An isolated peptide comprising the sequence (I): TPA-Asn-Leu-His-Phe-Cys-Gln-Leu-Xaaa-Cys-Lys-Ser-Leu-Gly-Leu-Leu-Gly-Arg-Cys-Xaab-Xaac-Xaad-Xaae-Cys-Ala-Cys-Val-NH2, wherein: TPA represents thiopropionic acid; Xaaa represents Arg, Lys; Xaab represents Ala, Arg; Xaac represents a D-amino acid; Xaad represents Thr, Ser, Asn; Xaae represents phenylalanine or a phenylalanine derivative having the structure (II), where A is absent or represents S, O, NH or CH2, B is absent or represents a C1 to C6 branched or straight-chain alkyl, and R represents a C3 to C6 alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloheterocyloalkenyl, aryl, or heteroaryl, and the use of the peptide for manufacturing anti-HIV therapeutic or vaccine compositions are disclosed herein.

The invention relates to optimized CD4 mimic peptides derived from the CD4M33 peptide (Martin et al., Nat. Biotechnol., 2003, 21, 71-76 and International PCT Application WO 02/059146) and to the use of these peptides for the manufacture of new anti-HIV medicines and vaccines.
The human immunodeficiency virus (HIV) has been implicated as the primary cause of the slowly degenerative immune system disease termed acquired immune deficiency syndrome (AIDS). In humans, HIV replication occurs prominently in CD4 T lymphocyte populations, and HIV infection leads to depletion of this cell type and eventually to immune incompetence, opportunistic infections, neurological dysfunctions, neoplastic growth, and ultimately death.
HIV-1 treatment includes a combination of anti-HIV compounds, which target the HIV reverse transcriptase (azidothymidine (AZT), lamivudine (3TC), dideoxyinosine (ddI), tenofovir, neviparine, efavirenz), or protease (saquinavir, nelfinavir, indinavir, amprenavir, lopinavir), and only one new fusion inhibitor, enfuvirtide, has been recently approved (Richman, D. D., Nature, 2001, 410, 995-1001; Lalezari et al., N. Engl. J. Med., 2003, 348, 2175-2185). However, the emergence of new HIV isolates resistant to existing drugs, in addition to difficulties in compliance with drug regimens because of pill burden and adverse side effects, suggests that new therapies with new drugs targeting different steps of the HIV cycle are urgently needed.
Although considerable effort has been expended on the design of effective vaccine, currently no vaccine against HIV infection exists.
The HIV viral particle comprises a viral core composed of capsid proteins, RNA genome and enzymes, surrounded by a shell of myristylated gag proteins. This shell is in turn surrounded by an outer lipid membrane envelope comprising the HIV envelope glycoproteins (gp120 and gp41). The HIV envelope glycoproteins are synthesized as a single 160 kilodalton precursor protein, which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gp120. gp41 is a transmembrane glycoprotein and gp120 is an extracellular glyco-protein, which remains non-covalently associated with gp41. gp120 is displayed as a gp41-associated trimer and forms envelope spikes on the surface of HIV virions.
The HIV entry is a multiple-step process initiated by the binding of the HIV surface envelope glycoprotein gp120 (Env) to the host cell CD4 receptor. This association induces conformational changes in Env that allow its binding to a chemokine co-receptor CCR5 or CXCR4 (Wu et al., Nature, 1996, 384, 179-183; Trkola et al., Nature, 1996, 384, 184-187; Feng et al., Science, 1996, 272, 872-877). Association with this co-receptor activates the fusogenic properties of the non-covalently associated gp41 transmembrane protein and subsequent entry of the virus into the cell (Wyatt R. and Sodroski J., Science 1998, 280, 1884-1888).
Each of these steps can represent a potential target for new drugs (Blair et al., Drug Discov. Today, 2000, 5, 183-194; Moore J. P. and Doms R. W., P.N.A.S., 2003, 100, 10598-10602; Vermeire, K., and Schols, D., Expert. Opin. Investig. Drugs, 2005, 14, 1199-1212; Ryser H. J. P and Flückiger, R., Drug discovery today, 2005, 10, 1085-1094).
Information on the cellular receptors involved in virus infection, as well as on the viral envelope structure and its interaction with host cells, may help in the design of entry inhibitors and HIV vaccines.
The three-dimensional structure of the gp120 "core" protein has been determined in the CD4-bound conformation (gp120HXB2:CD4:17b complex; PDB code 1g9m; Kwong et al., Nature, 1998, 393, 648-659; Huang et al., Science, 2005, 310, 1025-1028; Kwong et al., Structure, 2000, 8, 1329-1339) and the more recently published unliganded form of SIV gp120 (PDB code 2BF1; Chen et al., Structure, 2005, 13, 197-211), but so far there is no crystal structure available of the gp120 trimer.
In the CD4-bound conformation, gp120 consists in an inner and an outer domain connected by a four-stranded β-sheet (bridging sheet), whereas in the unliganded conformation, although it maintains this two-domain organization, the inner domain is significantly different and the β-sheet is not formed. CD4 binding creates a cavity of roughly 150 Å3, which extends deeply in the interior of gp120 at the intersection between the inner and outer domain, whereas this cavity is absent in the unliganded form.
In the complex, a large surface of the domain D1 (742 Å2) of CD4 binds to a large (800 Å2) conserved depression on gp120. The CD4 interface is comprised of 12 residues (positions 36 to 47 of CD4 amino acid sequence corresponding to the CDR2-like loop of CD4) contributing to gp120 binding with mixed hydrophobic, electrostatic, H-bonding interactions. In the complex, CD4 Phe43 side chain plugs the entrance of the gp120 cavity (Phe43 cavity or Phe43 pocket) and CD4 Arg59, just behind Phe43, is involved in a double H-bond with Asp368 in gp120.
Besides these cell receptors, HIV is capable of binding to other molecules present on the cells that it infects, such as DC-SIGN, sphingolipides or heparan sulphates. Heparin, sulfated polysaccharides and polyanions in general are known to bind to the V3 loop of the viral envelope gp120 (with a preference for envelopes of X4 tropism), (Harrop, H. A. and Rider, C. C., Glycobiol., 8, 131-137; Moulard et al, J. Virol., 2000, 74, 1948-1960) and to a CD4-induced (CD4i) region of gp120, close to V3, involved in co-receptor binding (Vivès et al., J. Biol. Chem., 2005, 280, 21353-21357). The association between V3 loop and those molecules seems to dominate the electrostatic effect of this double interaction and probably occurs through interactions between the acidic sulfate moieties of heparin derivatives and basic residues of V3 loop. Viruses of X4 tropism are known to have more basic V3 loops (Berger et al., Nature, 1998, 391, 240-) and would therefore be better binders to heparin derivatives. This does not exclude an affinity of heparin derivatives to the CD4i epitope of viruses of R5 tropism, since peptides containing sulfated tyrosine are also able to associate with those gp120 (Farzan et al., J. Biol. Chem., 2002, 277, 40397-40402).
Cell attachment is the first step in HIV-1 entry and a primary target for antiviral therapy and vaccine design.
Antiviral-Therapy
Different macromolecules have been demonstrated to inhibit gp120 binding to CD4, starting from soluble CD4 (Daar et al., P.N.A.S., 1990, 87, 6574-6578). However, monovalent potent inhibitors of CD4-gp120 binding such as soluble CD4 are shown to be effective in vitro (Daar et al., precited) but have reduced affinity for primary isolates. Evidence is arising that HIV-1 through its envelope trimers could bind several cell-surface CD4 receptors simultaneously (Kwong et al., Nature, 2002, 420, 678-682). Multimeric inhibitors targeting several CD4 binding sites on single spike or even on a virion could therefore be much more able to compete with CD4 for the attachment to the virus. Well-tailored multivalent ligands could lead to large avidity gains by decreasing the off-rate of the complex and increasing functional affinity of the ligand (Gestwicki et al., J. Am. Chem. Soc., 2002, 124, 14922-14933; Sadler et al., Rev. Mol., Biotech., 2002, 90, 195-229).
Only few multimeric compounds displaying several molecules of CD4 have been developed so far. Among them, complex constructs presenting four or twelve copies of CD4 domains in an immunoglobulin structure were reported (Allaway et al., AIDS Res. Hum. Retroviruses, 1995, 11, 533-539; Gauduin et al., J. Virol., 1996, 70, 2586-2592; Arthos et al., J. Biol. Chem., 2002, 277, 11456-11464) and led to promising results as HIV-1 inhibitors (Arthos et al., precited; Trkola et al., J. Virol., 1995, 69, 6609-6617). The increased stability of these molecules and the possibility that they may simultaneously block several gp120 subunits of the trimeric envelope at the surface of virions or spikes of infected cells may explain their superior antiviral potency. Nevertheless, the large size of these molecules and the possibility that they may induce an anti-CD4 auto-immune response might represent a limitation for their therapeutic applications.
However, in spite of many years of efforts worldwide, only a handful of small molecules targeting CD4 binding site on gp120 and inhibiting CD4 attachment has been discovered. The large size and complexity of the CD4 interface make the reproduction of such functional epitope into a small molecule a challenge, and explain the difficulty in the development of small molecule inhibitors of gp120-CD4 interaction.
For some time, the recently-described small molecule BMS-378806 developed by Bristol-Myers Squibb (Wang et al., J. Med. Chem., 2003, 46, 4236-4239) was believed to inhibit CD4-gp120 binding but more recent studies have demonstrated that BMS would interact with another region of gp120, thus hindering the conformational changes induced by CD4 binding (Si et al., P.N.A.S., 2004, 101, 5036-5041; Madani et al., J. Virol., 2004, 78, 3742-3752). This molecule was dimerized with a low increase in activity (Wang et al., Org. Biomol. Chem., 2005, 3, 1781-1786).
The International PCT Application WO 2005/121175 describes small molecule CD4 mimetics comprising fused bicyclic or tricyclic core structure. However, no antiviral activity has been demonstrated for these molecules.
Until now, the CD4 mimics designed from scorpion toxin scyllatoxin have remained the smallest potent inhibitors of that kind available (Vita et al., P.N.A.S., 1999, 96, 13091-13096; Martin et al., Nature Biotech., 2003, 21, 71-76; Stricher et al., Biochem. J., 2005, 390, 29-39; International PCT Application WO 02/059146). The mini-proteins mimic of CD4 were designed to reproduce the structure of the gp120 glycoprotein binding "hot spot" of the CD4 surface, on to the scaffold consisting of the scorpion (Leiurus quinquestriatus hebraeus) toxin scyllatoxin. This small (31-residues) toxin was selected since its structure, formed by an antiparallel β-sheet linked to a short helix by three disulphide bridges, contains an exposed positions 18-29 β-hairpin, which could superimpose its backbone atoms on those of positions 36-47 CDR2-like loop of CD4 with an r.m.s (root mean square) deviation of only 1.10 Å. On the basis of this structural similarity, the scaffold permissiveness in sequence mutations and stability, even after sequence replacements, critical functional residues of the CDR2-like loop of CD4 could be grafted on to the β-hairpin of scyllatoxin, leading to the initial low-affinity mimic (CD4M3).
A first optimization of the interactions with gp120 was achieved by structure-activity studies, leading to the first generation of mini-proteins, CD4M9. CD4M9 is able to inhibit the binding of soluble CD4 to gp120 with an IC50 (concentration causing 50% inhibition of sCD4 binding to gp120) about a hundred-fold higher than that of native CD4. Recently Li et al. have reported a dimeric version of the first generation of CD4 mimic M9 with a twenty-fold enhanced anti-HIV activity over the monovalent molecule (Li et al., Bioconj. Chem., 2004, 15, 783-789 and US Patent Application 2005/0176642).
Further optimization was achieved with the help of the NMR structure of the CD4M9 mini-protein combined to molecular modeling, leading to the second generation of mini-proteins, CD4M33 (27 amino acids, SEQ ID NO: 1). CD4M33 is able to bind different gp120s in competition with soluble CD4 with a nanomolar Kd, to induce CD4-like conformational changes in gp120, exposing the cryptic epitopes necessary to target co-receptor elements, as well as to inhibit infection of primary cells by primary clinical HIV-1 isolates.
In addition, heparin or heparin fragments of sufficient size, in the presence of CD4 mini-protein interact with the CD4i domain of the gp120 and this combination greatly inhibits the gp120/co-receptors interaction, as demonstrated by inhibition of the gp120/48D or 17b antibody interaction (International PCT Application WO 03/089000).
However, HIV-1 inhibition in cell-cell fusion and virus-cell fusion assays remains less efficient with these mimics than that with CD4s.
Some of those small and stable mini-proteins were co-crystallized in complex with gp120 and antibody 17b Fab fragment (Huang et al., Structure 2005, 13, 755-768), providing precise structural information about the binding of those compounds with the gp120 binding site. The three-dimensional structure of CD4M33, free or in complex with gp120 (PDB code 1YYL) has been solved (Stricher et al., Biochem. J., 2005, 390, 29-39; Huang et al., precited). In CD4M33, Biphenylalanine 23 was shown to play a key role in the interaction with gp120 binding pocket. Another important structural feature of this mini-protein is the β-hairpin which represents the "hotspot" of the binding region to gp120 (FIG. 1), accounting with about 80% of the interface. However, the residues defining this β-turn have not been well explored in the previous studies.
HIV-Vaccine
gp120 appears to be the primary target for inducing a humoral immune response to HIV. However, it has been difficult to generate protective responses against the HIV Env because the CD4 binding site is buried between the outer domain, the inner domain, and the V1/V2 domains of gp120. Thus, although deletion of the V1/V2 domain may render the virus more susceptible to neutralization by monoclonal antibody directed to the CD4 site, the conformation of Env prior to CD4 binding may prevent an antibody response.
It has been shown that CD4 and CD4 mimetics that bind to gp120 cause a conformational change in Env that exposes one or more cryptic or inducible epitopes in or near the CD4 binding site, which in turn allows the generation of a neutralizing antibody response to Env.
Therefore, the use of complexes of Env and CD4 or Env and CD4 mimics (mini-proteins derived from scyllatoxin or small cyclic molecules) as vaccine to generate a protective immune response against HIV has been proposed (International PCT Applications WO 2004/037847 and WO 2005/121175).
The use of small CD4 mimics should prevent the risk of inducing an anti-CD4 auto-immune response that might occur when using the CD4 molecule. Unlike CD4, CD4M33 was shown to be low immunogenic as indicated by lower level and antibodies induced by the mini-protein. Moreover, anti-CD4M33 antibodies did not cross-react with CD4. Therefore, the use of CD4M33 in a vaccine may be safer compared to CD4.


A system or method for controlling a vehicle having a normal operating mode and a performance operating mode include detecting a removable key unique to each vehicle associated with the performance operating mode, operating the vehicle in the performance operating mode in response to detecting the removable key, and operating the vehicle in the normal operating mode otherwise. Operation in performance or track mode may include adjusting valve timing using a variable cam timing device, adjusting idle speed control, adjusting torque response, and/or enhancing engine braking. Performance mode operation may also disable one or more features, such as a transmission skip shift feature.

Vehicle manufacturers design or select various aesthetic and functional characteristics of a vehicle to provide a characteristic "look and feel" desired by corresponding target groups of consumers. In addition to structural hardware components, vehicle engine, transmission, suspension, steering and other systems may be calibrated to meet desired performance and fuel economy goals consistent with the desired "look and feel". Vehicles may include special-purpose operating modes selectable by the operator for a particular application. For example, vehicles may include a trailering mode, an off-road or 4×4 mode, economy mode, performance mode, etc. A corresponding button or switch on the dashboard or gear selector may be provided to activate the special-purpose operating mode. In one example of a performance mode selected by a corresponding pushbutton or switch, automatic transmission shift points and shift feel are adjusted to extend shift points and provide a more aggressive or faster shift. To reduce the development time required to provide a complete performance calibration for the engine or transmission, this may be accomplished by providing a performance adjustment factor used to adjust corresponding values of the operating parameters stored in memory.
While use of dashboard switches or other hardware installed in the vehicle to select or activate a special-purpose operating mode is convenient for many applications, this strategy requires modification of the vehicle dashboard, console, gear selector, etc. and may be cost-prohibitive for low volume applications. In addition, the special purpose mode activation switch is integrated into the vehicle design such that the special purpose mode must be ordered/specified during the vehicle build or included in all similar vehicles. Likewise, if the activation or control switch is permanently installed in the vehicle, the special purpose mode is available to any vehicle operator.

Vehicle having key-based performance mode


Devices and methods are disclosed for characterizing point flaws (including pinholes and point defects) of an optical filter. A passband test is performed, including: illuminating the optical filter with passband illumination whose spectral range at least overlaps a passband of the optical filter; acquiring a passband map of the optical filter using a two-dimensional array of photodetectors while illuminating the optical filter with the passband illumination; and identifying point defects of the optical filter as low intensity locations of the passband map. A stopband test is performed, including: illuminating the optical filter with stopband illumination whose spectral range lies entirely outside of the passband of the optical filter; acquiring a stopband map of the optical filter using the two-dimensional array of photodetectors while illuminating the optical filter with the stopband illumination; and identifying pinholes of the optical filter as high intensity locations of the stopband map.

The following relates to the optical filter arts, optical characterization arts, and related arts, and to applications using same.
Optical filters are used in a wide range of optical applications, such as astronomy, still and video cameras and other imaging devices, televisions, computer monitors, cellular telephone screens, and other display devices, optical sensors such as motion sensors, gesture sensors, and the like, and so forth. Depending on the application, such filters can range in size up to a square meter or larger in area. Within a design-basis optical spectrum an optical filter generally has a passband for which the filter transmits light, and a stopband (or blocking band) for which the filter does not transmit light. In a bandpass filter, the passband is usually relatively narrow and most of the design-basis optical spectrum lies outside of the passband and is blocked. Passband filters with two or more separate passbands are also known. In a low-pass or high-pass filter, the passband includes all wavelengths of the design-basis spectrum below (or above) a cutoff wavelength or frequency. Filters can be further optically characterized by parameters such as the transmission in the passband and the stopband, passband full-width-at-half-maximum (FWHM), the slope of the transition at the edge(s) between the passband and the stopband, and so forth.
Optical filters can employ various designs. A common type of optical filter is an interference filter, in which a stack of optical layers are arranged with thicknesses and refractive indices that are precisely designed so that reflected and transmitted light rays within the stack constructively combine within the passband and destructively combine in the stopband. An interference filter can provide steep passband edges, high passband transmission (approaching 99% or higher) and very low transmission in the stopband (near 0% transmission). The stack of layers is typically formed on an optically transparent substrate (e.g. glass) by a technique such as sputter deposition, thermal vacuum evaporation, or the like which is performed in a vacuum chamber or other controlled atmosphere.
The manufactured filter is typically visually inspected for defects, and its filter characteristics are measured, usually by spectral measurement over the design-basis wavelength range, to confirm the filter specification is met (e.g. passband center wavelength and FWHM, cutoff slope, et cetera). Filter characterization is usually performed for each manufactured filter because for filters with demanding specifications filter characteristics can change significantly (enough to be out-of-specification) in response to even small errors in layer thicknesses or refractive indices. Since thickness non-uniformity over the area of the filter can occur, the filter spectral characterization may be repeated at several different areas. Those filters which pass inspection and meet the filter specification are delivered to the customer, or alternatively may first be mounted in a filter frame or optical sub-system before delivery.
Some improvements are disclosed herein.

Automated defect detection and mapping for optical filters


A filling member (43) in a medicament delivery device (1), the filling member (43) includes a first conduit (12) that fluidly communicates with a reservoir (4) and a second conduit (14) that fluidly communicates with a pump (3) and with the first conduit (12), wherein the filling member (43) provides two-way medicament flow that enters the reservoir (4) via the first conduit (12), exits the reservoir (4) into the first conduit (12) and the second conduit (14), and exits the second conduit (14) to the pump (3). The reservoir (4) includes a reservoir tube (44A) having one end that is formed with the reservoir (4), and the reservoir tube (44A) having another end that is press fit to the filling member (43) to establish fluid communication with the reservoir (4).

Diabetes is a group of diseases characterized by high levels of blood glucose resulting from the inability of diabetic patients to maintain proper levels of insulin production when required. Diabetes can be dangerous to the affected patient if it is not treated, and it can lead to serious health complications and premature death. However, such complications can be minimized by utilizing one or more treatment options to help control the diabetes and reduce the risk of complications.
The treatment options for diabetic patients include specialized diets, oral medications and/or insulin therapy. The main goal of diabetes treatment is to control the diabetic patient's blood glucose or sugar level. However, maintaining proper diabetes management may be complicated because it has to be balanced with the activities of the diabetic patient. Type 1 diabetes (T1D) patients are required to take insulin (e.g., via injections or infusion) to move glucose from the bloodstream because their bodies generally cannot produce insulin. Type 2 diabetes (T2D) patients generally can produce insulin but their bodies cannot use the insulin properly to maintain blood glucose levels within medically acceptable ranges. In contrast to people with T1D, the majority of those with T2D usually do not require daily doses of insulin to survive. Many people are able to manage their condition through a healthy diet and increased physical activity or oral medication. However, if they are unable to regulate their blood glucose levels, they will be prescribed insulin. For example, there are an estimated 6.2 million Type 2 diabetes patients (e.g., in the United States, Western Europe and Canada) taking multiple-daily-injections (MDI) which consist of a 24-hour basal insulin and a short acting rapid insulin that is taken at mealtimes for glycemic management control.
For the treatment of Type 1 diabetes (T1D) and sometimes Type 2 diabetes (T2D), there are two principal methods of daily insulin therapy. In the first method, diabetic patients use syringes or insulin pens to self-inject insulin when needed. This method requires a needle stick for each injection, and the diabetic patient may require three to four injections daily. The syringes and insulin pens that are used to inject insulin are relatively simple to use and cost effective.
Another effective method for insulin therapy and managing diabetes is infusion therapy or infusion pump therapy in which an insulin pump is used. The insulin pump can provide continuous infusion of insulin to a diabetic patient at varying rates to more closely match the functions and behavior of a properly operating pancreas of a nondiabetic person that produces the required insulin, and the insulin pump can help the diabetic patient maintain his/her blood glucose level within target ranges based on the diabetic patient's individual needs. Infusion pump therapy requires an infusion cannula, typically in the form of an infusion needle or a flexible catheter, that pierces the diabetic patient's skin and through which infusion of insulin takes place. Infusion pump therapy offers the advantages of continuous infusion of insulin, precision dosing, and programmable delivery schedules.
In infusion therapy, insulin doses are typically administered at a basal rate and in a bolus dose. When insulin is administered at a basal rate, insulin is delivered continuously over 24 hours to maintain the diabetic patient's blood glucose levels in a consistent range between meals and rest, typically at nighttime. Insulin pumps may also be capable of programming the basal rate of insulin to vary according to the different times of the day and night. In contrast, a bolus dose is typically administered when a diabetic patient consumes a meal, and generally provides a single additional insulin injection to balance the consumed carbohydrates. Insulin pumps may be configured to enable the diabetic patient to program the volume of the bolus dose in accordance with the size or type of the meal that is consumed by the diabetic patient. In addition, insulin pumps may also be configured to enable the diabetic patient to infuse a correctional or supplemental bolus dose of insulin to compensate for a low blood glucose level at the time when the diabetic patient is calculating the bolus dose for a particular meal that is to be consumed.
Insulin pumps advantageously deliver insulin over time rather than in single injections, typically resulting in less variation within the blood glucose range that is recommended. In addition, insulin pumps may reduce the number of needle sticks which the diabetic patient must endure, and improve diabetes management to enhance the diabetic patient's quality of life. For example, many of the T2D patients who are prescribed insulin therapy can be expected to convert from injections to infusion therapy due to an unmet clinical need for improved control. That is, a significant number of the T2D patients who take multiple-daily-injections (MDI) are not achieving target glucose control or not adhering sufficiently to their prescribed insulin therapy.
Typically, regardless of whether a diabetic patient uses multiple direct injections (MDIs) or a pump, the diabetic patient takes fasting blood glucose medication (FBGM) upon awakening from sleep, and also tests for glucose in the blood during or after each meal to determine whether a correction dose is required. In addition, the diabetic patient may test for glucose in the blood prior to sleeping to determine whether a correction dose is required, for instance, after eating a snack before sleeping.
To facilitate infusion therapy, there are generally two types of insulin pumps, namely, conventional pumps and patch pumps. Conventional pumps use a disposable component, typically referred to as an infusion set, tubing set or pump set, which conveys the insulin from a reservoir within the pump into the skin of the user. The infusion set includes a pump connector, a length of tubing, and a hub or base from which a cannula, in the form of a hollow metal infusion needle or flexible plastic catheter, extends. The base typically has an adhesive that retains the base on the skin surface during use. The cannula can be inserted onto the skin manually or with the aid of a manual or automatic insertion device. The insertion device may be a separate unit employed by the user.
Another type of insulin pump is a patch pump. Unlike a conventional infusion pump and infusion set combination, a patch pump is an integrated device that combines most or all of the fluidic components in a single housing. Generally, the housing is adhesively attached to an infusion site on the patient's skin, and does not require the use of a separate infusion or tubing set. A patch pump containing insulin adheres to the skin and delivers the insulin over a period of time via an integrated subcutaneous cannula. Some patch pumps may wirelessly communicate with a separate controller device (as in one device sold by Insulet Corporation under the brand name OmniPod®, while others are completely self-contained. Such patch pumps are replaced on a frequent basis, such as every three days, or when the insulin reservoir is exhausted. Otherwise, complications may occur, such as restriction in the cannula or the infusion site.
As patch pumps are designed to be a self-contained unit that is worn by the patient, preferably, the patch pump is small, so that it does not interfere with the activities of the user. Thus, to minimize discomfort to the user, it is preferable to minimize the overall thickness of the patch pump. However, to minimize the thickness of the patch pump, the size of its constituent parts and the number of parts should be reduced as much as possible.
In current patch pump designs, tubes, such as plastic tubes, are employed as fluid pathways to route fluid flow from one internal component to another. The use of multiple tubes can create multiple flow paths to transfer medicament. For example, there can be two flow paths connected to a reservoir. One flow path fills the reservoir with medicament and another flow path routes the medicament from the reservoir to various internal components in the patch pump. The use of tubes can increase cost and can result in additional complexity during device assembly. For example, such device assembly includes connecting the tubes, which adds steps to the assembly process. In addition, preventing leaks from such connections can give rise to additional challenges.
Accordingly, a need exists for an improved fluid path design for use in a limited space environment, such as in a patch pump device, which can cost-effectively transport medicament, while minimizing or reducing the overall size and complexity of the device.

Fluid interconnection scheme between reservoir, pump and filling member


To provide an optical clock signal extracting device with a simple configuration, by which an optical clock signal may be extracted without depending on the polarization direction of an input optical signal. A current is injected to a gain region 30 through an n-type common electrode 12 and a p-type electrode 24 in the gain region 30 by a constant current source 28. A reverse-bias voltage is applied by a constant voltage source 26 to a saturable absorption region 32 through the p-type electrode 12 and the n-type common electrode 72 in the saturable absorption region 32. An optical waveguide 16 in the gain region is formed with bulk crystal or a quantum well structure into which extension strain is introduced, and an optical waveguide 18 in the saturable absorption region is formed with a quantum well structure into which extension strain is introduced. Moreover, in the gain region, an optical gain for the TE mode is configured to be larger than that for the TM mode, and, in the saturable absorption region, absorption saturation energy for the TM mode is configured to be smaller than absorption saturation energy for the TE mode.

1. Field of the Invention
The present invention relates to a passive mode-locked semiconductor laser diode, and an optical clock signal extracting device using the diode.
2. Description of Related Art
In an optical communication network, longer-distance and larger-capacity transmission has been developed. Along with development of the longer-distance transmission, optical losses on an optical transmission line, reduction in signal-to-noise ratio, wherein the reduction is caused by use of multistage optical amplifier, the group velocity dispersion of an optical fiber, and generation of a waveform strain depending on nonlinear optical-effects in the optical fiber have raised a problem that the quality of an optical signal is deteriorated. The larger transmission capacity has caused distortion generation of frequency and time-pulse waveforms to become a more remarkable problem.
Therefore, there have been provided repeaters at intervals of from several tens to a few hundred kilometers in the middle of the optical transmission line. In these repeaters, the frequency and time-pulse waveforms of an optical signal have been returned to the original shape, that is, so-called reproduction of the optical signal has been performed. One of main roles of these repeaters is extraction of a clock signal. Extraction of a clock signal is to generate a signal an optical pulse train in which a series of optical pulses are arranged on a time axis with a frequency corresponding to that of the bit rate, or a radio frequency (RF) signal, which is a sinusoidal electric signal, from an optical signal including optical pulses with strained time-pulse waveforms, that is, an optical signal which has so-called deteriorated quality.
The clock signal is, extracted as an electric signal in some cases, and as an optical signal in other cases. Hereinafter, as long as it is required to clearly specify which way is used for extraction, an electric clock signal and an optical clock signal are distinguished from each other in writing. Moreover, a frequency corresponding to a bit rate of an optical signal is assumed to indicate a frequency of f GHz when the bit rate of the optical signal is f Gbit/s. Hereinafter, the frequency corresponding to the bit rate of an optical signal is called a bit-rate frequency in some cases.
One of general techniques which have been known as a method by which clock signal is extracted is a method according to which an optical signal with deteriorated quality is configured to be input to a photodiode, and the like for photoelectric conversion, and an electric output signal from the photodiode is filtered by a bandpass filter for extraction of only frequency elements corresponding to the bit rate of the input optical signal. Hereinafter, an optical signal, including an optical signal with deteriorated quality, from which a clock signal is extracted is assumed to be called an input optical signal.
An optical pulse train, in which a series of optical pulses are arranged on a time axis with a period, as a repetition frequency, corresponding to the bit-rate frequency of an input optical signal, is generated by activating an optical pulsed laser diode such as a semiconductor laser, using an electric clock signal generated through a photodiode and a bandpass filter. Hereinafter, an optical signal is assumed to be a signal which is generated as a return-to-zero (RZ) signal by optical modulation of a train of optical pulses which are regularly arranged on a time axis at constant periodic intervals, wherein the RZ signal is a binary digital signal which is a send signal. On the other hand, the optical pulse train is assumed to indicate an integrated whole of optical pulses which are regularly arranged on a time axis at constant periodic intervals.
Generally, a clock signal may be stably extracted by using the photodiode even if there are time fluctuations on the plane of polarization of an input optical signal as the photoelectric conversion characteristics of the photodiode has reduced polarization dependence.
On the other hand, multiple transmission technologies such as optical time division multiplexing have been researched as a technology to increase the transmission capacity of an optical communication network. The bit rate of a multiple signal becomes very large because the bit rate of the multiple signal is equal to a result obtained by multiplying the bit rate per one channel among multiple ones by a factor of a number of channels.
When the bit rate of the multiple signal exceeds 40 Gbit/s, it becomes difficult for an electronic device to extract an clock signal. The reason is that a photodiode applicable even for an optical signal with a bit rate which is 40 Gbit/s or more, and an electric narrow-band filter applicable even for an electrical signal with a frequency of 40 Gbit/s or more have not been developed so far.
Conventionally, a first method through a fifth one, which will be explained later, have been examined in order to extract a clock signal from a high-speed, optical signal. That is, there have been examined methods by which an optical clock signal is extracted directly from an input optical signal without requiring a step at which photoelectric conversion of the input optical signal is performed, using a photodiode and the like.
The first method is a method (refer to, for example, Japanese Patent Publication No. 3510247 (corresponding to WO93/022855)) using a fiber-type passive mode-locked laser. In this method, an optical pulse signal is extracted by inputting an input optical signal according to repetition with near the bit-rate frequency of the input optical signal to the fiber-type passive mode-locked laser which generates optical pulses, and by synchronizing the generation frequency of the optical pulses by the fiber-type passive mode-locked laser and the bit-rate frequency of the input optical signal.
Though the second method (refer to, for example, T. Ono, T. Shimizu, Y. Yano, and H. Yokoyama, "Optical clock extraction from 10-Gbit/s data pulses by using monolithic mode-locked laser diodes", OFC′ 95 Technical Digest, ThL4) has a similar configuration to that of the above-described first method, a passive mode-locked semiconductor laser diode, instead of the fiber-type passive mode-locked laser, is used in the second method. In the second method, an optical pulse train, in which a series of optical pulses are arranged at time intervals equal to the bit-rate frequency of an input optical signal, is generated by synchronizing orbiting optical pulses in the passive mode-locked laser and an optical pulse forming the input optical signal, based on modulation of an optical absorption coefficient in a saturable absorption region. The optical pulse train is an optical clock signal which has been extracted
The third method (refer to, for example, Japanese Patent Laid-Open Publication No. H11-326974) has a similar configuration to that of the above-described second method, and a passive mode-locked semiconductor laser diode is also used in the third method. However, the feature of the third method is that the passive mode-locked semiconductor laser diode is configured to include a coupling optical system such as a semiconductor optical amplifier, tunable filter, and lenses, and is a so-called external-cavity laser. Accordingly, the length of the resonator and the center wavelength of the tunable filter may be easily changed to bring about advantages that a frequency range in which optical clock signals may be extracted is wide, and the wavelengths of the extracted optical clock signals may be easily changed.
The fourth method (refer to, for example, Japanese Patent Laid-Open Publication No. 2001-94199) has a similar configuration to those of the above-described second and third methods, and a passive mode-locked semiconductor laser diode is also used in the fourth method. However, the feature of the fourth method is that there are used two passive mode-locked semiconductor laser diodes, that is, a first passive mode-locked semiconductor laser diode, and a second one. The first passive mode-locked semiconductor laser diode operates at a frequency near the bit-rate frequency of an input optical signal, and the second one operates at a frequency near a frequency which is an integral submultiple of the bit-rate frequency of an input optical signal. As the two passive mode-locked semiconductor laser diodes with different operating frequencies from each other are configured to be used as described above, it is possible to generate a frequency-divided optical clock signal with a frequency which is an integral submultiple of the bit-rate frequency of an input optical signal. Moreover, as a return-loop optical path is formed in the second passive mode-locked semiconductor laser diode, using an optical gate element, it is realized in the fourth method to generate a frequency-divided clock signal in a stable manner
The fifth method (refer to, for example, M. Jinno and T. Matsumoto, "All-optical timing extraction using a 1.5 μm self pulsating multielectrode DFB LD", Electron, Lett., vol. 24, No. 23, pp. 1426-1427, 1988) is a method in which an optical pulse signal is extracted, using a self pulsating multielectrode distributed feed-back laser diode. An optical pulse signal is extracted by synchronizing an optical-pulse frequency generated from the self pulsating multielectrode distributed feed-back laser diode and the bit-rate frequency of the input optical signal after the bit-rate frequency of an input optical signal and the input optical signal are input to the self pulsating multielectrode distributed feed-back laser diode.
However, there is caused a problem, in the above-described first through fifth methods, that extracting operation of an optical clock signal strongly depends on the plane of polarization of the input optical signal. As an optical fiber before reaching an optical repeater is not processed in such a way that the plane of polarization of an input optical signal, which is propagating, is kept constant, the plane of polarization of the input optical signal generally causes time fluctuation. That is, the extracting operation of the optical clock signal becomes unstable by the time fluctuation of the plane of polarization of the input optical signal.
In the above-described first through fifth methods, there will be illustrated as follows a reason that the extracting operation of the optical clock signal strongly depends on the plane of polarization of the input optical signal.
An electro-optical Kerr effect is used in the first method, and the Kerr effect has a strong dependence on the plane of polarization. That is, though a direction on the plane of polarization of an optical pulse forming an optical clock signal existing in the inside of a fiber-type mode-locked laser and the direction on the plane of polarization of an input optical signal are in parallel with each other in some cases, and are orthogonal to each other in other cases, a coefficient of an electro-optical Kerr effect obtained in the parallel case is three times a coefficient in the orthogonal case. Accordingly, when the direction of the plane of polarization of the input optical signal is in accordance with that of the plane of polarization of oscillation light by a fiber-type mode-locked laser, an optical clock signal is extracted with a high efficiency. However, when the both directions of the planes of polarization are orthogonal to each other, there is caused a situation in which no optical clock signal is extracted.
The gain region of the passive mode-locked semiconductor laser diode, which is used in the second through the fifth methods, is realized by a bulk crystal layer, a quantum well layer, or a strained quantum well layer. Moreover, the saturable absorption region is realized by the quantum well layer or the strained quantum well layer. The reason will be described as follows.
That is, the reason is that it is easy to stabilize the mode-locking operation because absorption saturation energy may be reduced by a configuration in which the saturable absorption region includes the quantum well layer or the strained quantum well layer. Moreover, the reason is that a phenomenon in which high-speed saturable absorption occurs may be realized, which is preferable for extraction of an optical clock signal with a high bit-rate frequency.
The optical properties of the quantum well layer has a strong dependence on polarization. Especially, the strained quantum well layer into which no strain or compressive strain is introduced has characteristics such as a high optical gain, a large differential gain, a low α parameter, or low absorption saturation energy for polarization (so-called transverse electric wave (TE) polarization) parallel to the laminated surface of the quantum well. Accordingly, when an optical clock signal is extracted, using the passive mode-locked semiconductor laser diode in which the quantum well layer is adopted into the gain region and the saturable absorption region, the following preferable effects may be expected.
That is, when the plane of polarization of an input optical signal is TE polarization, the input optical signal is amplified with a high efficiency by optical amplification in the gain region. Moreover, as the absorption saturation energy is low in the saturable absorption region, there may be realized the larger modulation factor of an optical absorption coefficient in a saturable absorption region generated by the absorption saturation induced by the input optical signal. Thereby, even when the intensity of the input optical signal is low, a required modulation factor of the optical absorption coefficient in the saturable absorption region for extraction of the optical clock signal may be easily realized. That is, even when the intensity of the input optical signal is low, the optical clock signal may be extracted in a stable manner. Here, the modulation factor of the optical absorption coefficient is a change in the optical absorption coefficient, that is, a ratio between the minimum value and the maximum one of the optical absorption coefficient. The large modulation factor means that the degree of change in the optical absorption coefficient is large.
One the other hand, when the plane of polarization of the input optical signal is TE polarization, and when the plane is orthogonal polarization (so-called transverse magnetic wave TM polarization), the effect of optical amplification is not obtained in the gain region, and, moreover, the absorption saturation energy of the saturable absorption region is high. Accordingly, a required degree of modulation of the optical absorption coefficient in the saturable absorption region for extraction of the optical clock signal may not be realized. That is, when the optical clock signal is extracted from the input optical signal, there is a problem that there is generated the dependence on the plane of polarization of the input optical signal, that is, the optical clock signal is extracted in a stable manner when the input optical signal is TE polarization, and the optical clock signal may not be extracted in the case of the TM polarization.
There is no guarantee that the input optical signal is kept in the TE polarization because the optical fiber before reaching an optical repeater is not processed as described above in such a way that the plane of polarization of the input optical signal, which is propagating, is kept constant, and extraction of the optical clock signal depends on the plane of polarization of the input optical signal. That is, it is meant that the optical clock signal may not be extracted in a stable manner.
Then, a sixth and a seventh methods (refer to, for example, Japanese Patent Laid-Open Publication No. 2004-363873 (corresponding to U.S. Pat. No. 6,954,559) and Y. Hashimoto, R. Kuribayashi, S. Nakamura, and I. Ogura, "Optical clock recovery using optical phase-locked loop with voltage-controlled mode-locked semiconductor laser," ECOC 2004, Vol. 3, paper We2.5.1.) have been examined in order to solve the problem related with the dependence on the plane of polarization of the input optical signal.
In the sixth method, the input optical signal is separated in the first place into a polarization element (called a TE polarization element) in accordance with the plane of polarization of oscillation light by the mode-locked semiconductor laser diode and an element (called a TM polarization element) having the plane of polarization orthogonal to the plane of polarization by the oscillation light. The TE polarization element is input to one end surface of the resonator in the mode-locked semiconductor laser, keeping the polarization state. The TM polarization element is input to the other end surface of the resonator in the mode-locked semiconductor laser after the polarization state is rotated by 90 degrees and the element is made in accordance with the plane of polarization of oscillation light by the mode-locked semiconductor laser diode. The optical clock signal is extracted by the above-described method without depending on the plane of polarization of the input optical signal.
In the seventh method, the optical clock signal is extracted, using a semiconductor optical amplifier (SOA) as a phase comparator. As SOA functioning without depending on the plane of polarization is used, the optical clock signal is extracted without depending on the plane of polarization of the input optical signal.
However, a device, which is provided with a number of components such as a polarization synthetic separation circuit, an optical delay device, a specially specified SOA, a photodiode, and the like, and has a complex structure, is required for the sixth or the seventh method. Industrially, it is the most preferable to extract the optical clock signal in a stable manner without depending on the plane of polarization of the input optical signal, using a simple device which may be realized by a single element. If the optical clock signal is realized by the single element, maintenance of the simple device is more easily performed, and stable operation is more reliably executed in comparison with a case in which the above-described device, which is provided with a number of components, and has a complex structure, is used.
If there is developed a single element which has a function by which an optical clock signal may be extracted from an input optical signal in a stable manner without depending on the plane of polarization of the input optical signal, the above element may be inexpensively provided, using a technology by which a high degree of integration and mass production of a semiconductor are realized.
Accordingly, an object of the present invention is to provide a passive mode-locked semiconductor laser diode and an optical clock signal extracting device including the above laser diode, wherein the passive mode-locked semiconductor laser diode is an element with a simple configuration having properties similar to those of a single element, and may extract, from an input optical signal without depending on the polarization direction of the input optical signal, an optical clock signal with a repetition frequency corresponding to the bit-rate frequency (called "clock frequency" in some times) of the input optical signal. Moreover, another object of the present invention is to provide a method by which the above passive mode-locked semiconductor laser diode and the optical clock signal extracting device are activated.

Passive mode-locked semiconductor laser diode, and optical clock signal extracting device


Systems, methodologies, media, and other embodiments associated with improving MRI scan times and mitigating the effects of aliasing artifacts when the Nyquist data sampling threshold is not satisfied are described. One exemplary method embodiment includes producing an oscillating phase encoding gradient during a readout phase, where the gradient facilitates acquiring data from multiple phase encoding lines during a single readout phase. The exemplary method embodiment may also include reconstructing an image from the data acquired from two or more phase encoding lines.

In rectilinear MRI (Magnetic Resonance Imaging) acquisition, k-space data are typically acquired while a constant amplitude read gradient is applied. This results in a straight line trajectory during data sampling intervals. For example, in FIG. 2, the five straight lines of black dots 210 represent five sampling trajectories used to sample k-space data points using conventional rectilinear acquisition. In this type of rectilinear acquisition, the scan time is equal to TR (repetition time) times the number of phase encoding lines. For example, on the left side of FIG. 2, data is acquired using five read gradients and thus the acquisition time would be TR times five. In this conventional system, attempts to reduce scan time have included reducing the number of read phases by increasing the phase encoding step size. However, these approaches have typically lead to aliasing artifacts.


A wireless communication device having an accessory port and a processor to detect when an external accessory is coupled to the accessory port, and then identify the type of external accessory. A data line connects the external accessory to the wireless communication device, the data line being a portion of a pulse code modulation (PCM) port in the accessory port. The processor senses activity on this data line, including a signal transmitted by the external accessory indicative of when the external accessory is coupled to the wireless communication device. The processor further senses identification data associated with the external accessory, with the identification data including an identification code of the external accessory. The processor generates a clock signal, and the external accessory transmits the identification data to the wireless communication device over the data line in response to the clock signal. In this fashion, the processor repeatedly senses the transmitted identification data. An input line in the accessory port carries a voltage indicative of whether the external accessory supplies external power to the wireless communication device. The identification code transmitted by the external accessory is compared to stored codes corresponding to a plurality of external accessories to identify the external accessory coupled to the wireless communication device.

The present invention is related generally to wireless communication devices and connectable external accessories, and more particularly, to a system and method for detecting when an external accessory has been connected to the wireless communication device and for identifying the type of external accessory connected.
Modern wireless communication devices, such as cellular telephones, are designed so that the user may connect external accessories to the cellular telephone, enabling the user to use the cellular telephone in a wider range of applications than if the cellular telephone were used by itself. For example, a headset accessory may be connected to some cellular telephones so that a microphone and earpiece are positioned in proximity of the user""s mouth and ear, respectively, to permit hands-free operation of the cellular telephone. Another example of a common external accessory connectable to a cellular telephone is a carkit accessory that allows the cellular telephone to be used while driving an automobile without the inconvenience of holding the cellular telephone. The kit includes a microphone that can be attached to a convenient location within the automobile, and the kit is connected to the automobile""s audio system so that the audible signals produced by the cellular telephone can be heard over the speakers of the audio system.
Other examples of common external accessory devices include a battery charger to recharge the internal battery of the wireless communication device and a computer interface that allows connection of a personal computer or laptop to the wireless communication device via a PCMCIA (Personal Computer Memory Card International Association) interface. Numerous other types of external accessories are available. These external accessories are connected to the wireless communication device by an extension cord having a fitting at its end. An accessory port of the wireless communication device receives the fitting, and in this fashion, the external accessory is electrically and communicatively coupled to the wireless communication device.
However, for a variety of reasons, there is an ongoing need to find a satisfactory way for the wireless communication device to identify when an external accessory has been coupled to the accessory port and to identify the type of external accessory. For example, if the user of the wireless communication device wishes to increase the volume of a call, the wireless communication device will need to know if the volume adjustments being made by the user are being directed towards the wireless communication device internal speaker or to a speaker of an external accessory. Without this ability to identify when and what kind of external accessory is coupled, the user may be mistakenly increasing the volume of the internal speaker within the device, instead of the volume of the speaker of the external accessory that the user intended to adjust. The present invention provides solutions to these problems, as will be apparent from the following detailed description and accompanying figures.
The present invention is embodied in a system and method directed to sensing when an external accessory is coupled to a wireless communication device, and to identifying the type of external accessory. In one embodiment, the wireless communication device includes an accessory port that allows an external accessory to be coupled to the wireless communication device, the accessory port including at least one data line, and a processor to sense activity on the data line when the external accessory has been coupled. The processor senses identification data associated with the external accessory to identify the external accessory.
In an exemplary embodiment, the data line is a portion of a pulse code modulation (PCM) port. The processor generates a clock signal coupled to the accessory port. The external accessory transmits identification data to the wireless communication device over the data line as determined by this clock signal.
In one embodiment, the phone detects activity on the data line as indicative of whether the external accessory is coupled to the wireless communication device. Also, the presence of voltage on an input line of the phone""s accessory port is indicative of whether the external accessory provides power to the phone. The identification data includes an identification code of the external accessory. The processor identifies the type of external accessory by comparing the identification code with stored codes corresponding to a plurality of external accessories. The invention allows a wireless communication device to identify a carkit, headset, computer interface, battery charger, and other types of external accessories.

System and method for the automatic identification of accessories coupled to a wireless communication device


Methods and systems for providing protection to an individual or party from penalties associated with late or missed payments of bills, invoices and other charges are described. The methods and systems can warn a user of possible penalties and take correction action to avoid incurring the penalty. In an example, a computerized method, and system for performing the method can include receiving data about a plurality of payments to be paid by at least one party, the data includes at least one penalty associated with at least one of the payments, ranking the payments based at least partially upon the penalty and determining an order for the payments to be paid. In an example, a computerized method, and system for performing the method can include receiving data about a plurality of bills for at least one user, determining at least one action to prevent incurring a penalty for at least one of the bills and allowing the user to select the action. In an example, a computerized method, and system for performing the method can include receiving data for a plurality of bills for at least one user, determining if at least one penalty event can occur and communicating the penalty event to the user.

Electronic bill payment systems allow a consumer, party or bill paying entity (payer(s)) to direct their bank, an agent of their bank, or a non-bank bill payment service or bureau to pay amounts owed to merchants, service providers and other billers (payee(s)) who bill or invoice consumers for amounts owed. A bill payer is any person or entity paying a bill, invoice, loan, or making a payment. A bill issuing party is any person or entity sending or issuing bills, loans, invoices or requests for payments.
Unfortunately, some bill issuers impose penalties on the bill payer in the event of late, partial or missed payments. Some examples of these types of penalties are late fees, interest rate increases, credit score reductions, accelerated payments, increased payments, line of credit reductions and reduced ability to borrow. Many bill issuers such as credit card companies take any opportunity to raise interest rates and collect late fees.
In some cases, the penalty is out of proportion to the amount and timing of the payment. For example, if a payment is one day late, the interest rate on a credit card may be increased by 100 percent or the entire credit card balance may become immediately due. In some situations, the penalty may cause undue hardship for the bill paying party.

System and method for providing warning and protection for bill payments

United Services Automobile Association (USAA)


A face protecting device comprising a generally concave shield having an inwardly projecting peripheral border portion and provided with an observation opening therein, said shield being further provided with two spaced angularly disposed hand grips in the lower portion thereof.

The present invention relates more particularly to hand-held shields of the type used by welders and others, such as supervisors and inspectors, for temporary observation as distinguished from the helmets or goggles which are normally worn by welders.
Temporary hand-held head shields are subjected to more or less rough usage and thus should be sturdy to withstand such usage but still be lightweight. Moreover, such shields should be compact and free of external appendages which are susceptible to breakage. Of course, hand held face shields should be convenient to grip and comfortably held by the user.

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Provided is a method of producing a wet master batch, including the step of: solid-liquid separating and dehydrating a coagulum slurry obtained by mixing a rubber latex with a carbon black slurry containing a carbon black dispersed in water and coagulating the mixture, the solid-liquid separating and dehydrating step including gravity filtering and vacuum filtering the coagulum slurry on a filtration filter and then pressurizing, by means of a pressurizer, the coagulum slurry on the outer peripheral surface of a drum, to thereby pressure dehydrate the coagulum slurry. Also provided is a solid-liquid separating and dehydrating apparatus for wet master batch production, which includes: a filtration filter; a filtration portion; a drum; and a pressurizer.

Wet master batches have been produced for the purpose of improving a rubber composition containing a filler such as a carbon black in terms of workability and dispersibility of the filler in the rubber composition. The wet master batches are generally produced through a method including: a given rubber latex solution preparation step of compounding and preparing a rubber latex solution by optionally adding a surfactant and water to a latex of natural rubber or synthetic rubber; a filler slurry preparation step of compounding and preparing a slurry solution containing a filler such as a carbon black dispersed in a solvent such as water; a mixing and coagulating step of continuously mixing and coagulating the rubber latex solution and the filler slurry prepared in the steps above so as to form a coagulation solution containing a coagulum; a solid-liquid separating step of separating and taking out only the coagulum from the coagulation solution thus formed; a cleaning step of cleaning the coagulum thus separated, so as to remove impurities such as solidifier attached or contained in the coagulum; a dehydrating step of removing water filled in the inner gaps of the cleaned coagulum; a drying step of drying the coagulum thus dehydrated; and an optional molding step of molding the dried coagulum into a desired shape such as in the form of granules or in the form of a sheet, to thereby form a wet master batch as a product.

Method of producing wet master batch, wet master batch, rubber composition, and solid-liquid separating and dehydrating apparatus for wet master batch production


A personal massage device is disclosed. The massage device includes a housing having an exterior surface defining first and second oppositely-disposed operative ends and an interior surface defining a cavity. Each of the operative ends includes a substantially smooth and continuous surface thereon. The massage device further includes a first motor disposed within the housing and adapted for creating vibration and a battery disposed within the housing and adapted to power the first motor.

The present invention relates generally to massagers and more particularly to rechargeable personal massagers, methods, and apparatuses.
Personal vibrators, also known variously as vibrators, massagers, vibrating massagers and by numerous other names, are well-known in the art. They come in a variety of configurations and perform a variety of functions, ranging from medical therapy to erotic stimulation. They typically are battery-powered or run on conventional alternating current electricity.
Vibrating massagers powered by internally contained, disposable batteries operate for a period of time on the battery power, subsequently requiring some degree of disassembly, battery replacement, and reassembly. It will be apparent to the reader that this type of battery operation has drawbacks, including for example, limited time of operation, the inconvenience, expense, and environmental impact associated with the necessary battery replacement, and the difficulty of creating a reliable waterproof seal around a user operated moving part such as a battery door.
While some vibrating massagers operate on AC power, for example U.S. 110V or European 220V power, these massagers tend to be large and unsafe for internal use or use in damp environments. They also have the inconvenience of requiring proximity to a wall plug.
More recently known in the art are rechargeable massagers. These massagers are generally connected to the charger using a cord and male plug connectable to a female jack in the massager. The metal connectors and their receptacles often collect unsanitary residue, are difficult to clean and are subject to corrosion. Further, such jacks are difficult to waterproof reliably. An alternative implementation of a rechargeable device uses external metal contacts for charging (such as a cordless phone, etc). Such devices rely on gravity to provide the force necessary to make the electrical connection. Further, such devices require care from the user to ensure proper alignment and contact.
Many known personal massagers are made so as to be water proof or water resistant. It may be desirable to be able to use a vibrating massager in damp conditions; further, it is desirable to be able to use a vibrating massager fully submerged without fear of damaging the device or endangering the user. Some manufacturers waterproof their products (with varying degrees of success) with o-rings and similar seals around part breaks and user operated moving parts, such as battery doors, charging plug seals, etc. Often the resulting product is at best splash-proof, not submersible. It is desirable for users to be able to clean massagers thoroughly, particularly before and after they come in intimate contact with the body, which is made easier by providing a massager that is waterproof. To further ease of cleaning, some manufacturers use materials that are have a low porosity and, therefore, less likely to harbor bacteria or other contaminants.
Rechargeable massagers generally use a built-in female plug, engageable with a male plug for recharging, that is difficult to waterproof. If water gets into the female plug, and the powered male plug is then inserted, it's possible that the charger will be short circuited by as little as a single droplet of water. This can harm the charger or the massager, and can potentially be hazardous for the user as well.
Users often prefer massagers that are at or above body temperature, or can be warmed to this point. Many users warm massagers by holding them against less temperature-sensitive areas of the body, such as the hands, before using them on more sensitive areas. A few waterproof products on the market can be warmed by immersing them in hot water, but this can be inconvenient for the user.
Each user's particular physiology and preferences are unique, so the more options presented for the use of the product the better. Most products available are designed to be used in only a single orientation (e.g., one end is used for massage, the opposite end is gripped in the hand) and only a fixed end is designed for contact with the body.
As such drawbacks in the art are recognized such as to require improvements relating to safety, effectiveness, and/or waterproofing, personal massage devices and related features and devices are provided.

This patent is subject to a terminal disclaimer.


An energy storage device having a variable momentum of inertia uses centrifugal forces acting on movable masses to self adjust its moment of inertia. The adjustment of the moment of inertia occurs without any additional energy input. Energy is stored as rotational kinetic energy and potential elastic and/or gravitational energy.

Flywheels are employed to store energy as rotational kinetic energy when the production exceeds demand or in machines that require large amounts of energy for short periods of time. In case of the production of electrical energy from wind, for example, it is typical to have excess energy with respect to demand in high wind conditions. For wind farm applications, the excess energy can be stored in a flywheel as rotational kinetic energy and released as electrical energy (power) when the demand becomes larger than the energy (power) produced.
To maximize the amount of stored energy, the moment of inertia and the angular velocity of a flywheel need to be as large as feasible. A flywheel with a fixed moment of inertia has the following characteristics: a) the release of rotational kinetic energy by the flywheel results in a decrease in its angular velocity, and b) the acceleration of the flywheel to the nominal angular velocity takes a long time. These characteristics are undesirable for certain applications partly because of they require output power conditioning. Thus, quickly achieving the nominal angular velocity and maintaining it within a narrow range while storing or releasing energy are desirable. These can be achieved by changing the moment of the inertia of the flywheel during operation. Accordingly, the moment of inertia should be small in the acceleration period, increase to a maximum to store the largest amount of energy possible, and then vary to maintain the nominal angular velocity as close to constant as possible.
Previous solutions of changing the moment of inertia of a flywheel have been based on hydraulic or mechanical systems. Some solutions consist of adding fluid to a hollow flywheel, fluid that is distributed to the outer region by the centrifugal force as described in U.S. Pat. No. 4,335,627 to Maxwell (1982) and U.S. Pat. No. 5,086,664 to Wagner (1992). Other solutions force the fluid between locations along the radius by pistons in cylinders placed radially as shown in U.S. Pat. No. 3,248,967 to Lewis (1966), by pumps between cavities that are placed at two different radii as described in U.S. Pat. No. 6,883,399 to Burstall (2004), or between cells that are arranged to control the mass distribution as presented by U.S. Pat. No. 4,546,264 to Pinson (1985). Mechanical means to vary the moment of inertia include the motion of two articulated counterweights that are moved away from the axis of rotation using a rack and pinion actuator as shown in U.S. Pat. No. 3,863,510 to Benson (1975). U.S. Pat. No. 4,725,766 (1988) and U.S. Pat. No. 4,730,154 (1988) both to Pinson describe the use of masses that can be moved along radial spokes by means of actuators. U.S. Pat. No. 4,926,107 to Pinson (1990) describes several methods to change the moment of inertia by employing either masses that are moved along spokes by actuator or fixed masses that are articulated at the hub in an "umbrella" configuration and swing away radially under the control of their respective drive motors. U.S. Pat. No. 4,995,282 to Schumacher (1999) describes a variable inertia flywheel using two masses that are mechanically pushed along the radial direction. U.S. Pat. No. 7,044,022 to Kim (2006) presents a variable inertia flywheel that is composed of a rotatable member and a body, both containing channels that guide movable masses. The rotatable member can be rotated with respect to the body hydraulically moving the masses along the radial direction. Leung in "IEEE Transactions on Magnetics, Vol. 27, January 1991" describes using a flywheel with variable moment of inertia for pulse conditioning for electromagnetic launch. U.S. Pat. No. 5,531,574 to Hiraishi et al. (1994) describes a variable inertia flywheel that is based on the motion of masses placed in cavities inside the flywheel. The masses are not connected to the cavities with the relative placement between the masses and the flywheel determined by the centrifugal force.
Many of the proposed solutions make the adjustment of the flywheel's moment of inertia by external means. Consequently, they require the input of additional energy into the system as well as separate means of control. This complexity introduces multiple potential points of failure and increases manufacturing and operation costs. Some of the proposed solutions are not designed primarily for efficient energy storage or conversion. Besides, flywheels operate at high velocities, imposing strict safety and durability constrains on the materials, and making implementation of some of the complex designs described in the literature even more challenging. The systems that employ liquids to adjust the moment of inertia do not have a large range of adjustment due to the smaller liquid density which results in a smaller mass Thus, a current need remains for energy storage devices that improve the energy storage and operational characteristics of existing flywheels.


A method for manufacturing an item in a series of sequential manufacturing steps, the method including the steps of conducting the series of sequential manufacturing steps according to instructions included in a manufacturer""s data record, prior to conducting one of the sequential manufacturing steps determining whether a customer data record exists, and if the customer data record exists, automatically replacing, supplementing and/or modifying the instructions included in the manufacturer""s data record with instructions included in the customer data record, and then completing the series of sequential manufacturing steps to produce the item so that it includes a characteristic specified by the customer in the customer data record.

The invention relates to a method for the process-controlled manufacture of an item.
In the prior art methods are known for the process-controlled manufacture of items, such as consumer goods or capital goods, in which, in the manufacture of a car, for example, the individual components are prefabricated by suppliers in a highly complex and specialized mass production and then gradually assembled on the car manufacturer""s assembly line. In this process the car manufactured represents an individual customer order corresponding to the set variants offered by the manufacturer, or for marketing reasons a standard car is produced, which is marketed at the dealers even without an individual customer order. Present day process-controlled mass production is inexpensive and also permits the manufacture of a certain number, albeit a limited number of variants determined by the manufacturer, in meeting customer requirements. Thus vehicles can be ordered and manufactured in different colours and with different trim packages.
Owing to the relatively small scope for conversion of process-controlled manufacturing methods, however, any adaptation to real, individual customer requirements is not feasible.
The object of the invention therefore is to provide a method for the process-controlled manufacture of an item, in which account can be taken of individual customer requirements. The intention is furthermore to provide an item, which has been produced by process-controlled manufacturing and has customized characteristics. Finally, yet another object of the invention is to provide a manufacturer""s data unit, which permits an customized production of items made by process-controlled manufacturing.
In the method according to the invention at least one process data record, which is used in a manufacturer""s data unit for the control of processing and/or test facilities, is replaced, supplemented and/or modified by a customer data record.
The customer data record contains specific characteristics of the item to be manufactured that have been requested by the customer. As the customer data record replaces, supplements and/or modifies the process data record, the data in the customer data record pass into the control system for the machining and/or test facilities, so that during the process-controlled manufacturing the manufactured item is endowed with the characteristics requested by the customer according to the customer data record.
This means that in process-controlled manufacturing and in the case of a continuous manufacturing process it is possible either to manufacture standard-versions of an item according to parameters set by the manufacturer i.e. according to existing process data records, orxe2x80x94if customer data-records are availablexe2x80x94it is then possible to customize the standard versions of the items to suit each customer. Production is furthermore organized cost-effectively and conversions to accommodate customer requirements can be accommodated immediately without interrupting the production flow. An item is produced which has precisely the individual characteristics requested by the customer according to the customer data record and which is thereby accepted and appreciated by the customer.
The method according to the invention therefore allows mass-produced items to be inexpensively customized so as to reliably meet the taste, wishes and appraisal of the customer. The manufacturer""s range is thereby adapted directly to customer requirements, so that no items are manufactured that the customer did not want or require.
Here the term xe2x80x9ccustomerxe2x80x9d must be taken in particular to mean the end user of the manufactured item, for example the purchaser of the manufactured motor vehicle, garment or other item.
The process data records, which serve for controlling the processing/test facilities (in short, the manufacturing machines) of the manufacturer in the manufacture of the item are usually concentrated in a manufacturer""s internal data bank and explicitly inaccessible from outside, especially by the customer.
According to the conventional method of manufacture, the manufacturer, especially in the case of highly complex, specialized equipment and products (for example, motor vehicles), receives a production order from a dealer, which the dealer has negotiated and defined together with the customer. The process data records of the manufacturer""s internal data bank are then generally activated according to the individual order and the car is manufactured in one of the defined variants that the customer has selected from the brochure at the dealer""s.
The method according to the invention now allows the customer, in this case the purchaser of the vehicle, direct access to the manufacturer""s data bank and the process data records filed therein by way of a (defined) interface without having to go through dealers or other such intermediaries. The actually internal manufacturer""s data bank therefore has at least one interface, which provides a connection to the outside world, that is, directly to the customer.
The customer data record is inserted into the manufacturer""s internal data bank by way of this minimum of one interface of the manufacturer""s internal data bank and replaces, supplements and/or modifies the existing process data records there, so that the item to be manufactured is no longer manufactured according to the standard process data records but according to the process data records which are replaced, supplemented and/or modified by the customer data record. An item is thereby produced which is manufactured for the individual customer.
In concrete terms this means, for example, that a customer who by way of a customer data record requests a certain interior colour scheme when ordering a car can achieve this by incorporating the customer data record into the manufacturer""s internal data bank by way of the (defined) interface.
In applying the interior colour scheme, which can be done by printing machines, for example, account is now taken of the customer information in the customer data record and the interior is designed, that it to say coloured or tinted directly according to the customer""s ideas.
All other sections of the process data records, such as those process data records relating to safety-relevant parts of the car remain unaltered.
The method according to the invention therefore allows the customer partial access, precisely definable by the manufacturer or the manufacturer""s supplier, to individual data fields of the process data records and allows him to customize these.
Combining of the customer data record with the process data records as described can be accomplished by way of a customer data unit, which is connected to the manufacturer""s data unit by way of a data line, e.g. on-line. The customer can therefore, for example, place orders for the manufacture of an item from home on their own personal computer, customize the item and possibly even modify it subsequently. The direct connection to the manufacturer""s data unit by way of at least one interface gives the customer constant access to the manufacturer""s data unit to the extent allowed by the manufacturer.
The customer data record can also be compiled with graphic, audio and/or visual elements according to an original supplied by the customer. Thus the customer himself can compile a graphic design or fabric pattern, which is then translated during printing of the respective fabric at the manufacturer""s. In another example the customer can record a personal photographic motif in the customer data record and then have this motif incorporated into the continuous manufacturing process for the printing of garments or the printing of a watch face, for example.
The customer can compile the customer data record by using conversion devices, such as a scanner, to transform the photographic original into the customer data record and data format according to the interface definition of the manufacturer""s data unit interface.
In order to ensure the safety of the manufacturing process, the manufacturer can block or fix specific data fields in the process data record relevant in terms of safety or other aspects, it being possible to replace, supplement or modify the data fields by means of the customer data record. In addition the manufacturer can define what data format (e.g. clock frequency, coding etc.) the customer must use in order to be able to combine the data present in the customer data record with the process data record by way of the interface.
According to a further variant of the method the manufacturer can also verify the content of the customer data record in order to ensure that despite the customized design the characteristics of the manufactured item still conform to the manufacturer""s product philosophy.
All of the manufacturer""s inspection and test procedures may also be omitted or automated, however, so that the customer has direct access to control of the manufacturing machines. For example, monitoring by the manufacturer can be confined to automated queries in connection with the customer data record (e.g. Is the data format correct? Can the specified customer data be translated by the manufacturing machine?). Such queries, however, may also be entirely omitted.
The item according to the invention is characterized by characteristics determined by the individual customer. An item produced by process-controlled manufacturing is thereby still inexpensive to manufacture by the continuous production process and can still possess the individual features required by the customer. The advantages of mass production (low costs) are combined with the advantages of a more manual one-off production (taking precise account of customer wishes).
The characteristics determined by the individual customer may be advantageously marked on the surface of the item, for example by inscription, coating or other method of surface application or removal. Every mass-produced item can thereby be visibly customized in accordance with the customer""s notions.
In a further advantageous embodiment the customized design features relate to the content of a memory module of the item, which is provided with individual customer features. Thus it is possible, for example to provide items having speech functions (for example a children""s toy), with the voice of the respective customer, thereby customizing the item. In general, many different functional and/or aesthetic characteristics of the manufactured item can be customized.
At least one process data record of the manufacturer""s data unit may be supplemented by data from a customer data record via the defined interface of the manufacturer""s data bank. In contrast to the conventional manufacturer""s data unit, which forms a closed data system, the manufacturer""s data unit according to the invention has at least one (defined) interface, which provides the customer with a connection for data communication or for data exchange and allows the customer, within limits set by the manufacturer himself, to control the manufacturing machines directly via the combination with the manufacturer""s internal process data records so that the manufactured item is customized.
The manufacturer""s data unit is connected by way of a data line (e.g. Internet) to the customer data unit (e.g. a personal computer). The customer data unit may be installed in the customer""s home, on the manufacturer""s sales premises or at the dealer""s. In the latter case the dealer may also advise the customer on compiling or preparing the original for the customer data record. An essential feature is, in particular, the direct access of the customer data unit to the manufacturer""s, data unit and the manufacturer""s manufacturing machines.
The customer data record, which is combined with at least one process data record of the manufacturer""s data unit, may comprise a large amount of data, which in addition to the characteristics of the item to be manufactured, that is the production data, may also contain order data and customer data. Thus, together with the customer data record, a production order can first be initiated at the manufacturer""s and the customer""s personal and address data can be transmitted to the manufacturer, so that the customized manufactured item can also be delivered directly to the customer.

Method and apparatus for process-controlled and client-specific production of an item


Disclosed are NgR proteins and biologically active Nogo (ligand) protein fragments. Also disclosed are compositions and methods for modulating the expression or activity of the Nogo and NgR protein. Also disclosed are peptides which block Nogo-mediated inhibition of axonal extension. The compositions and methods of the invention are useful in the treatment of cranial or cerebral trauma, spinal cord injury, stroke or a demyelinating disease.

Axons and dendrites of neurons are long cellular extensions from neurons. At the distal tip of an extending axon or neurite is a specialized region, known as the growth cone. Growth cones are responsible for sensing the local environment and moving toward the neuron's target cell. Growth cones are hand shaped, with several long filopodia that differentially adhere to surfaces in the embryo. Growth cones can be sensitive to several guidance cues, for example, surface adhesiveness, growth factors, neurotransmitters and electric fields. The guidance of growth at the cone depends on various classes of adhesion molecules, intercellular signals, as well as factors which stimulate and inhibit growth cones. The growth cone located at the end of a growing neurite advances at various rates, but typically at the speed of one to two millimeters per day. The cone consists of a broad and flat expansion, with numerous long microspikes or filopodia that extend like spikes. These filopodia are continually active. While some filopodia retract back into the growth cone, others continue to elongate through the substratum. The elongations between different filopodia form lamellipodia.
The growth cone can explore the area that is ahead of it and on either side with its lamellipodia and filopodia. When an elongation comes in contact with a surface that is unfavorable, it withdraws. When an elongation comes into contact with a favorable surface, it continues to extend and can manipulate the growth cone moving in that direction. Hence, the growth cone can be guided by small variations in surface properties of the substrata. When the growth cone reaches an appropriate target cell a synaptic connection is created.
Damaged neurons do not regenerate in the central nervous system (CNS) following injury due to trauma and disease. The absence of axon regeneration following injury can be attributed to the presence of axon growth inhibitors. These inhibitors are predominantly associated with myelin and constitute an important barrier to regeneration. Axon growth inhibitors are present in CNS-derived myelin and the plasma membrane of oligodendrocytes, which synthesize myelin in the CNS (Schwab et al., (1993) Ann. Rev. Neurosci. 16, 565-595).
CNS myelin is an elaborate extension of the oligodendrocyte cell membrane. A single oligodendrocyte myelinates as many as thirty different CNS axonal segments. Oligodendrocyte membrane extensions wrap around the axons in a concentric fashion to form the myelin sheath. Tightly compacted mature myelin consists of parallel layers of bimolecular lipids apposed to layers of hydrated protein. Active myelin synthesis starts in utero and continues for the first two years of human life. Slower synthesis continues through childhood and adolescence while turnover of mature myelin continues at a slower rate throughout adult life. Both developing and mature forms of myelin are susceptible to injury from disease or physical trauma resulting in degradation of the myelin surrounding axons.
Myelin-associated inhibitors appear to be a primary contributor to the failure of CNS axon regeneration in vivo after an interruption of axonal continuity, while other non-myelin associated axon growth inhibitors in the CNS may play a lesser role. These inhibitors block axonal regeneration following neuronal injury due to trauma, stroke, or viral infection.
Numerous myelin-derived axon growth inhibitors have been characterized (see, for review, David et al., (1999) WO9953945; Bandman et al., (1999) U.S. Pat. No. 5,858,708; Schwab, (1996) Neurochem. Res. 21, 755-761). Several components of CNS white matter, NI35, NI250 (Nogo) and Myelin-associated glycoprotein (MAG), which have inhibitory activity for axonal extension, have been also been described (Schwab et al., (1990) WO9005191; Schwab et al., (1997) U.S. Pat. No. 5,684,133). In particular, Nogo is a 250 kDa myelin-associated axon growth inhibitor which has been cloned and characterized (Nagase et al., (1998) DNA Res. 5, 355-364; Schwab, (1990) Exp. Neurol. 109, 2-5). The Nogo cDNA was first identified through random analysis of brain cDNA and had no suggested function (Nagase et al., (1998) DNA Res. 5, 355-364).
Schwab and colleagues published the sequence of six peptides randomly derived from a proteolytic digest of presumed bovine NI250 (Nogo) protein (Spillmann et al., (1998) J. Biol. Chem. 273, 19283-19293). A probable full-length cDNA sequence for this protein was recently deposited in the GenBank. This 4.1 kilobase human cDNA clone, KIAA0886, is derived from the Kazusa DNA Research Institute effort to sequence random high molecular weight brain-derived cDNA (Nagase et al., (1998) DNA Res. 31, 355-364). This novel cDNA clone encodes a 135 kDa protein that includes all six of the peptide sequences derived from bovine Nogo.
The human Nogo-A sequence shares high homology over its carboxyl third with the Reticulon (Rtn) protein family. Rtn1 has also been termed neuro-endocrine specific protein (NSP) because it is expressed exclusively in neuro-endocrine cells (Van de Velde et al., (1994) J. Cell. Sci. 107, 2403-2416). All Rtn proteins share a 200 amino acid residue region of sequence similarity at the carboxyl terminus of the protein (Van de Velde et al., (1994) J. Cell. Sci. 107, 2403-2416; Roebroek et al., (1996) Genomics 32, 191-199; Roebroek et al., (1998) Genomics 51, 98-106; Moreira et al., (1999) Genomics 58, 73-81; Morris et al., (1991) Biochim. Biophys. Acta 1450, 68-76). Related sequences have been recognized in the fly and worm genomes (Moreira et al., (1999) Genomics 58, 73-81). This region is approximately 70% identical across the Rtn family. Amino terminal regions are not related to one another and are derived from various alternative RNA splicing events.
From analysis of sequences deposited in the GenBank and by homology with published Rtn1 isoforms, three forms of the Nogo protein are predicted (Nogo-A, Nogo-B, Nogo-C). Nogo-B of 37 kDa might possibly correspond to NI35, and explain the antigenic relatedness of the NI35 and NI250 (Nogo-A) axon outgrowth inhibiting activity. Nogo-C-Myc exhibits an electrophoretic mobility of 25 kDa by SDS-PAGE and has been described previously as Rtn4 and vp2015. The ability of Nogo-A protein to inhibit axonal regeneration has been recognized only recently (GrandPré et al., (2000) Nature 403, 439-444; Chen et al., (2000) Nature 403, 434-439; Prinjha et al., (2000) Nature 403, 483-484).
The absence of re-extension of axons across lesions in the CNS following injury has been attributed as a cause of the permanent deleterious effects associated with trauma, stroke and demyelinating disorders. Modulation of NI250 has been described as a means for treatment of regeneration for neurons damaged by trauma, infarction and degenerative disorders of the CNS (Schwab et al., (1994) WO9417831; Tatagiba et al., (1997) Neurosurgery 40, 541-546) as well as malignant tumors in the CNS such as glioblastoma (Schwab et al., (1993) U.S. Pat. No. 5,250,414; Schwab et al., (2000) U.S. Pat. No. 6,025,333).
Antibodies which recognize NI250 have been reported to be useful in the diagnosis and treatment of nerve damage resulting from trauma, infarction and degenerative disorders of the CNS (Schnell & Schwab, (1990) Nature 343, 269-272; Schwab et al., (1997) U.S. Pat. No. 5,684,133). In axons which become myelinated, there is a correlation with the development of myelin and the appearance of Nogo. After Nogo is blocked by antibodies, neurons can again extend across lesions caused by nerve damage (Varga et al., (1995) Proc. Natl. Acad. Sci. USA 92, 10959-10963).
The mechanism of action whereby Nogo inhibits axonal growth has not yet been elucidated. Identification and characterization of this mechanism of action and the biochemical pathways associated with the effects of Nogo would be useful in treatment of disease states associated with axonal injury and axonal demyelination.

Nogo receptor-mediated blockade of axonal growth