period, the bubble 14 fully dissipates from the diameter "d3" in about 15 to 30 minutes at a second relaxation rate of approximately half a micron per minute (0.5 μm/min).
In light of the above, it is an object of the present invention to provide a system and method for performing laser induced optical breakdown (LIOB) in a substantially transparent material (i.e. the cornea of an eye) wherein a predetermined time period "τ" is interposed between adjacent laser focal spots in a spot pattern. Another object of the present invention is to provide a system and method for performing laser induced optical breakdown (LIOB) in a substantially transparent material (i.e. the cornea of an eye) wherein a pattern of successive focal spots are both spatially and temporally separated from each other. Yet another object of the present invention is to provide a system and method for performing laser induced optical breakdown (LIOB) in a substantially transparent material (i.e. the cornea of an eye) wherein LIOB is induced at a location where the residual influence of earlier LIOB is effectively avoided. Still another object of the present invention is to provide a system and method for performing laser induced optical breakdown (LIOB) in a substantially transparent material (i.e. the cornea of an eye) which is easy to use, relatively simple to manufacture, and comparatively cost effective.

Time-resolved scanning patterns for intrastromal surgery


This invention relates to an induction air handling unit of the type that uses a primary air flow to induce flow of secondary air through the air handling unit. It comprises an induction chamber (2) having an air flow entrance (22) and an air flow exit (23) and a nozzle (10) having an outlet (12) located within the induction chamber (20). The nozzle (10) is connected to a primary air flow that causes a secondary air flow to be induced through the induction chamber (20) via the entrance (22) and the exit (23). The nozzle (10) is characterized by the edge (12) forming an outlet that is of a scalloped shape. This has a dramatic effect on producing noise output from the nozzle (10).

This invention relates to an induction air handling unit, and in particular a nozzle design for an induction air handling unit.
When a gas is discharged from a duct or when it flows through a restriction in a duct, the momentum of the jet is dissipated through mixing with the downstream surroundings. A by-product of this process is the generation of noise which is radiated to the surroundings. It is well established that the sound power which is generated increases at approximately the eighth power of the jet velocity. The efficiency with which it is radiated into the far field of the surroundings depends strongly on both the rate and the scale of the mixing. For a turbulent jet of given mass flow emerging from an orifice of given cross-sectional area, the total sound power radiated decreases as the rate of mixing of the jet with the surroundings increases.
For many years it has been known that the theory of aerodynamic noise generation from turbulent shear flows advanced by Sir James Lighthill, and published in the Proceedings of The Royal Society of London, (On sound generated aerodynamically, Proc. Roy. Soc. A211, p.564, 1952--see also: Waves in fluids, Cambridge University Press, 1978) is incomplete in that it fails to yield reliable predictions of the noise generated by jets at low Mach number. The incompleteness of the Lighthill theoretical model is understandable when it is realised that it was devised before the discovery by G. L. Brown and A. Roshko (Journal of Fluid Mechanics, 64, 775-816, 1974) that the growth of the mixing layer, from which most of the noise emanates, is not continuous but is dominated by the formation of seemingly deterministic vortex-like structures of a scale which is comparable to or larger than the local thickness of the shear layer, and their non-deterministic, intermittent growth by a succession of "amalgamations" between themselves which appear to be little influenced by the turbulent shear layer which they wrap into their structures like jam into a Swiss roll. The magnitude of the disturbances in the flow is many times that which occurs in a simple turbulent shear flow and hence it is reasonable to surmise that these Brown-Roshko vortices may be generating much of the noise. Recent research by Professor N. W. M. Ko and his student Mr R. C. K. Leung at The University of Hong Kong, which has been submitted for publication in the Journal of Sound and Vibration, has advanced a new concept of the noise generation mechanism based on this surmise. The new concept derives from measurements of the processes by which successive Brown-Roshko vortex structures in the shear layer between the jet and the surroundings "pair" together causing the large scale folding, mixing and the intermittent expansion of the jet cross-section. Ko and Leung have found that if a vortex "ring" formed in the mixing layer at the edge of an axisymmetric jet is to "pair" with its predecessor, it must be accelerated rapidly by the pressure field of the leading vortex until it passes through the "eye" of that leading vortex. It is then rapidly retarded and the two vortices merge to become a single larger vortex. The process can be likened to an "extrusion" of the trailing vortex through the eye of the leading vortex. During this "extrusion" process the rates of change of the acceleration of the trailing vortex are very large. In the subject of Mechanics the rate of change of acceleration is known as the "jerk". It is expressed mathematically as the third derivative of distance with respect to time. (It will be recalled that the first derivative of distance with respect to time is the velocity and the second derivative is the acceleration. In solid mechanics it is well known that "jerk" is frequently accompanied by noise; the collision of two marbles and the tapping of a pencil on a table are typical examples). Associated with this extrusion process is a distortion of the shape of the trailing vortex from a nearly circular doughnut shape into a scalloped shape bearing similarities to the nozzle described herein.
The present invention relates to the design of nozzles which stimulate the rapid mixing of jets which discharge into either free or confined surroundings. Of particular interest is the discharge of conditioned air through nozzles for the purposes of cooling or heating a space. An example of this application which involves discharge into "free" surroundings is the "spot cooling" provided for passengers in aircraft. In this application the background noise level is such that the low level of noise achieved by the subject nozzle is of secondary importance compared with the feature of enhanced mixing with the air in the aircraft cabin. A high rate of mixing will allow the same degree of cooling with a smaller quantity of air supplied at a lower temperature than is used in present practice. This would both save energy and produce a more comfortable local cooling around the head and face of passengers without there being an aggressive draught. When applied to the main air conditioning outlets in the aircraft cabin the enhanced mixing and lower temperature of the supply air would also reduce the volume of air needed to cool the cabin when the aircraft is on the ground in a hot climate, or a higher temperature could be used to heat the aircraft when in flight or on the ground in a cold climate.
Other applications of a similar nature are the "spot" cooling or heating of the driver of, for example, an agricultural tractor, a fork lift truck, an excavator, a Load-Haul-Dump vehicle above or below ground, and a crane, among many others. The driver and passengers or crew of a bus, a heavy transport vehicle, a rail vehicle, an armoured military vehicle, an automobile or other transport vehicle would also benefit from the use of the present nozzles in the conditioned air supply system. Again, in these examples the background noise level is high and the low noise characteristic of the subject nozzle is of secondary interest relative to its ability to achieve rapid mixing of the primary air jet with the surroundings. This ability allows the conditioned air to be admitted close to the occupant of the vehicle without producing an undesirable level of draught. Other applications of the nozzles, in all of which excessive draught is undesirable and in most of which a low level of noise is desirable, are exemplified by "spot" cooling or heating of personal work spaces within a factory, an office, a space craft or a submarine, the cooling of electronic components or equipment, the cooling of processes and mechanisms.
An induction air conditioning system relies on the discharge through nozzles as jets of a first or primary stream of cooled and dehumidified, or heated and if necessary humidified air into a confined space within an induction air conditioning unit before discharging to the conditioned space, herein referred to as the room. One boundary of the confined space within the induction unit takes the form of heat exchange means through which a secondary stream of air, originating from the room, is drawn to replace the quantity of air from within said confined space which is entrained into the primary air jet or jets. This occurs naturally because the entrainment by the primary air jet or jets causes the static pressure in the confined space to be reduced below the pressure surrounding the induction unit. The psychrometric state of the secondary stream of air may be changed as it passes through the heat exchange means. The mixture of the primary air and the secondary air streams is then discharged into said conditioned space to provide the required cooling or heating and to provide ventilation.
In such induction air conditioning systems the primary air stream usually consists of air from outside the building often, but not necessarily, mixed with a proportion of air returned from the conditioned space. This primary air is treated in one or more primary air treatment plants before it is ducted to the induction units so that, after having been mixed with the induced secondary air stream within the induction air conditioning units, it is at the temperature and humidity ratio necessary to offset the sensible and latent heat loads in the conditioned space. When used in conjunction with the invention described in Australian Patent 662336 entitled Air conditioning for humid climates, which is now commonly referred to as the High Driving Potential, or HDP system, the primary air can be deeply cooled and dehumidified before being mixed with the entrained secondary air from the room. The efficient mixing produced by the jets from the multi-lobe nozzles will ensure that the air mixture which reaches the occupants is at the desired temperature and moisture content. The most common application of induction air conditioning systems is to condition the air in the space bounded by the building perimeter walls and an often imaginary line some 3 to 6 meters in from said perimeter walls on each level of the building.
The space so defined is referred to as the perimeter zone. A perimeter zone may be physically defined by partitioned offices or may be open space which merges with the interior zone of the building. A conventional air conditioning system usually feeds the whole of the treated air, at modest pressure, from a plant room or air supply shaft through ducts mounted above the ceiling, and thence to ceiling mounted supply air registers distributed throughout the space. Such supply air ducts, because they convey the whole of the conditioned supply air at low pressure, necessarily have relatively large cross-sections. In combination with the depth of the structural beams associated with the floor slab of the next level of the building, they set the required height of the ceiling space and therefore have a determining influence on the required slab-to-slab spacing. In many cities or parts of cities a height restriction is placed on buildings. Thus the size of the air conditioning ducts in the ceiling has a major influence on the number of levels or floors in the building, and hence on the rentable floor space.
Because perimeter induction units carry only primary treated air and do so at relatively high pressure, they are much smaller in cross-section than are the conventional supply air ducts. In one example in the city of Adelaide in South Australia, the use of an induction system to air condition the perimeter zones of the building allowed thirteen levels to be built within a height restriction appropriate to a conventional twelve story building.
The treated primary air streams in a perimeter induction system supply to the perimeter zone at least that quantity of pre-treated outdoor air which is required, by regulation or by best practice, to ventilate the zone. A common criterion used by designers is to require the primary air to offset heat which is transmitted through the perimeter walls and windows which bound the perimeter zone. The heat exchange means within the perimeter induction units which treat the induced secondary air are designed to offset all other loads which originate within the conditioned space of the perimeter zone including people, electrically powered devices, and lighting.
In addition to the abovementioned advantage of requiring less ceiling space than conventional air conditioning systems, induction systems require smaller and hence less expensive and less intrusive ducts to supply air from the primary air plant to each level of the building and to the conditioned space on each level. They do not require separate plant rooms which intrude into the potentially rentable space. Thus in terms of invested capital they are less expensive both to purchase and to install than are conventional air conditioning systems and they increase the proportion of the building which is counted as rentable space. Hence the return on investment can be larger than for conventionally serviced buildings. These advantages have in the past caused induction air conditioning systems to be preferred by many building owners and developers. Many such systems have been installed in buildings in many countries since the second world war.
Despite the apparent economic advantages of the system from the viewpoint of building developers, and from the viewpoint of building owners who pass on to their tenants the operating costs of the air conditioning, induction air conditioning systems have proved to be less than well received by tenants.
Because the induction units are located within the conditioned space, tenants are exposed to the noise generated by the primary air jets as they entrain the secondary air which is induced from the conditioned space to flow into the units through the heat exchange means. This noise has frequently been cause for complaint by tenants. Research by the Trane Company Inc (J. B. Custer, "The economics and marketing of tenant comfort", Proc. AIRAHFAIR-88, Sydney, AIRAH, 1988) has shown that discontent with the air conditioning, expressed through complaints about the operating cost, "staleness" of the air in the conditioned space, or the noise level, is one of the most common reasons reported by tenants for terminating a building lease. That research also showed that from the building owner's viewpoint, the cost of losing a tenant, finding and installing another is typically equivalent to approximately six months rental income from the leased space. Such losses can rapidly erode the advantage of the lower capital cost per unit of rentable area in the building.
A more important problem which magnifies tenant discontent is that in warmer climates the cooling capacity of that quantity of treated primary air which is required for ventilation is insufficient to offset the transmission load to the perimeter zone. Furthermore the quantity of secondary air which can be induced to flow through the secondary air heat exchange means by the jets supplying only ventilation air as the treated primary air is almost always inadequate to offset the internally generated load within the perimeter zone. Hence it has been necessary to increase the quantity of treated primary air both to offset the transmission load and to induce sufficient secondary air to flow through the secondary air heat exchange means to offset the loads generated within the perimeter zone. The increase of treated primary air is effected by increasing the pressure at which said primary air is supplied to the nozzles.
This increases the velocity at which the primary air is discharged from the nozzles. As indicated above, the noise generated by a jet is approximately proportional to the eighth power of its velocity.
Thus the increased cooling capacity is obtained at the direct cost of treating a greater quantity of hot and/or humid outdoor air. Another potential direct cost of the increased primary air pressure is tenant discontent due to the further increase in the noise radiated from the induction units into the conditioned space. For thirty years after the second world war the cost of energy remained low and operating costs were of small importance, thus the direct cost could be tolerated. That period was also one of rapid economic growth; office space was in short supply and hence tenants were unwilling to terminate a lease. Thus the inconvenience of the noise was tolerated. The very different economic climate of the 1990's with its surfeit of office space in many countries, higher cost of energy and growing concern about global warming has changed the situation substantially. Tenants find relocation both economically and environmentally attractive; owners find that while rental margins remain low and buildings are not fully occupied, operating costs are a serious concern.
To improve the occupational health of existing buildings equipped with induction air conditioning systems, and to improve their profitability for the owners of such buildings, it is an object of this invention to specify a nozzle and a means of profiling one or more of the boundaries of the confined space within existing induction air conditioning units in such manner that the interaction of the two will overcome the abovementioned problems. Similar principles are applicable also for new designs of induction air conditioning system and for the design of zone control boxes for conventional Variable Air Volume (VAV) systems.
It is a further object of the invention to specify a nozzle which can reduce the volume of noise generated at the outlet from a duct or at a change in the cross-section of a duct. More specifically, it is an object of the invention to increase the rate at which a primary air stream can induce a secondary air stream to flow through secondary air heat exchange means so to increase the effectiveness of induction air conditioning units and allow the velocity and hence the supply pressure of the primary air stream, and hence the noise generated by the jets, all to be reduced. As stated above, the noise generated by a jet is approximately proportional to the eighth power of the jet velocity. Hence it is apparent that a reduction in jet velocity can have a dramatic effect on the noise radiated from said induction air conditioning units or from VAV control boxes.


The present invention relates to a device for detecting and monitoring physiological conditions in mammalian tissue, and method for using the same. The device includes sensors for sensing physiological conditions and generating signals in response thereto and processor operatively associated with the sensors for receiving and manipulating the signals to produce a generalization indicative of normal and abnormal physiological condition of mammalian tissue. The processor is characterized to include a neural network having a predetermined solution spaced memory, the solution space memory including regions indicative of two (2) or more physiological conditions, wherein the generalization is characterized by the signals projected into the regions.

This invention is directed to a device which indicates abnormal physiological conditions, and more particularly to, but not by way of limitation, a device for monitoring mammalian temperature for use in determining cancerous conditions.
It is known that areas of mammalian tissue adjacent to carcinomas exhibit increased temperature from that exhibited contemporaneously by non-adjacent, non-cancerous areas. The temperature of the cancer-affected areas can fluctuate several degrees Centigrade from normal tissue; these differences having been demonstrated while monitoring such areas for a 24-hour period (one circadian cycle).
It had been thought that an abnormal temperature pattern associated with a tumor is a product of accelerated metabolism. Evidence now suggests that local metabolic heat generation may be a second order effect since the majority of thermal signals are related to the function of increased regional blood flow caused by local angiogenesis. A slight overall increase in the temperature of the surrounding tissue, for instance in localized areas of a woman's breast, can occur and is usually related to the vascular convection of heat that occurs as a result of capillary dilatation and the secondary increase in blood flow coupled with the higher temperature of the blood derived from the vascular bed and the possible vasodilator effect of catabolic products of tumor metabolism. These vascular manifestations of heat production are of prime importance in the detection of subclinical or minimal cancers.
A prior device used for detecting cancer is a brassiere which includes a plurality of temperature sensors, an analog multiplexer circuit, a control circuit, a sample and hold circuit, an analog/digital converter, a buffer register, a storage register, a clock and a data logger. The device allows for the storage of temperature readings in a digital form. This digital data may be uploaded to the data logger which converts the digital signals to decimal form so that the temperature differences may be read and analyzed by a supervising physician.
Several problems exist with the brassiere device. The brassieres must be capable of fitting a full range of breast sizes since tissue contact is essential to device performance. Also, this system would be expensive requiring individual brassieres to be prepared for each user since it is unlikely that an individual would wear a brassiere which was previously worn by another person for extended periods of time due to the nature of the device. Thus, a disposable brassiere would be desired.
Furthermore, the temperature sensors of the brassiere device are affixed on its inner surface. Ideally, all sensors are in contact with the skin when the brassiere is positioned about the breast. Realistically, however, in the normal course of wear, the sensors will frequently not be in contact with the skin. Lack of contact causes the sensors to produce false skin temperature readings. It is also noted that such device does not disclose a need or means for calibrating the sensors. Any diagnosis based on uncalibrated sensor readings could be faulty.
Other devices use a passive thermographic analytical apparatus which provides a direct readout of the results through analysis of a thermographic radiation pattern of the human body. Such devices include a matrix of infra-red energy sensors and reflectors which are mounted in a closed, spaced array to produce a pattern of temperature measurement of the aligned areas of the body. The sensors simultaneously or sequentially read a thermographic pattern and develop analog signals which are converted into the appropriate digital form and are stored in a memory. The digital signals are then analyzed by a central processing unit (cpu) in accordance with a particular spatial pattern recognition software program. The program includes an algorithm having a number of parameters used in comparing differences in temperatures throughout the breasts to give a probability of breast normality or abnormality.
Unfortunately, such devices are unable to detect small tumors on the order of less than 0.5 cm. This seems to be due to the resolution and sensitivity capabilities of the thermographic sensors. Another problem with such devices is that the cpu will give inaccurate results if internal failure occurs at any point in the computer's probability program. Faulty readings from the thermographic pattern cause the software program to generate inaccurate results.
Of even greater concern, such thermographic devices do not take into account the chaotic fluctuation of normal body temperatures over time and between locations on the body. The temperatures between the left and right breasts may vary as much as 7 degrees Centigrade during any one circadian cycle. Since the patient is required to remain i front of the scanning apparatus of the thermographic device for only a short period of time in order to take a thermographic picture, that picture only represents one moment in time and is not representative of the actual condition of the breast over a long period of time. An analysis based on such thermographic results could be totally inaccurate.
One common and widely used technique for determining existence of breast cancer is mammography. This radiological technique passes ionizing radiation through the breast, which is per se invasive, to produce a radiographic which should report tumors as darkened areas. This method of detecting breast cancer is limited by the age and condition of the tissue examined. If the tissue is dense, as is characteristic of breast tissue in younger women, the image produced is more uniform in color causing detection of tumors to be more difficult. Further disadvantages of the previous systems are that they are relatively expensive and cumbersome compared to the present invention.

Device for detecting cancerous and precancerous conditions in a breast


Approaches for controlling power supplied to an electric grid are disclosed. In embodiments, methods and systems control power supplied to an electric grid using an energy storage device. In an embodiment, a method receives an indication of power to be supplied to the electric grid, generates power from a power generator and adjusts, using the generated power, an energy level of the energy storage device to control power supplied to the grid in accordance with the received indication. In another embodiment, a system comprises a grid indication receiver for receiving an indication of power to be supplied to the electric grid; a power generator connected to the grid; an energy storage device coupled to the power generator; and a controller for adjusting, using the generated power from the generator, an energy level of the energy storage device to control power supplied to the grid in accordance with the received indication.

Typically, a utility obtains electric power from one or more primary power generation sources, such as gas-fired, coal-fired, nuclear and/or hydroelectric power plants, for delivery to customers via a distribution grid. The power supplied by these sources can vary moment-to-moment. Generally, the sources can be regulated to meet the demands of customers while at the same time conforming to the standards for such power, such as nominal voltage and frequency levels.
To supplement the power supplied by these primary sources, it is becoming more common to connect secondary sources of power, such as solar panels and windmills, to the electric distribution grid. Among other advantages, these secondary forms of energy are renewable, in contrast to the primary sources.

Hybrid electric generating power plant that uses a combination of real-time generation facilities and energy storage system


An apparatus for convolution operation is provided. The apparatus includes: a plurality of multipliers configured to receive matrix elements of two matrices, and multiply respective matrix elements to generate a plurality of product elements; a plurality of distributed caches each including a plurality of cache units and configured to respectively store the plurality of product elements in respective cache units; a register delay chain including a plurality of registers coupled in series and configured to receive a read control signal, delay the read control signal per stage to output a plurality of per-stage delayed read control signals, and respectively provide, to the plurality of distributed caches, the read control signal and the plurality of per-stage delayed read control signals; and an accumulator circuit configured to receive product elements in cache units corresponding to the read control signal and the plurality of per-stage delayed read control signals, and to generate an accumulation data based on the received product elements.

With the proposal and development of deep learning, convolutional neural networks have received increasing attention and have been developed. Convolution algorithm is the core algorithm of the convolutional neural network, and accounts for 90% of operation time of a convolutional neural network. Therefore, convolution operations are the primary optimization objects for designing a neural network hardware accelerator based on a field programmable gate array (FPGA). Hardware circuit design for convolution algorithm directly affects resource usage of the hardware accelerator and computing power that can be achieved.
An adder tree structure, which is defined based on a convolution algorithm, is employed in one of conventional solutions. In the implementation of adder tree for convolution, six dimensions of convolution calculation are fully expanded based on a 6-layer loop characteristics of the convolution algorithm. To be specific, multiplication is first performed between corresponding points in a filter matrix and in an input data matrix, and then accumulation is performed per point within a window of the filter matrix and in the direction of a channel. This implementation is simple and straightforward. However, this implementation also has obvious shortcomings. If the dimension of computing is increased, the depth of an adder needs to be increased, and the amount of consumed resource increases exponentially, which is unacceptable for a resource-sensitive FPGA.

Apparatus and method for convolution operation

APOLLO INTELLIGENT DRIVING TECHNOLOGY (BEIJING) CO., LTD.


An input-display device includes a display screen on a display substrate and capacitive sensing electrodes for capacitive sensing in a sensing region of the display screen. The input-display device also includes a touch and display driver integration (TDDI) circuit on the display substrate, the TDDI circuit including a source driver circuit driving a subset of display pixels of the display screen based on a processed image signal, and an analog frontend for the capacitive sensing, interfacing with the capacitive sensing electrodes to obtain touch signals. The input-display device also includes an image processing circuit generating the processed image signal based on a received image signal and a display parameter, a touch processing circuit generating a touch output signal by processing the touch signals based on instructions of a touch firmware, and a memory physically separate from the display substrate, the memory storing the display parameter and the touch firmware.

Input devices including proximity sensor devices (e.g., touchpads or touch sensor devices) are widely used in a variety of electronic systems. A proximity sensor device typically includes a sensing region, often demarked by a surface, in which the proximity sensor device determines the presence, location and/or motion of one or more input objects. Proximity sensor devices may be used to provide interfaces for the electronic system. For example, proximity sensor devices are often used as input devices for larger computing systems (such as opaque touchpads integrated in, or peripheral to, notebook or desktop computers). Proximity sensor devices are often combined with display devices to operate as input-display devices (such as touch screens integrated in cellular phones).
In an input-display device, the proximity sensor device may require memory, e.g., for the storage of a firmware. Further, in an input-display device, the display device may also require memory, e.g., for the storage of display parameters.


Methods, systems, and devices for wireless communications are described for transmissions of multiple instances of control information, such as remaining minimum system information (RMSI) that may be used for system access by a user equipment (UE). The multiple instances of the control information may be transmitted in a number of monitoring occasions that may be monitored by a UE, and within the monitoring occasions, the control information may be transmitted using different time locations, frequency locations, or combinations thereof. The locations may be identified based at least in part on one or more parameters associated with at least a first monitoring occasion. The one or more parameters may include an identification parameter associated with the base station or monitoring occasion, an index value associated with the monitoring occasion, a frequency parameter associated with the monitoring occasion, a control information multiplexing pattern, or any combination thereof.

The following relates generally to wireless communications, and more specifically to resource identification techniques for combining multiple instances of system information.
Wireless communications systems are widely deployed to provide various types of communication content such as voice, video, packet data, messaging, broadcast, and so on. These systems may be capable of supporting communication with multiple users by sharing the available system resources (e.g., time, frequency, and power). Examples of such multiple-access systems include fourth generation (4G) systems such as Long Term Evolution (LTE) systems, LTE-Advanced (LTE-A) systems, or LTE-A Pro systems, and fifth generation (5G) systems which may be referred to as New Radio (NR) systems. These systems may employ technologies such as code division multiple access (CDMA), time division multiple access (TDMA), frequency division multiple access (FDMA), orthogonal frequency division multiple access (OFDMA), or discrete Fourier transform-spread-OFDM (DFT-S-OFDM). A wireless multiple-access communications system may include a number of base stations or network access nodes, each simultaneously supporting communication for multiple communication devices, which may be otherwise known as user equipment (UE).
A base station may send control transmissions that may allow one or more UEs to identify various pieces of system information that may be used for system access. In some systems, a base station may transmit one or more synchronization signal blocks (SSBs) to one or more UEs, which may include system information. The UEs may be configured to monitor for system information within a search space, which may include multiple search candidates. For instance, each search space may include multiple control resource sets (CORESETs) containing multiple control channel elements (CCEs). The UE may be configured to monitor one or more search candidates in the search space, and may blindly decode the one or more CCEs of the search candidate to receive the control information. In some cases, one or more UEs may have channel conditions that may lead to lower reliability in receiving and decoding such control transmissions. Techniques for enhancing the likelihood of receiving control transmissions thus may be desirable and may enhance system efficiency and reliability.

This patent is subject to a terminal disclaimer.

Resource identification techniques for combining multiple instances of system information


An apparatus and a method for driving control of a vehicle include a sensor including a laser sensor disposed in front of the vehicle A controller is configured to calculate a defile width in front of the vehicle based on an angle between a reference segment and an inference segment by recognizing sensing data passing through a reference point at which a virtual standard segment is in contact with the inference segment and a reference segment after confirming a position of an obstacle positioning in front of the vehicle using the sensing data received from the sensor. The controller generates the virtual standard segment for the obstacle based on the confirmed position and generates the inference segment which is perpendicular to the virtual standard segment. An output outputs a driving guide to the calculated defile under control of the controller.

Generally, when a driver drives a vehicle in defile, the driver can use a side mirror of the vehicle or a room mirror mounted in the inside of the vehicle, or can directly use the naked eye to recognize a surrounding situation.
However, if the vehicle moves forward or backward in the defile, there exists a blind spot, in which the driver cannot see the entire surrounding area, in the front or rear sides of the vehicle even while using the side mirror or the rearview mirror or the naked eye. Therefore, a fender bender or damage of the vehicle can occur.
In addition, since many vehicles are parked or stopped in a narrow parking area, such as alleys in residential district, an unexpected defile often exits. Thus, it is difficult to drive vehicles on narrow streets and alleys due to the unexpected defile.

Apparatus and method for driving control of vehicle


A weld preparation process that translates a consumable or nonconsumable tool over an area that is subsequently to be welded to impart friction heating to the surface. Rotary or linearly oscillated motion between the tool and the workpiece is used to generate heat and produce deformation in the surface, resulting in recrystallization of the area being processed and a compressive residual stress.

1. Field of the Invention
The present invention relates in general to metal processing techniques and, more particularly, to processes involving the fabrication or welding of advanced nickel-base superalloys.
2. Related Art
The typical nickel-base superalloy is essentially a nickel-chromium solid solution (γ phase) hardened by the addition of materials such as aluminum and/or titanium to precipitate an intermetallic compound (γ′ phase). The predominant intermetallic compound precipitated, represented by the formula Ni3 (Al, Ti), is an ordered, face centered-cubic structure with aluminum and titanium at the corners of the unit cell and nickel at the face centers. These alloys also normally contain cobalt to raise the solvus temperature of the γ′ phase, refractory metal additions for solution strengthening, and carbon, boron and zirconium to promote ductility and fabricability.
In the gas turbine engine industry in which the nickel-base superalloys are widely utilized, progressive increases in the powerplant performance requirements have led to increases in engine operating temperatures which have in turn imposed increasingly stringent demands on the turbine materials. Historically, the extent of the engine temperature increases has been limited by the physical characteristics of the hot section alloys, particularly those used in the highly stressed components such as turbine blades and vanes. Recent alloy developments, promising advances in coating technology, and the use of internal cooling techniques, however, will now allow turbine operating temperatures to be significantly increased.
Repair of gas turbine got-section components made of superalloys are often carried out by welding. These nickel-base superalloys, especially those advanced grades containing relatively high contents of the strengthening γ′ phase, are susceptible to cracking during the post-weld heat treatment that is employed to regenerate the desired microstructure-dependent properties. As a result, these superalloys are considered to be difficult to weld materials. One way to improve the weldability of this group of superalloys is to subject the materials to a pre-weld averaging treatment. This increases the material ductility which, in turn, helps to limit the buildup of residual stress produced by welding, and reduces the susceptibility to post-weld heat treatment cracking of the material. One such averaging treatment is described in U.S. Pat. No. 5,509,980 and is complex, time consuming and costly.
Accordingly, it is an object of the present invention to provide a relatively short time pre-weld preparation treatment that renders difficult or marginally weldable precipitation hardenable nickel-base superalloys readily weldable without weld-associated cracking during post-weld heat treatment.
It is a further object of the present invention to provide a relatively short time pre-weld preparation treatment that renders difficult or marginally weldable precipitation hardenable nickel-base superalloys readily weldable without the need for alloy compositional modifications and without the need for changes to otherwise conventional fusion welding procedures.


A method and an apparatus for automatically extracting image features of electrical imaging well logging, wherein the method comprises the steps of: acquiring historical data of electrical imaging well logging; pre-processing the historical data of the electrical imaging well logging to generate an electrical imaging well logging image covering a full hole; recognizing and marking a typical geological feature in the electrical imaging well logging image covering the full hole, obtaining a processed image, and determining the processed image as a training sample according to types of the geological features; constructing a deep learning model including an input layer, a plurality of hidden layers, and an output layer; training the deep learning model using the training sample; using the trained deep learning model, recognizing type of a geological feature of an electrical imaging well logging image of a well section to be recognized, and performing morphological optimization processing on the recognition result to obtain a feature optimization recognition result. The solution can automatically, quickly and accurately recognize the typical geological features in the electrical imaging well logging image.

Electrical imaging well logging is the most widely used imaging well logging method at present, through which images can visually display stratum deposition and structural features such as mud, crumbs, calcite crystals, pores, fractures, bedding and faults, folds and the like, and provides an important basis for reservoir comprehensive analysis. The traditional electrical imaging well logging image interpretation is mainly that an expert performs qualitative discrimination directly on all kinds of features based on the experience, which highly depends on the expert experience, has a strong interpretation subjectivity, and is difficult to meet the urgent need of oil field exploration and production. How to accurately recognize, classify and quantitatively extract all kinds of geological features on electrical imaging well logging images is the key to realize automatic and intelligent processing of electrical imaging well logging data.
In the prior art, automatic recognition and extraction of electrical imaging well logging image features are carried out by performing binarization processing on the electrical imaging well logging images by an image segmentation algorithm to separate feature regions and then calculate feature parameters such as color, shape, texture and the like of the feature regions, and finally classify and extract the features by methods such as fuzzy mathematics, neural network and the like. Although such methods achieves certain effects in practical application, they still have the following problems: 1) the feature extraction effect is controlled by image segmentation quality, because of the complexity of the actual geological situation, in continuous processing in a long well section, it is difficult to achieve accurate separation of image features, which causes loss or misjudgment of feature extraction; 2) classification methods based on the statistics of the feature parameters are influenced by the selected parameter indexes, so that the recognition accuracy is limited, and the classification methods are usually related to geological conditions of specific regions, and thus the universality is poor; 3) in the prior art, generally only specific geological feature targets such as fracture and caves are recognized and extracted, which cannot meet differentiation and diversity needs of geological research and reservoir evaluation.

Method for automatically extracting image features of electrical imaging well logging, computer equipment and non-transitory computer readable medium


In some embodiments, therapeutic treatments for a disease such as a cancer are disclosed, including pharmaceutical compositions and methods of using pharmaceutical compositions for treating the cancer wherein the cancer cells overexpress arginine methyltransferase CARM1. In some embodiments, the therapeutic treatments disclosed include methods comprising the step of administering a therapeutically effective dose of an enhancer of zeste homolog 2 (EZH2) inhibitor to a subject, including a human subject, wherein the cancer cells of the subject overexpress arginine methyltransferase CARM1. In some embodiments, the EZH2 inhibitors are administered in conjunction with platinum-based antineoplastic drugs.

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the United States. Despite the recent advances in targeted therapy in different types of cancer, platinum based therapies such as cisplatin remain the standard of care for EOC patients. Recent discoveries have demonstrated that ovarian cancer is composed of multiple separate diseases. High-grade serous ovarian cancer (HGSOC) is the most common subtype (>70% of EOC cases) and accounts for the majority of EOC-associated mortalities. Although many patients initially respond to cisplatin, the majority of these patients become resistant and the mechanism of this resistance is not fully understood. Epigenetic regulation has been shown to play an important role in tumor progression and specifically in the development of platinum therapy resistance. Thus, it is important to identify epigenetic factors that are responsible for cisplatin resistance in EOC.
SWI/SNF (Switch/Sucrose Non-Fermentable) is a chromatin remodeling complex that is often dysregulated in different types of cancer. The activity of the SWI/SNF complex is tightly regulated and multiple subunits of SWI/SNF are post-translationally modified. BAF155, one of the subunits of SWI/SNF complex, is methylated by coactivator-associated arginine methyltransferase 1 (CARM1), also known as protein arginine methyltransferase 4 (PRMT4). This modification has been shown to enhance tumor progression and metastasis. Wang, et al., Cancer Cell, 2014, 25, 21-36. CARM1 has been shown to methylate substrates involved in epigenetic chromatin remodeling. This suggests that epigenetic mechanisms play a key role in CARM1-expressing cancers. Interestingly, the CARM1 gene is amplified in 10% of high-grade ovarian cancer patients and CARM1 amplification is associated with poor prognosis in EOC patients.
Polycomb-repressive complex 2 (PRC2) is a multiprotein complex that negatively regulates the expression of large numbers of genes by generating a silencing histone modification (H3K27me3) through its catalytic subunit enhancer of zeste homolog 2 (EZH2). Many of the genes regulated by PRC2 are involved in cancer progression, and dysregulation of PRC2 function is observed in many different types of cancer including EOC. Recent studies have shown that SWI/SNF and PRC2 complexes play an antagonistic role in tumorigenesis. Wilson, et al., Cancer Cell 2010, 184, 316-328. EZH2 is highly expressed in many cancers, including breast cancer, prostate cancer, and lymphoma, and is frequently associated with tumor progression and poor outcomes. Furthermore, mutated forms of EZH2, including somatic heterozygous mutations of the Y641 and A677 residues of the catalytic SET domain, are observed in some cancers including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Morin, et al., Nature 2011, 476, 298-303; Ryan, et al. PLoS ONE 2011, 6, e28585; Morin, et al., Nature Genet. 2010, 42, 181-185.
A number of selective small molecule EZH2 inhibitors have been identified and progressed into clinical development. Momparler and Côté, Expert Opin. Investig. Drugs 2015, 24, 1031-43; Melnick, Cancer Cell 2012, 22, 569-70. EZH2 inhibitors are currently being investigated for the treatment of cancers exhibiting overexpression of EZH2, including B cell lymphomas such as DLBCL, Germinal center B-cell DLBCL (GCB-DLBCL), and non-Hodgkin's lymphoma, follicular lymphoma, multiple myeloma, INI1-negative tumors, synovial sarcoma, breast cancer, prostate cancer, and other solid tumors. For example, the EZH2 inhibitor tazemetostat (EPZ-6438) has potent activity against EZH2-mutated non-Hodgkin's lymphoma. Knutson, et al., Mol. Cancer. Ther. 2014, 13, 842-854.
The present invention provides the unexpected finding that EZH2 inhibitors may be used to effectively treat cancers that overexpress CARM1. The present invention further provides the unexpected finding that combinations of EZH2 inhibitors and platinum-based antineoplastic agents are surprisingly effective in the treatment of any of several subtypes of cancers, such as solid tumor cancers, wherein a biological sample exhibits CARM1 overexpression.

Methods of treating cancers overexpressing CARM1 with EZH2 inhibitors and platinum-based antineoplastic drugs

The Wistar Institute of Anatomy and Biology


In a method for modifying at least one calculation algorithm in a biopsy system and a biopsy system operating according to the method, a phantom is placed in a specific position on an object table in a biopsy system and the phantom is irradiated with penetrating radiation from at least two angles to produce at least two images. The phantom contains markers at exact positions, and the calculation algorithm can be modified on the basis of information on the known positions of the markers and image information in the two exposures.

1. Field of the Invention
The present invention relates to a method for modifying at least one calculation algorithm in a biopsy system, the calculation algorithm having an influence on the determination of the position of a cell or tissue-sampling area in a stereotactic biopsy procedure.
2. Description of the Prior Art
The present invention also relates to a stereotactic biopsy system for examining the breast, the female breast in particular, of the type having a mammography apparatus, a biopsy apparatus and a calculation unit for stereotactic calculation of the position of a cell or tissue-sampling area.
Swedish Patent Application, SE-8306243-0, discloses a method for locating the position of a three-dimensional point in an object, e.g. a female breast, in conjunction with x-ray irradiation of that object. This is achieved by fixing the object in a predefined position, whereupon it is exposed with an exposure apparatus from two angles on either side of a center line perpendicular to the image plane, so that a first image and a second image are obtained. The two-dimensional position of the sought point in the two images is then determined in relation to an index in each of the images. The coordinates of the point in relation to the index are processed to obtain control signals for setting an aiming instrument, with an insertion instrument, to the desired point in the object.
U.S. Pat. No. 5,240,011 discloses a motor-driven unit for use in a biopsy system for automatic positioning of a biopsy needle in order to allow insertion of the needle to a previously identified point of interest in the breast of a patient.
Even though most contemporary stereotactic mammographic biopsies are made using film, systems incorporating digital image detectors have been introduced for mammography in recent years.
Extreme accuracy is required in all types of stereotactic biopsies in determining the x, y, z coordinates of a cell or tissue-sampling area in which a suspected tumor or some other tissue change has been discovered. The physician needs to be absolutely certain that a specimen has been taken from the interesting (suspicious) area. Locations are determined with a calculation algorithm which includes e.g. the apparatus constants of the system. If this very high degree of accuracy is to be achieved, very exact values for apparatus constants must be used, which truly correspond to system realities. Examples of apparatus constants are the x-ray tube's angle of inclination, the x-ray focus-detector distance, the distance to the axis of rotation, the table top-to-focus distance and the table top-to-detector distance.
Installation of a stereotactic biopsy unit is often a very time-consuming and patience-demanding procedure, since calibration of the tube's angle of inclination (an apparatus constant) is often necessary. Calibration is also performed during the manufacture and service of systems, especially when usage-induced wear can affect the apparatus constants which have been previously set.

Method for modifying at least one calculation algorithm in a biopsy system, and biopsy system operating according to the method


An ignition coil includes primary and secondary coils, center and outer cores, and an ion current detector for transmitting an ion current detection output. The center core has an axial upper end defining a center core upper end surface. The outer core has an axial upper end defining an outer core upper end surface. The center core upper end surface axially protrudes upwardly relative to the outer core upper end surface. The center core upper end surface is located at a stagger distance axially from the outer core upper end surface. The stagger distance is defined such that a detection period for residual magnetic noise in the ion current detection output falls within a system requirement period of a control unit.

An ignition coil provided with a sparkplug is mounted to an engine of a vehicle. The sparkplug generates spark to ignite mixture of fuel and air in each cylinder of the engine. When the mixture is burned in the cylinder, fuel contained in the mixture is ionized, so that an ion current flows between a pair of electrodes provided to the sparkplug. An ion current detector is provided to such an ignition coil to detect an ion current for monitoring misfire in the cylinder.
The ignition coil generates therein an inductive magnetic field by terminating electricity supplied to a primary coil of the ignition coil. The inductive magnetic field generates induced electromotive force in a secondary coil of the ignition oil, so that the pair of electrodes of the sparkplug generates spark. Immediately after generating the spark by forming the inductive magnetic field, residual magnetism remains in the ignition oil. The ion current detector may falsely detect noise, which is caused by the residual magnetism, as the ion current. Accordingly, the ion current detector detects the ion current by waiting a predetermined period after generating the spark.
According to U.S. Pat. No. 5,866,808 (JP-A-H9-195913), the ion current detector has a structure capable of stably detecting the ion current by reducing residual magnetism. Furthermore, according to the ignition coil in JP-U-3028977, the cross section of the outer core is set to be in a range between 75% and 100% of the cross section of the center core, thereby enhancing ignition energy of the ignition coil.
However, the above conventional structure of each ignition coil is not sufficient to stabilize detection of the ion current. Specifically, in the above conventional structure of each ignition coil, a relationship between axial end surfaces of the center core and the outer core on the axially opposite side of the spark plug is not considered. Accordingly, the above conventional structure is not sufficient to enhance accuracy in the detection of the ion current.

Ignition coil and ignition coil system having the same


A satellite positioning device is disclosed for determining position based on received satellite navigation signals and a received non-satellite signal. A local clock controls the epoch period of a satellite signal processor. Correction signals are applied to the local clock in order to improve the synchronization between the satellite signal processor and the non-satellite signal processor.

This invention relates generally to satellite navigation systems, and more particularly to controlling solution latency in a satellite navigation system.
Global Navigation Satellite Systems (GNSS) are well known and used to solve a wide variety of positioning/time related tasks. Two well known such systems are the Global Positioning System (GPS) of the United States and the GLObal NAvigation Satellite System (GLONASS) of Russia. This description will generally refer to the GPS system, but it is to be understood that the present description is equally applicable to GLONASS or other GNSS systems.
In recent years, there have been significant developments in the use of GPS receivers in the surveying and construction industries. In surveying applications, GPS is generally used to determine locations of points on the ground. GPS receivers are also being used for machine control in which the GPS position information is used to control construction machines. For example, GPS positioning information may be used to dynamically control a bulldozer blade. The use of GPS positioning in surveying and machine control provides many benefits, including responsiveness, reliability, autonomy, and all-weather operation.
The accuracy of GPS positioning has been improved by integrating other sources of positioning information with the GPS positioning receiver. These other sources provide additional positioning information which allows for a more accurate positioning solution. One example of such integration is in aviation, where it is common to integrate inertial sensors with GPS receivers. One reason for such integration is that inertial sensors have small short-term error and large long-term error, while GPS receivers have large short-term error and small long-term error. The integration of inertial sensors with GPS receivers provides a complement and allows a combined device to reduce both short-term and long-term errors. This improves the accuracy of positioning determination.
Typical examples of inertial sensors are accelerometers and gyros. Accelerometers measure acceleration and gyros measure angular rate. One typical integration technique is to provide an Inertial Measurement Unit (IMU) consisting of three accelerometers and three gyros. Sensors in each triad are orientated in mutually perpendicular directions. The sensor signals are digitized using an Analog to Digital Converter (ADC) and provided to the GPS receiver where they are combined with the GPS data.
An important requirement of an integrated IMU/GPS system is time synchronization of the GPS and IMU data. In other words, the data that is generated by each of the systems should have the same time reference point. Otherwise, the benefits of integrating the two systems will be reduced because there will be a reduction in accuracy of the ultimate positioning result obtained. In an IMU of the type described above, synchronization is generally accomplished as follows. The GPS receiver calculates position information at periodic time moments, referred to herein as epochs, which are defined by a local clock signal within the GPS receiver. The local clock signal is formed using a high quality quartz generator. The GPS receiver outputs this local clock signal to the IMU. The IMU outputs its data to the receiver in response to the local clock signal. The IMU and GPS are synchronized by controlling the timing of the IMU's data generation by the GPS clock signal.
There are sources of positioning and geometric information which are not so easily synchronized. For example, there exist devices which provide positioning/geometric information where the precise moment of data generation cannot be controlled via a GPS clock signal. One such device is a rotating laser system which may be used to determine additional positioning/geometric information. Such a system is described in detail in co-pending U.S. patent application Ser. No. 10/732,145 filed Dec. 10, 2003, entitled Working Position Measuring System. Such a rotating laser system generally includes a rotating laser at a fixed location, with a photodetector co-located with the GPS receiver. The photodetector periodically detects the rotating laser beam and generates a signal based upon receipt of the laser (i.e., when the laser beam strikes a photocell of the detector). The signal may be processed using various techniques in order to provide additional positioning/geometric information, such as the elevation angle between the photodetector and the transmitter. Knowledge of the elevation angle allows calculation of the height difference between transmitter and photodetector by multiplying the tangent of the angle and distance. Distance is calculated by the GPS receiver which is integrated in one housing with the laser detector. The accuracy of height estimation is improved because the elevation angle measurement is very precise within a small range. Such techniques are described fully in the above reference co-pending U.S. patent application Ser. No. 10/732,145. The details of such techniques are not important for the present discussion. What is important to recognize is that the data generation of the photodetector may not be synchronized with the GPS system by providing the GPS clock signal to the photodetector. The timing of the data generation of the photodetector is dependent upon the moment in time that the laser beam strikes the photocell of the photodetector. Such time is dependent upon the angular velocity of the rotating laser transmitter (and dependent upon dynamics (e.g., movement, if any) of the photodetector) and cannot be controlled by a clock signal received by the photodetector.
The above described synchronization problem results in a degradation of the position calculation. At the epoch moment when the GPS position calculation is made, the elevation angle data available from the photodetector is from some point in time prior to the epoch moment. The elevation angle is likely to have changed since this prior point in time, and thus the use of the old elevation angle data inserts error into the position calculation. Thus, stated another way, there is a latency between the time the elevation angle is calculated and the time when such elevation angle is actually used in conjunction with the GPS data to determine position. This solution latency results in reduced positioning accuracy.
One known solution to this problem is to extrapolate the elevation angle data to estimate the elevation angle at the epoch moment when the positioning determination is made. While this is an improvement over using the earlier calculated elevation angle, there is still a significant extrapolation error which reduces the accuracy of the position determination. In dynamic machine control applications, such as bulldozer blade control, such reduced accuracy has a significant effect on the overall effectiveness of the system.
While the solution latency problem has been described in connection with a rotating laser system which computes elevation angle, one of ordinary skill in the art will recognize that the latency problem exists anytime a non-satellite source of positioning information is integrated with a GPS system where the non-satellite source cannot be readily synchronized using a clock signal from the GPS receiver.
Thus, there exists a need to solve the solution latency problem described above.

Controlling solution latency in a global navigation satellite receiver


The high pressure discharge lamp is fitted with a discharge vessel that has an inside volume with an inside length IL and a maximum inside diameter ID, and that is subdivided into a middle region of constant inside diameter ID and two end regions of variable inside diameter, an electrode projecting into the discharge vessel in the end region in each case. In addition, the discharge vessel has an aspect ratio of 2.5 to 8, preferably 3 to 6, the end region exhibiting a given length LRD in which the inside diameter is reduced to at least 85% of ID.

U.S. Pat. No. 6,400,100 has already disclosed a high pressure lamp and associated operating method for the resonant operation of high pressure lamps in longitudinal mode, and an associated system. A method is specified there for finding the second longitudinal acoustic resonant frequency. It proceeds from the fact that during the continuous traveling of the frequency that excites the longitudinal mode, the resonant frequency in a vertical operating position can be found through the occurrence of a relative increase in the operating voltage of the lamp. It emerges that this method can be used to find the longitudinal frequency for a segregated arc state in vertical resonance, and then to retain it. However, depending on the filling composition of the metal halide filling and on the instant in the sequence of the search procedure, the frequency thus found can be placed substantially too high such that an excitation of the acoustic resonance at the frequency found with the aid of the abovenamed method results in an inadequate mixing and does not neutralize the segregation sufficiently well. Moreover, implementation in an electronic ballast is expensive. Further documents that are concerned with reducing the segregation by targeted excitation of the second longitudinal mode are, for example, US 2003/117075, US 2003/117085, US 2005/067975 and US 2004/095076. Use is made in all these documents of a ceramic discharge vessel with a high aspect ratio of at least 1.5, and which is cylindrical. The ends are straight or hemispherical.
Similar attempts have already been carried out with the aid of known metal halide lamps that still exhibit the previously customary discharge vessel made from silica glass, see U.S. Pat. No. 5,773,937. An attempt had been made here, as well, to use as straight as possible a discharge vessel with a cylindrical middle part. Only of necessity are the ends rounded off and then lead to the pinch seal. Ceramic discharge vessels are described there as well, but are obviously designed for sodium discharge lamps.
U.S. Pat. No. 6,469,442 and US-A 2004/104677 disclose a ceramic discharge vessel having beveled end parts. However, it is not operated in resonant mode.

High pressure lamp and associated operating method for resonant operation of high pressure lamps in the longitudinal mode, and an associated system

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