A manufacturing process of the thermoelectric conversion element is provided, wherein the system using semiconductor process technology to the construction of the thermoelectric conversion element nanoscale thermoelectric effect to increase, and the use of different type and surface state of the sample to increase the thermoelectric conversion element thermoelectric figure of merit. Through the use of a specific thickness of deposition of nanostructures on a nanoscale roughening of the substrate cannot affect the conductivity of thermoelectric materials under, and also can improve the Seebeck coefficient and lower thermal conductivity in order to significantly enhance the thermoelectric figure of merit.

1. Field of the Invention
The present invention relates to a manufacturing process of a thermoelectric conversion element, in particular with respect to a thermoelectric conversion element having a nanostructure on a surface thereof.
2. Description of the Related Art
When facing the gradual exhaustion of the global primary energy as well as the more and more critical greenhouse effect, development along with application of renewable energy has become an issue in an urgent need. The technique of thermoelectric conversion, which converts thermal energy of the primary energy into a more valuable electric energy, does not have noises and byproducts in the process of the conversion as having no movable parts, and thus, it matches up the green energy of a concept of environmental protection.
More and more scholars have been engaging in the development of nanotechnology, enabling the related research on the thermoelectric conversion element becoming a doctrine gradually. However, the limitation of thermoelectric material degrades the conversion efficiency. Wherein the thermoelectric conversion element is standardized by the thermoelectric figure of merit
      ZT    =                            S          2                        T                                                  σ            k        ,and S is Seebeck coefficient, T is absolute temperature, σ is electrical conductivity of the material, k is thermal conductivity. As the formula shows, increasing electrical conductivity of the material, or Seebeck coefficient S or decreasing thermal conductivity k all can enhance the thermoelectric figure of merit of elements so as to boost the thermoelectric conversion efficiency. The aforementioned parameters, however, are not individual, such that any one of them is not able to be fixed without affecting the remains, and thermoelectric figure of merit can't be boosted unlimitedly.
The thermal conductivity k and the electrical conductivity σ normally show a positive correlation change based on Wiedemann-Franz law
      LT    =          k      σ        ,wherein L is the Lorenz number of material, and when any of the thermal conductivity k or electrical conductivity σ is changed, the other corresponding parameters will change too, enabling that the thermoelectric figure of merit ZT doesn't have obvious modification. Consequently, metal material is less applied to the thermoelectric conversion element.
Compared with metal material, semiconductor material has better advantage of Seebeck coefficient S, and an order of magnitude difference of the Seebeck coefficient S is between the two materials. As semiconductor material is of lower thermal conductivity k, it is the commonly seen type used in the thermoelectric material. Because the electrical conductivity σ of semiconductor material is hard to be enhanced, most thermoelectric figure of merits of the existing thermoelectric conversion elements are less than 2, resulting that the technique has a long way to run in practical application.
In addition, regarding the prior art, it also uses semiconductor material as a substrate and then dopes a certain proportions or types of rare earth elements to adjust the effective electron concentration in the semiconductor material an as to enhance the thermoelectric figure of merit by boosting the electrical conductivity σ. But, by doping rare earth elements to change the electrical conductivity σ still has a technical bottleneck. For example, firstly, rare earth elements are not easy to obtain and the price thereof is expensive; secondly, the doping uniformity is not easy to be controlled; thirdly, the manufacturing process is too complicated, . . . and so on and so forth, leading the current thermoelectric conversion element to an unpopular way.
According to the preceding description, inventor of the present invention therefore designs a manufacturing process of a thermoelectric conversion element which aims to improve the shortcomings of the current technique so as to boost the industrial practicability.

Manufacturing process of the thermoelectric conversion element


A hydrostatic axial piston machine includes a pressing pressure chamber for the cylinder drum which is supplied with pressing pressure from a circular-arc-like elongate hole of a distributor plate or from a plurality of connection channels of the cylinder drum. The pressing pressure chamber is delimited radially outwardly by the cylinder drum and radially inwardly by the drive shaft. The pressing pressure chamber is delimited axially at both sides by seals which are both arranged between the radially inner rotating drive shaft and a radially outer stationary component. The radially outer component may be the cylinder drum or, in the case of the distributor-plate-side seal, also a gap seal between the drive shaft and a bearing bush of the distributor plate. Both seals are arranged at the distributor plate side with respect to a tooth arrangement or a retraction ball.

In axial piston machines, it is known that a cylinder drum is coupled to a drive shaft in a rotationally secure manner so that they rotate together. There extend along the drive shaft in the cylinder drum cylinders which are distributed over the periphery and in which pistons are displaceably guided. The pistons are coupled by means of respective piston bases and sliding blocks which rotate therewith to a stationary swash plate which is positioned obliquely with respect to the drive shaft. Therefore, each piston with every rotation about the drive shaft carries out a stroke, the size of which is dependent on the oblique position of the swash plate.
At the side opposite the swash plate, in an end face of the cylinder drum for each cylinder there is provided an opening which is connected by means of a respective connection channel to the respective cylinder. Since the end face of the cylinder drum rotates with the openings thereof, the openings run along a circular path. The end face is tensioned with the openings thereof against a stationary distributor plate so that the openings run in a sealed manner over circular-arc-shaped or kidney-like elongate holes of the distributor plate. More specifically, a high-pressure kidney-like member and a low-pressure kidney-like member are provided in the distributor plate.
As a result of the action of pressure medium of the high-pressure-side cylinder, the cylinder drum is tensioned at the high-pressure side thereof against the distributor plate. To this end, it is known from the prior art in order to increase the lift-off speed and with axial piston pumps in order to increase the self-priming speed to provide an additional pressing pressure chamber, which supplements and homogenizes the mentioned one-sided pressure.
In the publication DE 10 2012 110 485 A1, there is disclosed a pressing pressure chamber via which the cylinder drum is tensioned against the distributor plate. The pressing pressure chamber is concentric with respect to the drive shaft. In this instance, the pressing pressure chamber is delimited at the radially inner side by a sleeve which is arranged on the outer periphery of the drive shaft, whilst it is delimited at the radially outer side by a sleeve-like stepped pressure piston which is arranged on the inner periphery of the cylinder drum. When the pressing pressure chamber is acted on with high pressure, the pressure piston tensions the cylinder drum indirectly via a stop which is constructed as a securing ring against the distributor plate.
In the publication DE 10 2018 205 446 A1, a resilient chamber inside a retraction ball is used as a pressing pressure chamber. It is further proposed to extend this pressing pressure chamber in the direction toward the distributor plate by means of a pressure medium connection as a result of the tooth arrangement which is formed between the drive shaft and cylinder drum in the direction toward the distributor plate. Consequently, the pressing pressure chamber extends completely through the cylinder drum and also through the distributor plate as far as a bearing bush which is constructed as a gap seal. Via this bearing bush, the drive shaft is also supported in a connection plate. An annular end face which is arranged in the retraction ball and a radial step on the inner periphery of the cylinder drum act as pressure faces on the cylinder drum in the direction toward the distributor plate. Consequently, the pressing pressure chamber is delimited by the drive shaft, the cylinder drum and the retraction ball. Accordingly, a swash-plate-side and a distributor-plate-side seal and in addition a seal between the retraction ball and the cylinder drum are provided between the cylinder drum and drive shaft.
The disadvantage of the last-mentioned axial piston machines is that the pressing pressure chamber is delimited by three seals, which means a high level of technical device and technical assembly complexity.

Rotary axial piston machine with hydrostatic pressing device seal arrangement


A camera module package comprises an image sensor having a light receiving section formed in the central portion of the upper surface thereof and a plurality of bumps formed around the light receiving section; an FPCB that is closely bonded to the image sensor by a flip chip, the FPCB having a plurality of via holes perforated at bonding positions corresponding to the bumps such that the bumps and the via holes are closely bonded to each other one to one; and an optical unit having a housing received on the FPCB and a lens barrel screwed to the central portion of the housing.

1. Field of the Invention
The present invention relates to a camera module package in which via holes and bumps are flip-chip-bonded so as to correspond to each other one to one. In the camera module package, when an image sensor is bonded to the lower surface of an FPCB (flexible printed circuit board) by a flip chip, via holes passing through the FPCB are formed in positions corresponding to connection bumps provided on the upper surface of the image sensor, thereby enhancing a degree of freedom in designing an FPCB.
2. Description of the Related Art
With the recent development of mobile terminals such as portable phones and personal digital assistants (PDAs), the mobile terminals provide a phone call function and are used as multi-convergence devices. The most representative of the multi-convergence is a camera module. The resolution of the camera module changes from 300,000 pixels (VGA) to 8,000,000 pixels. Moreover, the camera module provides various additional functions, such as auto-focusing (AF) and optical zoom. Generally, camera modules are applied to various IT devices, such as camera phones, smart phones, and mobile communication terminals.
The camera modules are manufactured by using main parts of charge coupled device (CCD) or complementary metal oxide semiconductor (CMOS) image sensors. Incident light transmitted through the lens is condensed by the image sensor and is stored as data in the memory. The stored data is displayed as an image through a display medium, such as liquid crystal display (LCD) or PC monitor.
Packaging methods of the image sensor for camera module include a chip on film (COF) method using a flip-chip bonding, a chip on board (COB) method using a wire bonding, and a chip select package (CSP). Among them, the COF packaging method and the COB packaging method are widely used.
Hereinafter, the COF packaging structure will be described briefly with reference to FIGS. 1 to 2.
FIG. 1 is an exploded perspective view of a conventional COF type camera module, and FIG. 2 is a partial sectional view of the conventional COF type camera module of FIG. 1.
Referring to FIGS. 1 and 2, the conventional camera module 1 includes an image sensor 3 for converting an image signal inputted through a lens into an electric signal, a housing 2 for supporting the image sensor 3, a lens group 4 for collecting an image signal of an object in the image sensor 3, and a barrel 5 in which the lens group 4 is stacked in multi-layers.
A flexible printed circuit board (FPCB) 6 is electrically connected to a lower portion of the housing 2. Chip components (e.g., condensers and resistors) for driving the CCD or CMOS image sensor 3 are mounted on the FPCB 6.
In the camera module 1, an anisotropic conductive film (ACF) 8 or non-conductive paste (NCP) is inserted between the FPCB 6 and the image sensor 3 in such a state that a plurality of circuit components are mounted on the FPCB 6. Then, heat and pressure are applied to electrically attach the FPCB 6 to the image sensor 3, and an IR filter 7 is attached on the FPCB.
Furthermore, in such a state that the barrel 5 and the housing 2 are provisionally screwed to each other, the assembled FPCB 6 is fixed to the bottom surface of the housing 2 by a separate adhesive.
Because the COF type camera module package does not need a space for attachment of wires, the package area and the barrel height can be reduced. Therefore, the camera module can be lightweight and slim.
In addition, because a thin film or FPCB is used, the package can be robust against external impact and can be highly reliable, and a manufacturing process of the package can be more simplified. Moreover, the COF type camera module package can attribute to high-speed processing, high density, and multiple pins, due to miniaturization and reduction in resistance.
However, as the COF type camera module package is integrated in a minimum chip size of wafer level package, a manufacturing cost increases and products may not be accurately delivered on the appointed date. Because the conventional COF package has a single-layered structure, the advantages of the miniaturization of the module package are not exhibited in the modules that use mega-pixel image sensors with various functions.
Further, when the FPCB 6 is a one-sided FPCB, a bonding surface of the FPCB 6 on which the image sensor 3 is bonded is limited to the lower surface of the FPCB 6. Therefore, the electric-connection start points of connection terminals provided in the image sensor 3 and the FPCB 6 inevitably start from the lower surface of the FPCB 6 such that a circuit-design space for the connection of the respective terminals is increased. Accordingly, the size of the FPCB 6 increases as a whole.
In order to solve the problem, a flip-chip-type module is manufactured by using a double-sided FPCB on which a plurality of via-holes are formed, as shown in FIG. 3. However, when the image sensor 3 is closely bonded to the lower surface of the double-sided FPCB 6, the plurality of via-holes are formed so as to be inevitably spaced at a distance of 150 μm from a connection bonding portion 6a such that circuit short caused by the interference between the via-holes 6b is prevented from occurring in the connection bonding portion 6a which comes in contact with a plurality of bumps 3a formed on the image sensor 3. Therefore, when a circuit using the via-holes 6b is designed, there is a spatial limitation in designing a circuit pattern.


Provided is a power conversion system. The system includes a DC bus line including a common terminal, a power generation device configured to provide DC power to the common terminal, a first inverter configured to convert a first input power provided from the common terminal into a first AC power and output the first AC power, and a second inverter configured to convert a second input power provided from the common terminal into a second AC power in response to the first input power being greater than a first threshold power while the first inverter operates and output the second AC power.

The present disclosure herein relates to a power conversion system, and more particularly, to a power conversion system including a plurality of inverters and an operation method thereof.
A power conversion system is used in various fields of power generation systems such as solar power generation system and wind power generation system. In a solar power generation system, the inverter converts the direct current (DC) power produced by the solar panel to alternating current (AC) power. The inverter may be divided into a module-integrated converter (MIC), a string, a multi-string, a central, and a multi-central inverter depending on the combination of solar panels and arrays.
In relation to the MIC, installation is easy in a form of attaching the inverter to each panel, and even when the insolation conditions between panels are different due to differences in shadows or installation conditions, it has the advantage of being able to harvest maximum energy. However, since the power conversion efficiency is somewhat lower than that of a large inverter and a large number of inverters are used in the implementation of a large capacity system, the cost burden may be large.
To solve this problem, a power conversion system for efficiently operating an MIC has been studied. However, different hardware design of the MIC is required with previous methods, there may be difficulties in utilizing an existing MIC.

Power conversion system and operation method thereof

Electronics and Telecommunications Research Institute


There is provided a lock which can include a shackle which can be moved between an unlocked configuration and a locked configuration. A locking mechanism can be carried by the lock. The locking mechanism can include a guard which can be actuated in a manner such that an access region can be defined to facilitate movement of the shackle such that the shackle can be moved to be in an unlocked configuration. The guard can also be actuated in a manner so as to block the access region to impede movement of the shackle when in the locked configuration such that the shackle is maintained in the locked configuration.

The following discussion of the background to the invention is intended to facilitate an understanding of the present invention. However, it should be appreciated that the discussion is not an acknowledgment or admission that any of the material referred to was published, known or part of the common general knowledge in any jurisdiction as at the priority date of the application.
Presently a myriad of conventional electronic type or mechanical type locks (i.e., conventional locks) are available. There are various designs in relation to locking/unlocking strategies associated with such conventional locks.
The present disclosure contemplates that a lock associated with a locking mechanism which can be distinguished from the aforementioned locking/unlocking strategies associated with conventional locks.

Lock and a locking mechanism associated with the lock


The present invention relates to methods for preparing xcex2-ketoester fragrance pro-accords from activated acyl units, 1,3-dioxan-4,6-diones and fragrance raw material alcohols. The first step involves contacting an activated acyl unit, preferably an acid chloride, with a 1,3-dioxan-4,6-dione, an example of which is Meldrum""s acid, to form a 2-acyl 1,3-dioxan-4,6-dione which is then reacted with a fragrance raw material alcohol to form the final xcex2-ketoester fragrance pro-accord. The resulting xcex2-ketoester fragrance pro-accords are suitable for use in laundry detergent, personal care, and other formulations wherein aesthetic fragrance materials are employed.

The present invention relates to methods for preparing xcex2-ketoester fragrance pro-accords, said pro-accords useful for providing sustained fragrance to items which deliver perfume for aesthetic reasons inter alia laundry detergent compositions, fabric softeners, personal care and personal hygiene items, shampoos, body lotions, and fabric re-fresheners. The process of the present invention relates to the use of 1,3-dioxane-4,6-diones as a synthon for the facile formation of xcex2-ketoesters, especially xcex2-ketoesters which comprise a tertiary alcohol subunit.
Esters which release perfume alcohols are currently of interest for their different odor profiles in products, as well as their odor profiles during and after use. Particularly desirable are such esters which have a prolonged release characteristic from use in a home laundering process. Deposition onto a substrate, for example, onto fabric during the wash process followed by delayed release of the perfume after drying, is especially desirable. The challenge for using such esters include not only the right combination of storage stability and odor release profile, but also the challenge of making such esters in a cost effective manner.
xcex2-Ketoesters are a particularly desirable class of materials, but such materials can present a particular challenge for a cost effective production. The di-functionality (ketone and carboxylic ester functionality in the same compound) of these compounds limits the types of reactions and conditions under which these compounds can be made. Add on the industrial scale and cost constraints that the use of specialty reactants add to the possible synthesis methods, and the large scale of production of such xcex2-ketoester compounds for use in high volume consumer products becomes problematic.
Accordingly there remains a need in the art for a method for a simple, high yield, cost-effective means for preparing xcex2-ketoester fragrance pro-accords. In addition there is a need for convenient methods which produce xcex2-ketoesters capable of releasing tertiary alcohols inter alia dihydromyrcenol and linalool.
The following relate to the preparation of xcex2-ketoesters from 1,3-dioxane-4,6-diones. Oikawa et al., J. Org. Chem., Vol 43, No 10, 1978, pg. 2087; Capozzi et al., J. Org. Chem., Vol 58, No 27, 1993, pg. 7932; Organic Synthesis Collective Volumes, pg 359, Oikawa et al., submitters; and Houghton et al., xe2x80x9cA Modified Preparation of xcex2-Keto Estersxe2x80x9d, Synthesis, pg 451, (1982).
It has now been surprisingly discovered that molecules which releasably comprise fragrance raw material alcohols, namely xcex2-ketoester fragrance pro-accords, can be suitably prepared from activated acyl adducts, for example, acid chlorides, and 1,3-dioxan-4,6-diones followed by reacting the product with a fragrance raw material alcohol. It is especially desirable that the fragrance raw material alcohols which become a subunit of the xcex2-ketoester fragrance pro-accord are tertiary alcohols, for example, linalool and dihydromycenol.
The first aspect of the present invention relates to a process for preparing xcex2-ketoester fragrance pro-accords comprising the steps of:
a) reacting in the presence of a base a 1,3-dioxane-4,6-dione having the formula:
wherein R1 and R2 are each independently C1-C10 alkyl, C2-C10 alkenyl, C7-C22 alkylenearyl, C6-C10 aryl, and mixtures thereof; with an activated acyl group having the formula:
wherein R3, R4, and R5 are each independently hydrogen, C1-C30 substituted or unsubstituted linear alkyl, C3-C30 substituted or unsubstituted branched alkyl, C3-C30 substituted or unsubstituted cyclic alkyl, C1-C30 substituted or unsubstituted linear alkoxy, C3-C30 substituted or unsubstituted branched alkoxy, C3-C30 substituted or unsubstituted cyclic alkoxy, C2-C30 substituted or unsubstituted linear alkenyl, C3-C30 substituted or unsubstituted branched alkenyl, C3-C30 substituted or unsubstituted cyclic alkenyl, C2-C30 substituted or unsubstituted linear alkynyl, C3-C30 substituted or unsubstituted branched alkynyl, C6-C30 substituted or unsubstituted alkylenearyl; or R3, R4, and R5 can be taken together to form C6-C30 substituted or unsubstituted aryl; and mixtures thereof; X is an acyl activating unit; to form an acyl 1,3-dioxane-4,6-dione, the enol tautomer of which having the formula:
b) optionally, isolating said acyl 1,3-dioxane-4,6-dione; and
c) reacting said acyl 1,3-dioxane-4,6-dione from step (a) or (b) with a fragrance raw material alcohol having the formula:
ROH
to form a xcex2-ketoester fragrance pro-accord having the formula:
wherein R3, R4, and R5 are the same as defined herein above.
The present invention more specifically relates to the preparation of xcex2-ketoester fragrance pro-accords which comprise a secondary or tertiary alcohol subunit, more preferably a tertiary alcohol subunit. These and other objects, features and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims.
All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (xc2x0 C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.
The present invention relates to a process for preparing xcex2-ketoester fragrance pro-accords from 1,3-dioxan-4,6-diones, preferably from 2,2-dimethyl-1,3-dioxan-4,6-dione. Variations of the present process include isolation and purification of the intermediate acyl 1,3-dioxane-4,6-dione formed in Step (a) prior to subsequent reaction with a fragrance raw material alcohol. However, the formulator, depending upon several variables inter alia the structure of the final xcex2-ketoester, the amount of material to be produced, the type of process (i.e. batch reactions vs. continuous process) may produce the final product without isolation of the acyl 1,3-dioxan-4,6-dione intermediate.
For the purposes of the present invention the term xe2x80x9csubstitutedxe2x80x9d as it applies to linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, branched alkoxy, cyclic alkoxy, alkynyl, and branched alkynyl units are defined as xe2x80x9ccarbon chains which comprise substitutents other than branching of the carbon atom chainxe2x80x9d, for example, other than the branching of alkyl units (e.g. isopropyl, isobutyl). Non-limiting examples of xe2x80x9csubstituentsxe2x80x9d include hydroxy, C1-C12 alkoxy, preferably methoxy; C3-C12 branched alkoxy, preferably isopropoxy; C3-C12 cyclic alkoxy; nitrilo; halogen, preferably chloro and bromo, more preferably chloro; nitro; morpholino; cyano; carboxyl, non-limiting examples of which are xe2x80x94CHO; xe2x80x94CO2xe2x88x92M+, xe2x80x94CO2R9; xe2x80x94CONH2; xe2x80x94CONHR9; xe2x80x94CONR92; wherein R9 is C1-C12 linear or branched alkyl); xe2x80x94SO3xe2x88x92M+; xe2x80x94OSO3xe2x88x92M+; xe2x80x94N(R10)2; and xe2x80x94N+(R10)3Xxe2x88x92 wherein each R10 is independently hydrogen or C1-C4 alkyl; and mixtures thereof; wherein M is hydrogen or a water soluble cation; and X is chlorine, bromine, iodine, or other water soluble anion.
For the purposes of the present invention substituted or unsubstituted alkyleneoxy units are defined as moieties having the formula:
wherein R7 is hydrogen; R8 is hydrogen, methyl, ethyl, and mixtures thereof; the index x is from 1 to about 10.
For the purposes of the present invention substituted or unsubstituted alkyleneoxyalkyl are defined as moieties having the formula:
wherein R7 is hydrogen, C1-C18 alkyl, C1-C4 alkoxy, and mixtures thereof; R8 is hydrogen, methyl, ethyl, and mixtures thereof; the index x is from 1 to about 10 and the index y is from 2 to about 18.
For the purposes of the present invention substituted or unsubstituted aryl units are defined as phenyl moieties having the formula:
or xcex1 and xcex2-naphthyl moieties having the formula:
wherein R7 and R8 can be substituted on either ring, alone or in combination, and R7 and R8 are each independently hydrogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C4 alkoxy, C3-C6 branched alkoxy, nitrilo, halogen, nitro, morpholino, cyano, carboxyl (xe2x80x94CHO; xe2x80x94CO2xe2x88x92M+; xe2x80x94CO2R9; xe2x80x94CONH2; xe2x80x94CONHR9; xe2x80x94CONR92; wherein R9 is C1-C12 linear or branched alkyl), xe2x80x94SO3xe2x88x92M+, xe2x80x94N(R10)2, and xe2x80x94N+(R10)3Xxe2x88x92 wherein each R10 is independently hydrogen, C1-C4 alkyl or mixtures thereof; and mixtures thereof, R7 and R8 are preferably hydrogen, C1-C6 alkyl, xe2x80x94CO2xe2x88x92M+, xe2x80x94SO3xe2x88x92M+, xe2x80x94OSO3xe2x88x92M+, and mixtures thereof; more preferably R7 or R8 is hydrogen and the other moiety is C1-C6; wherein M is hydrogen or a water soluble cation and X is chlorine, bromine, iodine, or other water soluble anion. Examples of other water soluble anions include organic species such as fumarate, succinate, tartrate, oxalate and the like, inorganic species include sulfate, hydrogen sulfate, phosphate and the like.
For the purposes of the present invention substituted or unsubstituted alkylenearyl units are defined as moieties having the formula:
wherein R7 and R8 are each independently hydrogen, hydroxy, C1-C4 alkoxy, nitrilo, halogen, nitro, carboxyl (xe2x80x94CHO; xe2x80x94CO2xe2x88x92M+; xe2x80x94CO2R9; xe2x80x94CONH2; xe2x80x94CONHR9; xe2x80x94CONR92; wherein R9 is C1-C12 linear or branched alkyl), amino, alkylamino, and mixtures thereof, p is from 1 to about 14; M is hydrogen or a water soluble cation.
For the purposes of the present invention substituted or unsubstituted alkyleneoxyaryl units are defined as moieties having the formula:
wherein R7 and R8 are each independently hydrogen, hydroxy, C1-C4 alkoxy, nitrilo, halogen, nitro, carboxyl (xe2x80x94CHO; xe2x80x94CO2xe2x88x92M+; xe2x80x94CO2R9; xe2x80x94CONH2; xe2x80x94CONHR9; xe2x80x94CONR92; wherein R9 is C1-C12 linear or branched alkyl), amino, alkylamino, and mixtures thereof, q is from 1 to about 14; M is hydrogen or a water soluble cation.
The following summarizes the process of the present invention.
Step (a) Formation of a 2-acyl-1,3-dioxan-4,6-dione
The first step of the process of the present invention relates to reacting an activated acyl moiety of the general formula:
with a 1,3-dioxan-4,6-dione having the formula:
to form a 2-acyl-1,3-dioxan-4,6-dione having, in its enol tautomer form, the formula:
wherein R1 and R2 are each independently C1-C10 alkyl, C2-C10 alkenyl, C7-C22 alkylenearyl, C6-C10 aryl, and mixtures thereof, preferably methyl; wherein R3, R4, and R5 are each independently hydrogen, C1-C30 substituted or unsubstituted linear alkyl, C3-C30 substituted or unsubstituted branched alkyl, C3-C30 substituted or unsubstituted cyclic alkyl, C1xe2x80x94C30 substituted or unsubstituted linear alkoxy, C3-C30 substituted or unsubstituted branched alkoxy, C3-C30 substituted or unsubstituted cyclic alkoxy, C2-C30 substituted or unsubstituted linear alkenyl, C3-C30 substituted or unsubstituted branched alkenyl, C3-C30 substituted or unsubstituted cyclic alkenyl, C2-C30 substituted or unsubstituted linear alkynyl, C3-C30 substituted or unsubstituted branched alkynyl, C6-C30 substituted or unsubstituted alkylenearyl; or R3, R4, and R5 can be taken together to form C6-C30 substituted or unsubstituted aryl; and mixtures thereof; preferably two of R3, R4, and R5 are hydrogen and the remaining group is C1-C10 linear or branched alkyl, C2-C10 linear or branched alkenyl, preferably methyl and octyl, also preferably R3, R4, and R5 are taken together to form a substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, more preferably naphthyl.
X is an acyl activating unit. Non limiting examples of acyl activating units are acyloxy units having the formula xe2x80x94OC(O)Rxe2x80x2 which when taken together with the acyl moiety form a symmetrical or non-symmetrical anhydride, wherein Rxe2x80x2 is the same or different than the moiety which is formed by R3, R4, and R5. However, in cases where anhydride-like conditions are desired and formation of the acyl unit anhydride is either impractical or unobtainable, then the acyl carboxylic acid may be condensed with the 1,3-dioxan-4,6-dione in the presence of a condensing agent such as ethyl phosphonocyanidate. Other non-limiting examples of activated acyl units are acyl acid halides wherein X is chlorine, bromine, iodine, and mixtures thereof, activated esters, for example, 4-nitrophenyl esters of the acyl unit defined by R3, R4, and R5.
The reaction of Step (a) of the present process is conducted in the presence of a base suitable to de-protonate the 2-position carbon of the selected 1,3-dioxan-4,6-dione. The acidity of the protons on the 2-carbon of the 1,3-dioxan-4,6-dione, and therefore the strength of the base necessary for reaction of Step (a), is governed by a number of factors, notably the structure of the dione itself. Bases suitable for use are selected from the group consisting of alkylamines, aromatic amines, polymeric amines, organo lithium compounds, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonate, alkali metal hydrides, alkaline earth metal hydrides, and mixtures thereof.
Non-limiting examples of bases suitable for use in the present invention are aromatic amines, for example, pyridine, picoline, lutidine, collidine; mono-, di-, and tri-alkylamines, for example, methyl amine, trimethylamine, triethanolamine; alkali metal and alkaline earth metal hydrides, for example, lithium hydride, sodium hydride; alkali metal alkoxides, for example, sodium ethoxide, sodium methoxide; alkali metal and alkaline earth metal carbonates and bicarbonates, for example sodium carbonate, potassium carbonate; organo metallic compounds, for example, butyl lithium, t-butyl lithium; alkali metal and alkaline earth metal hydroxides, for example, sodium hydroxide, potassium hydroxide. Preferred bases are pyridine and sodium hydride.
Depending upon the reaction conditions desired by the formulator, Step (a) can be conducted in the presence of a suitable solvent. Non-limiting examples of suitable solvents include dichloromethane, 1,2-dichloroethane, 1,2,3-trichloroethane, pentane, hexane, tetrahydrofuran, diethyl ether, benzene, toluene, xylene, 1,4-dioxane, acetonitrile, and mixtures thereof. In addition, the formulator may wish to adjust the reaction conditions to stabilize the formation of charged reaction species in which the use of solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethyl phosphoramide (HMPA), and the like may be used alone or in combination with other suitable solvents. However, the formulator may generate the 1,3-dioxan-4,6-dione anion in water followed by isolation of the 1,3-dioxan-4,6-dione salt typically followed by thorough drying.
The reaction of Step (a) may be successfully conducted, depending upon the reactivity of the reagents, the scope of the reaction, and other mitigating parameters, at a temperature of from about xe2x88x9270xc2x0 C., preferably from about xe2x88x9233xc2x0 C., more preferably from about 0xc2x0 C., most preferably from about 22xc2x0 C.(approximately room temperature), to about 100xc2x0 C., preferably to about 80xc2x0 C., more preferably to about 60xc2x0 C., most preferably to about 40xc2x0 C. The reaction of Step (a) may be conducted at more than one temperature, for example, during the addition of reagents the temperature of the reaction may be held at a first temperature, for example 0xc2x0 C., and allowed to warm to a second temperature after the addition is complete. Alternatively, the reaction may be warmed to generate the 1,3-dioxane-4,6-dione anion, then cooled during the addition of the activated acyl adduct.
The reaction of Step (a) may be conducted in any order which insures formation of the desired acyl 1,3-dioxan-4,6-dione intermediate. For example, in a first reaction vessel a suitable 1,3-dioxan-4,6-dione is reacted with sufficient base to form a 1,3-dioxan-4,6-dione anion. This can be accomplished by first charging a dry reaction vessel with an equivalent of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran (THF). In a second reaction vessel a suitable 1,3-dioxan-4,6-dione is dissolved in a suitable solvent, for example, 2,2-dimethyl-1,3-dioxan-4,6-dione in a sufficient amount of dry THF Next the contents of the second reaction vessel is added to the contents of the first reaction vessel while cooling the admixture. Once the 1,3-dioxan-4,6-dione anion is sufficiently formed, in a third reaction vessel, an activated acyl unit is dissolve in a sufficient amount of solvent, for example, 2-naphthoyl chloride, is dissolved in THF, and this solution is subsequently added to the solution of 1,3-dioxan-4,6-dione anion.
However, in other embodiments of the present invention, it may be necessary to warm the admixture of base, suitable 1,3-dioxan-4,6-dione, and solvent in a reaction vessel in order to fully generate the 1,3-dioxan-4,6-dione anion prior to addition of the activated acyl unit.
Also included in Step (a) of the present invention is neutralization of any remaining base prior to proceeding to Steps (b) or (c). In a preferred embodiment of the present process, Step (a) is conducted under an inert atmosphere.
Step (b) Optionally Isolating the 2-acyl-1,3-dioxan-4,6-dione formed in Step (a).
The formulator may choose to optionally isolate the 2-acyl-1,3-dioxan-4,6-dione form in Step (a) of the process of the present invention. Isolation may include, distillation, crystallization, chromatography and the like. However, it is not necessary that the intermediate 2-acyl-1,3-dioxan-4,6-dione be isolated prior to Step (c).
Step (c): Reacting the acyl 1,3-dioxane-4,6-dione formed in Step (a) or alternatively isolated in Step (b) with a fragrance raw material alcohol
The 2-acyl-1,3-dioxan-4,6-dione form in Step (a) is then reacted with a fragrance raw material alcohol to form a xcex2-ketoester having the formula:
wherein xe2x80x94OR represents a unit derived form a fragrance raw material alcohol an dR3, R4, and R5 are the same as define herein above.
For the purposes of the present invention xe2x80x9cfragrance raw material alcoholsxe2x80x9d are herein defined as alcohols having a molecular weight and which are useful in imparting an odor, fragrance, essence, or scent either alone or in combination with other xe2x80x9cfragrance raw material alcoholsxe2x80x9d.
Non-limiting examples of preferred fragrance raw material alcohols include 2,4-dimethyl-3-cyclohexene-1-methanol (Floralol), 2,4-dimethyl cyclohexane methanol (Dihydro floralol), 5,6-dimethyl-1-methylethenylbicyclo[2.2.1]hept-5-ene-2-methanol (Arbozol), xcex1,xcex1,-4-trimethyl-3-cyclohexen-1-methanol (xcex1-terpineol), 2,4,6-trimethyl-3-cyclohexene-1-methanol (Isocyclo geraniol), 4-(1-methylethyl)cyclohexane methanol (Mayol), xcex1-3,3-trimethyl-2-norborane methanol, 1,1-dimethyl-1-(4-methylcyclohex-3-enyl)methanol, 2-phenylethanol, 2-cyclohexyl ethanol, 2-(o-methylphenyl)-ethanol, 2-(m-methylphenyl)ethanol, 2-(p-methylphenyl)ethanol, 6,6-dimethylbicyclo-[3.1.1]hept-2-ene-2-ethanol (nopol), 2-(4-methylphenoxy)-ethanol, 3,3-dimethyl-xcex942-xcex2-norbomane ethanol (patchomint), 2-methyl-2-cyclohexylethanol, 1-(4-isopropylcyclohexyl)-ethanol, 1-phenylethanol, 1,1-dimethyl-2-phenylethanol, 1,1-dimethyl-2-(4-methyl-phenyl)ethanol, 1-phenylpropanol, 3-phenylpropanol, 2-phenylpropanol (Hydrotropic Alcohol), 2-(cyclododecyl)propan-1-ol (Hydroxy-ambran), 2,2-dimethyl-3-(3-methylphenyl)-propan-1-ol (Majantol), 2-methyl-3-phenylpropanol, 3-phenyl-2-propen-1-ol (cinnamyl alcohol), 2-methyl-3-phenyl-2-propen-1-ol (methylcinnamyl alcohol), xcex1-n-pentyl-3-phenyl-2-propen-1-ol (xcex1-amyl-cinnamyl alcohol), ethyl-3-hydroxy-3-phenyl propionate, 2-(4-methylphenyl)-2-propanol, 3-(4-methylcyclohex-3-ene)butanol, 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)butanol, 2-ethyl-4-(2,2,3-trimethyl-cyclopent-3-enyl)-2-buten-1-ol, 3-methyl-2-buten-1-ol (prenol), 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol, ethyl 3-hydroxybutyrate, 4-phenyl-3-buten-2-ol, 2-methyl-4-phenylbutan-2-ol, 4-(4-hydroxyphenyl)butan-2-one, 4-(4-hydroxy-3-methoxyphenyl)-butan-2-one, 3-methyl-pentanol, 3-methyl-3-penten-1-ol, 1-(2-propenyl)cyclopentan-1-ol (plinol), 2-methyl-4-phenylpentanol (Pamplefleur), 3-methyl-5-phenylpentanol (Phenoxanol), 2-methyl-5-phenylpentanol, 2-methyl-5-(2,3-dimethyltricyclo[220.127.116.11(2,6)]hept-3-yl)-2-penten-1-ol (santalol), 4-methyl-1-phenyl-2-pentanol, 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol (sandalore), (1-methyl-bicyclo[2.1.1]hepten-2-yl)-2-methylpent-1-en-3-ol, 3-methyl-1-phenylpentan-3-ol, 1,2-dimethyl-3-(1-methylethenyl)cyclopentan-1-ol, 2-isopropyl-5-methyl-2-hexenol, cis-3-hexen-1-ol, trans-2-hexen-1-ol, 2-isoproenyl-4-methyl-4-hexen-1-ol (Lavandulol), 2-ethyl-2-prenyl-3-hexenol, 1-hydroxymethyl-4-isopropenyl-1-cyclohexene (Dihydrocuminyl alcohol), 1-methyl-4-isopropenylcyclohex-6-en-2-ol (carvenol), 6-methyl-3-isopropenylcyclohexan-1-ol (dihydrocarveol), 1-methyl-4-iso-propenylcyclohexan-3-ol, 4-isopropyl-1-methylcyclohexan-3-ol, 4-tert-butylcyclo-hexanol, 2-tert-butylcyclohexanol, 2-tert-butyl-4-methylcyclohexanol (rootanol), 4-isopropyl-cyclohexanol, 4-methyl-1-(1-methylethyl)-3-cyclohexen-1-ol, 2-(5,6,6-trimethyl-2-norbornyl)cyclohexanol, isobomylcyclohexanol, 3,3,5-trimethylcyclohexanol, 1-methyl-4-isopropylcyclohexan-3-ol, 1-methyl-4-isopropylcyclohexan-8-ol (dihydroterpineol), 1,2-dimethyl-3-(1-methylethyl)cyclohexan-1-ol, heptanol, 2,4-dimethylheptan-1-ol, 6-heptyl-5-hepten-2-ol (isolinalool), 2,4-dimethyl-2,6-heptandienol, 6,6-dimethyl-2-oxymethyl-bicyclo[3.1.1]hept-2-ene (myrtenol), 4-methyl-2,4-heptadien-1-ol, 3,4,5,6,6-pentamethyl-2-heptanol, 3,6-dimethyl-3-vinyl-5-hepten-2-ol, 6,6-dimethyl-3-hydroxy-2-methylenebicyclo[3.1.1]heptane, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol, 2,6-dimethylheptan-2-ol (dimetol), 2,6,6-trimethylbicyclo[1.3.3]heptan-2-ol, octanol, 2-octenol, 2-methyloctan-2-ol, 2-methyl-6-methylene-7-octen-2-ol (myrcenol), 7-methyloctan-1-ol, 3,7-dimethyl-6-octenol, 3,7-dimethyl-7-octenol, 3,7-dimethyl-6-octen-1-ol (citronellol), 3,7-dimethyl-2,6-octadien-1-ol (geraniol), 3,7-dimethyl-2,6-octadien-1-ol (nerol), 3,7-dimethyl-7-methoxyoctan-2-ol (osyrol), 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctan-1-ol (pelargol), 3,7-dimethyloctan-3-ol (tetrahydrolinalool), 2,4-octadien-1-ol, 3,7-dimethyl-6-octen-3-ol (dihydrolinalool), 2,6-dimethyl-7-octen-2-ol (dihydromyrcenol), 2,6-dimethyl-5,7-octadien-2-ol, 4,7-dimethyl-4-vinyl-6-octen-3-ol, 3-methyloctan-3-ol, 2,6-dimethyloctan-2-ol, 2,6-dimethyloctan-3-ol, 3,6-dimethyloctan-3-ol, 2,6-dimethyl-7-octen-2-ol, 2,6-dimethyl-3,5-octadien-2-ol (muguol), 3-methyl-1-octen-3-ol, 7-hydroxy-3,7-dimethyloctanal, 3-nonanol, 2,6-nonadien-1-ol, cis-6-nonen-1-ol, 6,8-dimethylnonan-2-ol, 3-(hydroxymethyl)-2-nonanone, 2-nonen-1-ol, 2,4-nonadien-1-ol, 3,7-dimethyl-1,6-nonadien-3-ol, decanol, 9-decenol, 2-benzyl-M-dioxa-5-ol, 2-decen-1-ol, 2,4-decadien-1-ol, 4-methyl-3-decen-5-ol, 3,7,9-trimethyl-1,6-decadien-3-ol (isobutyl linalool), undecanol, 2-undecen-1-ol, 10-undecen-1-ol, 2-dodecen-1-ol, 2,4-dodecadien-1-ol, 2,7,11-trimethyl-2,6,10-dodecatrien-1-ol (farnesol), 3,7,11-trimethyl-1,6,10,-dodecatrien-3-ol (nerolidol), 3,7,11,15-tetramethylhexadec-2-en-1-ol (phytol), 3,7,11,15-tetramethylhexadec-1-en-3-ol (iso phytol), benzyl alcohol, p-methoxy benzyl alcohol (anisyl alcohol), para-cymen-7-ol (cuminyl alcohol), 4-methyl benzyl alcohol, 3,4-methylenedioxy benzyl alcohol, methyl salicylate, benzyl salicylate, cis-3-hexenyl salicylate, n-pentyl salicylate, 2-phenylethyl salicylate, n-hexyl salicylate, 2-methyl-5-isopropylphenol, 4-ethyl-2-methoxyphenol, 4-allyl-2-methoxyphenol (eugenol), 2-methoxy-4-(1-propenyl)phenol (isoeugenol), 4-allyl-2,6-dimethoxy-phenol, 4-tert-butylphenol, 2-ethoxy-4-methylphenol, 2-methyl-4-vinylphenol, 2-isopropyl-5-methylphenol (thymol), pentyl-ortho-hydroxy benzoate, ethyl 2-hydroxy-benzoate, methyl 2,4-dihydroxy-3,6-dimethylbenzoate, 3-hydroxy-5-methoxy-1-methylbenzene, 2-tert-butyl-4-methyl-1-hydroxybenzene, 1-ethoxy-2-hydroxy-4-propenylbenzene, 4-hydroxytoluene, 4-hydroxy-3-methoxybenzaldehyde, 2-ethoxy-4-hydroxybenzaldehyde, decahydro-2-naphthol, 2,5,5-trimethyl-octahydro-2-naphthol, 1,3,3-trimethyl-2-norbornanol (fenchol), 3a,4,5,6,7,7a-hexahydro-2,4-dimethyl-4,7-methano-1H-inden-5-ol, 3a,4,5,6,7,7a-hexahydro-3,4-dimethyl-4,7-methano-1H-inden-5-ol, 2-methyl-2-vinyl-5-(1-hydroxy-1-methylethyl)tetrahydrofuran, xcex2-caryophyllene alcohol, vanillin, ethyl vanillin, and mixtures thereof.
More preferably, the fragrance raw material alcohol is selected from the group consisting of cis-3-hexen-1-ol, hawthanol [admixture of 2-(o-methylphenyl)ethanol, 2-(m-methylphenyl)ethanol, and 2-(p-methylphenyl)ethanol], heptan-1-ol, decan-1-ol, 2,4-dimethyl cyclohexane methanol, 4-methylbutan-1-ol, 2,4,6-trimethyl-3-cyclohexene-1-methanol, 4-(1-methylethyl)cyclohexane methanol, 3-(hydroxy-methyl)-2-nonanone, octan-1-ol, 3-phenylpropanol, Rhodinol 70 [3,7-dimethyl-7-octenol, 3,7-dimethyl-6-octenol admixture], 9-decen-1-ol, xcex1-3,3-trimethyl-2-norborane methanol, 3-cyclohexylpropan-1-ol, 4-methyl-1-phenyl-2-pentanol, 3,6-dimethyl-3-vinyl-5-hepten-2-ol, phenyl ethyl methanol; propyl benzyl methanol, 1-methyl-4-isopropenylcyclohexan-3-ol, 4-isopropyl-1-methylcyclohexan-3-ol (menthol), 4-tert-butylcyclohexanol, 2-tert-butyl-4-methylcyclohexanol, 4-isopropylcyclo-hexanol, trans-decahydro-xcex2-naphthol, 2-tert-butylcyclohexanol, 3-phenyl-2-propen-1-ol, 2,7,11-trimethyl-2,6,10-dodecatrien-1-ol, 3,7-dimethyl-2,6-octadien-1-ol (geraniol), 3,7-dimethyl-2,6-octadien-1-ol (nerol), 4-methoxybenzyl alcohol, benzyl alcohol, 4-allyl-2-methoxyphenol, 2-methoxy-4-(1-propenyl)phenol, vanillin, and mixtures thereof.
Step (c) of the present process can be conducted in the presence of a suitable solvent or an excess amount of the fragrance raw material alcohol may be used as a solvent. Non-limiting examples of suitable solvents include dichloromethane, 1,2-dichloroethane, 1,2,3-trichloroethane, pentane, hexane, tetrahydrofuran, diethyl ether, benzene, toluene, xylene, 1,4-dioxane, acetonitrile, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethyl phosphoramide (HMPA), and mixtures thereof.
The reaction of Step (c) may be successfully conducted, depending upon the reactivity of the reagents, the scope of the reaction, and other mitigating parameters, at a temperature of from about 0xc2x0 C., preferably from about 22xc2x0 C. (approximately room temperature), more preferably from about 40xc2x0 C., to about 200xc2x0 C., preferably to about 150xc2x0 C., more preferably to about 100xc2x0 C., most preferably to about 80xc2x0 C.
Included in Step (c) of the present invention is a provision for neutralizing any base present from Step (a) above. In a preferred embodiment of the present process, Step (c) is conducted under an inert atmosphere. In addition, an amount of a suitable acid catalyst may be added to the reaction of Step (c).
The product thus obtained from Step (c) of the present process can be purified by any conventional means depending upon the form physical form of the obtained xcex2-ketoester. Non-limiting examples include chromatography, crystalizedion, distillation, sublimation, etc.

Process for preparing xcex2-ketoester fragrance pro-accords from 1,3-dioxan-4,6-diones


A headset which is adjustable to two or more different levels of tightness. The headset includes a headband, and one or two earcups, each such earcup having an inner surface for engagement against the head of a user. At least one of the earcups includes a mounting bracket attaching the earcup to the headband. The mounting bracket is pivotally attached to the headband and to the earcup. An adjustment cam mechanism is associated with the headband and the mounting bracket for selectively adjusting the extent of outward pivotal movement of the mounting bracket with respect to the headband. This mechanism permits selective adjustment of the maximum at-rest distance from the inner surface of the earcup to the inner surface of the other earcup. Preferably the adjustment cam mechanism comprises a stop associated with an end of the headband, and a rotatable cam associated with the corresponding mounting bracket. The cam is engageable against the stop to limit the extent of outward pivotal movement of the first mounting bracket with respect to the headband. The cam may be rotated to two or more positions, making the headset adjustable to different degrees of tightness. The headset is comfortable for a range of head sizes and gives the headset user the ability to quickly and easily adjust the tightness of the earcups based on the conditions encountered, all without the use of tools.

In noisy environments, headsets having noise attenuating earcups are frequently used to facilitate communication by radio, intercom, etc. For example, aircraft pilots typically utilize headsets of the type having two noise attenuating earcups and a boom-type microphone. Similar headsets, having either one or two earcups, are frequently used in other settings, such as factories, stadiums, broadcast facilities, etc.
The passive noise attenuation capability of such headset earcups is significantly affected by the seal of the earcup noise attenuation ring against the user's head. The quality of that seal, in turn, is dependent on the amount of pressure exerted by the headset against the user's head--a tighter fit yields better attenuation, and a looser fit gives less attenuation. Tighter fitting headsets, however, can often be less comfortable. To balance comfort and noise attenuation effectiveness, most good quality headsets are adjustable to accommodate variations in the head sizes of potential users.
In some cases, once a headset is initially properly adjusted for a particular person no further adjustment of the headset is later required. Hence, many headsets, while being adjustable, are not easily adjusted. For example, some adjustable headsets require a tool of some type (such as a screwdriver, allen wrench, etc.) to make the adjustment. In other situations, however, periodic adjustment of the headset is required. For example, pilots usually own and use their own personal headset, but may find themselves in varying operating conditions. In one situation a pilot may be on a relatively noisy but short flight, and therefore might prefer to have a tight-fitting headset (to maximize noise attenuation). Although such a headset may not be very comfortable for long flights, on short flights the greater noise attenuation achieved by using a tighter headset may be a fair tradeoff against the slightly lower comfort of such a headset. In another situation, however, the same pilot may be on a longer flight in a quieter aircraft. In such a situation, the pilot may prefer the comfort of a looser fitting headset, even if it does not attenuate noise as well as a tighter fitting headset.
Accordingly, it would be desirable to provide convenient adjustability in the tightness of the fit of a communications headset. Many headsets provide adjustability in the length of the headband which connects the two earcups. Depending on the design, adjusting the length of the headband may incidentally also affect the tightness of the earcups on the user's head. In many cases, however, the headset is designed so that the headband is intended to rest on the top of the use's head, thereby at least partially supporting the weight of the headset. In such headsets, adjustment of the length of the headband therefore affects the alignment of the earcups with the user's ears, and the amount of weight carried by the headband. Accordingly, merely adjusting the length of the headband usually does not provide the desired degree of adjustability in the overall fit, earcup tightness, and comfort of the headset for the various noise environments described above. Some screw-type mechanisms have been utilized to provide adjustment of the degree of headset tightness, but such mechanisms often are found only in more expensive headsets. Moreover, such screw-type adjustment mechanisms often either require tools to make the adjustment (i.e., in order to make the adjustment mechanism inconspicuous), or utilize bulky knurl knobs for easier tool-free adjustment.


Systems and methods are disclosed for configuring a non-volatile memory (“NVM”). In some embodiments, each block of the NVM can include a block table-of-contents (“TOC”), which can be encoded (e.g., run-length encoded) and dynamically-sized. Thus, as user data is being programmed to a block, the size of a block TOC can be concurrently recalculated and increased only if necessary. In some embodiments, the NVM interface can use a weave sequence stored in the context information and at least one weave sequence associated with each page of a block to determine whether to replay across the pages of the block after system boot-up.

NAND flash memory, as well as other types of non-volatile memories ("NVMs"), are commonly used for mass storage. For example, consumer electronics such as portable media players often include flash memory to store music, videos, and other media.
Typically, each page of a NVM can be used to store a single logical block address ("LBA"). However, when the system needs to access smaller pieces of data (e.g., a portion of a page), an entire page has to be accessed. For example, during a read operation, the system may need to read an entire page and discard the unwanted data.

Systems and methods for configuring non-volatile memory


Engine starting device, including: a crank signal generation unit (13); and an engine control unit (10) for identifying a predetermined crank position of a crankshaft, and starting the engine, in which the engine control unit estimates, in a course of stopping the engine when a stop condition for the engine is established, based on an engine rpm at the identified predetermined crank position, whether or not the engine rotates backward before reaching the predetermined crank position for a next time, and after estimating that the engine rotates backward, sets an inhibition range which is prescribed from a starter drive inhibition start timing to a starter drive inhibition reset timing, and a permission range which is other than the inhibition range, and when the restart condition is established during rotation of the engine, inhibits restart in the inhibition range and carries out the restart in the permission range.

1. Field of the Invention
The present invention relates to an engine starting device and an engine starting method for an automatic idle-stop system for performing an engine idle stop when a predetermined idle-stop condition is satisfied and restarting an engine when a restart condition is thereafter satisfied.
2. Description of the Related Art
For the purposes of improving fuel efficiency and reducing an environmental load of automobiles, there have heretofore been developed automatic idle-stop systems for automatically performing an idle stop with the satisfaction of a predetermined condition.
However, when a restart request for an engine is generated while the engine is rotating backward, and the engine is started by the starter motor, the starter motor causes the engine, which is rotating backward, to rotate forward and an excessively large load acts on the starter motor. In view of this, there is known a configuration for detecting, by backward rotation detection means for detecting whether or not the engine is rotating backward, a backward rotation when the engine is rotating backward for some reason, inhibiting drive of the starter motor, and preventing the starter motor and a power transmission mechanism thereof from being damaged (for example, refer to Japanese Patent Application Laid-open No. 2005-140030).
However, the conventional technology has the following problem.
As described above, the invention according to Japanese Patent Application Laid-open No. 2005-140030 includes the backward rotation detection means for detecting whether or not the engine is rotating backward, and the means for inhibiting, when a backward rotation is detected, the motor from rotating, thereby preventing, when the engine is rotating backward, the motor from rotating. However, with the invention according to Japanese Patent Application Laid-open No. 2005-140030, it is necessary to provide the backward rotation detection means for detecting the backward rotation of the engine, and there thus poses a problem in that the device becomes complex and the cost increases.

Engine starting device and engine starting method


The present invention relates to new inhibitors of the nucleic enzyme poly(adenosine 5′-diphospho-ribose) polymerase [“poly(ADP-ribose) polymerase” or “PARP”, which is also sometimes called “PARS” for poly(ADP-ribose) synthetase]. More particularly, the invention relates to the use of PARP inhibitors to prevent and/or treat tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage resulting from ischemia and reperfusion injury; neurological disorders and neurodegenerative diseases; to prevent or treat vascular stroke; to treat or prevent cardiovascular disorders; to treat other conditions and/or disorders such as age-related macular degeneration, AIDS and other immune senescence diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis, osteoporosis, chronic and acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock), and skin aging; to extend the lifespan and proliferative capacity of cells; to alter gene expression of senescent cells; or to radiosensitize hypoxic tumor cells.

Poly(ADP-ribose) polymerase ("PARP") is an enzyme located in the nuclei of cells of various organs, including muscle, heart and brain cells. PARP plays a physiological role in the repair of strand breaks in DNA. Once activated by damaged DNA fragments, e.g., after exposure to chemotherapy, ionizing radiation, oxygen free radicals, or nitric oxide (NO), PARP catalyzes the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to nuclear acceptor proteins, and is responsible for the formation of protein-bound linear and branched homo-ADP-ribose polymers. The PARP's activation results in the attachment of up to 100 ADP-ribose units to a variety of nuclear proteins, including histones, topoisomerases, DNA and RNA polymerases, DNA ligases, Ca2+- and Mg2+-dependent endonucleases and PARP itself. While the exact range of functions of PARP has not been fully established, this enzyme is thought to play a role in enhancing DNA repair and maintaining DNA integrity.
During major cellular stresses, however, the extensive activation of PARP can rapidly lead to cell damage or death through depletion of energy stores. Four molecules of ATP are consumed for every molecule of NAD (the source of ADP-ribose) regenerated. Thus, NAD, the substrate of PARP, is depleted by massive PARP activation and, in the efforts to re-synthesize NAD, ATP may also be depleted.
It has been reported that PARP activation plays a key role in both NMDA- and NO-induced neurotoxicity, as shown by the use of PARP inhibitors to prevent such toxicity in cortical cultures in proportion to their potencies as inhibitors of this enzyme (ZHANG et al., Science, vol. 263, p: 687-89, 1994); and in hippocampal slices (WALLIS et al., NeuroReport, vol. 5(3), p: 245-48, 1993). The potential role of PARP inhibitors in treating neurodegenerative diseases and head trauma has thus been known. Research, however, continues to pinpoint the exact mechanisms of their salutary effect in cerebral ischemia, (ENDRES et al., J. Cereb. Blood Flow Metabol., vol. 17, p: 1143-51, 1997) and in traumatic brain injury (WALLIS et al., Brain Res., vol. 710, p: 169-77, 1996).
The PARP inhibitors are additionally useful for treating cardiovascular diseases. Ischemia, a deficiency of oxygen and glucose in a part of the body, can be caused by an obstruction in the blood vessel supplying that area or a massive hemorrhage. Two severe forms, heart attack and stroke, are major killers in the developed world. Cell death results directly and also occurs when the deprived area is reperfused. It has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of the PARP inhibitor, 3-amino-benzamide (10 mg/kg), either one minute before occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32-42%). Another PARP inhibitor, 1,5-dihydroxyisoquinoline (1 mg/kg), reduced infarct size by a comparable degree (38-48%; THIEMERMANN et al., Proc. Natl. Acad. Sci. USA, vol. 94, p: 679-83, 1997). This finding has suggested that PARP inhibitors might be able to salvage previously ischemic heart or skeletal muscle tissue. Presently, PARP inhibitors are being developed to treat ischemia/reperfusion injuries (ZHANG, The Prospect for Improved Medicines, Ashley Publications Ltd, 1999).
PARP activation has also been shown to provide an index of damage following neurotoxic insults by glutamate (via NMDA receptor stimulation), reactive oxygen intermediates, amyloid .beta.-protein, n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite N-methyl-4-phenylpyridine (MPP+), which participate in pathological conditions such as stroke, Alzheimer's disease and Parkinson's disease (ZHANG et al., J. Neurochem., vol. 65(3), p: 1411-14, 1995). Other studies have continued to explore the role of PARP activation in cerebellar granule cells in vitro and in MPTP neurotoxicity (COSI et al., Ann. N. Y. Acad. Sci., vol. 825, p: 366-79, 1997; COSI et al., Brain Res., vol. 729, p: 264-69, 1996).
Neural damage following stroke and other neurodegenerative processes is thought to result from a massive release of the excitatory neurotransmitter glutamate, which acts upon the N-methyl-D-aspartate (NMDA) receptors and other subtype receptors. Glutamate serves as the predominate excitatory neurotransmitter in the central nervous system (CNS). Neurons release glutamate in great quantities when they are deprived of oxygen, as may occur during an ischemic brain insult such as a stroke or heart attack. This excess release of glutamate in turn causes over-stimulation (excitotoxicity) of N-methyl-D-aspartate (NMDA), AMPA, Kainate and MGR receptors. When glutamate binds to these receptors, ion channels in the receptors open, permitting flows of ions across their cell membranes, e.g., Ca2+ and Na+ into the cells and K+ out of the cells. These flows of ions, especially the influx of Ca2+, cause overstimulation of the neurons. The over-stimulated neurons secrete more glutamate, creating a feedback loop or domino effect which ultimately results in cell damage or death via the production of proteases, lipases and free radicals. Excessive activation of glutamate receptors has been implicated in various neurological diseases and conditions including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia and neuronal loss following hypoxia, hypoglycemia, ischemia, trauma, and nervous insult. Recent studies have also advanced a glutamatergic basis for compulsive disorders, particularly drug dependence. Evidence includes findings in many animal species, as well as, in cerebral cortical cultures treated with glutamate or NMDA, that glutamate receptor antagonists block neural damage following vascular stroke (DAWSON et al., H. Hunt Batjer ed., p: 319-25, 1997). Attempts to prevent excitotoxicity by blocking NMDA, AMPA, Kainate and MGR receptors have proven difficult because each receptor has multiple sites to which glutamate may bind. Many of the compositions that are effective in blocking the receptors are also toxic to animals. As such, there is no known effective treatment for glutamate abnormalities.
The stimulation of NMDA receptors, in turn, activates the enzyme neuronal nitric oxide synthase (NNOS), which causes the formation of nitric oxide (NO), which more directly mediates neurotoxicity. Protection against NMDA neurotoxicity has occurred following treatment with NOS inhibitors (DAWSON et al., Proc. Natl. Acad. Sci. USA, vol. 88, p: 6368-71, 1991; DAWSON et al., J. Neurosci., vol. 13(6), p: 2651-61, 1993). Protection against NMDA neurotoxicity can also occur in cortical cultures from mice with targeted disruption of NNOS (DAWSON et al., J. Neurosci., vol. 16(8), p: 2479-87, 1996).
It is known that neural damage following vascular stroke is markedly diminished in animals treated with NOS inhibitors or in mice with NNOS gene disruption (IADECOLA, Trends Neurosci., vol. 20(3), p: 132-39, 1997; HUANG et al., Science, vol. 265, p: 1883-85, 1994; BECKMAN et al., Biochem. Soc. Trans., vol. 21, p: 330-34, 1993). Either NO or peroxynitrite can cause DNA damage, which activates PARP. Further support for this is provided in SZABO et al. (Proc. Natl. Acad. Sci. USA, vol. 93, p: 1753-58, 1996).
It is also known that PARP inhibitors affect DNA repair generally. CRISTOVAO et al. (Terato., Carcino., and Muta., vol. 16, p: 219-27, 1996) discusses the effect of hydrogen peroxide and .gamma.-radiation on DNA strand breaks in the presence of and in the absence of 3-aminobenzamide, a potent inhibitor of PARP. CRISTOVAO et al. observed a PARP-dependent recovery of DNA strand breaks in leukocytes treated with hydrogen peroxide.
Evidence also exists that PARP inhibitors are useful for treating inflammatory conditions such as inflammatory bowel disorders (SOUTHAN et al., Br. J. Pharm., vol. 117, p: 619-32, 1996; SZABO et al., J. Biol. Chem., vol. 272, p: 9030-36, 1997) or arthritis (SZABO et al., Portland Press Proc., vol. 15, p: 280-281, 1998; SZABO, Eur. J. Biochem., vol. 350(1), p: 1-19, 1998; SZABO et al., Proc. Natl. Acad. Sci. USA, vol. 95(7), p: 3667-72, 1998; SZABO et al., Proc. Natl. Acad. Sci. USA, vol. 93, p: 1753-58, 1996; BAUER et al., Intl. J. Oncol., vol. 8, p: 239-52, 1996; HUGHES et al., J. Immuno., vol. 153, p: 3319-25, 1994). Thus, SALZMAN et al. (Japanese J. Pharm., vol. 75 (Supp. I), p: 15, 1997) shows that 3-aminobenzamide, a specific inhibitor of PARP activity, reduced the inflammatory response and restored the morphology and the energetic status of the distal colon in rats suffering from colitis induced by intraluminal administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol. As another example, SZABO et al. (Japanese J. Pharm., vol. 75 (Supp. I), p: 102, 1997) discusses the ability of PARP inhibitors to prevent or treat collagen-induced arthritis.
Further, PARP inhibitors appear to be useful for treating diabetes and have been studied at the clinical level to prevent development of insulin-dependent diabetes mellitus in susceptible individuals (SALDEEN et al., Mol. Cellular Endocrinol., vol. 139, p: 99-107, 1998). In models of Type I diabetes induced by toxins such as streptozocin and alloxan that destroy pancreatic islet cells, it has been shown that knock-out mice lacking PARP are resistant to cell destruction and diabetes development (PIEPER et al., Trends Pharmacolog. Sci., vol. 20, p: 171-181, 1999; BURKART et al., Nature Medicine, vol. 5, p: 314-319, 1999). Administration of nicotinamide, a weak PARP inhibitor and a free-radical scavenger, prevents development of diabetes in a spontaneous autoimmune diabetes model, the non-obese, diabetic mouse (PIEPER et al., 1999, aforementioned). Hence, potent and specific PARP inhibitors may be useful as diabetes-prevention therapeutics.
Further still, PARP inhibitors have been shown to be useful for treating endotoxic shock or septic shock (ZINGARELLI et al., Shock, vol. 5, p: 258-64, 1996; CUZZOCREA, Brit. J. Pharm., vol. 122, p: 493-503, 1997). ZINGARELLI et al. suggests that inhibition of the DNA repair cycle triggered by poly(ADP ribose) synthetase has protective effects against vascular failure in endotoxic shock. ZINGARELLI et al. found that nicotinamide protects against delayed, NO-mediated vascular failure in endotoxic shock. ZINGARELLI et al. also found that the actions of nicotinamide may be related to inhibition of the NO-mediated activation of the energy-consuming DNA repair cycle, triggered by poly(ADP ribose) synthetase.
Yet another known use for PARP inhibitors is treating cancer. In fact, the PARP's activity can contribute to the resistance that often develops to various types of cancer therapies, because this cellular ADP-ribose transfer process is associated with the repair of DNA strand breakage in response to DNA damage caused by radiotherapy or chemotherapy. Consequently, inhibition of PARP may retard intracellular DNA repair and enhance the antitumor effects of cancer therapy. Indeed, in vitro and in vivo data show that many PARP inhibitors potentiate the effects of ionizing radiation (U.S. Pat. Nos. 5,032,617; 5,215,738; 5,041,653; 5,177,075) or cytotoxic drugs such as alkylating agents (WELTIN et al., Oncol. Res., vol. 6(9), p: 399-403, 1994). Thus, inhibitors of the PARP enzyme are useful as adjunct cancer chemotherapeutics.
Still another use for PARP inhibitors is the treatment of peripheral nerve injuries, and the resultant pathological pain syndrome known as neuropathic pain, such as that induced by chronic constriction injury (CCI) of the common sciatic nerve and in which transsynaptic alteration of spinal cord dorsal horn characterized by hyperchromatosis of cytoplasm and nucleoplasm (so-called "dark" neurons) occurs (MAO et al., Pain, vol. 72, p: 355-366, 1997).
PARP inhibitors have also been used to extend the lifespan and proliferative capacity of cells including treatment of diseases such as skin aging (U.S. Pat. No. 5,589,483), Alzheimer's disease, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy, degenerative diseases of skeletal muscle involving replicative senescence, age-related macular degeneration, immune senescence, AIDS, and other immune senescence diseases; and to alter gene expression of senescent cells.
Large numbers of PARP inhibitors have been described. For example, BANASIK et al. (J. Biol. Chem., vol. 267(3), p: 1569-75, 1992) examined the PARP-inhibiting activity of over one hundred compounds, the most potent of which were 4-amino-1,8-naphthalimide, 6(5H)-phenanthridone, 2-nitro-6(5H)-phenanthridone, and 1,5-dihydroxyisoquinoline. GRIFFIN et al. reported the PARP-inhibiting activity for certain benzamide compounds (Anti-Cancer Drug Design, vol. 10, p: 507-514, 1995; U.S. Pat. No. 5,756,510), benzimidazole compounds (WO 97/04771), and quinalozinone compounds (WO 98/33802). SUTO et al. reported PARP inhibition by certain dihydroisoquinoline compounds (Anti-Cancer Drug Design, vol. 7, p: 107-117, 1991). GRIFFIN et al. have reported other PARP inhibitors of the quinazoline class (J. Med. Chem., vol. 41, p: 5247-5256, 1998). Finally, WO 99/11622, WO 99/11623, WO 99/11624, WO 99/11628, WO 99/11644, WO 99/11645, and WO 99/11649 also describe various PARP-inhibiting compounds.
However, the approach of using these PARP inhibitors in the ways discussed above has been limited in effect. For example, side effects have been observed with some of the best-known PARP inhibitors (MILAM et al., Science, vol. 223, p: 589-91, 1984). Specifically, the PARP inhibitors 3-aminobenzamide and benzamide not only inhibited the action of PARP but also were shown to affect cell viability, glucose metabolism, and DNA synthesis. Thus, it was concluded that the usefulness of these PARP inhibitors may be severely restricted by the difficulty of finding a dose that will inhibit the enzyme without producing additional metabolic effects.
Accordingly, there remains a need for compounds that inhibit more specifically PARP activity, compositions containing those compounds, and methods utilizing those compounds, wherein the compounds produce more potent and reliable effects with fewer side effects, with respect to inhibiting PARP activity and treating the diseases and conditions discussed herein.
Macro-H2A1 and macroH2A2 histones are particularly enigmatic histone variants having an N-terminal region with high sequence homology to H2A, and also containing an extensive non histone C-terminal tail that comprises nearly two third of the protein (25 kDa). The human genome contains two genes that code for macroH2A histones. The MACROH2A1 gene encodes two subtypes MACROH2A1.1 and MACROH2A1.2 produced by alternative splicing. A second gene codes for MACROH2A2 (CHADWICK and WILLARD, Human. Mol. Genet., vol. 10, p: 1101-1113, 2001). These proteins appear to be enriched in heterochromatin such as the inactive X chromosome (Xi) in female mammals (COSTANZI and PEHRSON, Nature, vol. 393, p: 599-601, 1998), and discrete heterochromatic loci in senescent and quiescent cells (ZHANG et al., Dev. Cell, vol. 8, p: 19-30, 2005; GRIGORYEV et al., J. Cell. Sci., vol. 117, p: 6153-6162, 2004). MacroH2A is highly localized in female cells as a distinct nuclear body, referred to as a macro chromatin body (MCB), which is coincident with the Xi and the Barr body (COSTANZI and PEHRSON, aforementioned, 1998). The C-terminal region of macroH2A contains a domain termed "macro domain", which is found alone or in multiple copies in a number of otherwise unrelated proteins (PEHRSON and FUJI, Nuc. Acids Res., vol. 26, p: 2837-2849, 1998), and which is critical for macroH2A MCB formation (CHADWICK et al., Nuc. Acids Res., vol. 29(13), p: 2699-2705, 2001). It has been suggested that this macro domain defines a superfamily of phosphoesterases that act on ADP ribose derivatives (ALLEN et al., J. Mol. Biol., vol. 330, p: 503-511, 2003). Recently, KUSTATSCHER et al. (Nat. Struct. Mol. Biol., vol. 12(7), p: 624-5, 2005) shows that macroH2A1.1 binds to monomeric ADP-ribose and to O-acetyl-ADP-ribose (a NAD metabolite). The authors identify Phe348, Asp203, Gly224 and Gly314 as critical residues for O-acetyl-ADP-ribose binding. Nevertheless, the specific macroH2A function is still unknown.

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS)


Absorbable implant materials having controlled porosity are formed by a method comprising the steps of: providing a dispersion of a bioabsorbable polymer, such as collagen, in a first solvent, such as water; adding particles of a second material, e.g. frozen water droplets or ice particles to the dispersion; followed by freezing the dispersion to form a frozen dispersion having the particles embedded therein, and removing both the first solvent and the second material from the frozen dispersion by freeze-drying or solvent extraction to leave the porous implant material. The invention also encompasses the use of such implant materials for wound healing applications.

A number of attempts have been made to fashion solid, bioabsorbable implant and/or dressing materials for application to wounds to protect the wounds and assist wound healing and tissue regeneration.
A solid wound implant material should preferably include the properties of gradual, controllable degradation and absorption in situ as the wound heals, low antigenicity, mechanical strength, conformability, and optimised porosity. The controlled porosity is important because the healing of wounds depends on the production by the wound of substantial quantities of matrix materials and granulation tissue involving the migration of fibroblast cells and connective tissue into the implant.
Various naturally occurring biopolymers, including proteins and polysaccharides, have been used over the last 20-30 years in the treatment of wounds or the augmentation of soft tissues. Proteins such as collagen, the most common animal protein and the main component of most connective tissues in the animal body, have been used due to their convenient physical properties and their high degree of bioacceptability. Collagen exists as many genetically distinct types, but the higher mammals share in common these types and the homology between the various types in, for example, man, cattle, sheep, pigs or chickens, is remarkably high. This means that the immunogenicity of animal collagens when implanted into humans, is very low and, therefore, that adverse reaction is very low. Furthermore, collagen and many other biopolymers actively assist wound healing by promoting the proliferation of fibroblasts, and by promoting angiogenesis.
Other proteins, especially those of the connective tissue matrix of man have been suggested as possible components of wound healing or tissue implant materials. These proteins include fibronectin, laminin and fibrin. Similarly, the high molecular weight polysaccharides of the connective tissue matrix have also been used in various types of wound dressing or "synthetic skins". These include such molecules as heparan sulphate, chondroitin sulphate, hyaluronic acid and dermatan sulphate. Other naturally occurring polysaccharide materials, especially of plant origin, have been cited as useful in the manufacture of dressings for wounds (e.g. alginates, guar gum, various plant gums) although not, in the main, in fabrication of implants as they are not bioabsorbable.
U.S. Pat. No. 4,970,298 (Frederick H. Silver et al) describes a biodegradable collagen matrix allegedly suitable for use as a wound implant. The matrix is formed by freeze drying an aqueous dispersion containing collagen, cross-linking the collagen via two cross-linking steps and freeze-drying the cross-linked matrix. The matrix may also contain hyaluronic acid and fibronectin.
EP-A-0274898 (Ethicon Inc.) describes an absorbable implant material having an open cell, foam-like structure and formed from resorbable polyesters, such as poly-p-dioxanone, other polyhydroxycarboxylic acids, polylactides or polyglycolides. The open-cell plastic matrix is reinforced with one or more reinforcing elements of a textile nature formed from a resorbable plastic and embedded in the matrix. The open-cell plastic matrix is made by freeze-drying a solution or suspension of the plastic material in a non-aqueous solvent. The pore size of the open-cell plastic matrix is from 10 to 200 .mu.m.
JP-A-03023864 (Gunze KK) describes a wound implant material comprising a collagen sponge matrix reinforced with fibres of poly-L-lactic acid. The collagen sponge matrix is formed by freeze drying a solution of porcine atherocollagen.
EP-A-0562862 (Johnson & Johnson Medical, Inc.) describes bioabsorbable wound implant materials that are composites comprising a collagen sponge matrix having embedded therein oriented substructures of solid collagen fibers, films or flakes. The substructures reinforce the collagen sponge and also provide a scaffold for directional cellular migration into the implant. The composites are formed by immersing the substructures in an aqueous collagen slurry and then freeze-drying the slurry to form the collagen sponge matrix.
The above bioabsorbable sponge implants are formed by freeze-drying or solvent drying solutions or suspensions of a bioabsorbable material in a solvent. However, it is generally difficult to control the pore size and density of sponge materials made in this way. The structural integrity of these sponges has been enhanced by embedding bioabsorbable reinforcing fibres or substructures in the sponge matrix. The resorption of the sponges has been slowed by chemical cross-linking of the biopolymer.
Attempts have also been made to reduce the pore size of collagen sponges formed by freeze-drying. This was done in order both to increase the density of the sponges and to limit the pore size to the 50-250 .mu.m range that was thought to be optimum for invasion by fibroblasts.
In particular, WO90/00060 (Collagen Corporation) describes collagen implants that are formed by flash freezing and then freeze-drying a suspension of collagen fibrils without chemical cross-linking. The flash freezing results in smaller ice crystals, and hence in smaller pores in the finished sponge. The implants have a bulk density of 0.01 to 0.3 g/cm.sup.3 and a pore population in which at least about 80% of the pores have an average pore size of 35 to 250 .mu.m. This wound healing matrix also serves as an effective sustained delivery system for bioactive agents.
Many of these sponge materials are intended for use in tissue augmentation or repair and require to be invaded and replaced by cells and newly synthesised connective tissue. In this regard, it is crucial that a material placed into a wound to replace lost tissue, or used to augment deficient tissue, should be rapidly colonised by cells and newly forming connective tissue. If this does not happen, the material will be rapidly exfoliated by the wound bed and granulation tissue which will form outside of the matrix.
It has now been found that larger pores, in the size range 0.1-3.0, preferably 0.3-1.0 mm, enhance fibroblast invasion rates and result in enhanced wound healing properties.
Wake et al in Cell Transplantation vol. 3(4), pp 339-343 (1994) describe studies of pore size effects on the fibrovascular tissue growth in porous bioabsorbable polymer substrates. The substrates of poly-L-lactic acid (PLLA) were prepared with pore sizes of up to 500 .mu.m by a particulate leaching technique. Briefly, the PLLA was dissolved in methylene chloride and sieved sodium chloride particles having diameters similar to the desired pore size were dispersed in the solution. The resulting dispersion was then cast into disks and dried. The sodium chloride was then leached from the disks to leave the desired porous PLLA structure. It was found that fibrovascular tissue advances much faster into porous PLLA with a larger pore size (.about.500 .mu.m) than into porous PLLA having smaller pores (179 and 91 .mu.m).
Mikos et al in Polymer vol. 35(5), pages 1068-1077 (1994) describe the preparations of PLLA sponges by particulate leaching in more detail. They state that, when 70-90% by weight of sodium chloride particles is included in the PLLA, the resulting leached material is homogeneous with interconnected pores. There is no disclosure of leaching the sodium chloride from frozen aqueous dispersions of PLLA.


The invention provides a composition for topical treatment of hair loss/alopecia including three natural, active ingredients, caffeine, saw palmetto berry extract, and epigallocatechin-3-gallate (EGCG). The invention also provides methods for using this composition to treat hair loss.

Millions of Americans experience some degree of alopecia, commonly referred to as "balding" or simply "hair loss", resulting in ever-increasing amounts of money being spent in efforts to stop the loss and/or grow the hair back.
Countless pharmaceutical remedies, cosmetic treatments, and surgical methods of varying success have been devised in order to address the problem of hair loss. The difficulty in identifying effective treatments stems from the fact that there is no one cause for hair loss, but rather, there are many, such as: hormonal changes, heredity, disease, stress, medications, infections, genetic disorders, toxic agents, and/or food deficiencies.
The majority of cases are hormonal in origin, for example—androgenic alopecia (also known as male-pattern alopecia and androgenetic alopecia), which is a distressing problem for a large proportion of adult men. This male balding most often starts between the ages of 30-50 years old. Occasionally, it may begin at an even younger age.
In men developing androgenic alopecia, there is a gradual atrophy of hair follicles due to a genetically-inherited sensitivity to 5α-dihydrotestosterone (also know as "dihydrotestosterone" or "DHT"). The enzyme 5-α-reductase transforms testosterone into dihydrotestosterone in the hair follicles, which then directs follicles to progressively shrink and finally disappear. Thus, considering that 5α-dihydrotestosterone is a key contributing factor to the onset and progression of androgenic alopecia, blocking DHT is an area of interest for protecting hair.
Although there are currently many accepted oral and topical treatments for balding, only two drugs have been approved by the Food and Drug Administration (FDA) to treat alopecia; topical minoxidil (trademark name-Rogaine®) and oral finasteride (trademark name-Propecia®).
Minoxidil, (trademark name-Rogaine®), was originally developed as a treatment for individuals with high blood pressure. While treating these individuals, it was discovered that minoxidil moderately increased hair growth and prevented future hair loss. It is also believed that minoxidil may increase hair growth in thinning hair areas, but the mechanism of action (of minoxidil) remains unknown.
However, although these advantages of use exist, there are problems associated with the use of minoxidil. The most common side effect of topical minoxidil is skin irritation and/or a local allergic reaction called contact dermatitis. Additionally, if the medication is stopped after prolonged use, hair loss may actually increase rather than decrease. Further, major complications of minoxidil are rare, but possible, and can include decreased blood pressure with headache, fatigue, and dizziness. Patients who suffer from heart disease or hypertension cannot utilize minoxidil without medical supervision.
Minoxidil in lower concentration is a non-prescription product currently sold over-the-counter in multiple different formulations for treatment of hair loss in both men and women.
The second FDA-approved drug is finasteride (trademark name-Propecia®). Finasteride was originally used to treat prostate enlargement by inhibiting the 5-α reductase enzyme. The inhibition of the 5-α reductase enzyme interferes with the formation of DHT by blocking the action of 5-α reductase on testosterone. Men undergoing this treatment experienced an increase in hair growth. It is believed that the inhibition of the 5-α reductase enzyme may increase hair follicle growth or prevent future hair follicle loss.
However, although these advantages of use exist, there are also problems associated with the use of finasteride. Men may experience decreased libido, decreased volume of ejaculate, and a lowered level of prostate specific antigen (PSA). This lowered level of PSA may interfere with screening for prostate cancer.
Further, pregnant or nursing women may not use finasteride because it is teratogenic, and can harm the human fetus. Due to such a serious health risk, finasteride has been limited to use within male patient populations only, leaving a majority of female alopecia sufferers to seek alternative treatment options.
A topical treatment for androgenic alopecia will have lower internal exposure leading to a lower internal side effect profile than oral medications such as finasteride. Currently available topical medications, i.e. minoxidil, have not worked consistently or effectively for balding. In theory, topical medications targeted at interfering with the production of testosterone derivatives or blocking the effects of dihydrotestosterone on its receptor (stopping the trigger of male-pattern hair loss) would be beneficial, but to date, none have been satisfactorily successful.
For additional background information regarding hair loss/alopecia, see U.S. Pat. Nos. 6,878,145 B2; 7,713,557 B2; and 8,080,524 B2.
Citation or identification of any reference/document in the instant application is not and should not be interpreted as an admission that such reference/documents is available as prior art to the present invention.

This patent is subject to a terminal disclaimer.

Method for treatment of hair loss with a combination of natural ingredients


A head-mounted device includes a case including a body and a cover covering the body, the case having a display panel accommodating space between the body and the cover, an optical system in the body facing the cover, and a filter in the body, the filter being spaced apart from the optical system in a first direction corresponding to a thickness direction of the optical system and being configured to repeatedly move in a direction.

1. Field of Disclosure
The present disclosure relates to a head-mounted device and a display device.
2. Description of the Related Art
A head-mounted device is a device worn on a head of a user and includes a display panel unit or is coupled to the display panel unit. The head-mounted device is used to realize an augmented reality or a virtual reality. The head-mounted device used to realize the augmented reality provides a virtual graphic image through a semi-transparent display. In this case, the user simultaneously perceives the virtual graphic image and a real object. The head-mounted device used to realize the virtual reality provides the virtual graphic image to eyes of the user. The user experiences the virtual reality through virtual contents.


The invention relates to the finding that the VHL tumour suppressor protein regulates hypoxia inducible factor α subunits, by targeting HIF α for destruction in normoxic, but not hypoxic cells. The invention provides assays for modulators of this interaction, and peptides based upon HIF α subunit sequences which may modulate this interaction.

Enhanced glucose metabolism and angiogenesis are classical features of cancer involving up-regulation of genes which are normally inducible by hypoxia. In addition to stimulation by the hypoxic microenvironment, genetic alterations contribute to these effects. A striking example is von Hippel-Lindau (VHL) disease, a hereditary human cancer syndrome predisposing to highly angiogenic tumours, particularly of the central nervous system, kidney, retina and adrenal glands.
VHL syndrome is caused by germline mutations in the VHL tumour suppressor, and VHL tumours are associated with loss or mutation of the remaining wild-type allele. VHL is also inactivated in −80% of sporadic clear cell renal carcinomas (RCC), the predominant form of kidney cancer. The ability of RCC cells to form tumours in nude mice can be abrogated by introduction of wild-type VHL.
VHL-associated tumours are highly vascularized, and this supports the current model that VHL negatively regulates the production of hypoxia-inducible factors such as the angiogenic vascular endothelial growth factor (VEGF). VHL−/− tumour cells have high levels of these factors, and reintroduction of VHL down-regulates them under normoxic conditions. The mechanism of this VHL activity is not well understood.
Stebbins et al (Science, 1999, 284; 55-61) report that the VHL protein forms a complex with the Elongin C and Elongin B proteins, and that the complex (the VCB complex) is formed by a direct interaction of VHL and Elongin C, with a second interaction between the Elongin C and B proteins. The interface of VHL which interacts with Elongin C contains a number of residues which are commonly mutated in VHL syndrome. The authors also found a second domain of VHL, not involved in binding Elongin C, which they speculate may correspond to another macromolecular binding site of VHL.
Hypoxia inducible factor-1 (HIF-1) plays a key role in a wide variety of cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, vasomotor control, angiogenesis, proliferation, apoptosis and matrix remodelling. HIF is a heterodimer of an HIF α subunit and the aryl hydrocarbon receptor nuclear translocator (ARNT) protein, a member of the PAS superfamily of basic helix-loop-helix proteins. A major regulatory mechanism involves proteolysis of HIF α subunits which are rapidly degraded by the proteasome in normoxia but stabilised by hypoxia.

Interaction between the VHL tumor suppressor and hypoxia inducible factor, and assay methods relating thereto


The programming techniques include the step of providing a memory device that includes a plurality of memory cells that are divided into at least two groups including a first group and a second group. The first group includes memory cells that are coupled to full select gate drains (SGDs), and the second group includes memory cells that are coupled to partial SGDs. The method continues with the step of applying a programming voltage to a selected word line that includes at least one memory cell of the first group and at least one memory cell of the second group. Simultaneous to the application of the programming voltage, the method continues with applying voltages to bit lines coupled to memory cells. The voltages being determined based on if the memory cells are of the first group or are of the second group.

Many memory devices are provided as internal, semiconductor, integrated circuits in computers or other electronic devices. There are many different types of memory, including random-access memory (RAM), read only memory (ROM), dynamic random-access memory (DRAM), synchronous dynamic random-access memory (SDRAM), an electrically erasable programmable read-only memory (EEPROM), a flash memory, and/or the like. In an EEPROM or flash NAND array architecture, memory cells may be arranged in a matrix of rows and columns such that gates of each memory cell are coupled by rows to word lines. The memory cells may be arranged together in strings such that memory cells in a given string are coupled together in series, from source to drain, between a common source line and a common bit line.
In some NAND memory devices, a shallow etching features (SHE) partially cuts through portions of a plurality of memory holes that include memory cells and drain-side select gates (SGDs), thereby changing the programming characteristics of those memory cells.

Programming techniques for memory devices having partial drain-side select gates