A positioner which can move an object such as a magnetic recording head. The positioner includes a housing with an inner opening. The housing is located within a coordinate system that includes an x axis, a y axis and a z axis. An electrical/mechanical transducer is coupled to the inner opening of the housing by at least two flexure joint inserts. Expansion or contraction of the transducer creates a movement of the housing along the x or y axis. The flexure joint inserts allow the transducer to be adjusted within the inner opening during assembly to minimize the out of plane movement of the housing along the z axis.

1. Field of the Invention
The present invention relates to a positioner that can move an object such as a magnetic recording head, or the probe of an atomic microscope.
2. Description of Related Art
Hard disk drives contain a plurality of magnetic recording heads that write and read information from a number of adjacent rotating magnetic disks. There is typically a recording head associated with each surface of a disk. The magnetic heads write and read data by magnetizing and then sensing the magnetic field of the disks. Each recording head has an air bearing surface which cooperates with an airflow created by the rotating disk to form an air bearing. The air bearing separates the recording head from the disk surface to prevent mechanical wear. The air bearing also reduces the magnetic coupling between the head and the disk. It is desirable to minimize the height of the air bearing without inducing undesirable contact between the two components.
Each magnetic recording head is typically mounted to a gimbal of a flexure arm. Each flexure arm is attached to an actuator which has a voice coil motor. The voice coil motor can be actuated to move the heads across the surfaces of the disks to access different tracks of data. The flexure arm, gimbal and head are commonly referred to as a head-gimbal assembly (HGA). The HGA is designed to create an optimum air bearing for the recording head.
There have been developed various types of recording heads such as ferrite, thin film and magnetoresistive (MR) heads. MR heads typically have an element for magnetizing the disk (writing data) and a separate magnetoresistive element for sensing the magnetic field of the disk (reading data). As a result of manufacturing processes the MR element may be spatially offset from the write element. It is desirable to measure the offset between the two elements so that the disk drive controller can be programmed to compensate for the deviation between the read and write elements.
Recording heads are typically measured in a dynamic head tester. Dynamic head testers include a rotating magnetic disk and a fixture that can support either an HGA or an individual head. The fixture is coupled to a course positioner which moves the head adjacent to the rotating magnetic disk. The tester contains test circuitry which is coupled to the head and performs various routines to test various dynamic electrical characteristics of the head. The tester may contain a fine positioner which can move the head over very small increments to obtain test data such as the offset of an MR head. The movement by the fine positioner can be on the order of nanometers.
Some of the dynamic values measured by the tester are stored in the memory of the disk drive in which the head is assembled. It is desirable to obtain accurate dynamic values to assure a proper optimum functioning of the drive. It is therefore imperative that the fine positioner accurately move the heads during test.
Many disk drive manufacturers test every recording head before assembly into a hard disk drive. The dynamic testing therefore becomes a manufacturing step of the drive. A reduction in the time that it takes to test each recording head can save millions of dollars for the manufacturer. The test time includes a mechanical settling time for the positioner each time the head is moved relative to the disk. It would be desirable to provide a fine positioner which has a very fine resolution and relatively low settling time.
FIG. 1 shows a nanopositioner of the prior art sold by Piezosystem Jena of Germany. The Jena positioner has a piezoelectric transducer 1 that is located within an opening 2 of the positioner housing 3. One end 4 of the housing 3 is mounted to a substrate and fixed in space. A fixture (not shown) is typically mounted to the other end 5 of the housing. The application of a voltage across the transducer 1 will cause the piezoelectric material to expand and move the free end 5 of the housing along the y axis.
To provide a highly accurate positioner it is desirable to eliminate any movement of the housing free end 5 along the z axis, also referred to as out of plane movement. The Jena positioner creates an out of plane movement in the range of 80 nanometers when the free end 5 moves 100 microns. It would be desirable to provide a nanopositioner that creates less out plane movement than positioners of the prior art.


A method for modulating Nod1 activity wherein said method comprises the steps of providing cells expressing a functional Nod1; and bringing said cells into contact with a molecule related to compositions comprising a molecule related to MTP and use of a molecule related to MTP for modulating inflammation and/or apoptosis.

This invention relates to the first described pathogen-recognition molecule Nod1, which senses specifically Gram-negative bacteria through a peptidoglycan motif, muramyl tripeptide. More particularly, this invention relates to the modulation of Nod1 activity by a molecule related to the muramyl tripeptide (MTP). The invention also relates to a screening process for identifying a molecule capable of modulating Nod1 activity and the therapeutic use of such a molecule for modulating inflammation and/or apoptosis. The invention also relates to a new compound, which can be used for modulating inflammation and/or apoptosis or as an adjuvant agent.
In multicellular organisms, homeostasis is maintained by balancing the rate of cell proliferation against the rate of cell death. Cell proliferation is influenced by numerous growth factors and the expression of proto-oncogenes, which typically encourage progression through the cell cycle. In contrast, numerous events, including the expression of tumor suppressor genes, can lead to an arrest of cellular proliferation.
In differentiated cells, a particular type of cell death called apoptosis occurs when an internal suicide program is activated. This program can be initiated by a variety of external signals as well as signals that are generated within the cell in response to, for example, genetic damage. For many years, the magnitude of apoptotic cell death was not appreciated because the dying cells are quickly eliminated by phagocytes, without an inflammatory response.
The mechanisms that mediate apoptosis have been intensively studied. These mechanisms involve the activation of endogenous proteases, loss of mitochondrial function, and structural changes, such as disruption of the cytoskeleton, cell shrinkage, membrane blebbing, and nuclear condensation due to degradation of DNA. The various signals that trigger apoptosis are thought to bring about these events by converging on a common cell death pathway that is regulated by the expression of genes that are highly conserved from worms, such as C. elegans, to humans. In fact, invertebrate model systems have been invaluable tools in identifying and characterizing the genes that control apoptosis. Through the study of invertebrates and more evolved animals, numerous genes that are associated with cell death have been identified, but the way in which their products interact to execute the apoptotic program is poorly understood.
Caspases, a class of proteins central to the apoptotic program, are cysteine proteases having specificity for aspartate at the substrate cleavage site. These proteases are primarily responsible for the degradation of cellular proteins that lead to the morphological changes seen in cells undergoing apoptosis. For example, one of the caspases identified in humans was previously known as the interleukin-1β (IL-1β) converting enzyme (ICE), a cysteine protease responsible for the processing of pro-IL-1β to the active cytokine.
Many caspases and proteins that interact with caspases possess domains of about 60 amino acids called a Caspase Recruitment Domain (CARD). Others have postulated that certain apoptotic proteins bind to each other via their CARDs and that different subtypes of CARDs may confer binding specificity, regulating the activity of various caspases, for example.
Innate immunity to bacterial pathogens relies on the specific sensing of pathogen-associated molecular patterns (PAMPs) by pattern-recognition molecules (PRMs). In mammals, Toll-like receptors (TLRs) represent the most extensively studied class of PRMs, which have been shown to sense various PAMPs, such as lipopolysaccharide (LPS), peptidoglycan (PGN), lipoproteins, double-stranded RNA and CpG DNA (S. Akira et al., Nat. Immunol., 2, 675, 2001; R. Medzhitov, Nat. Rev. Immunol., 1, 135, 2001). While TLRs are mainly expressed at the plasma membrane, it has been recently proposed that the Nod molecules, a family of intracellular proteins including Nod1/CARD4 and Nod2/CARD15, could represent a new group of PRMs that sense bacterial products within the cytoplasmic compartment, thus allowing to detect the presence of intracellular invasive bacteria (N. Inohara et al., J. Biol. Chem. 274, 14560, 1999; J. Bertin et al., J. Biol. Chem., 274, 12955, 1999; N. Inohara et al., J. Biol. Chem., 276, 2551, 2001; S. E. Girardin et al., EMBO Rep., 2, 736, 2001; Y. Ogura et al., J. Biol. Chem., 276, 4812, 2001; Y. Ogura et al., Nature, 411, 603, 2001; J. P. Hugot et al., Nature, 411, 599, 2001).
The partial sequences (cDNA and protein) of Nod1, also named CARD4 for Caspase Recruitment Domain, have been disclosed in patent application Ser. No. 09/019,942, filed Feb. 6, 1998, and now granted as U.S. Pat. No. 6,033,855. Furthermore, Bertin et al. (1999) disclosed the entire amino acid sequence of CARD4 and one of its functions, already mentioned in the above-patent: CARD4 coordinates NF-κB and apoptotic signaling pathway. Girardin et al. (2001) disclosed that CARD4/Nod1 mediates NF-κB activation by invasive Shigella flexneri. In this article, the interaction between S. flexneri LPS and CARD4 is especially studied.
Stimulation of Nod1/CARD-4 activity is desirable in situations in which CARD-4 is abnormally downregulated and/or in which increased CARD-4 activity is likely to have a beneficial effect. Conversely, inhibition of CARD-4 activity is desirable in situations in which CARD-4 is abnormally upregulated, e.g., in myocardial infarction, and/or in which decreased CARD-4 activity is likely to have a beneficial effect. Since CARD-4 may be involved in the processing of cytokines, inhibiting the activity or expression of CARD-4 may be beneficial in patients that have aberrant inflammation.
It has recently been shown that Nod1 senses the presence of the Gram-negative pathogen, Shigella flexneri, within the cytoplasmic compartment of epithelial cells (S. E. Girardin et al., 2001), and it was hypothesized that the detected PAMP was LPS since commercial preparations of LPS were shown to activate Nod1 (N. Inohara et al., J. Biol. Chem., 276, 2551, 2001). However, as these LPS often contain bacterial cell wall contaminants, there is a need in the art for more detail on whether a particular molecular motif or motifs are actually detected by Nod1 and modulate Nod1 activity.

Method for modulating Nod1 activity, use of a MTP related molecule for modulating Nod1 activity, and therapeutic applications thereof

Institut National de la Sante et de la Recherche Medicale


A device for preparing a fluid food at a desired consumption temperature on demand, comprising two reservoirs of water, a container containing a formula, a data processor and a controller for dispensing water of the correct temperature from each of the reservoirs and the formula from the container into a vessel. Also provided is a method to prepare a fluid food at a desired consumption temperature on demand.

The present invention relates to the field of food preparation and, more particularly, to a device and a method for the preparation of fluid food from formula at a desired consumption temperature. The present invention is useful, for example, in preparing food for infants.
The need for substitutes for mother's milk predates history with biblical and legendary references to human or canine, especially lupine, wet nurses as alternatives for mothers who were unable to nurse their babies. While wet nurses are still the alternative most approximating mother's milk, milk substitutes prepared from powdered or liquid formulas are now the preferred alternative. Most present-day baby caregivers use commercially available formulas for preparing fluid food to feed the babies in their care. The use of formula generally involves the following five steps:
1. Water is heated, generally by boiling for a few seconds, and then cooled to near a consumption temperature;
2. An appropriate amount of powdered or concentrated formula is placed in a serving vessel such as a baby bottle;
3. An appropriate amount of the cooled sterilized water is put into the serving vessel;
4. A fluid food is achieved by mixing, for example by vigorous agitation of the serving vessel; and
5. The temperature of the fluid food is tested. If the temperature is not the proper consumption temperature, steps are taken to either increase or decrease the temperature of the food as may be required.
Because infants must be fed approximately five or six times a day, it is not uncommon that this process takes place in the middle of the night. Moreover, it is commonly carried out with one hand while holding a hungry and screaming infant in the other hand. As a result there is a demand for a device that quickly and easily prepares ready to consume fluid food, especially for infants. Further, as all these steps are manual, the temperature at which the food is served is not precise. Many such devices are known in the art, all with certain limitations and none that prepare, on demand, a bottle of fluid food from formula at a desired consumption temperature.
U.S. Pat. No. 5,808,276 discloses a device that attempts to solve the stated problem, by allowing a caregiver to prepare a bottle with the desired formula in advance of its need. The device therein disclosed heats and agitates an already prepared bottle of fluid food.
U.S. Pat. No. 3,352,460 provides a device for storing and dispensing liquid formula. This device employs two compartments, one for heating water and another for cooling the water by refrigeration. The device has a number of drawbacks, including not sufficiently sterilizing the water; dispensing the fluid food at too high a temperature so that it must cool in the bottle before serving. The food is therefore not ready on demand and the baby is in risk of being burned. Overheating may reduce the nutritional value of the food. Further, not all the food may be consumed. Even further, there are no provisions for the addition of any ingredients to the food beyond water and formula.
Other attempts made to address the need for prepared fluid food for infants, include:
U.S. Pat. No. 5,397,031 which discloses a device for preparing fluid food from formula at a baby's bedside. The device does not sterilize the water used, does not provide for the addition of other ingredients, and the baby must wait for the food to reach consumption temperature.
U.S. Pat. No. 5,419,445 shows a device that provides a complex method of separating the components of fluid food for convenient mixing at a later time, preferably by agitation of the bottle in order to cause the formula to dissolve in the water. It makes no provision for preparing fluid food at a desired consumption temperature.
U.S. Pat. No. 5,570,816 shows a device which only begins heating food when activated by the user, requiring the infant to wait. In addition, the device does not boil the water long enough for it to be sufficiently sterilized and it makes no provision for the addition of other ingredients to the food.
U.S. Pat. No. 5,797,313 shows a device governed by a timer which allows a user to determine when a bottle of fluid food made from formula will be ready. This is a useful feature if it is known precisely when the infant will wake up in the middle of the night. If the infant wishes to eat at times other than the set times or to consume different amounts of food at different times, the device must be activated and the infant must wait for the food to be prepared and heated to the desired consumption temperature.
U.S. Pat. No. 6,118,933 and U.S. Pat. No. 6,253,028 disclose a device for preparing fluid food from formula which uses filtered water, rather than boiling the water for sterilization.
PCT WO97/47224 discloses a multiple bottle preparing device which heats up a bottle of fluid food to consumption temperature when activated. This device provides certain advantages for caregivers with multiple babies to feed but still requires the infant to wait for a bottle of food to be brought to the desired consumption temperature.
There exist many other devices which mix ingredients in order to prepare fluid food which are used in the food service industry, as shown in U.S. Pat. No. 3,218,175; U.S. Pat. No. 4,139,125; U.S. Pat. No. 4,651,862; U.S. Pat. No. 4,753,370; U.S. Pat. No. 4,791,860; U.S. Pat. No. 4,993,593 and British Patent GB 2 019 813 A. These devices are not compatible with infant formula.
In addition, it is known that many infants have special nutrition needs, ranging from those with preferences for different consumption temperatures to those that require medication or other additives or specific combination of ingredients and additives in their food. A device that can individualize the composition of fluid food according to specific requirements and automatically prepare and provide that food on-demand does not exist.
There is thus a widely recognized need for, and it would be highly advantageous to have, a device for the preparation of fluid food from formula that overcomes the disadvantages of prior art devices.


The invention concerns a lighting or signalling equipment for a motor vehicle comprising a housing and adjustable means for fixing said housing on a structural part of the vehicle, and stop means countering the headlamp displacement in a specific direction to define a reference position for said headlamp relative to the car body. The invention is characterized in that the adjustable fixing means comprise a rotary fixing member capable of co-operating with said structural part and driving during an initial phase of its rotation means forming a cam capable of urging the equipment in said specific direction. The invention also concerning adapted structural element.

The present invention relates in general to the fixing of lighting and/or signaling apparatus into motor vehicles.
Conventionally, a device for fixing a headlamp casing, for example, to the front of a vehicle comprises mounting means which, in a first state known as pre-mounting state, allow slight displacement of the casing with respect to the fixed part onto which it is mounted, particularly in order to make it possible to adjust the position of the glazing of the headlamp with respect to the adjacent bodywork. In a second state, locking is effective, so that the headlamp is fixed into the previously adjusted position.
These devices are more or less complex, and rely in particular on relatively bulky additional pieces mounted on the casing of the headlamp, which exhibits the double drawback of increasing the cost price of the headlamp and the space necessary for housing it under the engine hood.
Moreover, these known devices generally rely on a first locking of the headlamp (pre-mounting) by the use of first means, then on a final fixing by the use of second means, separate from the first ones. This further increases the cost price and complicates the mounting operations.
The present invention aims to remedy these drawbacks of the state of the art and to propose a lighting or signaling apparatus equipped with adjustable fixing means which are very simple and reliable to employ, which are economical to produce, and which moreover offer good inviolability of the apparatus once it has been mounted into the vehicle. A further object of the invention is to propose pre-mounting arrangements designed in keeping with such adjustable fixing means in order further to reinforce the inviolability and avoid play, which is particularly a source of vibration, due to manufacturing tolerances.
Hence the invention, according to a first aspect, proposes a lighting or signaling apparatus for a motor vehicle, including a casing and means for adjustable fixing of the said casing onto a structural part of the vehicle, as well as abutment means opposing a displacement of the headlamp in a given direction in order to define a reference position of the said headlamp with respect to the bodywork of the vehicle, characterized in that the said adjustable fixing means comprise a member for fixing by rotation able to interact with the said structural part and driving a cam-forming means, during an initial phase of its rotation, able to push the apparatus in the said given direction.
Preferred, but not limiting, aspects of the apparatus according to the invention are as follows:
the said fixing member consists of a screw,
the said cam-forming means comprises a dowel exhibiting an essentially circular part forming a cam and traversed eccentrically by the said screw,
the said screw entrains the said dowel in rotation via the interaction of limited friction between the threading of the screw and a passage formed in the dowel for the screw to pass into,
the dowel has a barrel accommodating the said screw and able to be engaged closely in an aperture formed in the said structural part of the vehicle,
the said barrel comprises a plurality of branches able to be stressed by the said screw, when it is screwed up, towards a wall of the said structural part delimiting the said aperture,
the said dowel consists of two parts linked by at least one frangible area, an inner part being integral in rotation with the screw while an outer part forming [sic] a cam,
the said screw is screwed directly into an aperture formed in the structural part of the vehicle,
the said cam-forming part acts on a low wall surrounding a housing in which it is held,
the casing of the apparatus possesses at least one pre-mounting lug possessing a terminal hooking part and able to interact with an aperture formed in the said structural part.
According to a second aspect, the invention proposes a structural element for a motor vehicle, characterized in that it consists of a single-piece component intended to extend at the front of the vehicle over a substantial part of its width and possessing, in the region of its two lateral extremities, arrangements for the mounting and the fixing of two items of apparatus as defined above, constituting left-hand and right-hand headlamps.
The invention also proposes an assembly of a structural element as defined above and of two items of lighting apparatus as defined above, constituting left-hand and right-hand headlamps.
According to a third aspect, the invention proposes a structural element for a motor vehicle, intended to accommodate at least one item of apparatus the casing of which possesses at least one pre-mounting lug possessing a terminal hooking part and able to interact with an aperture formed in the said structural element, characterized in that it possesses at least one first aperture for accommodating the member for fixing by rotation belonging to the adjustable fixing means of the apparatus, and at least one second aperture intended to accommodate a pre-mounting lug of the apparatus of the apparatus [sic] while allowing it to be displaced in the said given direction, the said second aperture having a width, measured transversely to the said given direction, which reduces when the said slot is traveled along the said given direction.
Advantageously, each second aperture, along the said given direction, comprises a first part with a constant width followed by a second part with a second constant width less than the first one; for example, the said first constant width is greater than the overall thickness of an associated pre-mounting lug, while the second constant width is slightly greater than the thickness of a linking part of the said lug.
In order to compensate for play and avoid vibration, the element may also comprise, in the vicinity of each second aperture, a ramp able to force the associated pre-mounting lug in a direction tending to extract it from the said second aperture.
Finally the invention proposes an assembly of a structural element according to the third aspect above and of at least one lighting or signaling apparatus as it is defined therein.

Lighting or signalling equipment provided with improved adjustable fixing means and associated structural element for motor vehicle


The disclosed embodiments illustrate a method for real time management of transportation services. The method includes determining a discrete control process with respect to a plurality of states of a vehicle. Each state in the plurality of states corresponds to a station and a count of vacant seats in the vehicle at the station. A set of rules is generated to maximize a key performance parameter of the vehicle, based on at least the determined discrete control process. A valuation parameter is determined, in real time, for one or more vacant seats in the vehicle at each of one or more subsequent stations based on the generated set of rules. The determined valuation parameter for the one or more vacant seats corresponding to each of the one or more subsequent stations is transmitted to a plurality of mobile computing devices associated with a plurality of commuters.

Generally, in public transit systems, price paid for availing a transportation service in terms of tickets is either fixed or priced per travel leg or the distance traveled. This type of pricing scheme is beneficial when the demand is balanced. However, there may be a scenario whereby there is a surge in demand, for example, during peak times, and the supply of vehicles (such as buses, shared cabs, and/or the like) for transportation services is not able to match the demand. One factor that may contribute to such an imbalanced demand is that the passengers adopt a strategy to minimize their travel time by boarding the first vehicle that arrives, even if the vehicle is overcrowded. Therefore, there is an uneven load across the vehicles running along a route, which in turn decreases the operational efficiency of the transit network.
In such scenarios, the public transit systems may adopt various pricing schemes, such as surge pricing or discount offers, for the vehicles to match the demand to the supply. In such pricing schemes, the price for availing the transportation service is varied dynamically for every passenger at same route. For example, two seats in a vehicle may be charged differently to two persons traveling from the same source to the same destination. Nevertheless, the supply is matched to the demand by use of such pricing schemes but the revenue generated by the public transit systems is adversely affected. Thus, an automatic and robust technique is required that not only matches the supply to the demand but also generates optimal revenue for the public transit systems.
Further limitations and disadvantages of conventional and traditional approaches will become apparent to one of skill in the art, through comparison of described systems with some aspects of the present disclosure, as set forth in the remainder of the present application and with reference to the drawings.

Method and system for real time management of transportation services


The present invention relates to automatic registration and tracking of the eyes of at least one subject. An optical system, including a lens structure, a mask and an image sensor, receives incoming light from a scene containing the subject and directs at least a portion of this light towards the image sensor, which registers spatially distributed light and thus produces primary data. The mask is to alter a basic optical transfer function of the lens structure and the image sensor into an enhanced optical transfer function, which is substantially less sensitive to variations of an unknown distance between the optical system and the subject than the basic optical transfer function. The processing unit is to receive the primary data and process this data to produce resulting eye-tracking data representing a position estimate of the at least one eye and/or a gaze direction for the at least one eye.

The present invention relates generally to automatic eye tracking wherein the tracking precision is enhanced based on an optical-transfer-function modifying mask, which enables the eye tracker to work within a relatively large range of distances. More particularly the invention relates to a system according to the preamble of claim 1 and a method according to claim 14. The invention also relates to a computer program according to claim 23 and a computer readable medium according to claim 24.
The concept of eye tracking is well known in the art, and a number of different techniques have been developed for accomplishing automatic eye and gaze tracking. In the area of remote, non-obtrusive eye tracking, the most commonly used designs are based on pupil center corneal reflection (PCCR) methods. The basic idea behind this approach is to use at least one light source, and by means of a camera, capture a series of images of the eye. In each image the light source's reflection, the glint, in the cornea and the pupil are identified. A vector defined from the glint to the center of the pupil is then used to estimate the eye's gaze direction. Furthermore, within the PCCR-eye-tracking field there exist two main strategies to identify the pupil in the above-mentioned images. The light source may be positioned as close as possible to the camera's optical axis. This results in that a part of the eye's retina illuminated by the light source reflects light back into the camera, and hence the pupil appears bright in the registered images. Tracking solutions based on this strategy are therefore categorized as bright-pupil (BP) PCCR. Alternatively, the light source can be positioned at a distance from the camera's optical axis. As a result, essentially no light from the light source will be reflected via the retina into the camera, and the pupil appears dark in the registered images. Tracking solutions based on this strategy are therefore categorized as dark-pupil (DP) PCCR.
Whether BP- or DP-PCCR is preferable depends on i.a. the ambient light conditions, the subject's age and gender because these factors influence the pupil area. Moreover, the BP response is highly influenced by the ethnicity of the person whose eyes are being tracked. For instance, it has been found that Hispanics generally have a very strong BP response and Caucasians have a somewhat weaker BP response, however still fair enough. Nevertheless, Asians in many cases have an in adequate BP response. Hence, in order to ensure a reliable eye tracking, a combination of BP- and DP-PCCR tracking is often desirable.
The published International Patent Application WO 2004/045399 describes a system wherein the eyes' positions and gaze directions are detected and tracked. The system includes a camera and a number of light sources, which are distributed around a display, e.g. a computer screen. By sequentially illuminating a subject viewing the display with light from different light sources it is possible to alternatively detect the eyes' position and the gaze direction. However, in order to perform this evaluation, the camera must generate data of high image quality. This, in turn, requires high-class optics, a high-performance image sensor and/or well-controlled light conditions. It is also very important that the subject's eyes remain in focus during the tracking procedure. To this aim, the camera must either be equipped with an auto-focus arrangement, or operate with an optical system that has a comparatively small numerical aperture (i.e. a high F-number) to accomplish a sufficiently large depth of field. The former alternative renders the camera complex, heavy and expensive, while the latter alternative further increases the performance requirements on the image sensor, which is a parameter that also translates into cost.
The U.S. Pat. No. 5,748,371 discloses a system for increasing the depth of field and decreasing the wavelength sensitivity and the misfocus-producing aberrations of the lens of an incoherent optical system. This technique is referred to as wavefront coding. Here, a special purpose optical mask is included in the incoherent optical system. The mask alters the optical transfer function, such that it remains essentially constant within some range from the in-focus position of the unaltered system. Signal processing of a resulting intermediate image undoes the optical transfer modifying effects of the mask, which provides an in-focus image over an increased depth of field. Although this system is efficient in terms of enabling a long focus range based on relatively simple and low-cost optics and sensors, the design is not well suited for direct implementation in an automatic eye tracking system. Namely, here, eye-tracking specific image parameters, such as eye positions and gaze directions, must be derivable with very high accuracy, whereas essentially all other image data may be discarded. For example, when a rough estimation of the eyes' position has been made the eye-tracking camera normally zooms in (optically, or digitally) towards this position, and/or selects a so-called region of interest (ROI) on the image sensor around this position, to improve the gaze tracking precision and/or reduce the data rate to the image processor. Nevertheless today, there is no wavefront-coding based design, which is adapted to enable any operations of this kind.

Eye tracker having an extended span of operating distances


An electrical connector shield is provided that includes a metal shield member, a dielectric spacer, and a fastener for fastening the shield member to a first connector. The shield member has a first section adapted to be connected to the first connector and a second section offset from the first section and spaced from the first connector to thereby form a second connector receiving area. The shield member is suitably sized and shaped to shield at least one substantially entire side of both of the first and second connectors when connected to each other.

1. Field of the Invention
The present invention relates to electrical connectors and, more particularly, to an electrical connector with a controlled impedance shield.
2. Prior Art
There are various different types of shielded electrical connectors known in the prior art including those disclosed in U.S. Pat. Nos. 5,112,251; 5,094,627; 5,059,140; 5,035,631; 4,959,024; 4,853,659; 4,806,109; 4,678,260; and 3,474,377. However, as new high speed connectors are being developed, there has emerged a need for an improved shield for electrical connectors that can enhance system performance by controlling impedance with higher inductance ground return paths.
Therefore, it is an object of the present invention to provide a new and improved electrical connection system that has enhanced controlled impedance characteristics.

Controlled impedance shield for an electrical connector


A line driver is coupled by a pair of signal lines to a receiver. Preprocessing circuitry, for processing signals arriving on the pair of signal lines at the receiver, includes regulating circuitry for regulating the voltage between the signal lines between predetetermined limits and thereby modifying the sensitivity of the system to compensate for changes in line conditions and reject interference when the line driver is powered down. The regulating means includes: bias circuitry, for putting a bias on the signal passing through to the receiver, so as to hold the receiver input away from the triggering voltage level so that it is not triggered by noise; and bias limiting circuitry, responsive to signals from the driver so as to limit or reduce the effective bias, so that the sensitivity of the system to true signals from the driver is not reduced below a desired level. A resistor is connected between the two signal lines. A current regulating circuit includes circuitry for feeding a current through the resistor; and, for each signal line, there is current adjustment circuitry, responsive to the conditions on the signal lines for adjusting the current passing through the corresponding end of the resistor.

The present invention relates to the suppression of interference on signal lines.
In the computer field, there are many situations in which signals have to be transmitted between different units of equipment. One common signalling technique uses DC signalling. This technique is commonly used where the distance between the two units of equipment is in the region of a meter up to around 1000 meters, and the bit rate is not excessively high.
This technique is largely free of interference if a single channel (of say 8 lines in parallel) is operated continuously. However, a problem can arise if the channel is not always in operation but the circuitry at the receiving end is left turned on. Interference can be generated on the channel, and this may be large enough to produce false triggering of the receiving circuitry.
Considering this in more detail, the receiving circuitry often has to be left turned on permanently, since it may not be known when the unit at the transmitting end will be in operation and it will not be feasible for the receiving circuitry to be turned on and off with the transmitting unit. A typical example is a microcomputer or workstation coupled to a host computer located elsewhere in a large building. The host computer has to keep its receiving circuitry permanently operating, while the various units to which it is coupled are powered up and powered down at unpredictable times.
The present signalling technique is effective at distances of up to around 1000 m. The signals are carried by a signal line which is referenced to a common return or ground line. The signal line is driven by a driver circuit, and the output impedance of such a driver circuit when powered own is typically high. The voltage on a signal line is therefore largely governed by the receiver circuit when the driver is powered down. However, variations in the local ground voltage between the two locations will be imposed on the return line at the driver end. Thus such local ground voltage fluctuations will appear between the signal and return lines at the receiver.
Also, it will often happen that the lines of two or more channels (between the same or different units) will run close to each other for substantial distances. There will then be substantial capacitive coupling between the lines of the different channels. Since the output impedance of a powered down driver is high, this can induce substantial voltages on the lines of a powered down channel. This cross-coupling will thus also appear at the receiver of a powered down channel.
There are various recognized standards for this type of transmission system. These specify, among other things, the sensitivity of the receivers. This sensitivity is such that interference (from either of these causes) can easily cause false triggering of the receivers of a powered down channel. This is clearly undesirable. Although the receiving unit can be designed to detect such false triggering, e.g. by detecting that it violates system protocols, this makes the system design more complicated, and incurs the overhead of processing these false signals (which are normally treated as attempts at logging into the system).


A method for modulating in a cell the expression of one or more genes involved in the biosynthesis of a metabolite or a precursor for this metabolite by inserting into a cell a nucleotide sequence coding for a transcription factor comprising an AP2 DNA-binding domain, and/or by modifying the expression of a nucleotide sequence coding for such a transcription factor already present in the cell is provided. The method is useful for enhancing the biosynthesis of secondary metabolites in plants such as alkaloids including terpenoid indole alkaloids. Also provided is a method for enhancing stress tolerance in plants by the use of such transcription factors.

Generally, two basic types of metabolites are synthesised in cells, i.e. those referred to as primary metabolites and those referred to as secondary metabolites. A primary metabolite is any intermediate in, or product of the primary metabolism in cells. The primary metabolism in cells is the sum of metabolic activities that are common to most, if not all, living cells and are necessary for basal growth and maintenance of the cells. Primary metabolism thus includes pathways for generally modifying and synthesising certain carbohydrates, proteins, fats and nucleic acids, with the compounds involved in the pathways being designated primary metabolites.
In contrast hereto, secondary metabolites usually do not possess a basal function in cell growth and maintenance. They are a group of chemically very diverse products that often have a restricted taxonomic distribution. Secondary metabolites normally exist as members of closely related chemical families, usually of a molecular weight of less than 1,500, although some bacterial toxins are considerably larger. Two examples of fungal cell secondary metabolites are penicillin and ergotamine.
Plant metabolites include a diverse array of chemically unrelated compounds such as carbohydrates and lipids (e.g. mono-, oligo- and polysaccharides, sugar alcohols, organic acids, fatty acids and lipids, acetylenes and thiophenes), nitrogen-containing compounds (e.g. amino acids, amines, glycosides, glucosinolates, purines, pyrimidines and polypeptides) of which most, but not all, generally are referred to as primary metabolites. Accordingly, some compounds such as fatty acids, sugars and steroids may e.g. be categorised both as primary metabolites and secondary metabolites (see e.g. Dewick, P. M., 1997, Medicinal Natural Products A Biosynthetic Approach, John Wiley & Sons, Chichester).
Secondary plant metabolites include e.g. alkaloid compounds (e.g. terpenoid indole alkaloids and indole alkaloids), phenolic compounds (e.g., quinones, lignans and flavonoids), terpenoid compounds (e.g. monoterpenoids, iridoids, sesquiterpenoids, diterpenoids and triterpenoids). In addition, secondary metabolites include small molecules (i.e., having a molecular weight of less than 600), such as substituted heterocyclic compounds which may be monocyclic or polycyclic, fused or bridged.
Many plant secondary metabolites have value as pharmaceuticals, food colours, flavours and fragrances. Plant pharmaceuticals include e.g.: taxol, digoxin, colchicine, codeine, morphine, quinine, shikonin, ajmalicine and vinblastine. Examples of secondary metabolites that are useful as food additives include anthocyanins, vanillin, and a wide variety of other fruit and vegetable flavours and texture modifying agents.
Plant secondary metabolites such as terpenoid indole alkaloids (TIA) represent a class of pharmaceutically useful compounds which naturally occur in many plant species.
Some plant secondary metabolites are linked to plant or plant cell defence mechanism and may e.g. confer to the plant antimicrobial activity, protection against UV light, herbivores, pathogens, insects and nematodes, and the ability to grow at low light intensity.
There are numerous examples of the application of plant secondary metabolites such as TIA's in medicine. The monomeric alkaloids serpentine and ajmalicine found in Catharanthus roseus are e.g. used as tranquillisers and to reduce hypertension, respectively. The dimeric alkaloids vincristine and vinblastine, also found in C. roseus, are potent antitumor drugs. Camptothecin, a monomeric TIA found in Camptotheca acuminata, also possesses anti-tumor activity. Quinine from Cinchona officinalis is used in malaria treatment.
However, a major problem associated with the industrial use of the above metabolites is that only very small or variable amounts of these compounds are present in plants. The recovery of useful metabolites from their natural sources is thus in many instances difficult due to the enormous amounts of source material which may be required for the isolation of utilisable quantities of the desired products. As an example, over 500 kg of Catharanthus roseus is needed to obtain 1 g of vincristine. Extraction is both costly and tedious, requiring large quantities of raw material and extensive use of chromatographic fractionation procedures. The low levels of these compounds in plants may also imply that many of the compounds are not detected when performing normal screening procedures, hence many unknown compounds may exist.
Biosynthesis of TIA compounds proceeds in most plants via many enzymatic steps. TIA compounds consist of an indole moiety provided by tryptamine and a terpenoid portion provided by the iridoid glucoside compound secologanin. Tryptamine is derived from primary metabolism by a single enzymatic conversion of the amino acid tryptophan, a reaction catalysed by the enzyme tryptophan decarboxylase (TDC) (EC 22.214.171.124). The biosynthesis of secologanin requires a number of enzymatic conversions of which the first step is the hydroxylation of geraniol by the enzyme geraniol 10-hydroxylase (G10H). Tryptamine and secologanin are condensed by the enzyme strictosidine synthase (STR) (EC 18.104.22.168) to form strictosidine, which is the general precursor of all terpenoid indole alkaloids found in plants. The first enzymatic conversion of strictosidine into strictosidine aglucon is catalysed by strictosidine-β-D-glucosidase (SGD) (EC 220.127.116.11). Many different enzyme activities convert strictosidine aglucon into the large variety of terpenoid indole alkaloid end products.
The best progress on molecular characterisation of the terpenoid indole alkaloid pathway has been made with C. roseus or Madagascar periwinkle, a member of the Apocynaceae family. C. roseus cells have the genetic potential to synthesise over a hundred terpenoid indole alkaloids. The biosynthesis of terpenoid indole alkaloids is strongly regulated, and depends on plant cell type and environmental conditions. Their biosynthesis is e.g. induced by fungal elicitors, jasmonates and auxin starvation. Many monomeric TIA compounds are found in all plant organs, but vindoline and vindoline-derived dimeric alkaloids are only found in chloroplast-containing plant tissues.
Until now, only a limited number of genes coding for enzymes involved in terpenoid indole alkaloid biosynthesis have been cloned, such as cDNA clones encoding STR and TDC isolated from C. roseus. In addition, cDNA clones for NADPH:cytochrome P450 reductase (CPR), which is essential for the G10H-catalysed reaction, and SGD have been isolated.
Gene expression studies by the present inventors have shown that the regulation of terpenoid indole alkaloid biosynthesis is controlled largely, if not uniquely, at the level of the expression of biosynthetic genes. Accordingly, analysis of the expression of the terpenoid indole alkaloid biosynthetic genes Tdc and Str1 showed that their expression is low, especially in cell cultures. It was found, that the level of gene expression is likely to be limiting for alkaloid production. Overexpression of a single biosynthetic gene (Tdc or Str1) in transgenic C. roseus cells resulted in significantly elevated levels of the corresponding enzyme activity. However, this did not result in elevated alkaloid levels, presumably because many other enzymes are limiting and would need to be overexpressed.
These studies have further demonstrated what is already known, that the genes are coordinately regulated depending on cell type or environmental conditions. Str1 and Tdc mRNA accumulate in suspension-cultured cells after auxin starvation or phosphate starvation, exposure to fungal elicitors or (methyl) jasmonate and their distribution in the plant is developmentally regulated with the highest levels in the roots. In leaves Tdc and Str1 are induced by a UV-B light pulse. Cpr mRNA accumulation is rapidly induced by fungal elicitor.
The observations that mRNA from genes involved in the biosynthesis of TIA compounds such as Tdc and Str1 mRNAs coordinately accumulate in response to fungal elicitors, (methyl)-jasmonate, UV light, auxin depletion, phosphate depletion, and have similar tissue-specific distributions, have led the present inventors to hypothesise that the Tdc and Str1 genes might be controlled by one or more common regulating factor(s) or substance(s). It was further hypothesised that among possible regulating factors, transcription factors could have such a regulating effect.
It is known that certain transcription factors can regulate complex cell differentiation processes in animals involving numerous target genes. A notable example is muscle differentiation, where either one of a set of myogenic bHLH transcription factors (MyoD, myogenin, Myf5, MRF4) in combination with the MADS-domain transcription factor MEF2 induces muscle cell differentiation and switches on numerous muscle-specific genes. Other examples include homeodomain transcription factors in the fruit fly that regulate cell processes resulting in the determination of segment identity.
The pathway that is most extensively studied in plant secondary metabolism at the transcriptional level, is the one leading to the formation of the anthocyanin pigments. The genes encoding flavonoid biosynthetic enzymes are controlled by a combination of two distinct transcription factor species, one of which has homology to the protein encoded by the vertebrate proto-oncogene c-Myb, and the other with the vertebrate bHLH protein encoded by the proto-oncogene c-Myc. These transcription factors bind to specific sequences in the promoters of the target genes.
The DNA-binding domain of plant MYB proteins consists of two, or for some of them, one imperfect repeat(s). The MYC proteins have a bHLH-type (basic helix-loop-helix) DNA-binding domain and recognise variants of the sequence CANNTG. About ten enzymes are involved in the biosynthesis of anthocyanins starting from phenylalanine. In maize, the entire set of genes encoding these enzymes are thought to be regulated coordinately by the Myc gene R and the Myb gene C1 in the aleurone (epidermal layer of the kernel endosperm), and by homologous genes in other parts of the plant.
Overexpression of the maize Lc gene encoding a MYC-type regulatory protein in Petunia upregulated the whole flavonoid biosynthetic pathway starting from Chs and including the earlier and later genes, resulting among others in intensely pigmented leaves. The expression of the general phenylpropanoid genes Pal and C4h was not affected by Lc overexpression, indicating that Lc only regulates structural genes in the flavonoid branch.
Introduction of the maize R and C1 MYC-type regulators in Arabidopsis intensified pigmentation in normally pigmented tissues and induced pigmentation in plant tissues that are normally unpigmented. In maize cell suspension, ectopic expression of C1 and R led to the accumulation of anthocyanins and a number of other related 3-hydroxy flavonoids. In addition, six anthocyanin structural genes that are targets for Cl/R were expressed at high levels in the transgenic cell line.
In the plant Arabidopsis thaliana, it has been shown that overexpression of the transcription factor CBF-1 that belongs to the AP2 domain class transcription factors resulted in coordinate upregulation of a set of cold-regulated genes. However, there are no suggestions that transcription factors of this class may have an effect on the biosynthesis of metabolites in plant cells and other cells.
The present inventors have now discovered that transcription factors having an AP2 DNA-binding domain are highly useful as central regulators of complex metabolite pathways involving numerous target genes for such transcription factors. This discovery has opened up for providing novel effective means of generating novel metabolite compounds, significantly enhancing the yield of commercially valuable metabolite compounds and also for enhancing the tolerance of plants towards exogenous stress factors and conditions.
Besides such activation of metabolic pathways for the production of metabolites, it is also envisaged that the method of the invention may be used for such purposes as:                study of (plant) metabolism, in which the method of the invention may for instance be used to activate the metabolic pathway(s) under investigation;        study of gene expression, including but not limited to expression profiling, in that the method of the invention allows (the simultaneous) overexpression of one or more genes involved in one or more metabolic pathway(s), the expression or gene products of which may then be studied/determined;        to determine whether one or more specific (usually secondary) metabolites are formed in a plant, by enhancing the levels of said metabolites present in and/or formed by the plant (e.g. from a level below the detection limit of the assay/equipment used to a level above said limit);        lowering or removal of unwanted or toxic metabolites present in a plant or plant material;        discovery enzymes or regulators thereof involved in primary or secundary metabolism.
Further applications will become clear to the skilled person on the basis of the description given hereinbelow.

Method of modulating metabolite biosynthesis in recombinant cells


A multiple toilet seat assembly which consists of an adult seat and a child seat with the child seat being formed in an adult seat lid. The child seat has a splash shield as well as a lid that is attached by a vertical pivot enabling the child seat lid to pivot parallel to the adult seat lid. The adult seat lid has a pair of slots and the child seat lid has a stop engageable with the slots to define fully open and fully closed positions of the child seat lid.

1. Field of Invention
The field of invention relates to commode apparatus and more particularly pertains to an improved child commode seat wherein the same is used for both adults and small children.
2. Description of Prior Art
Various commode seat constructions are utilized in prior art for use with children, such as exemplified in U.S. Pat. Nos. 4,461,046 and RE 32,807 to Adams (1984 & 1988) wherein a multiple toilet seat assembly of the type that permits the selective use of an appropriate sized opening for the selective use by a particular individual. Having a lid or cover, a child seat and an adult lid, with multiple splash shields. Both U.S. Pat. Nos. 4,461,046 and RE 322,807 require multiple toilet seats and multiple hinges making this toilet seat costly to manufacture and costly to the consumer. Due to the design of each seating component having an extended lip portion designed to protrude into the lower opening to prevent lateral movement in the seats when in the in-use or operative position would also add considerable amount of labor and materials at the time of manufacture. Also, the needed expense of having to purchase additional bumpers for the toilet seat would add an additional cost to this family toilet seat.
U.S. design 305,357 to Ritzer (1991) wherein multiple toilet seat assembly is used without the use a splash shield, thus permitting liquid to come in contact with the adult commode seat. This toilet seat assembly also utilizes two separate seats and a lid.
U.S. Pat. No. 5,182,818 to Nawoj (1993) wherein a child seat insert apparatus consisting of a central tubular conduit projecting down from the seat outer edge, comprising of an "S" shaped interior cavity splash shield with several mesh antisplash sock coverings to cover the splash shield. The need for the tubular conduit projecting down from the seat would increase the amount of material needed for manufacturing the child commode seat apparatus, thus increasing the cost to the public. The need for the mesh antisplash sock coverings for the splash shield would cause an unsanitary condition in use as well as in replacing the sock covering.
U.S. design 309,176 to Sessions (1990) wherein a multiple toilet seat assembly is used with the use of a small splash shield. The manufacture of the multiple seat apparatus would be costly to manufacture and costly to the consumer.
U.S. design 333,345 to Strahan (1993) wherein a combination toilet seat does not provide a splash shield and the child's seat does not adequately cover the commode, thus enabling the child's legs to come into contact with the top rim of the commode. Also, the adult seat straddles the child seat in the rear, thus weakening the adult seat structure.
U.S. design 306,899 to Miller (1990) wherein a multiple toilet seat assembly is used with the use of a small splash shield with the small seat nestled inside the open cover. This design uses two toilet seats and a lid, as well as a special hinge assembly which would increase the cost and resale to the consumer.
As such, it may be apparent that there continues to be a need for a new and improved family toilet seat as set forth by the instant invention which addresses the problem of ease of use, cost of manufacture as well as the effectiveness in construction in the proper orientation of a child in the use of a toilet structure and in this respect, the present invention substantially fulfills the needs for the adult as well as the child.


A machining tool of the present invention is used for finishing an end face having an arcuate cross section on a machined portion of a workpiece. A machining tool 30 has a tool body 31 and a cutting portion 32 provided integrally on a tip of the tool body 31. The cutting portion 32 is formed in substantially semispherical shape, and has a substantially spherical flank 33 and a substantially flat rake 35 joined to the flank 33 via an arcuate cutting edge 34. In the state that the cutting edge 34 abuts the arcuate end face of the rotated workpiece, the arcuate end face is finished using the machining tool 30 by varying the position of the cutting edge 34 abutting the arcuate end face in a circumferential direction.

A pneumatic circuit has a pressure control valve for reducing high-pressure air from a compressor to supply it to an actuator and a proportional control valve for controlling air quantity supplied to the actuator. The pneumatic circuit also has an opening/closing control valve for opening and closing an air passage and a directional control valve for varying an air supply direction. The control valves, such as the opening/closing control valve, used for the pneumatic circuit are of the type to bring a valve element made of rubber or metal into contact with an annular valve seat at a right angle thereto. There are such control valves of the poppet and diaphragm types.
As described in Japanese Patent Application Laid-Open publication No. 2002-286157, in the opening/closing control valve of the diaphragm type, a control valve element, that is, a valve housing, is formed with an inflow passage and an outflow passage, the inflow passage and the outflow passage communicate with each other through a communication hole formed in the valve housing, and the opening end of the communication hole has an annular valve seat. A diaphragm moving to the position in which it is brought into contacts with the valve seat to close the communication hole and to the position in which it moves away from the valve seat to open the communication hole is fitted as a valve member in the control valve element.
In the control valves of the poppet and diaphragm types, used for the pneumatic circuit, in order not to cause air leakage between the valve seat and the valve member in the state that the valve member is in contact with the valve seat, the contact surface of the valve seat needs to be machined at high accuracy. In addition, in the control valve used for the pneumatic circuit, in order not to cause air leakage between the valve seat and the valve member, the valve seat is annularly projected to the valve member and its surface is formed in arcuate shape.
To machine an end face having an arcuate cross section on the annular valve seat of the valve housing, conventionally, after the communication hole is cut into the valve housing a drill, the end face of the valve seat is cut using a cutting tool. As described in Japanese Patent Application Laid-Open publication No. 64-64702, there is a cutting tool for superfine cutting.


In an example method, a device presents a user interface on a touch sensitive surface of the device. The user interface includes a first portion for displaying a sequence of code and a second portion for displaying suggested segments of code. The device receives one or more character inputs in the first portion of the user interface, and determines, based on the one or more character inputs, one or more suggested segments of code. The device presents the one or more suggested segments of code in the second portion of the user interface, and receives a touch input selecting a particular suggested segment of code. The device inserts the selected suggested segment of code into the first portion of the user interface.

Learning how to program a computer to perform tasks from a textbook can be challenging for many students. To learn how to code quickly, a student will often write code, compile the code, and execute the code on a computer to see if they get the expected results. If the results are unexpected, the student will "debug" the code, compile the code, and execute the compiled code on the computer again. This learning process can be frustrating to students due to the delay between writing, compiling, and executing the code and seeing the results. Most students would prefer to see the results in near real-time in an interactive learning environment. The computers that students are learning to program come in a variety of form factors, including smartphones, smart watches and tablet computers. The use of touch-based tablet computers in classrooms is becoming ubiquitous due to their portable nature and ease of use. Writing programming constructs using touch gestures presents a new challenge to designers of user interfaces for touch-based computers.

Touch-based interactive learning environment


An electrical connector assembly comprises a receptacle connector having a receptacle housing and a plurality of receptacle contacts, and a plug connector engaging with the receptacle connector. Said receptacle housing defines a space and a plurality of alternate channels and slots in two lateral sidewalls beside the space. Said receptacle contacts each has a retaining portion and a first elastic portion with a first contacting portion, which are both transversely extending and respectively disposed in the slot and the channel of the receptacle housing, with the first contacting portion exposed in the space. The plug connector inserts into the space of the receptacle connector and electrically contacts with the receptacle contacts.

1. Field of the Invention
The present invention is generally related to an electrical connector assembly for connecting two printed circuit boards.
2. Description of Related Art
It is well known that a board-to-board connector assembly is widely used for connecting two printed circuit boards (PCBs) together and includes a plug connector mounted on a PCB and a receptacle connector mounted on another PCB and electrically connected with the plug connector.
U.S. Pat. No. 5,975,916 discloses a connector assembly including a plug connector and a receptacle connector, the plug connector has an elongated first housing and a plurality of first contacts assembled to the first housing, a receptacle connector has a second housing with a space for receiving the plug connector and a plurality of second contacts fixed in the second housing. Each of the first contact and the second contact is formed with a soldering portion for being soldered to corresponding printed circuit boards, a retaining portion and a contacting portion. The retaining portion of the second contact is in an inverse U-shape completely abutting the second housing. However, the insertion direction of the retaining portions is same as the insertion of the plug connector into the receptacle connector, so when the plug connector is pulled out from the receptacle connector, the retaining portions of the second contacts may also be pulled along the same direction, and that will lead to unreliable retaining of second contacts and affect the engaging between the second contacts and the first contacts. And once the retaining portions are not retained, the soldering portions will also be pulled from the print circuit board. Otherwise, the contacting portion transversely extends for a certain distance from an end of the U-shaped retaining portion and then upwardly, since the U-shaped retaining portion occupy a certain transverse space, a transverse dimension of the connecting porting is limited and may not has enough elasticity.
Japanese Patent Unexamined Publication. No 2003-323925 discloses another connector assembly including a plug connector and a receptacle connector. The receptacle connector has female contacts, each having a vertical portion, an M-shaped extending portion transversely extending from the vertical portion with a contacting portion in an end and a retaining portion extending from the vertical portion. However, since the retaining portion is upon the extending portion, that will increases a height of the female contact and the receptacle connector.
Hence, am improved connector is required to overcome the disadvantages of the related art.


Grooves are cut into an under pad of a polishing pad assembly formed by an under pad and an over pad. The grooves cause channeling of the over pad so that slurry received on the polishing face of the pad assembly is delivered across the pad assembly's surface in a controlled fashion.

The present invention pertains to a method and system for improving delivery of a slurry across a face of a multilayered polishing pad and, more particularly, to polishing large scale assemblies, for example, those used in the manufacture of large area field emission display devices.
Field emission display (FED) technology, as represented for example by U. S. Pat. No. 5,210,472, the disclosure of which is incorporated herein by reference, utilizes a matrix addressable array of pointed, thin film, cold field emission cathodes in combination with a phosphor luminescent screen. The FED incorporates a column signal to activate a column switching driver and a row signal to activate a row switching driver. At the intersection of both an activated column and an activated row, a grid-to-emitter voltage differential exists sufficient to induce a field emission, thereby causing illumination of the associated phosphor of a pixel on the phosphorescent screen. Extensive research has recently been made into the manufacture of an inexpensive, low power, high resolution, high contrast, full color FED.
However, the known FEDs have several structural shortcomings; first and foremost has been their size. It has been possible to produce FEDs of rather small area, but it has theretofore been difficult to produce an FED of sufficient area, for example for the display of a laptop computer or a hand held portable television set. One of the problems in making larger FEDs is producing a uniform surface on the substrate. The present invention addresses this problem.
Fibrous polishing pads per se are well known. For example, U.S. Pat. Nos. 4,728,552; 4,841,680; 4,927,432; and 4,728,552, each disclosure of which is incorporated herein by reference, all describe poromeric pads made from microporous materials. Likewise polishing slurries are known; see for example U.S. Pat. Nos. 4,959,113; 5,264,010; 5,382,272; 5,389,352; and 5,391,258, the disclosures of which are also incorporated herein by reference. A suitable apparatus for planarization of large area substrates for use in field emission displays, and which would benefit from the present invention, is described in U.S. Pat. No. 5,257,478, the disclosure of which is also incorporated herein by reference.
Microchannelling in polishing is a problem that can cause the leading edge of substrates to bind and break. This is true with substrates which have more than one leading edge transition. It becomes even more important when the area to be polished increases and the tolerances decrease. For example, in large area field emission displays, it is important that the substrates be microscopically flat, which means that the surface will have undulations in the range of between about 0.1 and about 4.0 microns from a median plane of the surface. Conventional slurry delivery is concentrated on the edges of a pad without much concern for uniform delivery of the slurry across the face of the surface to be polished. Slurry delivery to the center of larger substrates, of the type contemplated for use in large area field emission display devices, is necessary to accomplish uniform polishing and finish. Thus, there is a need for a method and device to provide for improved polishing and controlled delivery of slurry. It is an object of the present invention to address these needs.

Method and system to increase delivery of slurry to the surface of large substrates during polishing operations


A ratchet device for an electrical component that can be adjusted by rotation, such as a rotary switch or a rotary potentiometer, is provided. The ratchet device includes a leaf spring, resting against a ratchet contour by means of spring pressure, whereby the ratchet contour is applied on an outer side of a symmetrical ratchet disc. The leaf spring substantially encloses the ratchet disc, rests diametrically on the ratchet disc, and the ends of the leaf spring have an essentially radial embodiment, the leaf spring being otherwise free to move.

1. Field of the Invention
The present invention relates to a ratchet device for an electrical component that may be adjusted by rotation, in particular a rotary switch or rotary potentiometer, having a leaf spring that contacts a ratchet contour under spring force.
2. Description of the Background Art
Examples of electrical components that may be adjusted by rotation include rotary switches or rotary potentiometers, such components being used where frequent adjustment of the operating states or preset values is intended. In such circumstances, a ratchet device makes it easy for an operator to locate operating states, which the ratchet device makes perceptible by tactile and sometimes also audible means during the rotary motion. Particularly in the case of resistors that can be adjusted by rotation, the adjustment is made perceptible by a ratchet device. The ratchet means of a ratchet device typically includes a spring element, which generally has a curved projection called a detent projection, and a ratchet disk having one or more adjacent ratchet indentations that has a ratchet contour which cooperates with the detent projection. One of the two ratchet means, either the detent projection or the ratchet contour, is rotationally fixed to an actuator of the relevant component. The other ratchet means, in contrast, is held stationary on the component. The two ratchet means slide relative to one another during the rotary motion, and in the process the ratchet means produce tactile ratchet indications.
Known from German utility model 295 01 692 is a ratchet device consisting of an outer housing and an inner rotor, which rotor is connected to a rotationally adjustable operating element, and a leaf spring arranged in the interior of the rotor. At one point on the rotor, a detent projection of the leaf spring projects out of the cylindrical rotor wall into a ratchet contour located on the inner circumferential surface of the outer housing. During rotary motion, the detent projection initially twists and is pushed back by the rotor wall. When the detent projection snaps into a recess of the ratchet contour, the leaf spring immediately relaxes and strikes the side wall. This impact is audible.
Another arrangement of this generic type of a ratchet device in a component, which may be adjusted by rotation is disclosed in DE 195 05 737. In order to facilitate the defined setting of an angle of rotation, two flat springs are clamped on the inside floor of the housing base. These springs have convexities to interact with a ratchet disk. On its periphery the ratchet disk has, associated with each spring, two corresponding ratchet notches for the adjustable angle of rotation. In addition, the ratchet disk has on its peripheral surface a ramp for each flat spring; when the switch cam is rotated counterclockwise, these ramps provide a return torque to automatically return the switch cam to its base position. In addition, two stops are provided on the ratchet disk which interact with a projection formed on the inside floor of the housing base to limit the rotation of the switch cam.

Ratchet device for an electrical component which may be adjusted by rotation


This invention relates to neurotrophic low molecular weight, small molecule N-oxides of heterocyclic esters amides, thioesters, and ketones having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

1. Field of Invention
This invention relates to neurotrophic low molecular weight, small molecule N-oxides of heterocyclic esters having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
2. Description of Related Art
The term immunophilin refers to a number of proteins that serve as receptors for the principal immunosuppressant drugs, cyclosporin A (CsA) FK506 and rapamycin. Known classes or immunophilins are cyclophilins and FK506 binding proteins, or FKBPs. Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKBP12. These immunophilin-drug complexes interface with various intracellular signal transduction systems, especially the immune and nervous systems.
Immunophilins are known to have peptidyl-prolyl isomerase (PPIase) , or rotamase, enzyme activity. It has been determined that rotamase enzyme activity plays a role in the catalyzation of the interconversion of the cis and trans isomers of peptide and protein substrates for the immunophilin proteins.
Immunophilins were originally discovered and studied in the immune tissue. It was initially postulated by those skilled in the art that inhibition of the immunophilins"" rotamase activity leads to inhibition of T-cell proliferation, thereby causing the immunosuppressive activity exhibited by the immunosuppressant drugs, such as cyclosporin A, FK506 and rapamycin. Further study has shown that the inhibition of rotamase activity, in and of itself, does not result in immunosuppressive activity. Schreiber et al., Science, 1990, vol. 250, pp. 556-559. Instead, immunosuppression appears to stem from the formulation of a complex of immunosuppressant drugs and immunophilins. It has been shown that the immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al., Cell, 1991, vol. 66, pp. 807-815. In the case of FKBP-FK506 and cyclophilin-CsA, the immunophilin-drug complexes bind to the enzyme calcineurin and inhibit the T-cell receptor signalling which leads to T-cell proliferation. Similarly, the immunophilin-drug complex of FKBP-rapamycin interacts with the RAFT1/FRAP protein and inhibits the IL-2 receptor signalling.
Immunophilins have been found to be present at high concentrations in the central nervous system. Immunophilins are enriched 10-50 times more in the central nervous system than in the immune system. Within neural tissues, immunophilins appear to influence nitric oxide synthesis, neurotransmitter release and neuronal process extension.
It has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite outgrowth in PC12 cells and sensory neurons, namely dorsal root ganglion cells (DRGs) Lyons et al., Proc. of Natl. Acad. Sci., 1994, vol. 91, pp. 3191-3195. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury.
Surprisingly, it has been found that certain compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects. Furthermore, these rotamase inhibitors are devoid of immunosuppressive activity. These findings suggest the use of rotamase inhibitors in treating various peripheral neuropathies and enhancing neuronal regrowth in the central nervous system (CNS). Studies have demonstrated that neurodegenerative disorders such as Alzheimer""s disease, Parkinson""s disease, and amyotrophic lateral sclerosis (ALS) may occur due to the loss, or decreased availability, of a neurotrophic substance specific for a particular population of neurons affected in the disorder.
Several neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer""s disease results from a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat Senile Dementia Alzheimer""s Type (SDAT) patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain derived growth factor, glial derived growth factor, ciliary neurotrophic factor and neurotropin-3, to increase the survival of degenerating neuronal populations.
Clinical application of these proteins in various neurological disease states is hampered by difficulties in the delivery and bioavailability of large proteins to nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity. However, when administered chronically, immunosuppressant drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al., J. Am. Soc. Nephrol., 1991, 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina, such as non-localized headaches (De Groen et al., N. Engl. J. Med., 1987, 317:861); and vascular hypertension with complications resulting therefrom (Kahan, et al., N. Engl. J. Med., 1989, 321:1725)
In order to prevent the side effects associated with use of the immunosuppressant compounds, the present invention provides non-immunosuppressive compounds containing small molecule FKBP rotamase inhibitors for enhancing neurite outgrowth, and promoting neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated, including: peripheral nerve damage caused by physical injury or disease state such as diabetes; physical damage to the central nervous system (spinal cord and brain); brain damage associated with stroke; and neurological disorders relating to neurodegeneration, such as Parkinson""s disease, SDAT (Alzheimer""s disease), and amyotrophic lateral sclerosis.
The present invention relates to neurotrophic low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity. A key feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity in addition to their neurotrophic activity. Another significant feature is the novel addition of the oxidation of specific amine groups to the corresponding N-oxide to provide an unexpected increase in bioavailability and potency as compared to compounds lacking the N-oxide group.
Specifically, the present invention relates to a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH or NR1 in any chemically stable oxidation state;
W is O, S, CH2, or H2;
R is a C1-C6 straight or branched chain alkyl or alkenyl group optionally substituted with C3-C9 cycloalkyl, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, or Ar1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, and where Ar1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hyrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C5 straight or branched alkyl or alkenyl, C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or C(R1)2;
Y is a direct bond, or a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C3-C8 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms or said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR2, S, SO, or SO2, where R2 is selected from the group consisting of hydrogen, (C3-C4)-straight or branched chain alkyl, (C3-C4) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; and
Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C5 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C3-C8 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR1, S, SO, or SO2; and,
R1 is hydrogen, (C1-C4) -straight or branched chain alkyl, (C3-C4) -straight or branched chain, alkenyl or alkynyl, or R1 is Y-Z, as defined above.
Another preferred embodiment of this invention is a compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
E, F, G and H are independently CH2, O, S, SO, SO2, NH or NH1;
W is C, S, CH2, or H2;
R is a C1-C6 straight or branched chain alkyl or alkenyl group optionally substituted with C3-C8 cycloalkyl, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, or Ar1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, and where Ar1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from one group consisting of hyrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or alkenyl, C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or C(R1)2;
Y is a direct bond, or a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C1-C8 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms or said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR2, S, SO, or So2, where R2 is selected from branched chain alkyl, (C3-C4) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; and
Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C5 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; wherein the heterocyclic ring contains 1-5 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C3-C8 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR1, S, SO, or SO2; and,
R1 is hydrogen, (C1-C4) -straight or branched chain alkyl, (C3-C4) -straight or branched chain alkenyl or alkynyl, or R1 is Y-Z, as defined above.
Another preferred embodiment s a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH or NR1;
W is O, S, CH2, or H2;
R is a C1-C6 straight or branched chain alkyl or alkenyl group optionally substituted with C3-C8 cycloalkyl, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, or Ar1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, and where Ar1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hyrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or alkenyl, C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or C(R1)2;
Y is a direct bond, or a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C1-C3 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C1C4 alkyl, C1-C4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR2, S, SO, or SO2, where R2 is selected from the group consisting of hydrogen, (C1-C4) -straight or branched chain alkyl, (C1-C4) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; and
Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C3-C8 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with C, NH, NR1, S, SO, or SO2; and,
R1 is hydrogen, (C1-C4) -straight or branched chain alkyl, (C3-C4) -straight or branched chain alkenyl or alkynyl, or R1 is Y-Z, as defined above.
A further particularly preferred embodiment of this invention is a compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
n is , 1, 2 or 3 forming a 5-7 member heterocyclic ring;
W is O, S, CH2, or H2;
R is a C1-C6 straight or branched chain alkyl or alkenyl group optionally substituted with C3-C8 cycloalkyl, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, or Ar1, where said alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may be optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, and where Ar1 is selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, having one to three substituents which are independently selected from the group consisting of hyrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or alkenyl, C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or C(R1)2;
Y is a direct bond, or a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C3-C8 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR2, S, SO, or SO2, where R2 is selected from the group consisting of hydrogen, (C1-C4)-straight or branched chain alkyl, (C3-C4)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group; and
Z is an aromatic or tertiary alkyl amine oxidized to a corresponding N-oxide, wherein the aromatic amine is Ar oxidized to a corresponding N-oxide where Ar is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in none to three position(s) with halo, hydroxyl, nitro, trifluoromethyl, C1C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the individual ring sizes are 5-6 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) selected from the group consisting of O, N, S, and a combination thereof wherein at least one of the heteroatoms is N, and wherein the alkyl amine is oxidized to a corresponding N-oxide where alkyl is a C1-C6 straight or branched chain alkyl or alkenyl which is optionally substituted in one or more positions with C1-C6 straight or branched chain alkyl or alkenyl, or C1-C9 cycloalkyl, or C5-C7 cycloalkenyl, or hydroxyl, or carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl, cycloalkyl, or Ar group is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, or hydroxy, or carbonyl oxygen, or wherein any of the carbon atoms of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar group is optionally replaced with O, NH, NR1, S, SO, or SO2; and,
R1 is hydrogen, (C1-C4)-straight or branched chain alkyl, (C3-C4)-straight or branched chain alkenyl or alkynyl, or R1 is Y-Z, as defined above.
In preferred embodiments, Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl.
Particularly preferred compounds of the present invention include:
3-(2-3Pyridyl)-1-propyl(2S)-1-(3,3-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(2-Quinolyl)-1-propyl(2S)-1-(3,3-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinecarboxylate, N-Oxide;
3-(3-Quinolyl)-1-propyl(2S)-1-(3,3-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide; and
3-(4-Quinolyl)-1-propyl(2S)-1-(3,3-Dimethyl-1,2-dioxo-pentyl)-2-pyrrolidinecarboxylate, N-oxide.
The present invention also relates to a pharmaceutical composition comprising a neurotrophically effective amount of the compound of formula I, II, III, or IV, and a pharmaceutically acceptable carrier.
The present invention further includes methods of using the compounds of the present invention. One preferred embodiment includes a method of stimulating damaged neurons in an animal, comprising:
administering to the animal neurotrophically effective amount of a compound of the present invention.
Another preferred embodiment of the present invention includes a method of promoting neuronal regeneration in an animal, comprising:
administering to the animal a neurotrophically effective amount of a compound of the present invention.
Yet another embodiment of the present invention includes a method of preventing neurodegeneration in an animal, comprising:
administering to the animal a neurotrophically effective amount or a compound of the present invention.
Another embodiment includes a method of treating neurological disorders in an animal, comprising:
administering to the animal a neurotrophically effective amount of a compound of the present invention.
The neurological disorders for which the compounds of the present invention are particularly useful are selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration. Examples of neurological disorders relating to neurodegeneration are Alzheimer""s Disease, Parkinson""s Disease, and amyotrophic lateral sclerosis.

N-oxides of heterocyclic esters, amides, thioesters, and ketones


A method for providing telecommunications services in an environment in which a plurality of telecommunications systems operate according to different standards (WLAN, UMTS) and are reachable from a terminal (T) in an integrated manner, wherein at least one of said services can be provided by more systems. Upon the provision request for the above-cited service, the method according to the invention envisages the steps of: —verifying the availability for the provision of the requested service, of at least a first (WLAN) and a second (UMTS) system, and —selecting, in an automatic and dynamic way, one between at least said first (WLAN) and said second (UMTS) system for the provision of the service being requested.

As an example—which should however not be regarded as limiting the scope of the invention, that is fully general—the two telecommunications systems may be two mobile communication systems working according to the UMTS (Universal Mobile Telecommunications System) standard and according to a Wireless Local Area Network (WLAN) standard such as for instance the standard currently denoted as 802.11.
In the document titled "Stand-Alone Data-Cells for UMTS", presented as Tdoc FEW-0032/01 paper at the 3GPP Future Evolution Workshop held on Oct. 18-19 2001 at Helsinki (Finland), there is described an architectural solution allowing the implementation of a full integration of both systems; such an integration is performed in the radio mode and offers the possibility of an optimum management of the network.
Closely related topics are discussed in the document "Location-based Radio Resource Management in Multi Standard Wireless Network Environments" by M. Hildebrand, G. Cristache, K. David and F. Fechter presented at the IST Mobile & Wireless Telecommunications Summit 2002, held at Thessaloniki (Greece) on Jun. 17-19, 2002. This document emphasizes among other things the importance of defining solutions aimed at improving the throughput of such systems and providing the user with the best service quality.

Method for providing telecommunications services, related system and information technology product