A word line driver includes multiple current paths for driving a word line of a memory device to a negative voltage and a positive voltage. When driving the word line from the negative voltage to the positive voltage, the word line driver uses a first current path to drive the word line to the positive voltage in one stage. When driving the word line from the positive voltage to the negative voltage, the word line driver drives the word line from the positive voltage to ground using the first current path in a first stage. In a second stage, the word driver further drives the word line from ground to the negative voltage in using a second current path.

The present, invention relates generally to semiconductor devices, and in particular to drivers for word lines in memory devices.
Memory devices often reside in computers and electronic products to store data. A memory device has many memory cells, each holding an electrical charge that represents a bit of data. External data is stored in the memory cells during a write operation. The stored data is retrieved from the memory cells during a read operation. The write and read operations are memory access operations.
A typical memory device has a number of control lines, each connecting to one or more corresponding memory cells. During a memory access operation, the memory device controls a voltage on each control line to access the memory cells to either store data or retrieve data. Control lines of these types are usually called word lines.
A typical memory device has a number of word line drivers. Each word line driver drives a corresponding word line to various voltages. For example, some memory devices have word line drivers that drive the corresponding word lines to a positive voltage during a memory access operation. After the memory access operation, the word line drivers drive the corresponding word lines to a negative voltage.
Some memory devices have word line drivers that drive the corresponding word lines from a positive voltage to a negative voltage using one discharge path. In some of these memory devices, driving the word lines from a positive voltage to a negative voltage using one discharge path generates excessive noise, causing the memory device to perform inefficiently.
The present invention provides circuits and methods for driving word lines of memory devices to a negative voltage without generating excessive noise.
In one aspect, a memory device includes a memory cell connected to a word line. A word line driver drives the word line to various voltages. The word line driver has multiple paths: a first path and a second path, each connecting to the word line. The first path serves as both a charging path and a discharging path. The second path serves as another discharging path. During a first state of a control signal, the first path charges the word line to a positive voltage. During a second state of the control signal, the first path discharges the word line to ground. The second path further discharges the word line from ground to a negative voltage during the second state of the control signal.
Another aspect offers a method that includes driving a word line connected to a memory cell to a first voltage via a first path to access the memory cell. After the memory is accessed, the method drives the word line to a second voltage via the first path. The method further drives the word line from the second voltage to a third voltage via a second path. The first voltage, the second voltage, and the third voltage are unequal.


The invention relates to a combination ramp and gate that is releasably securable to a truck bed using a three point adjustable attachment system with carabineers, with two of the three carabineers being partially concealed. The combination ramp and gate is lightweight and when collapsed into a closed position, the sections of the combination ramp and gate are coplanar for easy storage and portability.

1. Field of the Invention
This invention relates generally to a combination truck bed ramp and gate, and more particular to an improved combination truck bed ramp and gate allowing easy loading and unloading of wheeled vehicles for pickup trucks and for extending the length of the truck bed onto the tailgate.
2. Description of the Related Art
Loading, unloading and transporting wheeled vehicles, like motorcycles, into a truck bed can be difficult due to the weight and unbalanced aspect of the wheeled vehicle. These tasks become even more difficult when performed by a single person. Further, truck beds tend not to be long enough to accommodate the wheeled vehicle, particularly with the tailgate closed. Various devices have previously been used as ramps for trucks, and specifically trucks having tailgates; however, none have satisfactorily solved the problem of easily getting motorcycles into the truck bed.
It is therefore desirable to provide a combination truck bed ramp and gate having a hinge design that allows the ramp/gate to fold flat for easy transport and storage.
It is further desirable to provide a combination truck bed ramp and gate having an easy and versatile three point adjustable attachment system with climbing style carabineer clips, with two of the three attaching carabineer clips being concealed.
It is yet further desirable to provide a combination truck bed ramp and gate constructed of a resilient, lightweight, non-rusting material, such as aluminum.
It is still further desirable to provide a combination truck bed ramp and gate having a length that reduces loading angle.


There is disclosed herein a fenestration for a building having a fenestration-securing opening cut therein. The fenestration includes a mounting frame assembly for fitting within the opening and a glazed sash carried in the mounting frame. The mounting frame and the sash each includes an extruded I-beam-like shaped core portion. The mounting frame core is constructed for securement to (a) an interior frame part, (b) exterior brick moulding or extrustion, (c) a sash weatherstripping and (d) a building flashing or seal. The sash core is an I-beam-like shaped extruded core having an interior member, exterior member, and glazing grasping portions. This construction permits the selective and flexible use of clear, finished, primed, unprimed, painted, stained, clad, etc., interior or exterior members and minimizes storage and inventory problems.

This invention relates to a fenestration construction, usually a window or a door, and more particularly, to a construction wherein the window can be selectively provided with a wood, vinyl, or aluminum appearance.
Fenestration refers to the arrangement, positioning and design of windows and doors in a building. Both windows and doors include a frame assembly for mounting in the building opening and a glazed sash assembly carried in the mounting frame assembly. Usually the sash assembly is movable with respect to the mounting frame assembly between closed and open positions. The movable sash assembly pivots in a casement or awning style window or slides in a double hung window or sliding door.
The mounting frame assembly and the sash assembly each include a frame that has been fabricated from wood members--namely, head, sill and jamb members. A generally transparent pane, usually glass, is fitted into the sash and counterweights, hinges, etc., are provided as necessary. Wooden brick moulding, vinyl or metal nailing fin are provided for securement to the mounting frame assembly to cover the space or interface between the mounting frame assembly and the building opening.
In some cases the customer orders windows with stained, primed or unprimed interior members. The exterior members can be stained, primed, unprimed, vinyl or aluminum clad. Cladding is usually bonded onto preformed base members and is intended to match the building exterior.
In order to manufacture these windows and doors, a large number of separate member parts are required as the head, sill and side members are generally uniquely shaped, of different lengths, and different finishes can be required for different applications.
It is therefore an object of this invention to minimize the number of different parts required to be manufactured and to be kept in inventory for windows and doors.
It is usually desirable to provide fully wooden interior surfaces which have been stained, primed or unprimed. It is also desirable to sometimes provide a clad exterior or a stained, primed or unprimed exterior. For example, a primed pine interior and a clad exterior may be requested. Another combination may be an oak interior and a cedar exterior. In this case, the shapes of the various parts are the same, but the wood or clad materials are different.
It is another object to provide a system or construction in which the desired finishes and combinations thereof can be easily and readily provided.
In devising a door or window construction, it is desirable to maximize the performance of the window or door by, inter alia, minimizing thermal conductivity therethrough.
It is therefore another object of this invention to provide a window construction in which performance is maximized.
In mull installations, window units are usually butted side-by-side against each other. Current window installation requires that a 28-inch building opening is cut for each 271/2-inch window. Thus, a 551/2-inch opening is cut for two 271/2-inch windows, etc. Thus, opening/window unit side spacing for a single unit may be one-half inch, one inch, etc. When assembling multiple units, it is seen that the end clearance or gap with the building will get larger.
It is another object to provide a construction in which the clearance or gap remains essentially the same regardless of the number of units.
These and other objects of this invention will become apparent from the following disclosure and appended claims.

Extruded core sections for wood fenestration mounting frames and sashes


A braking corrector governed by the height of a vehicle, comprises a body (10), in which is slideably mounted at least one piston controlled by an actuating rod (12) and arranged so as to interact with at least one valve element, in order to control at least one brake-fluid passage between at least one inlet (14,16) and at least one outlet (18,20) of the corrector. The corrector possesses a sensor detecting the height of the vehicle and formed from a lever (32), the pivot (34) of which is stationary relative to the body (10) of the corrector and one end (36) of which is connected to an unsuspended part of the vehicle, the distance between this end (36) and the pivot (34) defining a first lever arm, and the lever (32), which actuates the actuating rod (12) at a distance from the pivot (34), defining a second lever arm. The corrector possesses a mechanism (40,46,48,54) for varying the ratio between the lengths of the first and second lever arms.

The present invention relates to braking correctors and, more particularly, to such correctors governed by the height of a vehicle.
It is known that it is desirable to connect such a braking corrector directly to the suspension of a vehicle, in order to vary the braking of the wheels of a vehicle as a function of its height which is itself usually a function of its load.
Such correctors are well known in the art of braking and typically comprise a body, in which is slideably mounted at least one piston controlled by an actuating rod and arranged so as to interact with at least one valve element in order to control at least one brake-fluid passage between at least one inlet and at least one outlet of the corrector, the corrector possessing a sensor detecting the height of the vehicle and formed from a lever, the pivot of which is stationary relative to the body of the corrector and one end of which is connected to an unsuspended part of the vehicle, the distance between this end and the pivot defining a first lever arm, and the lever, which actuates the actuating rod at a distance from the pivot, defining a second lever arm.
Likewise conventionally, the connections between the lever and the actuating rod or the unsuspended part of the vehicle are made by elastic means, such as springs, so as to obtain a corrector-actuating force which is proportional to the distance between the suspended and unsuspended parts of the vehicle as a function of the rigidity of the spring.
It can happen that springs produced in large series have a considerable spread of their characteristics, especially their rigidity, which has a direct influence on the functioning of the corrector. Thus, in some cases, the activation pressure of the corrector can be well beyond acceptable tolerance limits.
Because it is not feasible to machine a spring on an industrial scale, it is therefore necessary to adjust the rigidity of the spring or its conditions of use.
The French Pat. No. FR-A-2,534,208 makes known a braking corrector of the type recalled above, possessing means of calibration at the time of assembly of the vehicle. These calibration means consist of an auxiliary element located between one of the ends of the spring for connection to the unsuspended masses, and an element of the unsuspended masses. This auxiliary element consists of a bent lever which is articulated on the unsuspended element and of which one of the arms carries a log for the fastening of the spring and the other arm can be locked in position of the unsuspended element by means of a screw engaged into a slot made in this other arm.
This device has several disadvantages. First of all, it requires an intermediate piece, the fastening of which experiences tangential shearing forces and is therefore fragile. Moreover, it makes it possible only with difficulty to carry out a fine adjustment of the prestress exerted on the spring. Finally, the main disadvantage of this corrector is that the adjustment is made only after it has been installed on the vehicle, thus necessitating additional and complicated manipulations for the mechanic during the assembly of the vehicle.

Braking corrector governed by the height of a vehicle


Disclosed is a library consisting essentially of a plurality of antigen-binding molecules differing in sequence from each other, wherein an antigen-binding domain in each of the antigen-binding molecules comprises at least one amino acid residue that changes the antigen-binding activity of the antigen-binding molecule depending on ion concentration conditions. Also disclosed are a composition comprising a plurality of polynucleotide molecules each encoding the antigen-binding molecules, a composition comprising a plurality of vectors each comprising the polynucleotide molecules, a method for selecting the antigen-binding molecules, a method for isolating the polynucleotide molecules, a method for producing the antigen-binding molecules, and a pharmaceutical composition comprising any of the antigen-binding molecules.

Antibodies have received attention as pharmaceutical agents because of their high stability in plasma and few adverse reactions. Among others, many IgG antibody drugs have already been launched, and a large number of antibody drugs are still under development (Non Patent Literatures 1 and 2). Meanwhile, various techniques applicable to second-generation antibody drugs have been developed. For example, techniques of improving effector functions, antigen-binding ability, pharmacokinetics, or stability or of reducing the risk of immunogenicity have been reported (Non Patent Literature 3). Possible problems of such antibody drugs are the difficult preparation of subcutaneous administration preparations (this is because the antibody drugs are generally administered at very high doses), high production cost, etc. Methods for improving the pharmacokinetics of antibodies and methods for improving the affinity of antibodies for their antigens may be used for reducing the doses of the antibody drugs.
The artificial substitution of amino acids in constant regions has been reported as a method for improving the pharmacokinetics of antibodies (Non Patent Literatures 4 and 5). Previously reported affinity maturation, a technique of enhancing antigen-binding ability and antigen-neutralizing ability (Non Patent Literature 6), involves mutating amino acids in, for example, CDR regions of variable regions, to thereby achieve enhanced antigen-binding activity. Such enhancement in antigen-binding ability can improve biological activity in vitro or reduce doses and can further improve drug efficacy in vivo (Non Patent Literature 7).
The amount of an antigen that can be neutralized by one antibody molecule depends on affinity. Stronger affinity allows the antibody in a smaller amount to neutralize the antigen. The antibody affinity can be enhanced by various methods (Non Patent Literature 6). An antibody capable of covalently binding to an antigen with infinite affinity would be able to neutralize, by one molecule, one antigen molecule (or two antigens in the case of a divalent antibody). Previous methods, however, have a stoichiometric limitation of neutralization reaction up to one antigen molecule (or two antigens in the case of a divalent antibody) per antibody molecule and are unable to completely neutralize an antigen using an antibody in an amount below the amount of the antigen. In short, there is a limitation of the effect of enhancing affinity. (Non Patent Literature 9). A given duration of the neutralizing effect of a neutralizing antibody requires administering the antibody in an amount above the amount of an antigen produced in vivo for the period. Only the above-mentioned technique for improvement in the pharmacokinetics of antibodies or affinity maturation is not sufficient for reducing the necessary antibody doses. In this respect, one antibody must neutralize a plurality of antigens in order to sustain its antigen-neutralizing effect for the period of interest in an amount below the amount of the antigen.
In order to attain this object, an antibody binding to an antigen in a pH-dependent manner has been reported recently as a novel approach (Patent Literature 1). This literature discloses that histidine residue is introduced to an antigen-binding molecule to prepare a pH-dependent antigen-binding antibody whose property is changed between neutral pH and acidic pH conditions. This pH-dependent antigen-binding antibody binds to the antigen strongly under the neutral condition in plasma and dissociated from the antigen under the acidic condition in endosome. Thus, the pH-dependent antigen-binding antibody can be dissociated from the antigen in endosome. The pH-dependent antigen-binding antibody thus dissociated from the antigen can bind to an antigen after being recycled back to plasma by FcRn. This allows one antibody to bind to a plurality of antigens repeatedly.
Antigens have very short plasma retention, compared with antibodies, which are recycled through binding to FcRn. Antibody-antigen complexes of antibodies having long half life in plasma (long plasma retention) and such antigens having short half life in plasma (short plasma retention) have plasma retention as long as that of the antibodies. The binding of an antigen to an antibody therefore rather prolongs its plasma retention and raises antigen concentration in plasma. In such a case, even improvement in the affinity of the antibody for the antigen cannot promote the clearance of the antigen from plasma. Reportedly, the pH-dependent antigen-binding antibody mentioned above is also more effective as an approach for promoting antigen clearance from plasma than conventional antibodies (Patent Literature 1).
Thus, the pH-dependent antigen-binding antibody can bind to a plurality of antigens by one antibody molecule to promote the clearance of the antigens from plasma, compared with the conventional antibodies, and as such, has effects that cannot be achieved by the conventional antibodies. An amino acid in an existing antibody sequence can be substituted to thereby impart thereto pH-dependent antigen-binding activity. Meanwhile, a method for obtaining antibodies from immunized animals or a method for obtaining antibodies from a human antibody library may be used for obtaining such a novel antibody, but has possible limitations as described below.
A method which involves immunizing non-human animals might produce the pH-dependent binding antibody, but may rarely yield pH-dependent antigen-binding antibodies against various types of antigens in a short time or selectively yield antibodies specifically binding to particular epitopes. Alternatively, an antibody may be enriched from a human antibody library with pH-dependent antigen-binding ability as an index. The frequency of appearance of histidine residues in the variable regions of a human antibody (registered in the Kabat database), however, is generally known to be not high, as seen from 5.9% for heavy chain CDR1, 1.4% for heavy chain CDR2, 1.6% for heavy chain CDR3, 1.5% for light chain CDR1, 0.5% for light chain CDR2, and 2.2% for light chain CDR3, suggesting that the human antibody library contains only a very small number of sequences that can have pH-dependent antigen-binding ability. Accordingly, there has been a demand for providing an antibody library that has the increased frequency of appearance of histidine in antigen-binding sites and is rich in sequences that can have pH-dependent antigen-binding ability.
Effects such as the promotion of antigen clearance from plasma may be achieved if the dependence of antigen-binding ability on a factor (other than pH) different between the environments of plasma and early endosome can be imparted to the antibody.
Citation lists of the present invention will be given below.

Ion concentration-dependent binding molecule library


A wireless mobile device in data communication with a platform may present on a display of the wireless mobile device graphic images and/or icons that may represent different information as a function of time, location, type of activity, type of event, anonymized trend data, push notifications and electronic messages. The graphic images and/or icons may be selectably visible on the display based on context-relevance of the information being displayed relative to an event, such as a rental of property by a traveler, for example. The graphic images and/or icons displayed may be determined by a data file that includes information configured to cause a visual characteristic of the graphic images and/or icons to dynamically change during different periods associated with an event, such as a pre-event, during-event, and post-event periods. Image/icon color, shape, size, opacity, position, transparency, intensity, invisibility, or other visual characteristics may be changed among images/icons being displayed.

Users (e.g., a guest, a traveler, a customer, a patron, a client) attending an event may often require relevant information at different times and/or at different locations while attending the event. In an example where the event may be a rental of property a traveler will stay at, relevant information may be dependent on factors such as time and location. As for time, some information may be more relevant to the traveler during different stages of their stay at the vacation rental, such as a pre-stay stage before the traveler has checked-in to the vacation rental, such as driving directions, where to park, etc., a during-stay stage where the traveler may require information to gain access to the vacation rental (e.g., keys or access codes), location of the vacation rental (e.g., in a complex of many similar rental units), locations for entertainment, dining, food, drink, etc., and a post-stay stage where the traveler may need information on check-out procedures, where to buy gas (e.g., if the traveler drove a car), etc.
In some examples, the traveler may be required to obtain relevant information from disparate sources during their stay; however, some of that information may not be contextually relevant for the stage of the stay the traveler is currently experiencing. For example, the traveler need not know a policy for use of swimming pools or location of the swimming pools during the pre-stay stage; however, what may be more contextually relevant to the traveler in preparation for arrival at the vacation rental are driving directions and a helpful list of items to pack. In some circumstances, the traveler may have to rely on other persons to provide the information, and those persons may not be available when the traveler needs them or may provide inaccurate or biased information. As one example, a traveler may desire an espresso drink and may need information on a location for a good espresso shop in walking distance of their vacation rental. Accordingly, information such as a trustworthy recommendation for one or more espresso shops and directions/locations of those espresso shops may be what is needed by the traveler. Ideally, information relevant to the traveler at the different stages of their stay would be provided by a central source that is available to the traveler on a continuous basis, such as 24/7, for example.
Thus, there is a need for devices, systems, methods and software that present contextually relevant information that may be customized for individual travelers.

Dynamic interface to present customized information contextually in relation to access to a property


A warewash machine includes a chamber for receiving wares, the chamber having at least one wash zone. A refrigerant medium circuit includes a first heat exchanger arranged to deliver refrigerant medium heat to a first fluid and a second heat exchanger arranged to provide a heat exchange relationship between the refrigerant medium and a second fluid, the first heat exchanger located upstream of the second heat exchanger in the refrigerant medium circuit. A bypass arrangement for causing at least some refrigerant medium to selectively bypass at least one of the first condenser or the second condenser based upon subcooled refrigerant medium condition.

Commercial warewashers commonly include a housing area which defines washing and rinsing zones for dishes, pots, pans and other wares. Heat recovery systems have been used to recover heat from the machine that would ordinarily be lost to the machine exhaust.
Waste heat recovery systems such as a heat pump or refrigeration system uses evaporator(s), compressor(s) and condenser(s) such that the operation involves thermal fluids (including refrigerant) for recovering waste energy and re-using captured energy at areas of interest. The systems require the thermal fluid to operate within a specified envelope to prevent system shut down from high or low pressure, hence, the need for effective controls.
It would be desirable to provide a heat recovery system that adapts to machine operating condition in order to make more effective use of heat recovery. It would also be desirable to provide a heat recovery system that is able to more effectively maintain desired subcooled condition of refrigerant medium.

This patent is subject to a terminal disclaimer.


Methods for modulating (inhibiting or stimulating) retinoid-related orphan receptor γ (RORγ) activity. This modulation has numerous effects, including inhibition of TH-17 cell function and/or TH-17 cell activity, and inhibition of re-stimulation of TH-17 cells, which are beneficial to treatment of inflammation and autoimmune disorders. Stimulation of RORγ results in stimulation of TH-17 cell function and/or activity which is beneficial for immune-enhancing compositions (e.g., vaccines).

Many forms of serious human disease result from an autoimmune attack on the body. Many forms of autoimmune disease, such as rheumatoid arthritis, multiple sclerosis, psoriasis, and Crohn's disease, are particularly difficult to treat. An activated CD4+ T cell that releases interleukin-17 (IL-17), a powerful pro-inflammatory cytokine (Aggarwal, Ghilardi et al. 2003), and is referred to as a TH-17 cell (Bettelli, Carrier et al. 2006; Mangan, Harrington et al. 2006; Veldhoen, Hocking et al. 2006), may be a significant pathogenic factor autoimmune disease, based on observations that patients have high levels of IL-17 expression in target tissues. For example, the level of IL-17 mRNA was found to be elevated in brain autopsy tissue from patients with MS compared with controls, and the number of IL-17 positive mononuclear cells was also increased in the cerebrospinal fluid of affected patients (Matusevicius, Kivisakk et al. 1999; Lock, Hermans et al. 2002; Vaknin-Dembinsky, Balashov et al. 2006). Rheumatoid arthritis (RA) also appears to involve a T cell-mediated autoimmune reaction. The level of IL-17 mRNA in synovial fluid of rheumatoid arthritis patients is predictive of disease progression (Kirkham, Lassere et al. 2006). Furthermore, TH-17 cells have been isolated from intestinal biopsies of patients with Crohn's Disease (Annunziato, Cosmi et al. 2007), and their frequencies are elevated in comparison to T cells isolated from normal intestine or peripheral blood. In disease tissue of psoriasis patients, levels of IL-22, another proinflammatory cytokine produced by TH-17 cells, are elevated (Zheng, Danilenko et al. 2007).
TH-17 cells, also referred to as IL-17+CD4+ T or TIL-17 cells, have only been recently characterized and are distinct from the TH1 and TH2 lineages of CD4+ effector T cells. The relationship of TH-17 cells to the TH1 and TH2 lineages is diagrammed in FIG. 1. TH1 and TH2-derived cytokines (such as IFN-γ and IL-4) block TH-17 formation (FIG. 1) and targeted deletion of some transcription factors considered to be central for maintenance of the TH1 and TH2 phenotype have no major effect on TH-17 differentiation (Harrington, Hatton et al. 2005; Park, Li et al. 2005). IL-23 expression in mouse is required for induction of T cell-derived IL-17, and in culture IL-23 seems to act as a survival factor for pre-existing TH-17 cells but does not stimulate TH-17 formation from naïve CD4+ T cells. Instead, the combination of TGFβ and IL-6 is required to stimulate the formation of TH-17 cells from naive mouse CD4+ T cells, and there is genetic evidence in mouse for the involvement of IL-6 and TGFβ in TH-17 formation in vivo (Bettelli, Carrier et al. 2006; Mangan, Harrington et al. 2006; Veldhoen, Hocking et al. 2006). The cytokine requirements for TH-17 differentiation in human are somewhat different that in mouse but the TH-17 phenotype is similar, including expression of IL-17, IL-22, and RORγ (Annunziato, Cosmi et al. 2007; Kebir, Kreymborg et al. 2007).
The older view that autoreactive CD4+ TH1 cells are a prime cause for the development or progression of MS and other forms of autoimmune disease has been challenged (Steinman 2007) by recent results from rodent models showing that mice with a targeted deletion in the p35 subunit of IL-12, which is required for the formation of TH1 cells, are still highly susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) after immunization with myelin antigens (Becher, Durell et al. 2002; Gran, Zhang et al. 2002). In contrast, the knockout of either p19, the unique subunit of the cytokine IL-23, or p40, a common subunit of the two cytokines IL-12 and IL-23, create mice that are resistant to the induction of EAE (Cua, Sherlock et al. 2003; Langrish, Chen et al. 2005).
In addition to EAE, development of disease in a mouse model of rheumatoid arthritis, collagen-induced arthritis (Courtenay, Dallman et al. 1980), is also dependent on IL-23 function and is correlated with an increased level of TH-17 cell activity, such as release of IL-17 in affected tissues (Murphy, Langrish et al. 2003; Sato, Suematsu et al. 2006). Inhibition of IL-17 may be a viable alternative to inhibition of TNFα in treatment of RA (Lubberts, Koenders et al. 2005). Further, IL-23 expression is required for induction of IBD in mouse, and TH-17 cells appear to be an important downstream mediator of IL-23 effect in this model (Yen, Cheung et al. 2006). Disease progression in EAE models is partially suppressed in IL-17−/− mice or after treatment with anti-IL-17 antibodies (Iwakura and Ishigame 2006). IL-17−/− mice also show reduced incidence and severity in a collagen-induced arthritis (CIA) model for rheumatoid arthritis and IL-17 antibodies have been shown to attenuate development of intestinal inflammation in rodent models of IBD (Nakae, Nambu et al. 2003; Yen, Cheung et al. 2006). Further, purified autoreactive TH-17 cells strongly induce encephalomyelitis when transferred to naive mice, leading to more dramatic disease manifestation compared to disease induction by TH1CD4+ T cells (Langrish, Chen et al. 2005; Komiyama, Nakae et al. 2006). The IL-27 receptor is prominently expressed in TH-17 cells and the action of IL-27 as an inhibitor of murine EAE is correlated to reduced TH-17 cell number in the animal (Batten, Li et al. 2006; Stumhofer, Laurence et al. 2006). Therefore, the activity of murine TH-17 cells is well correlated to disease.
Inhibition of the human equivalent of the mouse TH-17 cell is a highly desirable target for new therapeutic agents to treat autoimmune disease. Recent findings implicate TH-17 cells in the pathogenesis of Crohn's disease and more generally inflammatory bowel disease (IBD). Antibody to the common subunit of IL-23 and IL-12, p40, is safe and may be clinically effective in treatment of Crohn's disease (Mannon, Fuss et al. 2004). A recent Phase 2 clinical trial also shows that anti-p40 is highly effective in the treatment of psoriasis (Krueger, Langley et al. 2007). The identification of TH-17 cells has not only provided insight into autoimmune pathogenesis, it has also revealed a major pathway of adaptive immunity for extracellular microbes (Mangan, Harrington et al. 2006; Annunziato, Cosmi et al. 2007). Stimulation of TH-17 differentiation, function and cytokine release therefore has the potential to enhance protective immunity by increasing T cell reactivity to pathogenic organisms and other targets, such as cancer-associated antigens.
Structure and Function of RORγ
RORγ (NR1F3), a ligand-regulated nuclear transcription factor from the steroid/retinoid/thyroid family (Jetten, Kurebayashi et al. 2001), has been shown to be essential for CD4+ TH-17 development and/or function. RORγ participates in and is required for the development of TH-17 cells. TH-17 cells are absent from genetically-engineered mice that fail to express a specific splicing isoform of RORγ, RORγt (Ivanov, McKenzie et al. 2006; Littman and Eberl 2006). Furthermore, an RORγt-GFP transgene that expresses GFP from the RORγt promoter is expressed in CD4+IL-17+ T cells from the lamina propria of the gut and other tissues. In cell culture, transfection of RORγt into naïve murine CD4+ T cells induces differentiation of these cells into IL-17 expressing T cells even in the absence of the inducing cytokines IL-6 and TGFβ. The data suggest that the transcriptional activity of RORγt is of major importance to TH-17 cell differentiation and function (Ivanov, McKenzie et al. 2006). RORγt expression is induced in the presence of TGFβ and IL-6 or by TGFβ and IL-21, an autocrine cytokine released from developing TH-17 cells in response to IL-6 (Ivanov, McKenzie et al. 2006; Korn, Bettelli et al. 2007; Nurieva, Yang et al. 2007; Zhou, Ivanov et al. 2007).
The expression of RORγ follows a similar pattern in human as in mouse T cells: RORγ is more highly expressed in IL-17 or IL-17/IFNγ expressing CD4+ T cells (Th-17) than in CD4+ T cells that express IFNγ alone (Th-1) (Acosta-Rodriguez, Napolitani et al. 2007; Acosta-Rodriguez, Rivino et al. 2007; Annunziato, Cosmi et al. 2007; Wilson, Boniface et al. 2007). Finally, it has been reported that other murine T cell types express RORγt, including γδTCR+ cells, CD8+ T cells, and iNKT cells (Ivanov, McKenzie et al. 2006; Ivanov and Littman 2007). Since these cells are also express IL-17, it is possible that RORγt is required for the differentiation of the IL-17+ subpopulations of several other types of T cells.
Finally, in the absence of RORγt, mice are much less susceptible to the induction of EAE (Ivanov, McKenzie et al. 2006). These studies were carried out in immunodeficient mice. RORγt−/− mice lack lymph notes, and although they are resistant to the development of EAE, a further study was carried out by adoptive transfer of RORγt wild type or RORγt−/− bone marrow to immunodeficient mice. While transfer of normal bone marrow rendered the mice sensitive to the induction of EAE by peptide immunization, the RORγt−/− transfectants were substantially resistant (Ivanov, McKenzie et al. 2006). These data suggest that RORγt mediated regulation of T cell differentiation is involved in the development of autoimmune disease.
RORγStructure. RORγ, like other members of the nuclear receptor family, has a bipartite structure with two major functional domains, a DNA binding domain (DBD) and a ligand binding domain (LBD, see FIG. 2) (Medvedev, Yan et al. 1996). Ligand-regulated transcription of the nuclear receptors is mediated through the LBD, which has been crystallized for many receptors (Li, Lambert et al. 2003), including RORα and RORβ, the receptors most closely related to RORγ. The RORγ LBD is predicted to have a binding pocket similar to RORα and RORβ (Stehlin, Wurtz et al. 2001; Kallen, Schlaeppi et al. 2004). The retinoic acid receptors (RARα, RARβ, and RARγ) are more distantly related and appear not to have a functional overlap with the RORs (Jetten, Kurebayashi et al. 2001).
The nuclear receptor LBD recruits transcriptional coregulators (FIG. 2) in response to small molecule compounds (Li, Lambert et al. 2003; Savkur and Burris 2004). These coregulatory proteins act as sensors for the conformational state of the ligand-bound complex and in turn regulate the recruitment of transcriptional factors to chromatin adjacent to the receptor. Short peptide domains of the coregulatory proteins required for interaction with the nuclear receptor contain the conserved sequence LXXLL (SEQ ID NO: 1), and synthetic peptide recruitment assays based on this motif are widely used to monitor the binding of agonists and antagonists to the nuclear receptor LBD (Lee, Elwood et al. 2002; Savkur and Burris 2004), including for an assay described herein for RORγ.
Functional Studies of RORγ.
Recognition of specific DNA motifs by the nuclear receptor DBD determines specificity for gene transcription; however, little is known about specific gene targets for RORγ, and the major findings on RORγ function have been derived from studies of gene-targeted mice (Kurebayashi, Ueda et al. 2000; Sun, Unutmaz et al. 2000; Eberl and Littman 2004; Eberl, Marmon et al. 2004). RORγ has two splicing isoforms, RORγ and RORγt (He, Deftos et al. 1998). RORγt differs from RORγ by a truncation of 21 amino acids at the N-terminal and is the isoform specifically expressed in thymus, lymph node precursors, and TH-17 cells (Eberl and Littman 2004; Eberl, Marmon et al. 2004; Ivanov, McKenzie et al. 2006; Littman and Eberl 2006), the major tissues affected in knockout studies of RORγ. The significance of the N-terminal deletion of RORγ is not known, but it is unlikely to affect ligand specificity or LBD function, which is encoded at the receptor's C-terminal and is identical in the two splicing isoforms.
In addition to its requirement for TH-17 differentiation, RORγ has other discrete functions in the immune system. In its absence, the survival of the major subtype of developing T lymphocytes, the CD4+CD8+ double positive (DP) thymocytes, is reduced (Kurebayashi, Ueda et al. 2000; Sun, Unutmaz et al. 2000), and the embryonic formation of lymph nodes and Peyer's patches is blocked (Eberl, Marmon et al. 2004). RORγt is an early marker for the embryonic formation of lymphoid tissue inducer or LTi cells. LTi cells are involved in lymph node and Peyer's patch formation during embryogenesis (Eberl, Marmon et al. 2004). After birth, an LTi-like cell participates in formation of intermediate lymphoid follicles (ILFs) of the gut. These lymphoid structures appear to participate in the gut immune response (Eberl and Littman 2004). RORγ is also expressed in liver, muscle, and fat (Jetten, Kurebayashi et al. 2001; Fu, Sun et al. 2005). A recent study of RORγ−/− mice also suggests that the receptor has some regulatory effects on Phase 1 and Phase 2 detoxification enzymes (Kang, Angers et al. 2007).
Clinical Significance.
Three major points of action of RORγ in the immune system have been identified in gene knockout studies; T cells, including the TH-17 cell, lymph node formation, and survival of DP thymocytes. Of these, regulation of IL-17+ T cell function, including TH-17 differentiation, appears to be most relevant to human therapeutics. Not only is the receptor absolutely required for TH-17 differentiation, but the supply of pathogenic TH-17 cells must be constantly replenished since they are destroyed in target tissue (Gold, Linington et al. 2006). Inhibition of new TH-17 formation will therefore have important benefits. RORγ is expressed in human memory TH-17 cells (Acosta-Rodriguez, Rivino et al. 2007; Annunziato, Cosmi et al. 2007), and data presented herein shows that RORγ antagonists block IL-17 expression in human peripheral blood mononuclear cells (PBMCs). The primary source of IL-17 in PBMCs has been reported to be memory T cells (Shin, Benbernou et al. 1999). Finally, RORγ enhances, but is not absolutely required for, the survival of the major developing T cell type of the thymus, the DP thymocyte. In the knockout animal, there is no evidence of immunodeficiency although splenic and peripheral frequencies of some immune cell types are changed. However, there is a much higher rate of apoptosis among thymocytes and thymocyte number is reduced (Kurebayashi, Ueda et al. 2000; Zhang, Guo et al. 2003). The thymus of an adult has already atrophied to a considerable degree and can be reversibly suppressed by many forms of pharmacological treatment, including exposure to steroids (Haynes, Markert et al. 2000). These data suggest that secondary effects of an RORγ antagonist on thymic function in human may not be clinically significant.
Prior to 1990, no drugs to treat MS were available. In the last 15 years, several treatment options have emerged, primarily various forms of INFβ (Avonex, Rebif, Betaseron), Glatiramer acetate (Copaxone) and the chemotherapeutic drug mitoxantrone (Novantrone) (Rolak 2003). INFβ and Glatiramer acetate both appear to inhibit T cell activation and both drugs reduce the number of attacks in relapsing-remitting MS but have little effect in the progressive phase of the disease (Dhib-Jalbut 2002; Rolak 2003). The long-term benefits of these drugs are unclear. Mitroxantrone appears to retard progression and delay disability in secondary progressive MS. However, toxicity of this drug is very limiting and Mitroxantrone is considered a short-term treatment option. More recently, a humanized antibody to α4β1 integrin (NATALIZUMAB, Tysabri) has been approved for the treatment of MS and has been shown to slow disease progression and reduce relapse rate in several clinical trials using different outcome measures (Steinman 2005). Compared to existing treatments, the efficacy of Tysabri is quite dramatic. However, several cases of progressive multifocal leukoencephalopathy (PML), a lethal resurgence of a latent viral infection linked to the immunosuppressive action of the drug, led to withdrawal (Rudick, Stuart et al.). Tysabri has now been reintroduced into the market with much stricter patent monitoring. Tysabri likely blocks both TH-17 and TH1 cells. A novel small molecule drug that is specific for TH-17 cells and does not compromise the antiviral activity of TH1 cells could be safer and more effective for several reasons: (1) a small molecule drug, administered daily, can be rapidly withdrawn if significant side effects occur; (2) a small molecule drug is more readily manufactured and more easily administered than a biologic, such as Tysabri; and (3) TH1 cells suppress TH-17 differentiation and thus specific inhibition of TH-17 cells may be more effective.
A number of other small molecule drugs are marketed for autoimmune diseases such as rheumatoid arthritis, IBD, and psoriasis. Many of these, such as methotrexate or azathioprine, carry significant toxicity because of anti-metabolite or anti-mitotic effects. Dosing is usually limited. A small molecule drug that has a more specific mechanism of action, such as inhibition of TH-17 cells or other IL-17 expressing T cells, are likely to be safer and, hence, more efficacious as dosages may be elevated to have a substantial inhibitory effect on target cells.
Pharmacologically useful ligands to members of the ROR family of orphan nuclear receptors have not been identified in the published literature. Cholesterol and cholesterol sulfate occupy the ligand binding pocket within the receptor LBD of RORα as determined by x-ray crystallography (Kallen, Schlaeppi et al. 2002; Kallen, Schlaeppi et al. 2004), but, due to the fact that these molecules are plentiful in normal cells, it has not been possible to use these molecules in order to characterize RORα as a pharmacological target (Moraitis and Giguere 2003). A series of RORα ligands was published in 1996 (Missbach, Jagher et al. 1996; Wiesenberg, Chiesi et al. 1998), but these findings have not been independently replicated or evaluated by functional criteria described below. One of the proposed ligands for RORβ, melatonin, has been challenged in the literature (Becker-Andre, Wiesenberg et al. 1994; Greiner, Kirfel et al. 1996; Becker-Andre, Wiesenberg et al. 1997). More recently, it was proposed that all-trans retinoic acid and the synthetic retinoid ALRT 1550 are functional ligands for RORβ and that these two ligands also regulate RORγ in a similar manner, in both cases inhibiting the transcriptional activity of the receptors. All-trans retinoic acid and ALRT 1550 were referred to as "functional" ligands because they were presumed to both bind and regulate transcription through RORβ. The ligands are unlikely to be useful pharmacologically because they are potent activators of the retinoid receptors, RARα, RARβ, RARγ (Thacher, Vasudevan et al. 2000). Therefore all of these ligands fail the test of functional usefulness either on the criterion that their effects have not been reproducible, or because they are ubiquitous, or because they lack specificity. This application describes assay for RORγ, and RORγ ligands that have pharmacologically useful potency (in the range of 50 nm to 1 that have good selectivity, as demonstrated by assays for other members of the nuclear receptor family. These ligands, both agonists and antagonists, have drug-like properties as indicated by rational structure activity relationships among analogues as well as other drug-like properties such as bioavailability and activity in cellular and animal models. Specific RORγ antagonists are predicted to be highly useful in treatment of autoimmune disease by blocking TH-17 function. Agonists of RORγ are predicted to enhance immunity and to have application in stimulation of vaccination and in adjuvant cancer therapy.

Modulators of retinoid-related orphan receptor gamma


An apparatus for executing a computer game are provided. The apparatus includes an output unit configured to transmit a first image generated based on a form of a first user participating in the computer game and a second image generated based on a form of a second user participating in the computer game to a display apparatus, and a control unit configured to predict a possibility of a collision between the first user and the second user, and to control transmitting warning information indicating the possibility of the collision to the display apparatus via the output unit, according to a result of the predicting.

A computer game, executed based on a gesture by a user participating in the computer game, has been developed. For example, a computer game, in which it is determined whether a mission is complete according to a motion of a user, has been developed.
However, while a computer game is being executed, a user may collide with another user who is in a place near the user or a thing that is disposed near the user, according to a motion of the user.
Accordingly, there is a demand for development of a method or an apparatus for preventing a collision of a user participating in a computer game with another user or a thing.
The above information is presented as background information only to assist with an understanding of the present disclosure. No determination has been made, and no assertion is made, as to whether any of the above might be applicable as prior art with regard to the present disclosure.

Method and apparatus for preventing a collision between users of an interactive computer game


Systems and methods for core network topology router placement planning are provided. The systems and methods may use existing network data to create a data set and use the data set to optimize a network for the placement of routers.

A computerized network contains more than one node and more than one link between the nodes. In large scale networks involving large amounts of nodes and links and transporting a large amount of traffic, IP network design and transport network design is crucial. Efficient network designs reduce network traffic problems, try to ensure that all nodes can access and send traffic efficiently, and may ensure that the failure of one node or link does not endanger the rest of the nodes and links from functioning effectively. Efficient network designs also minimize the overall cost of the network, by effectively utilizing links and positioning core routers in a way to minimize the total number of core routers.
IP network design and transport network design are typically completed as separate tasks. Implementing and optimizing one first and then the other may not optimize the overall network, resulting in an overall sub-optimal network design.

System and method for core network topology router placement planning


Apparatus and methods for sharing electronically rendered information between a plurality of devices over a data communications network with limited used of network data storage is described. Content may be shared automatically between members of a share group, without interactive content-sharing operations being executed by users. The embodiments include content tagging, commenting, searching, and syncing of content. Action metadata messages, that are not viewed by a user of a device, may be sent separately from content portions to notify share-group members of content to be shared. Sharing of content can be accomplished via peer-to-peer links as well as intermediary links, which may execute concurrently.

Since the development of networked computers, there have been various ways in which documents and other informational content can be shared between one or more computers or devices connected to the network. In the early days of networked-based communications, file sharing or file exchange may have taken place in active peer-to-peer sessions. Typically, both a sending device and a receiving device would be required to be active and on line concurrently so that data could be transferred from a sending device to a receiving device. In some cases, manual execution of specific data transmission procedures was required by at least one user at the sending node and/or the receiving node for successful transfer of the content to be shared.
One example of an early file-sharing paradigm is the file transfer protocol (FTP). In the early FTP protocols, both sending and receiving devices were required to be active at a same time so that data communications could be carried out using two communication channels. One channel might be used to transport the desired content, whereas the second channel might be used to communicate message transfer commands and replies between the sender and receiver. In some cases, a user would be required to enter file transfer commands at a terminal to at least initiate the FTP process.
Recent developments in file sharing offer web-based solutions that require web-based or cloud data storage. One such solution is the Dropbox service offered by Dropbox, Inc. In a web-based file sharing approach, a sender may store any content for later retrieval at an intermediary device, e.g., a data-storage node, on the network. Once stored, the content is available from any location at which access may be gained to the network, and at any time. Such web-based solutions can offer convenience of use, since both sender and receiver need not be active and on-line simultaneously. However, these solutions can require large amounts of data storage space depending on the number of users and amount of content that is shared by each user.

Content sharing with limited cloud storage


The invention relates to a method for the combined analysis of a sample with objects to be analyzed, in particular a sample with biological objects, in which measurement results for one or more of the objects to be analyzed in the sample are obtained by analyzing the one or more objects to be analyzed by an imaging method of measurement, probe-microscopic measurement results are obtained for the one or more objects to be analyzed by analyzing the one or more objects to be analyzed by a probe-microscopic method of measurement, and the measurement results and the probe-microscopic measurement results are assigned to one another, after optional prior intermediate processing. Furthermore, the invention relates to an apparatus for carrying out combined analysis of a sample with objects to be investigated, in particular a sample with biological objects.

Cell biology and biomedical and pharmacological/biotechnological research and production that are dependent thereon are increasing in importance. This is embedded in research into gene and protein characterization, influenced by the Human Genome Project. This now also includes the creation and analysis of siRNA libraries (cf. for example Pepperkok et al., Nat Rev Mol Cell Biol 2006; 7: 690-696, High-Throughput Fluorescence Microscopy for Systems Biology) connected with methods for high throughput with automated imaging, optical methods and dispensing.
Several, already existing modules can be defined for this automated image-based high throughput for cell evaluation. To date, a core element of high throughput is automated micrography. This also includes image analysis with the corresponding data management (cf. for example the product Opera from the company Evotec Technologies). Another module can comprise various aspects of fluidic manipulation. This means for example the addition/dispensing of further agents, changing of media etc. For working with cells, the manipulation of cell culture vessels, so-called multi-plates such as 96-well and 384-well plates is essential. This means automated plate changing. In order to keep the cells as viable as possible even for longer-lasting analysis of quite large quantities of plates, various designs of a climate-control module are also offered by commercial suppliers. Meanwhile, some suppliers have developed automated systems, in particular for cultivating adherent animal cells and evaluating them by microscopy. The highly complex systems will not be explained in detail here, as they are commercially available (see for example Terstegge et al., Nature Methods 1, 271-272, 2004, Hamilton's new cellhost system for full automation of embryonic stem cell cultures). As a result of analysis, optical (mainly image-based) properties of the biological sample are used in particular for assessment, and features such as pH changes and ion-selective change of the medium only to a small extent.
A technique originally designed for the analysis of individual cells is the classical patch-clamp technique. For the screening of active substances, later on automatic systems were developed, which automate measurement and rinsing procedures and in addition are operated in parallel in a modified planar structure (cf. for example the description of the MDC PatchXpress 7000A, 16-Channel Automated Patch Clamp System, http://www.chantest.com/fastpatch.html). Manual patching is the gold standard—with sensible protocols there are hardly any false-negatives and false-positives. With planar patching, the sensitivity is reduced and the deviation can be at a factor of three, and even more with increased automation, and additionally false-negative results in particular may be increased. Therefore, in the search for active substances, various patch techniques—varying in price, throughput, and accuracy of the information obtained—are employed in the preliminary, main, and final phases of measurement campaigns.
Automated systems and automated imaging techniques for investigating cell-biology processes are known, and are used in the pharmacological, medical and cell-biology research and analysis of active substances including substance screening. Typically, fluorescence-optical properties are evaluated, such as change in intensity of fluorescence, distribution of fluorescence or a shift of fluorescence, which can for example result from energy transport (FRET: fluorescence resonance energy transfer). Measured values are recorded both by confocal and non-confocal techniques. Camera-based image recording is very quick. Depending on fluorescence labelling, camera sensitivity, the objective lens, the resolution and the excitation intensity, typically about 2 to about 100 cells with a cell size of about 10×10 μm2 and a cell height of 5 μm are recorded simultaneously at an exposure of for example 40 ms. This speed generally also allows recording of images in different z-heights (z-stack). In optical imaging techniques, image evaluation is the time-limiting factor.
In addition to optical imaging techniques, there are also methods of measurement using scanning probe microscopy (SPM). Scanning probe microscopy is a technique in which a measuring probe scans a sample to be analysed and for example records the topography of the sample. In this connection there is relative motion between the measuring probe and the sample, which is achieved by moving at least the measuring probe or at least the sample. Usually the relative motion is performed as a lateral movement. Additionally, there can also be relative motion in the vertical direction. One form of scanning probe microscopy is scanning force microscopy (SFM). In a scanning force microscope used for this, the measuring probe is designed as a cantilever, which carries a fine measuring tip. The SFM techniques include the AFM technique (AFM: atomic force microscopy).
An SPM measurement can be carried out as a slow, label-free imaging technique. On a cantilever measuring beam there is a suitable measuring tip, for example a ligand-coated particle. The measuring beam and the measuring tip form a measuring probe, which is also called a cantilever. For measurement, a relative motion is performed between the measuring probe and a sample to be analysed, which can for example be cells with a set of receptors corresponding to the ligand. Molecular interactions between the sample (receptors) and the measuring tip (ligand) can lead to a deflection of the measuring probe, which can be documented in particular as bending of the measuring beam.
The SPM technique finds application both in the analysis of molecular interactions between isolated proteins and in the analysis of for example receptor-ligand interactions on cell-cell, cell-particle or cell-substrate samples. The result of the analysis typically comprises a description of mechanical characteristics such as viscoelasticity, strength of adhesion and surface topology. Automation of the SPM technique has been considered, as disclosed for example in documents DE 10 2004 048971 and WO 2006/040025. These describe an automated set-up for measurement and evaluation by scanning microscopy.
If, during probe-microscopic analysis of a sample, there is lateral movement of the measuring probe relative to the sample, a surface image can be recorded with the corresponding mechanical-elastic properties of the sample. A disadvantage is that for imaging when using an AFM microscope, depending on the local resolution of measurement, about 10 min to 1 h is required for one cell. Therefore there are clear limitations on the use of the AFM technique for the industrial screening of active substances. To improve the time factor, the use of multi-cantilevers has been proposed (cf. DE 10 2007 023 435). Alternatively, the areal imaging property of the AFM technique is abandoned and the sample is only scanned at points, so that measurements of local interaction are carried out. This measurement principle is usually known as single cell force spectroscopy (SCFS). The mechanical properties that can be determined by AFM include for example elasticity, e.g. the elasticity of one cell, and measurement of the forces on cell-cell or cell-substrate contacts. With a suitable choice of measuring probe design, the sample can also be analysed electrically.
There are essential differences between the measurement of mechanical properties such as protein-protein interactions and measurements on cell-free preparations and cellular samples. These include the far larger height dimension of cells (z-height) and the discontinuous distribution of the cells. Typically, the cells do not form a uniform continuum on a cultivation substrate in vitro. Their height profile itself and the relative position of important cell organelles can vary, so too can the cell-cell distance and the cell shape. Therefore it is also important in single-cell force microscopy to employ special placement of the measuring tip. A property of confocal microscopy is that only an image segment limited in height to about 1 to 2 μm is obtained. With a larger height dimension of the object to be analysed, in certain circumstances it is important to record several camera images from different heights and evaluate them individually or combine them as a so-called z-stack for 3D illustration.
Furthermore, not every measurement of interaction in single-cell force microscopy is successful. This is strongly dependent on the initial biological situation. Thus, an adhesion frequency of <30% in force measurements (LFA-1/ICAM-1 on A39 cells) has been reported (Wojcikiewicz et al., Biol. Proced. Online 2004:6 1-9, Force and compliance measurements on living cells using atomic force microscopy). This effect can greatly increase the measurement time and the number of cells required. At the same time, however, single-cell force microscopy (SCFS) makes it possible, in contrast to bulk adhesion assays, to resolve various subpopulations and to observe the effect of active substances, for example inhibitors, at the level of the individual cell and even the individual molecule.
It should be noted that optical detection of cells at higher resolution, for example by means of fluorescence, typically requires thin glass, with a thickness of about 170 μm, as substrate. It is important to ensure that the reduced mechanical stability of the thin glass does not lead to vibrations, which can disturb the AFM measurement.

Method and apparatus for the combined analysis of a sample with objects to be analyzed


Provided is a cutting equipment for automatically cutting off workpieces from a material tape. The cutting equipment includes an electrical control box, a base board, a material-feeding mechanism, a material-transferring mechanism, a material-pulling mechanism and a cutting mechanism. The material-feeding mechanism includes a supporting bracket, a material disc and a disc-driving device. The material-transferring mechanism mounted on the base board includes a pad board, a first supporting board and a second supporting board. The material-pulling mechanism disposed above the material-transferring mechanism includes a driving component and a material-pulling component. The cutting mechanism mounted on the base board includes a lower supporting plate, an upper cutting plate and a transferring cylinder. The upper cutting plate disposes at least one cutting blade. The cutting equipment can enhance the working efficiency, reduce the defective rate and the manufacture cost, lighten the labor intensity of operators, and be suitable for mass production.

1. Field of the Invention
The present invention relates to a cutting equipment, and more particularly to a cutting equipment for cutting off workpieces from a material tape.
2. Description of the Prior Art
At present, during the process of manufacturing electronic components, every workpiece is commonly connected to a material tape, and a pre-cut section is configured between the workpiece and the material tape. When needing to use the workpiece, it is needed to bend up and down the pre-cut section for separating the workpiece from the material tape. To a certain extent, the pre-cut section can enhance the manufacture efficiency of assembling, but the manual operation can result in many problems such as the workpiece easy to be oxidized and deformed. As a result, the workpiece quality is difficult to be ensured and the defective rate of the workpiece is high. Moreover, the manual operation can increase the labor intensity of operators, therefore this prior operating mode has disadvantages of low productivity and high cost, and can not be suitable for mass production.
Hence, it is needed to provide a cutting equipment to solve above problems.


A method for the production of a security card (1) having a card body (2) and a film (3) which is irreversibly attached to the card body (2) is provided. The method comprises the steps of: provision of the card body (2); provision of the film (3), wherein at least one of a side or a surface of the film (3) that faces the card body (2) is at least slightly smaller than at least one of a side or a surface of the card body (2) that faces the film (3); coating of at least one of the card body (2) or the film (3) with a transparent adhesive agent (4); at least one of combining or pressing of the card body (2) and the film (3) such that an edge region (5) of the surface of the card body (2) which is not covered by the film (3) is also covered by a layer of the adhesive agent (4), and the edges of the film (3) are at least one of enclosed by or embedded in the adhesive agent (4); and curing of the adhesive agent (4) by an application of electromagnetic waves.

1. Technical Field
The invention relates to a method for the production of a security card, particularly a finance card or a card for the purpose of identification, preferably an ID card, wherein the same is a personal identification card or another identification card, access authorization card, etc., by way of example, and the security card has a card body and a film which is irreversibly attached to the card body. In addition, the invention relates to a corresponding security card.
2. Description of Related Art
The security cards addressed here can be, by way of example, a finance card—meaning a cash card, money card, debit card, credit card, or other card which serves as a method of payment. In addition, the term 'security card' also means a card used for the purpose of identification—for example an ID card, a personal identification card, another identification card, or an access authorization card. These security cards can particularly be plastic cards.
Such security cards have a card body which is imprinted for the purpose of personalization, and/or which is configured with security elements which serve the purpose of providing protection against counterfeit. These can be, by way of example, holograms or visually- and/or electronically readable information. After being personalized and/or after being equipped with other visually- and/or electronically readable information, the card bodies are covered by a transparent and/or holographic film. This serves as protection for the card body and for the information on the same, and also serves as protection against counterfeit.
For the purpose of attaching the film to the card body in an irreversible manner, a method is used whereby a transparent hot melt adhesive functions as an adhesive between the card body and the film, at a very high temperature. The transparent adhesive is most commonly placed on the film, which is pressed onto the card body by the application of temperature and pressure.
In addition, the practice is known in the prior art of irreversibly attaching the film to the card body by means of an adhesive agent which cures when electromagnetic waves are applied to the same.
In the production method which defines the class, and in the case of the security cards which are produced using said method, it is problematic that the film attached to the card body can become detached from the card body. This is due in no small part to the heavy loads which such cards are subjected to during everyday use.
By way of example, finance cards are carried by the owner in a wallet, and repeatedly inserted into a corresponding compartment of the wallet. In addition, such finance cards are inserted into—among other things—automatic teller machines. As a result, the security cards are subjected to strong mechanical loads by the repeated impacts—particularly along their edge regions. This leads to a separation of the film from the card body after a certain amount of time.
In addition, it is problematic with the known security cards that the edges, in particular, of the film offer a point of engagement for detaching the film from the security card. As such, the known security cards are only protected against counterfeit to a limited degree.

Method for the production of a security card, and a corresponding security card


A vehicle traction mat for use to extricate a vehicle stuck on a slippery road surface is provided. The traction mat comprises at least a main mat segment having a plurality of surface cleats, knobs, and knob cleats on a road-facing surface thereof. The cleats and knobs provide traction between the traction mat and the slippery surface. The traction mat may be provided with edge mat segments foldably connected to opposite ends of the main mat segment. The traction mat may have cleats, knobs, and knob cleats on the tire-facing surface thereof.

As vehicles are driven in various road conditions such as mud, snow, or sand, the possibility of the vehicle being stuck increases. This is due to the reduced traction of the road. Often vehicle tires may be stuck in potholes, or ruts which are long deep tracks made by the repeated passage of the wheels of vehicles. To enable a stuck vehicle to be driven out of a rut or a pothole, for example, motorists have typically placed miscellaneous objects under the rotating tires of drive wheels, such as sand, salt, floor mats, wooden boards, and pieces of carpeting. Such objects are typically ineffective, and in some cases hazardous, as they may get caught by the rotating tire and simply fly away thus potentially injuring bystanders.
Vehicle traction mats have been known for many years and are used to provide additional traction to a rotating tire to extricate a stuck vehicle from snow, mud, sand, or any other slippery road condition. They provide an advantage in time and costs savings to stranded motorists who would otherwise have to wait for an emergency service provider truck for winching the stranded vehicle back to the roadway, and pay for that service. Some prior art mats use metal studs to engage the snow, or mud surface. Such vehicle traction mats are hard to handle and pose a risk of injury to the hands. Other vehicle traction mats rely on pins that are captivated therein, but such vehicle traction mats are complicated to make, and the pins may sometimes break off.

SBI SMART BRANDS INTERNATIONAL (AMERICA) LIMITED


A stun grenade is provided with a housing; al receptacle including a bottom hole and a hollow externally threaded member; an air canister in the receptacle; an internally threaded cap including a top opening and a top bifurcation including two opposite through holes in an intermediate portion, and two opposite first pivot holes in a rear portion; a striker unit including a striker and a spring loaded hinge pivotably fastened between the first pivot holes; a needle inserted through the hollow externally threaded member to have one end engaged with the air canister and an other end projecting out of the top opening; a lever having a front end pivotably secured to a front end of the bifurcation and including two opposite second pivot holes at an intermediate portion; and a safety pin inserted through the second pivot holes and the through holes to anchor the needle below.

1. Field of the Invention
The invention relates to stun grenades and more particularly to a stun grenade having a time delay mechanism.
2. Description of Related Art
A conventional stun grenade comprises a housing having a tubular body with end members brazed to the ends of the tubular body, and a collar member threadedly received in a threaded central opening in one end member for supporting an explosive charge in the housing. At the inner end of the collar member is a cylinder to which a tubular container filled with explosive charge is attached. Outer diameter of the tubular container is less than a minimum diameter of the threaded opening in the one end member to permit the tubular container to be inserted through the threaded opening while attached to the collar member. At the outer end of the collar member is a threaded recess for receipt of a fuse member externally of the housing. A flash hole in the collar member directs a flash which is produced when the fuse member is activated into the tubular container to ignite the explosive charge.
While it has some utility, improvements in these products are desired, and these improvements are provided by the invention.


The present invention relates to a rotating barbeque grill assembly that allows a user to put various food in a carrying frame thereof, parallelly install insert rods at both ends of the carrying frame into position-limit slots on both sides of a metal frame thereof respectively, and insert two transmission shafts into ends of fixed portions on both sides of the metal frame respectively. After the transmission shafts are fixed in the fixed portions, the user can turn on the barbeque apparatus, such that the metal frame can be rotated along the same axis of the two transmission shafts, and the carrying frame then slides from an original position far away from a heat source along the position-limit slots to a position proximate to the heat source, such that the food on both sides of the carrying frame can be heated uniformly and be barbequed to be a delicious dish quickly.

As the five-day work week system is carried out, more and more people pay attentions to leisure activities in recent years. Among various leisure activities, barbeque is an indispensible and popular one, particularly conducted in a picnic or a short trip. In view of the popularity of barbeque, manufacturers developed various types of rotisseries and barbeque grills or stoves. For example, a conventional rotating barbeque grill 10 as shown in FIG. 1 comprises a metal frame 11, two metal plates 12 and a fixed frame 13, wherein the metal frame 11 is formed by a plurality of metal rods arranged with an interval apart and alternately soldered with each other, and the metal frame 11 includes a containing space defined therein for accommodating food. The metal plates 12 are symmetrically installed on both corresponding sides of the metal frame 11 for latching both ends of the fixed frame 13 respectively, such that the fixed frame 13 can be latched to the metal frame 11 and covered onto the top of the containing space. After a user puts various different kinds of food into the containing space of the metal frame 11, latches the fixed frame 13 with the metal plates 12, and covers the fixed frame 13 onto the top of the containing space, the fixed frame 13 will be able to limit various different kinds of food in the containing space. In the meantime, the user connects a motor transmission shaft 15 of a barbeque apparatus 14 to the conventional rotating barbeque grill 10 which contains various different kinds of food and turns on the barbeque apparatus 14 to rotate the conventional rotating barbeque grill 10, such that a heat source (such as charcoal fire) at the bottom of the barbeque apparatus 14 is used for barbequing the food in the conventional rotating barbeque grill 10, and users can turn and barbeque each kind of food by a combination of the conventional rotating barbeque grill 10 and barbeque apparatus 14.
Although the aforementioned conventional rotating barbeque grill 10 comes with a simple structure and becomes a popular barbeque tool, yet its practical application still has the following drawbacks. For example, a conventional rotating barbeque grill 10 is rotated in the barbeque apparatus 14, and food is heated and cooked by the heat source provided at the bottom of the barbeque apparatus 14. When the conventional rotating barbeque grill 10 is rotated, both left and right sides of the barbeque grill 10 are at positions closer to the heat source. As a result, the food near the left and right sides in the conventional rotating barbeque grill 10 will be cooked for a longer time and at a faster speed. On the other hand, the food placed at the top and bottom sides of the barbeque grill 10 is farther from the heat source will take much more time for the cooking, so that users have to extend the overall rotating and barbeque time of the conventional rotating barbeque grill 10. However, this arrangement will overcook the food near both sides in the conventional rotating barbeque grill 10. In other words, when the food at the top and bottom sides in the conventional rotating barbeque grill 10 is cooked, the food near the left and right sides is overcooked, not only ruining the delicious taste of the food, but also affecting our physical health.
Therefore, it is an important subject for related designers and manufacturers to design and develop a rotating barbeque grill assembly capable of repeatedly sliding food contained in a carrying frame of a barbeque apparatus along a position-limit slot of the rotating barbeque grill assembly to a position near the heat source to achieve the effect of heating the food on both sides in the carrying frame uniformly and avoid overcooking the food, since the conventional rotating barbeque grill has the drawbacks of taking too much time for cooking the food, which may be cooked either too raw or overcooked easily.


The present invention provides a VCSEL system comprising forming a first mirror, forming a vertical cavity on the first mirror, the vertical cavity including integrated multiple gain regions and forming a transverse p/n junction laterally to the integrated multiple gain regions, wherein forward biasing the transverse p/n junction causes photon emission in the integrated multiple gain regions.

The present invention relates generally to multiple gain region systems, and more specifically to VCSEL systems with transverse P/N junction.
Vertical cavity surface emitting lasers (VCSELs) are revolutionizing the field of telecommunications. They generally consist of a pair of semiconductor mirrors defining a resonant cavity containing a gain medium of semiconductor materials for amplifying light.
VCSELs are generally characterized by a pair of mirrors, generally referred to as distributed Bragg reflectors (DBRs), between which an optical cavity is located. The entire structure can be formed over a substrate wafer by a process called organometallic vapor phase epitaxy (OMVPE), sometimes referred to as metal organic chemical vapor deposition (MOCVD). The optical cavity generally also includes spacer layers and an active region. The active region typically includes one or more quantum wells. The quantum wells, which typically include a quantum well layer sandwiched by a pair of adjacent barrier layers, are the layers into which carriers, i.e., electrons and holes, are injected. The electrons and holes recombine in the quantum well and emit light at a wavelength determined by the material layers in the quantum well. The quantum well layer typically comprises a low bandgap semiconductor material, while the barrier layers typically have a bandgap higher than the bandgap of the quantum well layers. In this manner, when the device is subject to forward bias, electrons and holes are injected into and trapped in the quantum well layer and recombine to emit coherent light at a particular wavelength.
Electrically-pumped VCSELs include a P-I-N junction structure in which the intrinsic material that forms a quantum well is sandwiched between layers of p-type and n-type material. For optimal light emission, the quantum well should be located at a peak of the standing wave (the axial or longitudinal mode) generated in the optical cavity. However, in a VCSEL having multiple quantum well active regions, each set of the quantum wells is separated by fifty to several hundred nanometers.
The number of quantum wells in a VCSEL determines the optical gain of the VCSEL. Before coherent light is emitted from a VCSEL, many losses inherent in the VCSEL must be overcome to reach lasing threshold. Losses in a VCSEL are created by the mirrors, diffraction, and distributed losses. Losses in the mirrors are due to the mirror reflectivity being less than 100%. Indeed, if the mirrors were 100% reflective, light could not be emitted from the VCSEL. Diffraction losses are caused when the emitted light expands as it propagates away from a guiding aperture in the VCSEL. Distributed losses are caused by scattering and by absorption of light in the VCSEL structure. The QW gain must be sufficient to overcome these combined losses. Therefore multiple QW active regions are advantageous, especially for high temperature operation and for enabling modulation at high data rates.
If more QWs are required than can fit under one maximum of the standing wave that exists in the cavity, additional QW active regions may be included in a resonant periodic gain (RPG) arrangement. An RPG VCSEL structure includes two or more active regions, with each active region lying under separate maxima in the standing wave (thus separated by some multiple of ½ wavelength). This RPG structure is used to maximize the optical gain of VCSELs.
While RPG VCSELs have been demonstrated in the more common GaAs- and InP-based materials used for red and near-infrared emitters, GaN-based VCSELs are far more challenging. This is due to their relatively poor optoelectronic characteristics, including less efficient carrier transport, defective structure, etc., which translate into low gain and high loss. Thus, for GaN-based ultraviolet or visible VCSELs exhibiting high efficiency and low threshold current and voltage, an active region incorporating several sets of QWs in an RPG arrangement is especially beneficial for achieving the requisite optical gain.
However, uniform electrical pumping of multiple GaN-based active regions has not been demonstrated. Moreover, pumping multiple GaN-based active regions with a single p-n junction is very challenging, due in part to the poor hole-transport in GaN.

VCSEL system with transverse P/N junction

Avago Technologies General IP (Singapore) Pte. Ltd.


The present invention relates to novel substituted quinoline derivatives according to the general Formula (Ia) or the general Formula (Ib)

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a world-wide distribution. Estimates from the World Health Organization indicate that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly. In the last decade, TB cases have grown 20% worldwide with the highest burden in the most impoverished communities. If these trends continue, TB incidence will increase by 41% in the next twenty years. Fifty years since the introduction of an effective chemotherapy, TB remains after AIDS, the leading infectious cause of adult mortality in the world. Complicating the TB epidemic is the rising tide of multi-drug-resistant strains, and the deadly symbiosis with HIV. People who are HIV-positive and infected with TB are 30 times more likely to develop active TB than people who are HIV-negative and TB is responsible for the death of one out of every three people with HIV/AIDS worldwide.
Existing approaches to treatment of tuberculosis all involve the combination of multiple agents. For example, the regimen recommended by the U.S. Public Health Service is a combination of isoniazid, rifampicin and pyrazinamide for two months, followed by isoniazid and rifampicin alone for a further four months. These drugs are continued for a further seven months in patients infected with HIV. For patients infected with multi-drug resistant strains of M. tuberculosis, agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin and ofloxacin are added to the combination therapies. There exists no single agent that is effective in the clinical treatment of tuberculosis, nor any combination of agents that offers the possibility of therapy of less than six months' duration.
There is a high medical need for new drugs that improve current treatment by enabling regimens that facilitate patient and provider compliance. Shorter regimens and those that require less supervision are the best way to achieve this. Most of the benefit from treatment comes in the first 2 months, during the intensive, or bactericidal, phase when four drugs are given together; the bacterial burden is greatly reduced, and patients become noninfectious. The 4- to 6-month continuation, or sterilizing, phase is required to eliminate persisting bacilli and to minimize the risk of relapse. A potent sterilizing drug that shortens treatment to 2 months or less would be extremely beneficial. Drugs that facilitate compliance by requiring less intensive supervision also are needed. Obviously, a compound that reduces both the total length of treatment and the frequency of drug administration would provide the greatest benefit.
Complicating the TB epidemic is the increasing incidence of multi-drug-resistant strains or MDR-TB. Up to four percent of all cases worldwide are considered MDR-TB—those resistant to the most effective drugs of the four-drug standard, isoniazid and rifampin. MDR-TB is lethal when untreated and can not be adequately treated through the standard therapy, so treatment requires up to 2 years of "second-line" drugs. These drugs are often toxic, expensive and marginally effective. In the absence of an effective therapy, infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB strains. There is a high medical need for a new drug with a new mechanism of action, which is likely to demonstrate activity against MDR strains.
The purpose of the present invention is to provide novel compounds, in particular substituted quinoline derivatives, having the property of inhibiting growth of mycobacteria and therefore useful for the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum.
Substituted quinolines were already disclosed in U.S. Pat. No. 5,965,572 (The United States of America) for treating antibiotic resistant infections and in WO 00/34265 to inhibit the growth of bacterial microorganisms. None of these publications disclose the substituted quinoline derivatives according to our invention.

Abstract: the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. The claimed compounds are useful for the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum. In particular, compounds are claimed in which, independently from each other, R1 is bromo, p=1, R2 is alkyloxy, R3 is optionally substituted naphthyl or phenyl, q=1, R4 and R5 each independently are hydrogen, methyl or ethyl, R6 is hydrogen, r is equal to 0 or 1 and R7 is hydrogen. Also claimed is a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the claimed compounds, the use of the claimed compounds or compositions for the manufacture of a medicament for the treatment of mycobacterial diseases and a process for preparing the claimed compounds.