A method for allowing a mobile station to find a code transmitted by a base station which has a propagation delay to the mobile station which is much larger or smaller than a propagation delay between the mobile station and a base station from which it derived a time reference is provided. In the context of IS-95, a PN offset is sent to the mobile station to identify which target base station pilot signals to search for. By sending a virtual PN offset which differs from the real PN offset, the mobile station can find the target base station signals where normally they would fall outside the mobile station""s search window.

The invention relates to a method and an apparatus for performing soft handoff between cells of large differing radii, and particularly for application in systems which, due to a search window size which limits searching capabilities, can only perform handoff between cells having similar cell sizes.
CDMA (code division multiple access) communications systems are currently designed to accommodate a maximum cell size difference of about 55 km. For certain applications, such as in large service areas, it would be advantageous to be able to provision for larger cell size differences, and to be able to perform handoff between larger cells and much smaller cells.
Mobile stations search for base stations within a CDMA communications system by looking for an identification code, such as the IS-95 PN (pseudo-random number) short codes (in-phase code and quadrature code), transmitted by every base station, different sectors of different base stations sending the same short code with a different time shift, known as a PN offset, which provides a unique base station sector identifier. Mobile stations on power-up acquire their time reference from the first base station they make contact with. This time reference is delayed by the RF propagation delay between the base station and the mobile station, Before a soft handoff, a mobile station which has been informed by a serving base station of the different time shifts of the short code for target base stations knows at what time to look for the short code generated by these target base stations. The serving base station is a base station with which the mobile station has an active communications channel. The mobile station""s time reference is set according to the earliest path received from the serving base station(s). Potential target base stations are candidates for handoff which are identified, for example, on the basis of their proximity to the serving base station. The mobile station performs a search for the code over a time period known as the search window. This search window is placed according to the mobile station""s notion of time which is derived from the serving base station. After a change in serving base station, the mobile station""s search window slowly migrates so as to be centred about a time reference derived from the new base station. A problem with existing systems is that if a handoff is to be performed between two cells of large differing radii, then there is a big difference in delay between firstly, (the propagation delay between the mobile station and the target base station) and secondly (the propagation delay between the mobile station and the base station from which the mobile station has previously established a time reference) and this causes the short code of the target base station to arrive earlier or later than expected because, as indicated above, the time reference of the mobile station is derived from a different base station. If the difference in delay is sufficiently large, then the short code of the target base station will arrive outside the search window, the mobile station will fail to identify the short code, and the mobile station will by unable to perform soft handoff to the target base station.
One solution which has been proposed is to modify the mobile station such that it has a large enough search window or a search window offset so that it can find the short code regardless of the difference in delay. Problems with this are that every mobile station must be changed so as to not follow the CDMA IS-95 standard, and also that a larger search window takes a longer time to search.
It would be advantageous to be able to use existing mobile stations in environments with cells having large differing radii for interoperability reasons.
It is an object of the invention to obviate or mitigate one or more of the above identified disadvantages.
The invention is for application in a system in which base stations each transmit a known identification code, for example a CDMA short PN code with a respective PN offset. A method is provided for allowing a mobile station to search for and find the identification code of a target base station transmitting with a particular offset and having a cell size with a large cell size difference compared to that of a serving base station, and having a large propagation delay difference between the target base station and the serving base station, without making any changes to how the mobile station operates. The method involves providing information to the mobile station which makes it look for the identification code with a different offset than the particular offset.
Preferably, the different offset is selected to have a difference from the particular offset which compensates for a difference between firstly, (the propagation delay between the mobile station and the target base station) and secondly (the propagation delay between the mobile station and the base station from which the mobile station previously established a time reference).
In the event that the identification code is a CDMA short PN code, and the respective offset is a PN offset, the information provided to the mobile station consists of a virtual PN offset for the particular target base station which is different from the target base station""s actual PN offset.
Even more generally, the invention provides a method of compensating for a large difference in propagation delay between a first signal sent with a first propagation delay and a second signal sent with a second propagation delay comprising sending information which makes a receiver search for the second signal at a time which is substantially equal to the second signal shifted by the large difference in propagation delay, within plus or minus half a search window size.

Method and apparatus for performing soft handoff between cells of large differing radii


A rail including a number of slots being longitudinally formed therein and a number of options each including a guide being slidably engageable in the slots. Each slot consists of a wide portion and a narrow portion. The wide portion of each slot is proximate to the axis of the rail while the narrow portion of the same is distal from the axis of the rail. Each guide has a form being compensative to that of each slot. Thus, each option will not be radially disengaged from the rail when the guide of the option is engaged in a corresponding slot formed in the rail.

1. Field of Invention
The present invention relates to a versatile rail for supporting objects in a kitchen, e.g., hooks and trays.
2. Related Prior Art
There are often a sink, a preparation table and a cabinet in a kitchen. Preparation utensils are disposed on the preparation table and in the cabinet. However, it is inconvenient to take preparation utensils from the cabinet which is closed by a door. It is easy to take preparation utensils from the preparation table, but such preparation utensils occupy too much space of the preparation table, thereby causing troubles for the preparation of food. Therefore, there is a long unfulfilled need to provide a device for supporting objects in a kitchen.

Versatile rail for supporting objects in kitchen

No. 32, Alley 48, Lane 179, Sec. 2, Nei Hu Rd.


Described is a method for the production of 3-hydroxy-3-methylbutyric acid by enzyme-catalyzed covalent bond formation between the carbon atom of the oxo group of acetone and the methyl group of a compound which provides an activated acetyl group. Also described are recombinant organisms which produce 3-hydroxy-3-methylbutyric acid, and related compositions and methods.

3-hydroxy-3-methylbutyric acid (also referred to as beta-hydroxyisovalerate or HIV; see FIG. 1) is a metabolite of the essential amino acid leucine and is synthesized in the human body. It can be found in small quantities in grapefruit, alfalfa and catfish. It is also known to occur in some metabolic disorders of leucine catabolism, i.e. hypovaleric acidemia. It has been shown that 3-hydroxy-3-methylbutyric acid may have an effect on increasing muscle weight and strength (Nissen et al., J. Appl. Physiol. 81 (1996), 2095-2104). Wilson et al. (Nutrition & Metabolism 5 (2008)) proposes as the mechanisms of action the following:                increased sarcolemmal integrity via conversion by HMG CoA reductase        enhanced protein synthesis via the mTOR pathway        depression of protein degradation through inhibition of the ubiquitin pathway.
3-hydroxy-3-methylbutyric acid is supposed to help muscles combat protein breakdown, assist in muscle repair and support increased endurance. It has been described to help patients with chronic obstructive pulmonary disease in hospital intensive care units, muscle wasting associated with HIV and cancer and trauma victims with severe injuries. Thus, it is of commercial interest because of its use as a muscle enhancer for bodybuilding and as a medicament for avoiding muscle wasting.
U.S. Pat. No. 7,026,507 describes a process for preparing solid formulations of sodium 3-hydroxy-3-methylbutyrate in which, in a first process step, 4,4-dimethyloxetan-2-one is reacted with aqueous sodium hydroxide to form a solution of sodium 3-hydroxy-3-methylbutyrate, and then, if appropriate after concentration, the solution is applied, in a further process step, to synthetic silica, and in which the resultant product is, if appropriate, dried.
It would be desirable to provide a process for the production of 3-hydroxy-3-methylbutyrate which would be independent of inorganic production steps and which could be effected in living organisms thereby being environmentally sound and inexpensive. In this context, Lee et al. (Appl. Environ. Microbiol. 63 (1997), 4191-4195) describes a method for the production of 3-hydroxy-3-methylbutyrate by converting 3-methylbutyric acid to 3-hydroxy-3-methylbutyric acid using the microorganism Galactomyces reessii. However, although this process allowed the production of 3-hydroxy-3-methylbutyrate there is still a need to provide alternative efficient and cost effective ways of producing 3-hydroxy-3-methylbutyrate in particular by biological processes.
The present invention meets this demand for an alternative process for the production of 3-hydroxy-3-methylbutyrate and provides a method which is based on biological resources and allows to produce 3-hydroxy-3-methylbutyrate in vitro or in vivo in a microorganism and other species.

Method for the enzymatic production of 3-hydroxy-3-methylbutyric acid from acetone and acetyl-coa


An apparatus and method for dispensing liquid at a controlled temperature in a spin coating or developer machine are disclosed. The apparatus is a thermal control line that has an inner core wall that encloses at least one conduit for a liquid dispense line and an outer annular wall that encloses at least one chamber for circulation of coolant. The inner core wall and the outer annular wall are formed of such materials as to permit efficient heat exchange between the coolant and the liquid. The coolant is circulated in the annular chamber at a rate sufficient to maintain the dispensed liquid at a desired temperature.

A photoresist mask is formed on a semiconductor substrate by first coating the substrate with a thin layer of photoresist, exposing the resist with the desired pattern, and then developing the photoresist layer. In the first step, the substrate is coated with photoresist by a spin coating machine. In the spin coating machine, a liquid that includes photoresist dissolved in a solvent is applied to the top surface of the substrate while the substrate is spun slowly. During this process, a solvent in the liquid evaporates, causing the photoresist to solidify. The liquid is applied via a liquid dispense line. Ordinarily when the liquid is dispensed, there is no thermal control as it passes through the dispense line. Applicants have found that this lack of thermal control results in non-uniform coatings. Therefore, Applicants have found it necessary for liquids dispensed in a spin coating machine to be temperature controlled. Similarly, Applicants have also found it necessary for liquids dispensed in a developer machine to be temperature controlled.
FIG. 1 illustrates an exploded view of the spin coating machine which has been in use by the industry for a number of years. Spin coating machine 100 is illustrated schematically as containing a liquid dispense line 120 that dispenses liquid from a nozzle assembly (point of use) 104C on a substrate 103. Substrate 103 is supported by a flat vacuum chuck 102 connected to a spin motor 101.
Spin coating machine 100 has an exhaust system that includes a liquid drain line 105, an air purge line 106 and a safety line 107. Lines 105 and 106 connect to a coating chamber 100A and line 107 connects to a motor chamber 100B of spin coating machine 100. Lines 105 and 106 lead to a drain tank 109, which is used to collect excess liquid. Line 107 leads to an exhaust manifold 110, which is connected to the factory exhaust system. A connecting line 111 allows vapor from drain tank 109 to enter exhaust manifold 110.
As each substrate is processed, in order to prevent the liquid from drying too quickly, a selected concentration of vapor is maintained in the atmosphere in coating chamber 100A. This may be done advantageously with the arrangement described in commonly-owned copending application Ser. No. 07/904,795, U.S. Pat. No. 5,289,222 filed Jun. 26, 1992, which is incorporated by reference herein in its entirety. During the spin coating process, programmable exhaust unit 112 closes a butterfly valve (not shown) in conduit 111 so as to restrict the flow of air and vapor from drain tank 109 to exhaust manifold 110. This in turn limits the flow of vapor and air in lines 105 and 106 and maintains the vapor concentration in coating chamber 100A at an increased level. When the coating process is completed, programmable exhaust unit 112 opens the butterfly valve and the normal flow of the vapors and air through lines 105 and 106 into the factory exhaust system is reestablished.
Applicants have found several disadvantages with the prior art apparatus and method. The main disadvantage of the prior art apparatus and method is that the temperature of the liquid dispensed over the top of the substrate is uncontrolled. Therefore, variations in the temperature of the surroundings may lead to non-uniform coatings even though a selected vapor concentration is maintained by use of the butterfly valve.
Some prior art systems may control the temperature of a liquid dispense line to a limited extent. Even in such prior art systems, there is no temperature control at the liquid exit end (point of use) of the liquid dispense line and for a significant distance (several feet) upstream from the liquid exit end. The lack of temperature control over this distance results in a change in temperature of the liquid. This problem becomes especially acute if the liquid is not continuously dispensed. For example, if liquid dispensing is suspended over-night, temperature of the liquid around the liquid exit end cannot be controlled when the system is started up again.
Also, in some prior art systems that provide cooling of the dispense liquid, the coolant is circulated in a jacket around a single liquid dispense line. Since mechanical fittings are used to mount the jacket on to the liquid dispense line, such prior art fittings occasionally leak and coolant is discharged. Even though the jacket terminates at a significant distance upstream from the liquid exit end (point of use), any coolant discharge from the jacket may result in damage to the substrate or to other machinery in the system.
Finally, prior art devices used to cool the dispense liquid are generally of a size sufficiently large to block air flow to the substrate and around the substrate. Such improper blockage of air flow leads to non-uniform coatings.

Thermal control line for delivering liquid to a point of use in a photolithography system


The present invention is directed to the improved synthesis of compounds of formula I:

In 1994 cancer of the prostate gland is expected to be diagnosed in 200,000 men in the U.S. and 38,000 American males will die from this disease (Garnick, M. B. (1994). The Dilemmas of Prostate Cancer. Scientific American, April:72-81). Thus, prostate cancer is the most frequently diagnosed malignancy (other than that of the skin) in U.S. men and the second leading cause of cancer-related deaths (behind lung cancer) in that group.
Compositions useful in the treatment of prostatic cancer and related conditions are described in U.S. Pat. Nos. 5,599,686, 5,866,679 and 5,948,750, and U.S. patent applications Ser. No. 08/950,805, filed Oct. 14, 1997, now U.S. Pat. No. 8,948,750, (PCT Publ.No. WO 98/18493). Said compositions comprise chemical conjugates comprising known cytotoxic agents and oligopeptides having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen and that include a cyclic amino acid having a hydrophilic substituent. The oligopeptide moieties are selected from oligomers that are selectively recognised by free prostate specific antigen (PSA) and are capable of being proteolytically cleaved by the enzymatic activity thereof.
Ideally, the cytotoxic activity of the cytotoxic agent is greatly reduced or absent when the intact oligopeptide containing the PSA proteolytic cleavage site is bonded directly, or through a chemical linker, to the cytotoxic agent. Also ideally, the cytotoxic activity of the cytotoxic agent increases significantly, or is restored completely, upon proteolytic cleavage of the attached oligopeptide at the cleavage site. Anthracycline antibiotics, in particular doxorubicin, are among the cytotoxic agents that were described in the published patent applications as preferably incorporated into such conjugates, which may be referred to as PSA conjugates.
It is the object of this invention to provide an efficient, scaleable and reproducible process for the preparation of PSA conjugates having an anthracycline antibiotic moiety as the cytotoxic agent and having the cleavable oligopeptide directly attached, via the C-terminus amino acid, to the glycosyl amine of the anthracycline antibiotic moiety.
Another object of this invention is to provide intermediate compounds useful in the preparation of such PSA conjugates.
A chemical process for the preparation of a PSA conjugate which comprises an anthracycline antibiotic and an oligopeptide, having an amino acid sequence that is selectively proteolytically cleaved by free prostate specific antigen (PSA) is disclosed. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hyperplasia (BPH).
The present invention is directed to a process for the preparation of compounds as illustrated by formula I:
or a pharmaceutically acceptable salt thereof
xe2x80x83wherein
oligopeptide is an oligopeptide which is selectively recognized by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen,
Ra is xe2x80x94CH3, xe2x80x94CH2OH, xe2x80x94CH2OCO(CH2)3CH3, or xe2x80x94CH2OCOCH(OC2H5)2;
Rb is xe2x80x94OCH3, xe2x80x94OH or xe2x80x94H;
Rd is xe2x80x94OH, xe2x80x94OTHP or xe2x80x94H; and
Re is xe2x80x94OH or xe2x80x94H, provided that Re is not xe2x80x94OH when Rd is xe2x80x94OH or xe2x80x94OTHP;
R is selected from:
a) acetyl;
e) hydrogen;
R1 and R2 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R3Oxe2x80x94, R3C(O)NR3xe2x80x94, (R3)2NC(O)xe2x80x94, R32Nxe2x80x94C(NR3)xe2x80x94, R4S(O)mNH, CN, NO2, R3C(O)xe2x80x94, N3, xe2x80x94N(R3)2, or R4C(O)NR3xe2x80x94,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R3Oxe2x80x94, R4S(O)mNH, R3C(O)NR3xe2x80x94, (R3)2NC(O)xe2x80x94, R32Nxe2x80x94C(NR3)xe2x80x94, CN, R3C(O)xe2x80x94, N3, xe2x80x94N(R3)2, and R4OC(O)xe2x80x94NR3xe2x80x94; or
R1 and R2 are combined to form xe2x80x94(CH2)sxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, xe2x80x94NC(O)xe2x80x94, NH and xe2x80x94N(COR4)xe2x80x94;
R3 is selected from: hydrogen, aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl and C3-C10 cycloalkyl;
R4 is selected from: aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl and C3-C10 cycloalkyl;
m is 0, 1 or 2;
n is 1, 2, 3 or 4;
p is zero or an integer between 1 and 100;
q is 0 or 1, provided that if p is zero, q is 1;
r is an integer between 1 and 10; and
s is 3, 4 or 5.
The process comprises the step of preparing the compound of the formula Ia:
or a salt thereof;
xe2x80x83wherein
oligopeptide, R, Ra, Rb, Rd and Re are described as above
Rxe2x80x2 is selected from:
a) R,
b) a protected precursor to R, and
c) an N-terminus protecting group;
by mixing an oligopeptide of the formula A:
xe2x80x83wherein oligopeptide and Rxe2x80x2 are described as above, or a salt thereof;
with an anthracycline antibiotic of the formula B:
xe2x80x83or a salt thereof,
wherein Ra, Rb, Rd and Re are as described hereinabove,
in the presence of a carboxyl activating agent and, optionally, in the presence of a base.
In an embodiment of the instant process, if Rxe2x80x2 is a protected precursor to R or an N-terminus protecting group, the process further comprises the step of removing the protecting group to produce the compound of the formula I.
In an embodiment of the instant process, the oligopeptide of formula A is mixed with a salt of the anthracycline antibiotic of the formula B in the presence of a carboxyl activating agent and a base.
In an embodiment of the instant process, the carboxyl activating agent is selected from dicyclohexylcarbodiimide (DCC), N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide (EDC), and 1,3-diisopropylcarbodiimide (DIC).
In a preferred embodiment, the carboxyl activating agent is EDC.
In an embodiment of the instant process, the base is selected from 2,4,6-collidine, lutidine, pyridine, triethyl amine and (iPr)2NEt.
In a preferred embodiment, the base is 2,4,6-collidine.
It has been surprisingly discovered that use 2,4,6-collidine as the base in the instant process for the formation of the compound of the formula Ia results in lower epimerization of the C-terminus amino acid moiety than when other bases previously described are utilized.
In a further embodiment of the instant process, the mixing of the compounds of formula A and formula B is additionally in the presence of an additive.
In a preferred further embodiment of the instant process the additive is selected from HOAt, HOBt, HOPO or a combination thereof.
In a preferred embodiment of the further embodiment of the instant process, the additive is HOAt.
In a second preferred embodiment of the further embodiment of the instant process, the additive is a combination of HOPO and HOAt.
In a further embodiment of the instant process, the oligopeptide of the formula A is mixed with the anthracycline antibiotic of the formula B in the presence of a carboxyl activating agent, an additive and a base.
In a preferred further embodiment of the instant process, the oligopeptide of the formula A is mixed with the anthracycline antibiotic of the formula B in the presence of an additive and a base, and a carboxyl activating agent is thereafter added to the mixture.
It has been surprisingly discovered that when the carboxyl activating agent is added last to a preformed mixture of the process components the amount of epimerization that occurs at the C-terminus amino acid of the oligopeptide moiety in the compound of formula Ia is less than when the base is added last to the reaction mixture.
In a more preferred further embodiment of the instant process, the oligopeptide of the formula A is mixed with the anthracycline antibiotic of the formula B in the presence of an additive and a base, and a carboxyl activating agent is thereafter added to the mixture in two or more portions.
In an embodiment of the instant invention, the anthracycline antibiotic is doxorubicin (Ra is xe2x80x94CH2OH, Rb is xe2x80x94OCH3, Rc is H and Rd is xe2x80x94OH).
In another embodiment of the instant invention, R is selected from:
a) acetyl; and
b)
In another embodiment of the instant invention, R is
and Rxe2x80x2 is
In another embodiment of the instant invention, R is
and Rxe2x80x2 is
and the process further comprises the step of removing the protecting group by contacting the compound of formula Ia with piperidine.
In a preferred embodiment of the instant invention, the oligopeptide comprises an oligomer selected from:
a) 4-HypXaaSerTyrGln|SerSer (SEQ.ID.NO.: 1),
b) 4-HypXaaSerTyrGln|SerAla (SEQ.ID.NO.: 2),
c) Ala-4-HypXaaSerTyrTyr|Ser (SEQ.ID.NO.: 3),
d) AlaAsn4-HypXaaSerTyrGln|Ser (SEQ.ID.NO.: 4),
e) 4-HypXaaSerTyrGln|SerSerThr (SEQ.ID.NO.: 5),
f) 4-HypTyrGln|SerSerThr (SEQ.ID.NO.: 6),
g) 4-HypXaaSerTyrGln|SerSerSer (SEQ.ID.NO.: 7),
h) 4-HypTyrGln|SerSerSer (SEQ.ID.NO.: 8),
i) 4-HypXaaLysTyrGln|SerSerSer (SEQ.ID.NO.: 9),
j) 4-HypXaahArgTyrGln|SerSerSer (SEQ.ID.NO.: 10),
k) 4-HypXaaSerTyrGln|SerSerLeu (SEQ.ID.NO.: 11);
l) 4-HypTyrGln|SerSerLeu (SEQ.ID.NO.: 12);
m) 4-HypXaaSerTyrGln|SerLeu (SEQ.ID.NO.: 13);
n) 4-HypTyrGln|SerLeu (SEQ.ID.NO.: 14);
p) 4-HypXaaSerTyrGln|SerNle (SEQ.ID.NO.: 15);
q) 4-HypTyrGln|SerNle (SEQ.ID.NO.: 16);
r) 4-HypXaaSerTyrGln|SerTIC (SEQ.ID.NO.: 17);
s) 4-HypTyrGln|SerTIC (SEQ.ID.NO.: 18);
t) 4-HypXaaSerChgGln|SerLeu (SEQ.ID.NO.: 19);
u) 4-Hyp ChgGln|SerLeu (SEQ(ID.NO.: 20);
v) 4-HypXaaSerChgGln|SerNle (SEQ.ID.NO.: 21);
w) 4-HypChgGln|SerNle (SEQ.ID.NO.: 22);
x) 4-HypXaaSerChgGln|SerTIC (SEQ.ID.NO.: 23);
y) 4-HypChgGln|SerTIC (SEQ.ID.NO.: 24);
z) AlaSerTyrGln|SerSerLeu (SEQ.ID.NO.: 25);
aa) SerhArgChgGln|SerLeu (SEQ.ID.NO.: 26);
bb) hArgSerSerTyrGln|SerNle (SEQ.ID.NO.: 27);
cc) hArgAlaSerChgGln|SerLeu (SEQ.ID.NO.: 28);
dd) hArgSerSerTyrGln|SerLeu (SEQ.ID.NO.: 29);
ee) hArgSerSerChg|SerLeu (SEQ.ID.NO.: 30);
ff) SerhArgChgGln|SerLeu (SEQ.ID.NO.: 31);
gg) hArgTyrGln|SerLeu (SEQ.ID.NO.: 32);
hh) hArgSerSerChgGln|SerLeu (SEQ.ID.NO.: 33);
ii) SerhArgTyrGln|SerLeu (SEQ.ID.NO.: 34);
jj) SerSerTyrGln|SerLeu (SEQ.ID.NO.: 35);
kk) SerSerSerChgGln|SerLeu (SEQ.ID.NO.: 36);
ll) 3PAL-SerSerChgGln|SerLeu (SEQ.ID.NO.: 37);
mm) SerSerChgGln|SerLeu (SEQ.ID.NO.: 38);
nn) SerSerSerChgGln|Ser(dLeu) (SEQ.ID.NO.: 39);
oo) SerSerSerChgGln|SerVal (SEQ.ID.NO.: 40);
pp) ProSerSerChgGln|SerVal (SEQ.ID.NO.: 41);
qq) GlySerSerChgGln|SerLeu (SEQ.ID.NO.: 42);
rr) hSerSerSerChgGln|SerLeu (SEQ.ID.NO.: 43);
ss) hArgSerSerChgGln|SerNle (SEQ.ID.NO.: 44);
tt) hArgTyrGln|SerSerSerLeu (SEQ.ID.NO.: 45);
uu) LysTyrGln|SerSerSerLeu (SEQ.ID.NO.: 46);
vv) SerTyrGln|SerSerSerLeu (SEQ.ID.NO.: 47);
ww) SerSerChgGln-Ser(dLeu) (SEQ.ID.NO.: 48);
xx) 3PAL-SerSerChgGln-Ser(dLeu) (SEQ.ID.NO.: 49); and
yy) AlaSerChgGln-SerLeu (SEQ.ID.NO.: 50).
xe2x80x83wherein 4-Hyp is 4-hydroxyproline, Xaa is any amino acid, hArg is homoarginine, hSer is homoserine, TIC is 1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid, Cha is cyclohexylalanine and Chg is cyclohexylglycine.
Preferably Xaa in the more preferred embodiment is selected from Ala, Ser and Ile.
In a preferred embodiment the present invention is directed to a process for the preparation of the compound of formula 4:
or a pharmaceutically acceptable salt thereof;
which comprises the step of mixing an oligopeptide of the formula 2a:
xe2x80x83wherein Rxe2x80x3 is xe2x80x94OH or a protected precursor to xe2x80x94OH;
or a salt thereof;
with an anthracycline antibiotic of the formula 1:
xe2x80x83or a salt thereof;
in the presence of a carboxyl activating agent and, optionally, in the presence of a base, to form a compound of the formula 3a:
xe2x80x83or a salt thereof.
In a further embodiment of this preferred embodiment, the process further comprises the step of converting Rxe2x80x3 to a xe2x80x94OH moiety.
In a more preferred embodiment, the present invention is directed to a process for the preparation of the compound of formula 4:
or a pharmaceutically acceptable salt thereof;
which comprises the steps of:
a) mixing an oligopeptide of the formula 2:
xe2x80x83or a salt thereof;
with an anthracycline antibiotic of the formula 1:
xe2x80x83or a salt thereof;
in the presence of a carboxyl activating agent and, optionally, in the presence of a base, to form a compound of the formula 3:
xe2x80x83or a salt thereof.
In a further embodiment of the more preferred embodiment of the instant process, the oligopeptide of the formula 2 is added to the reaction mixture that comprises a solvent, in particular DMF, at about xe2x88x926xc2x0 C. to about xe2x88x923xc2x0 C. to form a first slurry and the anthracycline antibiotic of the formula 1 is added to that slurry to form a second slurry. It has been surprisingly discovered that maintaining such a low temperature for addition of the oligopeptide to the reaction mixture and then adding the doxorubicin to the slurry at low temperature avoids the formation of a gel in the reaction mixture which is detrimental to a large scale preparation of the compound of the formula 3.
In a second further embodiment of the more preferred embodiment of the instant process, the anthracycline antibiotic of the formula 1 is mixed in a solvent, in particular DMF, optionally with an additive and optionally with a base, to form a first slurry, which is then cooled to about xe2x88x926xc2x0 C. to about xe2x88x923xc2x0 C. and the oligopeptide of the formula 2 is added to that slurry to form a second slurry.
In an embodiment of the further embodiments of the instant process, the oligopeptide of formula 1 is mixed with a salt of the anthracycline antibiotic of the formula 2 in the presence of a carboxyl activating agent and a base. Preferably, the salt of the anthracycline antibiotic of the formula 2 is the hydrochloride salt.
In an embodiment of the further embodiments of the instant process, the process further comprises the step of removing the fluorenylmethoxy protecting group of the compound of formula 3 to produce the compound of the formula 4.
In a further embodiment of the instant process, the step of removing the fluorenylmethoxy protecting group of the compound of formula 3 comprises contacting the compound of formula 3 with piperidine.
The phrase xe2x80x9coligomers that comprise an amino acid sequencexe2x80x9d as used hereinabove, and elsewhere in the Detailed Description of the Invention, describes oligomers of from about 3 to about 100 amino acids residues which include in their amino acid sequence the specific amino acid sequence decribed and which are therefore proteolytically cleaved within the amino acid sequence described by free PSA. Preferably, the oligomer is from 5 to 10 amino acid residues. Thus, for example, the following oligomer:
hArgSer4-HypChgGln|SerLeu (SEQ.ID.NO.: 53); comprises the amino acid sequence:
4-HypChgGln|SerLeu (SEQ.ID.NO.: 54); and would therefore come within the instant invention.
The inclusion of the symbol xe2x80x9c|xe2x80x9d within an amino acid sequence indicates the point within that sequence where the oligopeptide is proteolytically cleaved by free PSA.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. Unless otherwise specified, named amino acids are understood to have the natural xe2x80x9cLxe2x80x9d stereoconfiguration. When any variable (e.g. aryl, heterocycle, R3 etc.) occurs more than one time in any constituent, its definition on each occurence is independent of every other occurence. For example, HO(CR1R2)2xe2x80x94 represents HOCH2CH2xe2x80x94, HOCH2CH(OH)xe2x80x94, HOCH(CH3)CH(OH)xe2x80x94, etc. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The following abbreviations are utilized in the specification and tables to denote the indicated amino acids and moieties:
As used herein, xe2x80x9calkylxe2x80x9d and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
As used herein, xe2x80x9ccycloalkylxe2x80x9d is intended to include non-aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
xe2x80x9cAlkenylxe2x80x9d groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.
xe2x80x9cAlkynylxe2x80x9d groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein means fluoro, chloro, bromo and iodo.
As used herein, xe2x80x9caryl,xe2x80x9d and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyt, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the terms xe2x80x9csubstituted C1-8 alkylxe2x80x9d, xe2x80x9csubstituted arylxe2x80x9d and xe2x80x9csubstituted heterocyclexe2x80x9d include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Such additional substituents are selected from F, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, NO2, CN, (C1-C6 alkyl)Oxe2x80x94, xe2x80x94OH, (C1-C6 alkyl)S(O)mxe2x80x94, (C1-C6 alkyl)C(O)NHxe2x80x94, H2Nxe2x80x94C(NH)xe2x80x94, (C1-C6 alkyl)C(O)xe2x80x94, (C1-C6 alkyl)OC(O)xe2x80x94, N3, (C1-C6 alkyl)OC(O)NHxe2x80x94 and C1-C20 alkyl.
The term xe2x80x9can integer between 1 and 10xe2x80x9d represents the numbers 1 and 10 as well as those integers between those numbers. The term xe2x80x9can integer between 1 and 100xe2x80x9d represents the numbers 1 and 100 as well as those integers between those numbers.
When R1 and R2 are combined to form xe2x80x94(CH2)sxe2x80x94, the cyclic moieties and heteroatom-containing cyclic moieties so defined include, but are not limited to:
As used herein, the term xe2x80x9cPEGxe2x80x9d represents certain polyethylene glycol containing substituents having the designated number of ethyleneoxy subunits. Thus the term PEG(2) represents
and the term PEG(6) represents
As used herein, the term xe2x80x9c(2R)(2,3-dihydroxypropionyl)xe2x80x9d represents the following structure:
As used herein, the term xe2x80x9c(2R,3S) 2,3,4-trihydroxybutanoylxe2x80x9d represents the following structure:
The following compounds are specific examples of a oligopeptide-cytotoxic agent conjugate that may be prepared by the process of the instant invention:
wherein X is:
or an optical isomer or pharmaceutically acceptable salt thereof.
Other PSA conjugate compounds that may be prepared by the process of the instant invention include, but are not limited to, the compounds described in the following patents and patent publications:
U.S. Pat. No. 5,599,686, issued Feb. 4, 1997;
U.S. Pat. No. 5,866,679, issued Feb. 2, 1999;
WO 96/00503 (Jan. 11, 1996); U.S. Ser. No. 08/468,161 filed on Jun. 6, 1997 now U.S. Pat. No. 6,143,864;
WO 98/10651 (Mar. 19, 1998); U.S. Ser. No. 08/926,412 filed on Sep. 9, 1997 now U.S. Pat. No. 5,978,362; and
U.S. Pat. No. 5,948,750, issued Sep. 7, 1999; WO 98/18493 (May 7, 1998);
U.S. Ser. No. 08/950,805, filed on Oct. 14, 1997, now U.S. Pat. No. 5,948,750.
The pharmaceutically acceptable salts of the conjugates that may be prepared by the process of this invention and salts of Compounds of the formulae A, B, 1, 2a and 3a utilized in the instant processes include the conventional non-toxic salts of the compounds, e.g., non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
With respect to the conjugates described herein which comprise a N-terminus blocking group on the peptide which contains a carboxylic acid moiety, a pharmaceutically acceptable salt may take the form xe2x80x94COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium and the like.
For the purpose of the process of the instant invention, the carboxyl activating agent may be selected from the group including, but not limited to, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (known as HBTU), 1-hydroxybenzotriazole hydrate (known as HOBt), dicyclohexylcarbodiimide (DCC), N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide (EDC), diphenylphosphorylazide (DPPA), benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP), 1,3-diisopropylcarbodiimide (DIC) and the like, used in combination or singularly. Preferably the carboxyl activating agent is selected from EDC, DIC and DCC. Most preferably the carboxyl activating agent is EDC.
The coupling reaction of the amine moiety to the carboxyl terminus may also comprise a base, such as 2,4,6-collidine, lutidine, pyridine, triethyl amine, Hxc3xcnig""s base ((iPr)2NEt) and the like. Preferably the base is selected from 2,4,6-collidine and lutidine. Most preferably the base is 2,4,6-collidine. The coupling reaction may also comprise an additive, such as 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 2-hydroxypyridine-N-oxide, (HOPO), N-hydroxysuccinimide, pyridine N-oxide and the like, or combinations thereof Preferably the additive is selected from HOAt, HOPO, HOBt or combinations thereof. More preferably the additive is HOAt. Also, more preferable the additive is a combination of HOPO and HOAt. The coupling reaction may also comprise a solvent. Such a solvent may be selected from N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methylpiperidone (NMP), aqueous THF, and the like. Preferably the solvent is selected from a polar aprotic organic solvent, such as DMF, DMAc, NMP and the like. Most preferably, the solvent is DMF.
One skilled in the art understands that in the synthesis of compounds of the invention, one may need to protect various reactive functionalities on the starting compounds and intermediates while a desired reaction is carried out on other portions of the molecule. After the desired reactions are complete, or at any desired time, normally such protecting groups will be removed by, for example, hydrolytic or hydrogenolytic means. Such protection and deprotection steps are conventional in organic chemistry. One skilled in the art is referred to Protective Groups in Organic Chemistry, McOmie, ed., Plenum Press, N.Y., N.Y. (1973); and, Protective Groups in Organic Synthesis, Greene, ed., John Wiley and Sons, N.Y., N.Y. (1981) for the teaching of protective groups which may be useful in the preparation of compounds of the present invention.
By way of example only, useful amino-protecting groups may include, for example, C1-C10 alkanoyl groups such as formyl, acetyl, dichloroacetyl, propionyl, hexanoyl, 3,3-diethylhexanoyl, xcex3-chlorobutryl, and the like; C1-C10 alkoxycarbonyl and C5-C15 aryloxycarbonyl groups such as tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, 4-nitrobenzyloxycarbonyl, fluorenylmethyloxycarbonyl and cinnamoyloxycarbonyl; halo-(C1-C10) alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl; and C1-C15 arylalkyl and alkenyl group such as benzyl, phenethyl, allyl, trityl, and the like. Other commonly used amino-protecting groups are those in the form of enamines prepared with xcex2-keto-esters such as methyl or ethyl acetoacetate.
Useful carboxy-protecting groups may include, for example, C1-C10 alkyl groups such as methyl, tert-butyl, decyl; halo-C1-C10 alkyl such as 2,2,2-trichloroethyl, and 2-iodoethyl; C5-C15 arylalkyl such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, triphenylmethyl, diphenylmethyl; C1-C10 alkanoyloxymethyl such as acetoxymethyl, propionoxymethyl and the like; and groups such as phenacyl, 4-halophenacyl, allyl, dimethylallyl, tri-(C1-C3 alkyl)silyl, such as trimethylsilyl, xcex2-p-toluenesulfonylethyl, xcex2-p-nitrophenylthio-ethyl, 2,4,6-trimethylbenzyl, xcex2-methylthioethyl, phthalimidomethyl, 2,4-dinitro-phenylsulphenyl, 2-nitrobenzhydryl and related groups.
Similarly, useful hydroxy protecting groups may include, for example, the formyl group, the chloroacetyl group, the benzyl group, the benzhydryl group, the trityl group, the 4-nitrobenzyl group, the trimethylsilyl group, the phenacyl group, the tert-butyl group, the methoxymethyl group, the tetrahydropyranyl group, and the like.
With respect to the preferred embodiment of an oligopeptide combined with the anthracycline antibiotic doxorubicin, the following Reaction Schemes illustrate the synthesis of the conjugates of the instant invention. Other bases than piperidine are useful in the deprotection illustrated in Reaction Scheme IV, including dimethyl amine, diethyl, amine, pyrrolidine, quinuclidine and the like. Preferably piperidine is utilized.
Reaction Schemes V-VIII below illustrate other methods for the preparation of the PSA conjugates, in particular, the preparation of the compound of formula 4. Thus, as shown in Reaction Scheme V, an unblocked glutaryl peptide 5 may be prepared by methods well known in the art and coupled to the amine moiety of the anthracycline cytotoxic agent as described above. Specific preparation of the compound of formula 4 is illustrated in Reaction Scheme VI.
Alternatively, as illustrated in Reaction Scheme VII, a bis-blocked peptide 6 may be prepared by methods well known in the art and selectively deprotected to provide the benzyl ester analog of the compound of formula 2. After coupling to the anthracycline cytotoxic agent as described above, deprotection of the acid moiety can be accomplished by catalytic hydrogenation, thereby avoiding prolonged exposure of compound 4 to a base. Other carboxylic acid protecting groups that may be useful include t-butyl, sillyl and the like. It is known that the anthracyclines are chemically sensitive to base.
In yet another embodiment, the cleavable peptide portion of the instant conjugate may be attached in two or more fragments, as ilustrated in Reaction Scheme VIII. Such a synthetic strategy might allow more flexibility in selection and use of blocking groups. The particular selection of which peptide fragment to attach first that is shown in the scheme is illustrative only and is not meant to limiting.

Process for the preparation of conjugates useful in the treatment of prostate cancer

Abstract: which may be useful in the treatment of prostate cancer. Such compounds are synthesized in the presence of a carboxyl activating agent, an additive and a base for the preparation of a PSA conjugate which comprises an anthracycline antibiotic and an oligopeptide.


This invention relates to a process for preparing asymmetric isoindoline pigments of the formula ##STR1## in which R.sup.1 is an electron-withdrawing group, R.sup.2 and R.sup.3 are independently hydrogen, alkyl, or aryl, and R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are independently hydrogen, halogen, alkyl, alkoxy, or aryloxy. The process employs an initial reaction of a 1,2-dicyanobenzene with an alcohol in an organic medium in the presence of a base. The resultant imino-isoindoline intermediate composition reacts without isolation with a cyanomethylene compound NC--CH.sub.2 --R.sup.1 to form a partly condensed product that is then condensed without isolation in the presence of water with barbituric acid or a derivative thereof to form the asymmetric isoindoline pigment.

This invention relates to an improved process for preparing asymmetric isoindoline pigments having high brilliance and color strength and good light- and weather-fastness.
Compounds of formula I are valuable organic pigments previously described in the literature. Such compounds are disclosed, for example, in U.S. Pat. Nos. 3,991,054, 4,166,179, 4,316,023, and U.S. Pat. No. 4,401,815, and in Canadian Patent 1,140,130. These references, however, disclose processes that require an initial preparation of 1-amino-3-iminoisoindoline (also known as 1,3-diiminoisoindoline) (formula A) ##STR2## or ring-substituted derivatives thereof from 1,2 -dicyanobenzene and ammonia. Cf. F. Baumann et. al., Angew. Chem., 68, 133-150 (1956). Among the technical and economical disadvantages of these methods is the need to convert 1,2-dicyanobenzene into this intermediate in an additional step when compared to the s process of the present invention. In addition, the need to handle ammonia causes safety and environmental problems.
The use of dialkoxy isoindolines instead of 1-amino-3-amino-isoindoline avoids the need for ammonia. For example, U.S. Pat. No. 4,500,718 discloses a method using alcoholate bases (formed in situ from a strong base in an alcohol) to convert 1,2-dicyanobenzene into intermediate mixtures analogous to those of formula VIII (see below). The disclosed method, however, was used to form only symmetric bis(cyanomethylene) compounds.
U.S. Pat. Nos. 3,646,033 and 3,794,659 disclose a stepwise method for using 1-amino-3-amino-isoindoline, dialkoxy isoindolines, and other such reactive isoindoline derivatives to prepare asymmetric isoindoline derivatives. These patents, however, teach the importance of removing impurities from isolated intermediates and thus, do not suggest methods in which intermediates are not isolated. In addition, these patents exemplify the preparation of compounds different from those of the present invention.
Therefore, an object of the present invention was to develop a procedure for synthesizing isoindoline pigments of formula I in pure asymmetric form and without the use of ammonia and 1-amino-3-amino-isoindoline and without the need to isolate intermediates.

Process for preparation of asymmetric isoindoline pigments


A light emission device includes a vacuum chamber including a first substrate, a second substrate spaced from and facing the first substrate, and a sealing member between the first substrate and the second substrate. An electron emission unit is on the first substrate, the electron emission unit including a plurality of electron emission elements. A light emission unit is on the second substrate, the light emission unit including a phosphor layer. A barrier is spaced from the sealing member between the first substrate and the second substrate. At least one stud pin is fixed on at least one of the sealing member and the barrier and a getter unit is attached to the at least one stud pin, the getter unit fixed between the sealing member and the barrier.

1. Field of the Invention
The present invention relates to a light emission device having a getter in a vacuum chamber and a display device using the light emission device as a light source.
2. Description of the Related Art
There are many different types of light emission devices that radiate visible light. For example, a light emission device may include an anode electrode and a phosphor layer on a front substrate and electron emission regions, and driving electrodes on a rear substrate. The front and rear substrates are sealed to each other at their peripheries using a sealing member, and the inner space between the front and rear substrates is exhausted to form a vacuum chamber.
The electron emission regions emit electrons toward the phosphor layer, and the electrons excite the phosphor layer to cause the phosphor layer to emit visible light. In this case, the anode electrode functioning as an acceleration electrode receives a high voltage greater than several thousand volts and accelerates electrons to the phosphor layer.
When the light emission device is maintained at a high vacuum state, emission efficiency and a life-span of the electron emission regions may be improved. Accordingly, a conventional light emission device includes a getter in the vacuum chamber. After manufacturing the vacuum chamber, the getter is activated by a high frequency induction heating device to absorb or eliminate remaining gas in the vacuum chamber. The getter is usually fixed on an inactive area of either the front or rear substrates by a fixing agent.
However, since a fixing agent is required to fix each getter on the substrate, a configuration and an installation method thereof are complicated, outgassing may occur from the fixing agent to deteriorate a vacuum state, and fragments generated from the fixing agent may remain in the vacuum chamber. In addition, since the getter may be weak against external impact, the getter is easily moved or misshapen when impact or vibration is applied to the vacuum chamber.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the invention and therefore it may contain information that does not form the prior art that is already known in this country to a person of ordinary skill in the art.

Light emission device and display device using the light emission device as light source


A device for arbitrating access to a resource by a plurality of agents includes logic configured to associate requesting ones of the agents with access tokens. The number of the access tokens assigned to each requesting agent is proportional to its bandwidth or speed in comparison with the other requesting agents. A is selector configured to sequence through the access tokens and select respective ones of the requesting agents associated with the access tokens. The logic may dynamically reconfigure token allocation and distribution to only those agents having a pending service request or may skip tokens allocated to agents not having a pending request. The distribution of tokens is preferably uniform over the total bandwidth space of the agents or requesting agents. In one implementation tokens are in the form of binary numbers.

In computer systems, single resources are shared between competing multiple agents through arbitration algorithms that ensure that each of the agents has equitable access to the single resource. For example, if four comparable agents required access to a single device or resource, one arbitration algorithm might ensure that each agent had access to the single device, or resource, 25% of the time. A common arbitration scheme uses a round robin. In a round robin arbitration each of the multiple agents is given equal priority in the arbitration and the round robin arbitration algorithm cycles in a fixed order through the multiple agents that are competing for the resource. Typically, the successful agent is chosen through numerically increasing order. In a specific arbitration cycle, the reference number of a selected agent is stored and then, during the next arbitration window, the next highest agent number is selected. For example, if eight agents request access to a single device or resource, this scheme would assign the competitive agents reference numbers 0 through agent 7 respectively. If the requested device or resource had most recently been accessed by agent 0, this value would be stored and in the succeeding cycle, agent 1 would have exclusive use of the device or resource.
While each competing agent has equal priority for the single resource and receives a pro-rata allotment for accessing the resource, such equal distribution of time slots and periods between multiple agents does not readily adapt to competing agents having different bandwidth requirements or speed capabilities. For example, if one agent operates at a speed such that it requires a resource twice as often as a second agent, this technology makes no provision for these greater requirements. Instead, using the round robin arbitration described, both agents would win the arbitration equally often and each would have equal access to the single resource even though one agent requires the resource twice as often as the other agent. This mismatch between the agent""s bandwidth capabilities and its access to the shared resource impairs overall efficiency.
For example, in a computer system there are often many input/output (I/O) devices which have different bandwidth requirements. A system that supports different speeds of peripheral component interface (PCI) buses, may have cards which utilize data at different speeds. While the following description uses a PCI bus, the invention is not limited to any particular type of bus architecture. Some cards on a PCI bus may run at 33 MHZ while other cards run at 66 MHZ. Assuming an identical number of bits of data used by the two cards, the 66 MHZ card will use data twice as fast as the 33 MHZ card. The PCI card that runs at 33 MHZ are designated as 2X PCI bus cards. These cards use 64 bits of data. Conversely, the PCI bus cards that run at 66 MHZ are designated 4X PCI bus cards and also use 64 bits of data. A third speed of bus card is available which doubles the bandwidth of the 4X PCI bus cards and is designated the 8X PCI bus cards. The 8X PCI bus cards runs at double the bandwidth. If a 2X PCI bus card, a 4X PCI bus card, and an 8X PCI bus card were all configured with a standard round robin arbitration, the three speed cards would be given equal priority for the single resource. However, because of the greater data rates, the 4X PCI bus card and the 8X PCI bus cards are not being used efficiently in this round robin arbitration between the cards of various speeds and bandwidth.
Arbitration schemes have attempted to address this mismatch between high speed agents by devoting additional resource access periods to the higher speed agents. For instance, if an 8 cycle access period is divided between two 2X PCI bus cards (2X PCI#1 and 2X PCI#2), and a single 4X PCI card (4X PCI) a standard round robin arbitration scheme would allow each agent to access the resource {fraction (1/3)} of the time. However, prior arbitration schemes have attempted to give the 4X PCI card twice as much access to the resource then either of the two 2X PCI cards. In an 8 cycle access period, access to the resource could be divided as follows: cycle 0-2X PCI#1; cycle 1-2X PCI#2; cycle 2-4X PCI; cycle 3-4X PCI; cycle 4-2X PCI#1; cycle 5-2X PCI#2; cycle 6-4X PCI and cycle 7-4X PCI.
While this division of the resource among competing agents does lessen the problem, other difficulties are encountered. First, during the cycles in which 4X PCI card has exclusive access to the resource, both the 2X PCI#1 and 2X PCI#2 are deprived of access to the resource. Unless both 2X PCI bus cards have stored enough data to continue processing during that time, the overall efficiency of the system is reduced. Secondly, buffers associated with the 2X PCI bus cards may have to be increased to ensure their access to data during the excluded cycles. These problems are only exacerbated when an 8X PCI bus card is included within the system and increasingly the bandwidth mismatch. In addition, the startup time is delayed for the 2X device if the 4X of 8X card is selected first.
A need therefore exists for an efficient arbitration scheme which accommodates multiple speeds of the competing agents and which efficiently distributes access to the resource in accordance with the various speeds of the competing multiple agents. A further need exists for an efficient arbitration scheme that distributes access to the resource among the multiple agents in an efficient manner, allowing each of the competing agents to effectively use the single resource.
These and other objects, features and technical advantages are achieved by a system and method which according to one aspect of the invention, includes a device for arbitrating access to a resource by a plurality of agents includes logic configures to associate requesting ones of the agents with access tokens. The number of the access tokens assigned to each requesting agent is proportional to its bandwidth or speed in comparison with the other requesting agents. A selector is configured to sequence through the access tokens and select respective ones of the requesting agents associated with the access tokens. The logic may dynamically reconfigure token allocation and distribution to only those agents having a pending service request or may skip tokens allocated to agents not having a pending request. The distribution of tokens is preferably uniform over the total bandwidth space of the agents or requesting agents. In one implementation tokens are in the form of binary numbers. Sequencing through the binary numbers may be based on a reversal of the bits of the numbers or selection of winning agents may be based on a reversal of the bits.
According to another aspect of the invention, a method of arbitrating access to a resource by a plurality of agents associates requesting ones of the agents with access tokens. Numbers of access tokens are associated with each of the requesting agents in proportion to that agent""s bandwidth capabilities and/or requirements with respect to the total bandwidth of all agents. The access tokens are sequenced through and respective ones of the requesting agents are selecting in response to selection of one of its tokens. The method may further include dynamically allocating the access tokens to the requesting ones of the agents and/or skipping selection of nonrequesting ones of the agents in response to an arbitration request. The tokens may be binary numbers wherein the selecting step sequences through the token in a reverse bit sequence order. Selection of agents may be based on a reverse bit sequence order of the binary numbers. The tokens associated with a particular agent may be uniformly distributed amongst all of the tokens.
According to another aspect of the invention, a device equitably arbitrates access to a resource by a plurality of agents such as DMA by a plurality of I/O devices, memory access by plural processors, etc. The invention includes methods and structures to equitably distribute access to resources based on the bandwidth of the requesting device relative to the bandwidth of other requesting devices (i.e., the normalized bandwidth (or speed) of the device). An even distribution may be accomplished using a variety of techniques, including bit reversal of an appropriate sequence of binary numbers, use of a hash function, use of a pseudo-random number generator to spread requests evenly over a large number space, etc.
According to one implementation, the invention includes map logic, a clock and a selector. The map logic defines a plurality of consecutive time slots equal in number to a total normalized bandwidth requirement of the agents, each of the agents assigned a number of time slots proportionate to its own bandwidth requirements. A selector is responsive to a clock for sequencing through the time slots and selecting respective requesting ones of the agents assigned to the time slots.
According to a feature of the invention, the clock may be in the form of a counter providing a repeating sequence of values. The sequence may repeat in correspondence to a total number of time slots defined by the map logic.
According to another feature of the invention, the map logic evenly distributes the time slots assigned to respective ones of the agents over a total number of the consecutive time slots.
According to a still further feature of the invention, each of the time slots is identified by a corresponding one of a monotonically increasing sequence of binary numbers and the map logic maps each of the binary numbers to a target binary number formed by reversing a bit order thereof.
According to a still further feature of the invention, each of the agents is assigned a consecutive sequence of binary numbers starting with a integer multiple of its normalized bandwidth. For example, a device operating at a bandwidth four times that of a slowest device may be assigned four time slots corresponding to a forward binary sequence beginning at 0, 4, 8 or 12 (Chex) and including the next three binary numbers. When reversed, the sequence evenly distributes the assignments to this device over the entire space of, in this example, sixteen possible slots. Time slots assigned to devices or processes not requesting service and unassigned time slots may be skipped or excluded.
According to a still further feature of the invention, each of the agents is assigned a consecutive sequence of binary numbers having a minimized distance between the most significant bits thereof weighted from most to least significant. Thus such that a sequences of binary values associated with a particular agent begins on bit transition boundary minimizing transitions of the most significant bit through the next most significant bit of the series.
According to another feature of the invention, each of the agents is associated with a set of binary numbers corresponding to values obtained by reversing a bit order of respective ones of non-overlapping consecutive sequences of binary numbers, each of the sequences spanning a range proportionate to a bandwidth requirement of respective ones of the agents.
According to another feature of the invention, each of the agents is associated with a set of binary numbers included within respective non-overlapping consecutive sequences of binary numbers, each of the sequences spanning a range proportionate to a bandwidth requirement of respective ones of the agents.
According to another aspect of the invention, a method of arbitrating access to a resource by a plurality of agents includes defining a plurality of consecutive time slots, a number of the time slots assigned to respective ones of the agents in proportion to respective bandwidth parameters thereof. The time slots are then periodically sequenced through and respective ones of the agents assigned to the time slots are selected. Preferably, ones of the time slots assigned to respective ones of the agents are evenly distributed among all of the time slots.
According to a feature of the method, each of the time slots is identified by a corresponding one of a monotonically increasing sequence of binary numbers and the map logic maps each of the binary numbers to a target binary number formed by reversing a bit order thereof.
According to another feature of the inventive method, each of the agents is associated with a consecutive sequence of binary numbers having a minimized distance between the most significant bits thereof According to another feature, each of the agents is associated with a set of binary numbers corresponding to values obtained by reversing a bit order of respective ones of non-overlapping consecutive sequences of binary numbers, each of the sequences spanning a range proportionate to a bandwidth requirement of respective ones of the agents. Another feature includes associating each of the agents with a set of binary numbers included within respective non-overlapping consecutive sequences of binary numbers, each of the sequences spanning a range proportionate to a bandwidth requirement of respective ones of the agents.
The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims.

Arbitration scheme for equitable distribution of bandwidth for agents with different bandwidth requirements

Hewlett-Packard Development Company, L.P.


An analog signal monitoring (ASM) circuit (40, 42) non-intrusively monitors an analog circuit (20) within an electronic system. The ASM circuit (40,42) comprises input circuitry (80) that receives a plurality of analog signal inputs while the analog circuit (20) operates in a functional mode. Translation circuitry (142) associates with the input circuitry (80) for converting the analog signal inputs into digital signal representations of the analog signal inputs. Output circuitry (58) associates with the translation circuitry to output the digital representations. Control circuitry (114) controls the translation and output circuitry while the analog circuit (20) is in a functional mode. The ASM circuit (40, 42) also include an event qualification circuit (68) that includes input circuitry (236) to receive the digital signal representations, compare circuitry (104) to compare the received digital representations to an expected value and output a matched signal when a compared condition is identified.

Known test methods and systems for measuring and testing analog circuits on electronic circuit boards require the use of expensive external test equipment and signal node probing mechanisms. During test, the analog circuits operate together functionally while an external analog tester probes, stores and processes analog signals within the analog circuit. These external analog test systems do not provide the capability to easily monitor the analog signals while the analog circuitry operates normally in its system environment due to limited physical access to probe the circuit nodes. Moreover, known analog test methods are not easily used during the entire life cycle of a functional circuit, i.e., during production test, system integration, system test, on-line test or diagnostics, and field support and maintenance.
A particular limitation associated with traditional analog test methods is that the state of the art board designs are so densely populated with integrated circuits that physical probing of the analog signals is very difficult, if not impossible. Additionally, in traditional systems the necessity for external probes to make contact with the signal path often affects the analog signal. Probes add resistive and capacitive loads to an analog signal that potentially cause the signal characteristics (e.g., voltage amplitude, and wave shape) to change when these systems take voltage measurements. As a result, physical probing of analog signals can produce inaccurate measurements and distorted test results.
Yet another problem associated with traditional test methods is that these tests are dependent on the systems and availability of external testers and probing fixtures. These systems usually include complex and cumbersome electronic circuits housed within various cabinets or component chassis. In a field environment, the transportation and upkeep of these components can be a very expensive proposition.
U.S. patent application Ser. No. 07/374,896, entitled "Digital Bus Monitor Integrated Circuit," by L. D. Whetsel, the present inventor, filed on Jun. 30, 1989, and assigned to Texas Instruments Incorporated, ("Whetsel") describes a digital bus monitor used to observe data on a box connecting multiple integrated circuits. The monitor of that application comprises a memory buffer, a signature analysis register, a test port and output control circuits controlled by an event qualifying module. In response to a matching condition, the event qualifying module may perform a variety of tests on incoming data while the integrated circuits continue to operate at speed. The invention of that application further includes a plurality of digital bus monitors that may be cascaded for observation and test for variable width data buses and variable width signature analyses.
The digital bus monitor of Whetsel suffers from the limitation that to be useful for testing analog circuits an external analog to digital converter must be connected to the analog circuitry. Additionally, the digital bus monitor of Whetsel suffers from the limitation that it cannot make comparisons in value between a receive signal and a predetermined test value. For example, if the value of hexagonal A5A5 is anticipated from the tested circuitry, unless the received signal is exactly A5A5 the circuit may not respond. In the analog domain, however, it may be important not only that the signal exactly equal a test set point, but more importantly that the relative magnitude between the receive signal and a test set point may be analytically important. For example, if the analog equivalent to hexagonal A5A5 is the predetermined test set point, if the input signal is greater than the analog representation of A5A5, this information may help isolate the source of the signal variance in the analog circuit being tested.
As a result, there is a need for an analog test method and circuit to measure and test analog signals on circuit board designs that does not require the use of expensive external test equipment and signal node probing mechanisms.
There is the need for an analog test method that can effectively test densely populated analog circuit boards for testing.
There is the need for an analog test method that does not rely on the availability of test equipment in a field environment.
Moreover, there is a need for an analog signal testing method and circuit that does not include the resistive and capacitive loads to distort signal characteristics as is common in traditional analog test methods and circuits.

Analog signal monitor circuit and method


Methods and apparatuses for the direct electrochemical generation of high concentration, stable aqueous solutions comprised of mixtures of free halogen species, N-halosulfamate compounds, N-halosulfonamide, and other compounds for biocidal applications is disclosed. Solutions containing the desired content of these species, with the desired concentration and pH value, is achieved through the electrolysis of aqueous brines containing mixtures of metal halide compounds, sulfamic acid, and other additives as desired. Controlling the relative compositions of the brines used to prepare the desired biocidal solutions, as well as the electrolysis conditions, can produce the biocidal solution with the desired composition and properties.

Field of the Invention (Technical Field)
The present invention is related to the in situ production of high concentration stable aqueous biocidal solutions comprised of mixtures of free halogens, N-halosulfamic acid compounds, N-halosulfamate compounds, N,N-dihalosulfamic acid compounds and N,N-dihalosulfamate compounds, with or without additional biocidally active components, in any desired compositional mixture and at a desired pH through an electrolysis process, where the nature of the biocidal solution is determined by the nature of the brine used in the electrolysis process as well as the operational parameters of the electrolytic process.
Background Art
Note that the following discussion may refer to a number of publications and references. Discussion of such publications herein is given for more complete background of the scientific principles and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Aqueous free halogen species such as chlorine, bromine, iodine, hypochlorous acid, hypobromous acid, hypoiodous acid, hypochlorite, hypobromite, and hypoiodite are known to be very powerful anti-microbial agents and are often used in water disinfection applications. Along with a high level of biocidal activity, aqueous free halogens are also highly chemically reactive to other species often present in waters undergoing treatment. These species include natural organic matter, synthetic and natural organic chemicals, iron, manganese, hydrogen sulfide, ammonia, arsenic, and other chemicals. The presence of these free halogen demanding substances consume free halogens added to the water that would otherwise be useful in inactivating microorganisms, thus, this process could be considered detrimental to the overall treatment process if the free halogen consuming chemical reaction is not desirable. Reactions between aqueous free halogens and organic material present in the water being treated can also, in some cases, lead to the undesirable products such as the formation of halogenated organic chemicals such as trihalomethanes and haloacetic acids. Therefore, the treatment of waters containing high amounts of these halogen-reactive compounds is often advantageously accomplished through the use of biocides that are less chemically reactive than aqueous free halogen species.
Haloamines, which can broadly be considered as chemical species which contain at least one nitrogen-halogen bond, are often used in place of oxidizing free halogens to provide a disinfectant for water treatment. While haloamines are effective biocidal compounds, they are also much less chemically reactive as compared to free halogens. Thus, in waters containing substantial amounts of free halogen demanding substances, haloamines have the potential to provide a substantial benefit to the overall water disinfection process. Aqueous solutions of haloamines are typically produced through a chemical reaction between an aqueous free halogen species and a compound containing at least one nitrogen-hydrogen bond whereby the chemical reaction produces a compound containing at least one nitrogen-halogen bond. Ammonia or ammonium ions are the most common source of the nitrogen containing compound used in this process, although other nitrogen containing compounds are often utilized as well.
One major deterrent to the use of haloamines, and especially haloamines produced through the reaction of ammonia or ammonium ions with an aqueous free halogen species, is that they are highly unstable, especially at higher concentrations (i.e. greater than 10 mg/L); see for example Audrieth, L. F.; Rowe, R. A. "The Stability of Aqueous Chloramine Solutions" J. Am. Chem. Soc. 1955, 77, 4726-4728. Due to the instability of haloamines, it is typically not possible to produce concentrated haloamine solutions and ship them to a point of application. As a result, haloamines derived from ammonia or ammonium ions are often produced in situ during treatment by the action of aqueous free halogens on ammonia or organic amines naturally present or added to water being treated. Alternatively, it is sometimes desirable to prepare concentrated aqueous haloamine solutions derived from the reaction between ammonia or ammonium ions at the point of application and then use these formed haloamine solutions as a primary disinfectant. Situations where this could be advantageous include the treatment of waters which have a known or highly variable free halogen demand which would consume free halogens without the benefit of microbial inactivation but which can be effectively treated with a haloamine disinfectant.
Sulfamic acid and its organic compound derivatives, known as sulfonamides (for example, toluenesulfonamide), are chemically distinct from ammonia or other organic amine-containing compounds used to produce haloamines but, like ammonia or many amines, typically contain a nitrogen-hydrogend bond which can react with aqueous halogen species. Products of the reaction between sulfamic acid, having the chemical formula H3NSO3, and an aqueous halogen species are N-halosulfamate compounds (either N-halosulfamate, having the chemical formula HNSO3X−, or N-halosulfamic acid, having the chemical formula H2NSO3X), N,N-dihalosulfamate compounds (N,N-dihalosulfamic acid, having the chemical formula HNSO3X2, or N,N-dihalosulfamate, having the chemical formula NSO3X2−), or combinations thereof, where, in all cases, the letter X represents a halogen (i.e. Cl, Br, I). Products of the reaction between and organic sulfonamide compounds, having the chemical formula of RSO2NH2, and an aqueous halogen species are N-halosulfanomide compounds, having the chemical formula of RSO2NHX, N,N-dihalosulfonamide compounds, having the chemical formula of RSO2NX2, or combinations thereof, where, in all cases, the letter R represents and organic functional group comprising at least carbon and hydrogen and the letter X represents a halogen (i.e. Cl, Br, I). These compounds can stabilize the electrolyzed halogen species.
U.S. Pat. No. 3,776,825 to Vit entitled "Electrolytic Treatment" discloses that a brine comprising a halide ion source and an amine compound both dissolved in water is first pH adjusted through the addition of a base such as sodium hydroxide, and then electrolyzed, thereby producing a solution containing one or more haloamine compound, including N-chlorosulfamates or N-chlorosulfonamides produced from sulfamic acid or organic sulfonamides, respectively. Vit further teaches that when electrolysis is used to make these haloamine solutions they are unstable, and therefore the invention descried by Vit is focused entirely on the instantaneous production and immediate subsequent use of the produced haloamines as opposed to the production of stable haloamine solutions. Because Vit discloses the addition of NaOH to the brine prior to electrolysis, and discloses that the pH of the solution is thus greater than 12, the solution prior to electrolysis no longer comprises sulfamic acid, but instead comprises sulfamate ions.

Methods for the direct electrolytic production of stable, high concentration aqueous halosulfamate or halosulfonamide solutions


An opening (irradiation opening (90A)), which faces an opening portion of an outer peripheral member and through which an optical axis of an optical member (lamp unit (46)) passes, is formed in a trunk portion (88) that, together with a viewing means (door mirror) for assisting viewing by a vehicle occupant of a vehicle, is covered by the outer peripheral member (visor cover). Further, a wall portion (106), which runs along a peripheral wall of the opening portion and, at a vehicle rear side portion, faces the peripheral wall at a radial direction side, is formed at the trunk portion. Air, which enters into the opening portion while the vehicle is traveling, passes-through a flow path that is bent by the peripheral wall and the wall portion, and the flow rate is reduced, and noise is suppressed.

An outer mirror such as a door mirror or the like is provided at a vehicle as an exterior rearview mirror that assists viewing by a vehicle occupant.
Further, Japanese Patent Application Laid-Open (JP-A) No. 2012-091673 discloses a light emitting device that is provided at the interior of an outer mirror and that irradiates light toward the vehicle exterior from an opening portion that is formed in the visor cover of the outer mirror.
On the other hand, the visor cover of the door mirror receives airflow (wind) from the vehicle front side while the vehicle is traveling. Therefore, while the vehicle is traveling, if airflow advances straight through the visor cover interior from the interior of an illumination opening formed in the visor cover, noise such as wind noise and whistling and the like increases.


A composite article includes a plurality of fibers at least partially embedded within a matrix. The fibers may be adhered to the matrix at a level of adhesion. The adhesion level between the fibers and the matrix may be varied spatially within the composite article. For example, the adhesion level may vary along a length of one of the fibers. The adhesion level may also vary among the fibers of a given layer. Furthermore, the adhesion level may vary between the layers of the composite article.

Existing armor panels as currently known may be comprised of laminated sheets of various materials. For example, existing armor panels may be comprised of one or more sheets of glass and/or acrylic which may be laminated using suitable adhesives. In attempts to improve the ballistic resistance or performance of armor panels, manufacturers may add layers of polycarbonate material to the sheets of laminated glass and acrylic.
Although generally effective in absorbing energy from impacts and providing protection against projectiles, existing armor panels possess certain drawbacks which detract from their utility. For example, glass is a relatively dense material and therefore adds significantly to the overall mass and bulk of the armor panel at the thicknesses required to provide sufficient ballistic protection. A further drawback associated with certain armor panels is related to the mechanical properties of glass and other materials that make up certain armor panels. For example, it may desirable in certain applications such as in vehicular applications that an armor panel is transparent.
Unfortunately, certain currently available transparent armor panels may suffer a significant loss in optical performance following an impact event. For example, for certain currently available armor panels, an impact in a localized area of the armor panel from a projectile may result in loss of optical performance in a significant portion of the remainder of the armor panel. Such loss in optical performance may be a result of crack propagation from the impact site.
As can be seen, there exists a need in the art for an armor panel which provides a high degree of optical transparency with improved ballistic performance and minimal weight.

Controlled fiber-matrix adhesion in polymer fiber composites


An adjustable width brassiere strap for selectively providing arm support of a brassiere includes an elongate central panel having a front end and a back end; a bottom pleat affixed along a first edge of the elongate central panel; a top pleat affixed along a second edge, opposite the first edge, of elongate central panel; and wherein the pleats and said central panel are affixed, one to another, et each of the ends of the central panel. In use, the brassier strap is adjustable from an otherwise “conventional” dimension to a “widened” dimension.

For many women, finding a brassiere that is adequately supportive, comfortable and appropriate for selected attire is a daily exercise in futility. At the heart of this frustration, Applicant has discovered, is the fixed strap as generally ubiquitous in the art. While such straps typically comprise length adjustments, little more has heretofore been provided.
With the persistent shortcomings of the prior art clearly in mind, it is therefore an overriding object of the present invention to improve over the prior art by providing a brassier strap that is adjustable in width.
It is an additional object of the present invention to provide such an adjustable brassier strap that is stepwise adjustable.
It is a still further object of the present invention to provide such an adjustable brassier strap that is adjustable such that the width of the strap can be extended toward the user's arm, toward the user's neck, or both.
It is also an object of the present invention to provide such an adjustable brassier strap that also readily accommodates repositioning of the strap on and about the user's shoulder region.
Finally, it is an object of the present invention to provide such an adjustable brassier strap that is readily usable with virtually any otherwise conventional brassier design, and that is economically manufactured, thereby ensuring that the improved brassiere strap of the present invention may be made widely available.


An optical reflectometer includes an optical head having a measuring chamber defined therein and a measuring zone defined within the chamber. A pair of non-parallel bores are defined within the front wall of the head and optically lead into the measuring chamber so as to intersect at the measuring zone. A light source is optically associated with one of the bores while a photodetector is optically associated with the other one of the bores. A carrier, having a cut-away section defined within its front wall for accommodating the light path defined by the light source, the measuring zone, and the photodetector, is removably disposed within the optical head and serves to carry, and position, a test object with respect to the measuring zone, the object, in turn, being removably disposed within the carrier.

The normal concentration of glucose in the body is 3-7 millimoles per liter, and unless the concentration is regulated to within this normal range, there can be long term complications in the body leading for example to blindness.
For non-diabetics, this regulation is controlled automatically by an enzyme in the body. Diabetics, on the other hand, lack this enzyme and must therefore resort to use of a carefully controlled diet or, in some cases, the use of insulin injections.
Reflectometers have already been developed to determine the glucose content of a blood sample. The sample is taken and transferred to a test stick containing reagents including an enzyme which, indirectly, reacts with the glucose of the blood to change the colour of a dye. The greater the glucose content, the deeper becomes the colour of the dye. After a fixed period, the bood is washed or wiped off the test stick, and the stick is inserted into the reflectometer to provide a reading dependent on the colour of the dye.
Sophisticated reflectometers which include glass components such as prisms and mirrors would be too expensive for this type of application where accuracy need not be greater than about .+-.0.5 millimoles per liter. Attempts to produce a simple, inexpensive reflectometer have therefore been made. However, these meters are still rather bulky and difficult to use and are not therefore suitable for use by a diabetic at home. For example, one such meter requires a two-stage calibration each time the meter is used. It also relies upon the movement of a pointer over a graduated non-linear scale to provide its readout. Moreover, the test stick is inserted in a hinged cover which, as it closes, trips a microswitch to switch on the meter, and we have found that different readings can be obtained for the same sample depending on the point at which the cover is pressed to trip the microswitch. A need therefore exists for a more convenient and reliable meter.


A nonvolatile memory device includes a memory cell that stores data by presence or absence of electrons accumulated in a floating gate, a read reference current generator that generates a read reference current for reading data from the memory cell based on a constant current from a constant current generator included therein, and a read voltage generator that generates a read voltage to be applied to a control gate of the memory cell during data reading. The read reference current generator generates a monitor voltage that varies according to variation of the read reference current and a threshold voltage of the memory cell. The read voltage generator generates the read voltage based on the monitor voltage.

1. Field of the Invention
The present invention relates to a nonvolatile semiconductor memory device.
2. Description of Related Art
A flash memory and an EEPROM (Erasable Programmable Read Only Memory) are known as nonvolatile semiconductor memory devices. A memory cell of such a nonvolatile semiconductor memory device includes a control gate and a floating gate, and stores data by the presence or absence of electrons accumulated in the floating gate.
In order to stably read information stored in a memory cell, a structure is known which incorporates a dummy cell that is identical to the memory cell and uses an output from the dummy cell as a reference (e.g. Japanese Unexamined Patent Publication No. 2004-178621).
FIG. 9 is a circuit structure of the flash memory disclosed in Japanese Unexamined Patent Publication No. 2004-178621. Referring to FIG. 9, a flash memory 30 includes a memory cell 31, a reference cell (dummy cell) 32, control transistors 33 and 34 and a decision amplifier 35.
The symbols Vcc and Vss in FIG. 9 indicate a voltage source potential (generally, 5V) and a ground potential (generally, 0V), respectively.
When the memory cell 31 is selected by a word line, a read voltage Vwl is applied to a control gate of the memory cell 31 through the word line.
The read voltage Vwl being applied to the control gate, a memory cell current Icell corresponding to charges accumulated in a floating gate is output from the memory cell 31.
FIG. 10(A) is a view showing an example of I-V characteristics of the memory cell.
In FIG. 10(A), the I-V characteristics of the memory cell in written mode and the I-V characteristics of the memory cell in erased mode are both shown.
As shown in FIG. 10(A), the memory cell is designed in such a way that there is a sufficient difference between a current Icell1 output from the memory cell in written mode and a current Icell0 output from the memory cell in erased mode when a read voltage is applied.
The memory cell current Icell is supplied to the decision amplifier 35 through the control transistor 33, and information is read by the decision amplifier 35 based on the memory cell current Icell.
The decision amplifier 35 is connected to a bit line 36 and a reference bit line 37, and compares the magnitudes of a current Icell passing through the bit line 36 and a current Iref passing through the reference bit line 37.
The reference cell 32 is used to supply a reference current Iref to the decision amplifier 35.
FIG. 10(B) is view showing an example of I-V characteristics of the reference cell.
The reference cell is set in such a way that the magnitude of the reference current Iref that flows when a voltage Vcc is applied is between the current value Icell1 output from the memory cell in written mode and the current value Icell0 output from the memory cell in erased mode.
Such setting of the reference cell is made by controlling the charges accumulated in the floating gate or the voltage value Vcc applied to the reference cell.
The decision amplifier 35 can determine the data stored in the memory cell 31 by comparing the current Icell passing through the bit line 36 and the current Iref passing through the reference bit line 37.
At this point, a sufficient difference is made between the current value (Icell0, Icell1) output from the memory cell 31 and the reference current Iref, so that a sufficient operating margin is maintained to secure the reading operation.
Because the memory cell 31 and the reference cell 32 have the identical structure, the relative relationship between the I-V characteristics of the memory cell 31 and the I-V characteristics of the reference cell 32 is stable, and normal reading of data is assured.


A tactile area sensor for robots has an array of pneumatic flow passages. The air flow in each passage is dependent on a localized force exerted by an object pressing against an elastic pad on the face of the sensor. The air flow impinges on a metallic tab and its angular displacement is sensed by directing a light beam from an optical fiber onto the tab and monitoring the quantity of light reflected to a paired optical fiber. The array of optical outputs can be presented to a charge injection device and are dependent on the shape of the object.

There is a widely documented need for tactile area sensors to provide a sense of feel for computer controlled robots and programmed assembly machines. This type of sensor can be used for object identification as well as for insertion and mating tasks associated with assembly. The preferred location of the sensor is on the extremity of a movable finger. Consequently, the sensor must be compact and rugged and capable of being interrogated with a minimum of communication channels to the system computer. In addition, the sensor must be low cost, have good stability, and provide resolutions of better than one hundred bits per square inch to be compatible with industrial applications.
Many concepts for tactile area sensors have been proposed, but with the exception of low density sensors based on guided rods or force activated switches, most have not been reduced to practice. Those concepts based on resistance change of conductive rubber, graphite filled foam, or carbon fibers have the potential for low cost, durable sensors; however, technical problems have not been solved. Concepts based on arrays of conventional pressure sensors are technically feasible but the cost is prohibitive.


A display device including: a display cell that includes a first substrate and a second substrate that are arranged to be opposing, includes a wiring region that is wider than the first substrate on the second substrate, and includes an electrode in the wiring region; a wiring substrate in which at least a portion is arranged to be opposing the wiring region and which is electrically connected to the electrode; a front panel that is provided on a front surface of the first substrate; and a desiccating bonding agent that fixes the front panel to the first substrate while covering from at least a portion of a side surface of the first substrate to a connection portion between the electrode and the wiring substrate.

The present disclosure relates to a display device such as a liquid crystal display panel.
Although various types of display panels such as liquid crystal display panels and PDPs (Plasma Display Panels) have been developed, liquid crystal display panels are particularly thin and light, and have low power consumption. Liquid crystal display panels are therefore widely used for image display devices such as televisions, office equipment such as PCs (Personal Computers), and mobile terminals such as mobile phones, PDAs (Personal Digital Assistants), PDA phones, mobile game consoles, and tablet PCs, or the like.
Input of a signal or the like is used for driving various types of display panels including such liquid crystal display panels. For example, as a method of connecting a display panel and a driver IC (Integrated Circuit) that transmits an image signal, a method of connecting a printed circuit electrode of a printed circuit substrate and an electrode of a pixel via an ACF (Anisotropic Conductive Film) is widely known. With such a method, there is a case when a method of coating a connection portion of the ACF with a desiccant in order to prevent the infiltration of moisture into the connection portion is used.
In addition, with the various types of display devices, it is known that a front panel such as a cover substrate (decorative panel) or a touch panel is installed on a front surface (surface on the display side) of the display panel from the viewpoint of surface protection, aesthetics, or functionality. Such a type of front panel is used by being adhered on the entire surface of the front surface of a display panel. For example, a display device in which the front panel is bonded with the front surface of a liquid crystal display panel by a resin has been reported (for example, refer to Japanese Unexamined Utility Model Registration Application Publication No. 2-27121). Since a resin for bonding such a front panel with a display panel and a resin for coating a connection portion each have different objectives, different resin materials are used.

Display device having a display cell with bonding agent configuration