Chemical compounds which release nitric oxide in a controlled manner upon photolysis with light are provided. These compounds are O2-benzyl, O2-naphthylmethyl and O2-naphthylallyl substituted diazeniumdiolates. Also provided are methods of preparing these novel compounds in high chemical yields as well as methods of using these compounds.

The present invention relates generally to the fields of organic chemistry, biochemistry and/or biological treatment systems. In particular, the present invention is directed to compounds that are capable of releasing nitric oxide (NO) in a controlled manner, as well as methods for the preparation and use thereof.
Nitric oxide has been implicated in a variety of important bioregulatory processes, including neurotransmission, anticoagulation and vasodilation. In addition, NO is an effector molecule released by macrophages and other cells after immunological activation.
NO is synthesized from the amino acid L-arginine by an enzyme, NO synthase. It is believed that there are at least two forms of the enzyme: a constitutive form which releases NO for short periods in response to receptor or physical stimulation, and a second form which is induced after activation of macrophages, endothelial cells and certain other cells by cytokines and which, once expressed, synthesizes NO for extended periods.
The constitutive form of NO synthase is implicated in the transduction mechanism for soluble guanylate cyclase, and thus is involved in one of the mechanisms whereby cells regulate their own function or communicate with others. In addition, the release of NO in the cardiovascular system acts as a general adaptive mechanism whereby the vascular endothelium responds to changes in its environment and regulates blood flow and blood pressure through action on vascular smooth muscle. NO also regulates the interaction between the endothelium and the platelets; it may also play a role in the control of vascular smooth muscle proliferation. The NO released by the constitutive enzyme may also play regulatory roles in other cells; for example, it is known to be linked to the stimulation by the excitatory amino acids of specific receptors in the central nervous system, and it may participate in regulation of the secretion or action of various hormones.
NO released after immunological stimulation by the other form of the enzyme as part of the host defense mechanism has been shown to be cytotoxic or cytostatic for tumor cells and invasive organisms. Further, some forms of local or systemic tissue damage associated with immunological conditions could prove to be related as well to the release of NO. NO may also play a role in the normal regulation of the response of cells to mitogens, or contribute to the cytotoxic actions of other cells that play a role in specific immunity.
NO is itself extremely poisonous and reactive in the presence of oxygen. It is a highly reactive gas in its pure form, attacking metals and plastics, and can only be obtained in relatively low pressure cylinders. Moreover, NO has limited solubility in aqueous media, making it difficult to introduce reliably into most biological systems without premature decomposition.
In view of the central importance of NO as both a transducer and as an effector molecule, however, it is apparent that agents for the controlled release of NO would be invaluable in the ongoing research on the roles of NO in human physiology and pathology. Moreover, the therapeutic potential of agents that may be employed to release NO in a controlled manner is enormous.
Various vasodilators are known which release NO either spontaneously or upon activation by chemical or enzymatic means. For example, the release of NO from molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine) begins with an enzymatic hydrolysis catalyzed mainly by liver esterases, followed by a pH-dependent ring opening reaction catalyzed by hydroxyl ions; a subsequent oxidative process is then essential for further decomposition and NO release [Bohn, H. and K. Schoenafinger, "Oxygen and Oxidation Promote the Release of Nitric Oxide from Sydnonimines," J. Cardiovasc. Pharmacol. 14 (Suppl.11):S6-S12 (1989)]. The vasodilators glyceryl trinitrate and sodium nitroprusside release nitric oxide upon redox activation. Other agents, such as iron-sulfur cluster nitrosyls, decompose spontaneously to release NO [Flitney, F. W. et al., "Selective retention of iron-sulphur cluster nitrosyls in endothelial cells of rat isolated tail artery: association with protracted vasodilator responses, J. Physiol. 459:89P (1993)].
One example of a compound that spontaneously releases NO is a class of diazeniumdiolate compounds. Anions such as 1-(N,N-dialkylamino)diazen-1-ium-1,2-diolates (see compound 1 (X=NR2, R=alkyl)) are stable as solid salts, but release up to two moles of NO when dissolved in aqueous solution at physiologically relevant conditions. Compound 1 is shown below in its anionic form. Compound 1 appears in this state throughout the description, the sodium ion is not shown. Keefer et al. have shown that the rate of NO release from diazeniumdiolates is dependent on the nature of the organic anion (X−), and have developed diazeniumdiolate compounds with half-lives of between 1.8 seconds to 56 hours in aqueous buffer at a pH of 7.4 at 37° C. Maragos, C. M.; Morley, D.; Wink, D. A.; Dunams, T. M.; Saavedra, J. E.; Hoffman, A.; Bove, A. A.; Isaac, L.; Hrabie, J. A.; Keefer, L. K. J. Med. Chem. 1991, 34, 3242–3247. (b) Keefer, L. K.; Nims, R. W.; Davies, K. M.; Wink, D. A. Methods in Enzymology 1996, 268, 281–293.

Diazeniumdiolates have shown great potential in a variety of medical applications requiring the rapid production (e.g., to produce a fast, but transient drop in blood pressure) or gradual release of NO (e.g., to study the effects of prolonged cytostasis on vascular smooth muscle cells).
One such strategy proposes to deliver NO to a specific site by anchoring diazeniumdiolate in polymeric matrices, restricting the release of NO to only those cells to which the polymer is in physical contact. Another strategy proposes using pro-drug derivatives that are unable to release NO until they have been metabolically converted to diazenimdiolate by enzymes specific to the target cell type. For example, diazeniumdiolates masked by O2-alkylation were shown to protect the liver in rats from cell death while minimally affecting systemic blood pressure, after being selectively dealkylated by oxidative enzymes specifically found in the liver.
It is therefore an object of the present invention to provide compositions for controlled delivery of nitric oxide that remain stable until it is desired to release NO by a particular triggering means, as well as towards methods for the preparation and uses thereof.
A wide variety of groups labile to photolysis referred to as "caging" structures are known in the art. The commonly employed 2-nitrobenzyl photosensitive protecting group has been used to develop potential photochemical precursors (compound 2, R=H, OCH3, OCH2CO2Et) to diazeniumdiolates. These compounds of Makings and Tsien are described in U.S. Pat. No. 5,374,710 and have the general formula:

Photolysis of compound 2 results in poor yields of NO with correspondingly low quantum yields. Nonetheless, these phototriggered NO donors were used to inhibit thrombin-stimulated platelet aggregation, to study the induction of long-term depression in the cerebellum and to examine long-term potentiation in culture of hippocampal neurons.
However, in the literature, it has been determined that when photolyzed, simple O2-substituted diazeniumdiolates (such as compound 2) have been found to breakdown by at least two primary pathways upon exposure to light [Srinivasan, A.; Kebede, N.; Saavedra, J. E.; Nikolaitchik, A. V.; Brady, D. A.; Yourd E.; Davies, K. M.; Keefer, L. K. and Toscano, J. P. J. Am. Chem. Soc. 2001 123, 5465–5472]. As shown in the reaction pathway below (scheme 1) (and as further described in Example 9 below), the major breakdown pathway of the diazeniumdiolate compounds of Makings and Tsien, involves the formation of potentially carcinogenic nitrosamine (R2NN═O) (compound 12) and a reactive oxygen-substituted nitrene (RON) (compound 13) as by-products (Path A) (shown in scheme 1 below). Minor amounts of NO, potentially produced by secondary photolysis of the nitrosamine are observed. Due to the toxic nature of these breakdown products, pharmaceuticals based on such diazeniumdiolate derivatives should be avoided.

It is one aspect of this invention to avoid the production of toxic byproducts produced by Path A. The prevention of toxic by-products may be achieved by choosing alternate caging structures that help favor the formation of non-toxic by-products upon photolysis.

Compounds that release nitric oxide at controlled rates upon photolysis


Methods and apparatus are provided for establishing and controlling the stability and movement of a reaction wave of reacting gases in a matrix of solid heat-resistant matter, wherein such reacting gases may be recuperatively pre-heated. At least a portion of the bed is initially preheated above the autoignition temperature of the mixture whereby the mixture reacts upon being introduced into the matrix thereby initiating a self-sustaining reaction region, after which the pre-heating can be terminated. The stability and movement of the wave within the matrix is maintained by monitoring the temperatures along the flowpath of the gases through the bed and adjusting the flow of the gases and/or vapors or air to maintain and stabilize the wave in the bed. The method and apparatus provide for the reaction or combustion of gases to minimize NO.sub.x and undesired products of incomplete combustion. A recuperative heat exchange system is used to preheat the reactants with heat generated by the reaction by channeling hot exhaust gases through the matrix surrounding reactant inlet tubes.

Many process streams of vapors, such as effluents from chemical processing plants, refineries, paint booth units, etc., utilize combustors to destroy the toxic or reactive constituents of the process gases or vapors prior to release to the atmosphere. Combustors are also utilized to generate energy through the oxidation of fuels such as methane. However, with increasing demands on environmental control of emissions, the use of free flames to combust such effluents is in many cases unsatisfactory. For example, standard combustors are particularly undesirable when dealing with chlorinated hydrocarbons.
A free flame also results, in some instances, in incomplete combustion and uncontrollable production of undesirable side products. Because combustors typically operate at flame temperatures on the order of 3500.degree. F., significant amounts of unwanted NO.sub.x are often produced. Nitrous oxide (N.sub.2 O) and ammonia (NH.sub.3) are often by-products of NO.sub.x removal techniques.
In addition, prior systems that combust harmful emissions to reduce the noxious content have been unable to adequately deal with variations in emission levels. Thus, for example, if a particular plant utilizes a batch reactor such that the emissions produced reach a peak and then gradually decrease, prior art systems have been forced to maintain the addition of a high flowrate of supplemental air and fuel at all times to produce a consistent flame that is not blown out by the fluctuations of the batch reaction fume flow.
It is therefore an object of the present invention to provide a method and apparatus for oxidative reaction of gases or vapors to minimize or reduce NO.sub.x emission and products of incomplete combustion.
It is another object of the present invention to provide a method and apparatus for utilizing the heat generated in such a reaction to preheat fuel-air mixtures prior to reaction.
It is another object of the present invention to provide a highly efficient method of heat transfer from a hot gas stream to one or more cold fluids.
It is another object of the present invention to provide a combustion system with a large turndown performance ratio (the ratio of the maximum to the minimum heat output).
It is another object of the present invention to heat a working fluid or gas with the heat generated by an exothermic reaction in a reaction matrix with a recuperative heat exchange system for heating incoming reactants.
It is a further object of the present invention to provide a method and apparatus for the destruction of gases and vapors, or the combustion of fuel, such as natural gas or organic vapors, whereby the input mixture of gases may be outside the explosion limit of the constituents. Exemplary compounds include, simple hydrocarbons, oxygenated hydrocarbons, aminated hydrocarbons, halogenated compounds, and sulfur-containing compounds.
It is yet another object of the present invention to provide a method and apparatus for the minimization of thermal-and fuel-NO.sub.x combustion by-products to levels substantially below those achievable by conventional combustion technologies such as premixed, nozzle-mixed, or staged burners, or by NO.sub.x removal processes such as Thermal De-NO.sub.x (R. K. Lyon [1975]U.S. Pat. No. 3,900,554, assigned to Exxon, Corp.), Selective Catalytic Reduction, and Rap-Re-NO.sub.x (R. Perry [c.1985]patent assigned to Technor, Inc., Livermore, Calif.).
These and other objects will be apparent from the following description, appended drawings, and from practice of the invention. In the following description of the present invention the terms "process gases," "process vapors," "fuel," "fuel mixture," "reactants," and the like will be used interchangeably to indicate chemical mixtures that can be reacted.

Method and apparatus for recuperative heating of reactants in an reaction matrix


The invention relates to a sieving device provided with a sieving mat (2), which has sieving openings, and with beating elements (7), which are located underneath the sieving mat and which strike against the underside of the sieving mat (2) in order to free the sieving mat (2) from material to be sieved that is clogging the sieving openings. Said beating elements (7) are fastened to at least one elongated tensioned traction mechanism (5) such as a cable or band that extends underneath the sieving mat (2).

German utility model 84 35 585 describes a sieve with bar-shaped beaters that are secured to an elastic mat that is mounted underneath the flexible screen. Both screens are mounted on tensioning rods that reciprocate and thus insure that the lower screen is taut and strikes with its beaters against the lower face of the upper screen in order to knock big particles out of the upper screen. The provision of a second screen underneath the first one is expensive and entails considerable extra manufacturing time.

Ludwig Krieger Draht- und Kunststofferzeugnisse GmbH


To efficiently evaluate exchange of advertisement frames. A frame exchange evaluation system according to one aspect of the present disclosure includes: a control unit configured to decide a plurality of campaigns that are advertisement frame exchange targets; and an acquisition unit configured to acquire current frame information about each of the campaigns and setting information for frame exchange including information about an allowable predicted audience rating of at least one of the campaigns after the frame exchange; wherein the control unit decides candidates for the frame exchange based on the current frame information and the setting information.

In television broadcast, CMs (commercial messages) are broadcast as advertisements. The CMs are roughly classified into time CMs and spot CMs. The time CMs are CMs broadcast in slots that are bought and sold being integrated with a program and may be called program commercial messages, program CMs or sponsor CMs.
The spot CMs correspond to CMs broadcast in CM time slots determined by television stations. The spot CMs are classified into station breaks (SB) broadcast between programs, participations (PT) (or participating CMs) inserted in a program but are not attached with a sponsor display, and the like.
Work for deciding which CM is to be broadcast in which time slot (the work may be called advertisement frame selection, planning or the like) is very complicated work to be decided by a planner, a person in charge of planning management in a broadcasting station (the person may be called a planning desk manager) and the like based on their experience. The planner and the person in charge of planning management are required to, for many existing advertising campaigns, maximize advertising effectiveness of each campaign (for example, GRP (gross rating point), TRP (target rating point), Reach and the like). The planner decides a CM schedule in consideration of an audience rating of a program, a degree of recognition of a CM target product/service, sponsor competition and the like.
Therefore, in order to reduce a burden on the planner and the person in charge of planning management and enhance advertising effectiveness more, a method for automating planning of a CM has been considered (for example, Patent Literature 1).

Frame exchange evaluation system, frame exchange evaluation apparatus and program


A signaling bearer quality of service profile is pre-established and configured in various nodes in an access network. This is a new quality of service class designed to meet the needs of signaling bearers in multimedia sessions. A message requesting a bearer to support a communication between a mobile terminal and an access point to a packet data network is generated. That message includes a signaling quality of service indicator, which when detected, causes a bearer to be established between the mobile terminal and the access point in accordance with the pre-established signaling quality of service profile. The pre-established signaling quality of service profile typically includes low delay and low bit error rates in addition to high priority and accommodation of bursty traffic patterns. A signaling usage indicator may also employed to implement a standard set of minimum signaling bearer capabilities.

IP networks were originally designed to carry "best effort" traffic where the network makes a "best attempt" to deliver a user packet, but does not guarantee that a user packet will arrive at the destination. Because of the market success of IP networks, there is a clear requirement for mechanisms that allow IP networks to support various types of applications. Some of these applications have Quality of Service (QoS) requirements other than "best effort" service. Examples of such applications include various real time applications (IP Telephony, video conferencing), streaming services (audio or video), or high quality data services (browsing with bounded download delays). Recognizing these QoS requirements, the Internet Engineering Task Force (IETF), which is the main standards body for IP networking, standardized a set of protocols and mechanisms that enable IP network operators to build QoS-enabled IP networks.
FIG. 1 depicts a simplified high-level model of an IP network accessed by end users via associated access networks which may be useful in explaining QoS provisioning. As can be appreciated, the model includes two users, but could easily be expanded to include more users without changing the basic functionality of the network. In FIG. 1, User-A 10 may communicate with User-B 12 or with an application server 13. For example, in the case of an IP telephony session, User-A 11 may communicate with User-B 12. Similarly, in the case of streaming services, User-A 11 may communicate with the application server 13, which may be configured as a video server. In either case, User-A 11 accesses an IP backbone network 14 through a local access network 15, such as PSTN (dial-in access), Global System for Mobile Communications (GSM), or Universal Mobile Telecommunications System (UMTS) network. User-B 12 is similarly connected to the IP network 14 through a local access network 16. Of particular interest to this invention is the specific case where at least one of the access networks is a UMTS or GSM/GPRS network. However, User-A and User-B need not use the same type of access network. The IP network 104 may consist of a number of IP routers and interconnecting links that together provide connectivity between the IP network's ingress and egress points and thereby make two party communication possible. As far as the users are concerned, the QoS depends on both of the access networks 15, 16 and on the IP backbone network 14.
QoS is particularly important for multimedia type communications between a mobile host and a remote host in which a "session" established between the mobile and remote hosts includes two or more different forms of media that often require different types of QoS, e.g., voice, e-mail, video, etc. Consider the example, simplified data communications system shown in FIG. 2 which permits a Mobile Terminal (MT) 20 to initiate and conduct a multimedia session with a remote host 30. The remote host 30 can be a fixed or wireless device. The mobile terminal 20 is coupled to a radio access network (RAN) 22 over the radio interface. The RAN 22 is coupled to an Access Point in packet-switched access network (PSAN) 24, which in turn is coupled to a Packet Data Network (PDN) 28, e.g., the Internet, to which the remote host 30 is coupled. The basic traffic flow for a multimedia session (shown as solid lines) between the mobile terminal 20 and remote host 30) is transported via these three networks 22, 24, and 28. The PSAN 24 and the PDN 28 communicate multimedia control signaling (shown as dashed lines) to a Multimedia System 26 that can be separate from or an integral part of the Packet Data Network 28.
Various user applications may access network services through an application programming interface (API). An API provides application programmers with a uniform interface to access underlying system resources. For instance, an API may be used to configure a network resource manager to require that a particular IP packet originating from a given application receive a certain treatment from the network, such as a particular QoS. For example, if the IP network is a Differentiated Services IP network, then an application program may request that all of its IP packets receive the "Expedited Forwarding" treatment.
The User (and the API in the user's equipment) may not be aware of the different technologies that various access networks and IP backbone networks employ in order to provide QoS end-to-end, i.e., from User-A all the way to remote User-B. For instance, the application program may use an RSVP/IntServ based API, and the end-to-end embodiment in which he is involved may include a UMTS access network and a non-RSVP enabled IP network. In such cases, some "interworking" mechanisms between such different technologies and protocols are needed to make sure that the QoS is provided end-to-end.
Integrated Services (IntServ) provides a set of well-defined services which enables an application to choose among multiple, controlled levels of delivery service for their data packets. To support this capability, two things are required. First, individual network elements, such as subnets and IP routers, along the path followed by an application's data packets must support mechanisms to control the quality of service delivered to those packets. Second, a way to communicate the application's requirements to network elements along the path and to convey QoS management information between network elements and the application must be provided.
IntServ defines a number of services such as Controlled-Load (defined in IETF RFC 2211) and Guaranteed (defined in IETF RFC 2212). The service definition defines the required characteristics of the network equipment in order to deliver the service. The individual network elements (subnets and IP routers) that support the service must comply with the definitions defined for the service.
The service definition also defines the information that must be provided across the network in order to establish the service. This function may be provided in a number of ways, but it is frequently implemented by the resource reservation setup protocol RSVP (defined in IETF RFC 2205). RSVP (Resource reSerVation Protocol) is an IP-level resource reservation setup protocol designed for an IntServ-enabled Internet (defined in IETF RFC 1633, 2205, and 2210). The RSVP protocol is used by a host (e.g., User A's computer) to request specific service from the network for particular application data streams or flows. RSVP is also used by routers to deliver quality-of-service requests to all nodes along the path(s) of the flows and to establish and maintain the state(s) to provide the requested service. RSVP requests generally result in resources being reserved in each node along the data path.
In a Differentiated Services network, an "edge router" is at the network boundary, and a "core router" is within the network. The edge and core routers have different duties. The edge router must "condition" the traffic to ensure that it conforms to a service agreement, and marks traffic with the appropriate DSCP (Differentiated Services Code Point). It then forwards each packet according to the service behavior defined for that DSCP. The service behavior, called the Per Hop Behavior (PHB) may define the prioritization or weighting of that traffic to give it better service than other traffic. The core nodes examine the DSCP and apply per hop service behavior appropriate for that service.
To realize a QoS Service with clearly defined characteristics and functionality, a QoS bearer must be set up from the source to the destination of the service. A bearer is a logical connection between two entities through one or more interfaces, networks, gateways, etc., and usually corresponds to a data stream or data flow. A QoS bearer service includes all aspects to enable the provision of a contracted QoS. These aspects include control signaling, user plane transport, and QoS management functionality.
Mobile Radio Access Data Networks, like General Packet Radio Service (GPRS) and Universal Mobile Telecommunication System (UMTS), may form a part of the overall network and will typically be a significant factor in the end-to-end bearer service for customers connected to it. Hence, the bearer service over a GPRS/UMTS network is important to achieving the required end-to-end bearer service.
The GPRS/UMTS network includes a set of network elements between the host, referred to as the Mobile Station (MS), and an external packet switching network the user is connecting to like the Internet. These network elements are shown in FIG. 3. The radio access network (RAN) provides access over the radio interface to/from the mobile station (MS) host. The RAN is coupled to a Serving GPRS Support Node (SGSN) and a Gateway GPRS Support Node (GGSN). The GGSN provides the interworking with external packet-switched networks, e.g., the Internet.
Before a mobile host can send packet data to a remote host, the mobile host must "attach" to the GPRS network to make its presence known and to create a packet data protocol (PDP) context. The PDP context establishes a relationship with a GGSN towards the external network that the mobile host is accessing. The PDP attach procedure is carried out between the mobile host and the SGSN to establish a logical link. As a result, a temporary logical link identity is assigned to the mobile host. A PDP context is established between the mobile host and a GGSN selected based on the name of the external network to be reached. One or more application flows (sometimes called "routing contexts") may be established over a single PDP context through negotiations with the GGSN. An application flow corresponds to a stream of data packets distinguishable as being associated with a particular host application. An example application flow is an electronic mail message from the mobile host to a fixed terminal. Another example application flow is a link to a particular Internet Service Provider (ISP) to download a graphics file from a website. Both of these application flows are associated with the same mobile host and the same PDP context. User data is transferred transparently between the MS and the external data networks with a method known as encapsulation and tunneling: data packets are equipped with PS-specific protocol information and transferred between the MS and the GGSN.
Quality of Service (QoS) has an extremely important and central role in 3rd generation (3G) UMTS mobile networks, especially for multimedia sessions. QoS is a means for providing end users with satisfying service. QoS also enables efficient use of the spectrum resources. Because the invention will be described in terms of a UMTS QoS architecture, a brief overview of QoS in UMTS is provided. The 3G UMTS QoS architecture is described, including an explanation of the packet data protocol context (PDP context), a traffic flow template (TFT), and the QoS maintenance procedures for activated UMTS bearers. It is expected that the QoS characteristics associated with a radio communication are the most critical in the end-to-end chain. Within UMTS access networks, the radio network resources are managed on a per PDP context level, which corresponds to one or more user flow/data streams and a certain QoS level.
The QoS framework for 3G networks is specified in the 3G specification (3GPP) TS23.107. The main focus is on the QoS architecture to be used in the UMTS level, where the list of QoS attributes applicable to UMTS Bearer Service and the Radio Access Bearer Service are specified along with appropriate mapping rules. TS23.060 specifies the general mechanisms used by data packet connectivity services in the UMTS level, which includes the General Packet Radio Service (GPRS) in GSM and UMTS.
In a UMTS QoS Architecture, a network service is considered to be end-to-end, from a Terminal Equipment (TE) to another TE. To realize a certain end-to-end QoS, a bearer service with clearly defined characteristics and functionality is set up from the source to the destination of a service. Again, the bearer service includes those aspects needed to enable the provision of a contracted QoS, e.g., control signaling, user plane transport, QoS management and functionality.
A UMTS bearer service layered architecture is depicted in FIG. 5. Each bearer service on a specific layer offers its individual services using services provided by the layers below. Bearers at one layer are broken down into underlying bearers, each one providing a QoS realized independently of the other bearers. Service agreements are made between network components, which are arranged horizontally in FIG. 4. The service agreements may be executed by one or more service layers. For instance, the UMTS bearer service consists of a Radio Access Bearer (RAB) service and a Core Network (CN) bearer service. The RAB service is then divided into a radio bearer service and a Iu bearer service. The Iu interface is the interface between the radio access network and the core network.
The following are examples of the entities shown in FIG. 4. The terminal equipment (TE) may be a laptop and the mobile terminal (MT) may be a cellular radio handset. The UTRAN may be made up of a combination of radio base stations called Node B's and radio network controllers (RNCs). The Core Network (CN) Iu Edge Node may be a serving GPRS support node (SGSN), and the CN Gateway may be a gateway GPRS support node (GGSN).
The QoS management functions in UMTS are used to establish, modify, and maintain a UMTS Bearer Service with a specific QoS, as defined by specific QoS attributes. The QoS management functions of all the UMTS entities ensure provision of the negotiated UMTS bearer service. The UMTS architecture comprises four management functions in the control plane and four in the user plane. The four control plane management functions are shown in FIG. 5:                Bearer Service (BS) Manager sets up, controls, and terminates the corresponding bearer service. Each BS manager also translates the attributes of its level to attributes of the underlying bearer service during service requests.        Translation function converts between external service signaling and internal service primitives including the translation of the service attributes, and is located in the MT and in the CN Gateway.        Admission/Capability control determines whether the network entity supports the specific requested service, and whether the required resources are available.        Subscription Control determines whether the user has the subscription for the bearer being requested.The four user plane management functions shown in FIG. 6:        Classification function resides in the GGSN and in the MT. It assigns user data units (e.g. IP packets) received from the external bearer service from the remote terminal (or the local bearer service) from the local terminal to the appropriate UMTS bearer service according to the QoS requirements of each user data unit. This is where a traffic flow template (TFT) and packet filters are situated, as described below.        Mapping function marks each data unit with the specific QoS indication related to the bearer service to which it has been classified. For example, it adds different service code points to packets before putting them on the Iu or CN bearer.        Resource Manager distributes its resources between all bearer services that are requesting use of these resources. The resource manager attempts to provide the QoS attributes required for each individual bearer service. An example of resource manager is a packet scheduler.        Traffic conditioner is a shaping and policing function which provides conformance of the user data traffic with the QoS attributes of the concerned UMTS bearer service. This resides in the GGSN and in the MT as well as in the UTRAN.
The QoS management functions of the UMTS bearer service maintain the data transfer characteristics according to the commitments established by the UMTS bearer service control functions, expressed by the bearer service attributes. The user plane uses the QoS attributes. The relevant attributes are provided to the user plane management functions by the QoS management control functions.
Four different QoS classes standardized in UMTS are shown in FIG. 7. Data transport may be optimized for the corresponding type of application data or for a bearer service of a certain class. The main distinguishing factor between these classes is how delay sensitive the traffic is: Conversational class is meant for traffic which is very delay sensitive (for real-time services) while Background class is the most delay insensitive traffic class (for non-real time services). Bit error/packet loss rate is also a significant difference between the classes.
To characterize a bearer service in detail, a set of bearer service attributes are standardized in UMTS. FIG. 8 shows which example attributes might be applicable to which example traffic class. FIG. 9 provides an overview of uses for different QoS attributes. The exact definitions of QoS attributes can be found in TS23.107. A certain QoS is requested by selecting a set of attribute values that describes the bearer requirement. Parameters differ depending on the type of bearer service requested.
A UE subscription is associated with one or more Packet Data Protocol (PDP) addresses, i.e., IP addresses in the case of IP traffic. Each PDP address is described by one or more PDP contexts stored in the MS, the SGSN, and the GGSN. Default values are also available in the cellular system database, e.g., the HLR, which holds the subscription information. Each PDP context may be associated with a Traffic Flow Template (TFT). A Traffic Flow Template is a packet filter (or set of filters) that associates packets to the correct PDP context thereby ensuring that packets are forwarded with correct QoS characteristics. The relationship between PDP address, PDP context, and TFT is shown in FIG. 10. The TFT enables the possibility of having several PDP contexts with varying QoS profiles to be associated with a single PDP address. The TFT is managed and initiated by the MT both for the uplink and downlink flows. The uplink TFT resides in the MT, while the downlink TFT resides in the GGSN. The downlink TFT is sent from the MT to the GGSN during PDP context activation/modification.
A PDP context is implemented as a dynamic table of data entries having all needed information for transferring PDP PDUs between MS and GGSN, e.g., addressing information, flow control variables, QoS profile, charging information, etc. The relation between UMTS bearer services and PDP context is a one-to-one mapping, i.e., if two UMTS bearer services are established for one PDP address, two PDP contexts are defined. The PDP context procedures are standardized in TS23.060.
Because there are several data flows corresponding to the different communications media employed in a multimedia session, each data flow is supported by a PDP context in the UMTS network which ensures a certain quality of service for the data flow. Namely, a specific transport channel transporting such a flow will have sufficient resources to support that requested quality of service. However, before these data flows and supporting PDP contexts/bearers can be established for the multimedia session, a UE must first request the multimedia session to be set up, and a number of signaling operations over a signaling bearer must be performed. In addition to session setup services, there are also ongoing session signaling needs, (e.g., for streaming services), that must be transmitted over a signaling bearer. Even though there are quality of service classes already established for radio access bearers to support different types of data flows in a multimedia session, the characteristics for a UMTS signaling/radio access bearer are not optimally satisfied by any of the already-established quality of service classes. In this regard, the characteristics of an optimal signaling UMTS/radio access bearer are as follows:                low bit error ratio        bursty traffic pattern        low delay time (to provide short session setup times)        high priority (even to the point where it may be possible to permit signaling traffic to take priority over user traffic)
None of the established quality of service classes for traffic well satisfies all of these QoS requirements for signaling. For example, a conversational class does not provide the low bit error ratio and is not appropriate for bursty traffic. A streaming class does not provide low bit error ratio and low delay, and is also not appropriate for bursty traffic. A background class, although it may meet the low bit error ratio requirement and is appropriate for bursty traffic, does not provide the low delay and high priority requirements. An interactive class provides low bit error ratio and is appropriate for bursty traffic. But to achieve low delay would require network dimensioning and scheduling on the interactive bearer in order to be achieved. Nor is the high priority requirement satisfied since the traffic handling priority parameter of the interactive class only allows priority to be defined within the interactive traffic class; it does not allow priority over other traffic classes, e.g., conversational or streaming traffic classes.
Moreover, it is also desirable for network operators to permit UMTS signaling bearers to be handled differently once established. For example, an operator may want to provide multimedia signaling bearers free of charge to encourage users to set up multimedia sessions. In this circumstance, it may be desirable to restrict the usage of a signaling UMTS bearer to only sending session initiation protocol signals to a particular destination such as a multimedia system control server. This is useful in at least two instances. First, if an operator does not charge for a signaling UMTS bearer, such restrictions do not allow a user to improperly use a "free" UMTS signaling bearer for data traffic. Second, the quality of service established for a signaling bearer, as noted above, is quite rigorous, and it may well not be the most economical use of resources for typical multimedia data flows. Alternatively, there may be situations where an operator may want to offer a signaling quality of service for use with a normal traffic bearer, perhaps with an extra surcharge.
The present invention overcomes the problems set forth above and meets the above-identified objectives. A signaling bearer quality of service profile is pre-established and configured in various nodes in an access network. This is a new quality of service (QoS) class designed to meet the needs of signaling bearers in multimedia sessions that involve a plurality of media data streams. A message requesting a bearer to support communication between a mobile terminal and an access point to a packet data network is generated. That message includes a signaling QoS indicator, which when detected, causes a bearer to be established between the mobile terminal and the access point in accordance with the pre-established signaling QoS profile. In one preferred, non-limiting, example embodiment, the bearer is a signaling bearer restricted to carrying signaling information relating to the session. In other, example, non-limiting embodiments, the signaling QoS profile may be employed in setting up media packet access bearers.
The pre-established signaling QoS profile typically includes both low delay and low bit error rate quality of service characteristics. Additional QoS characteristics might include high priority and accommodation of a bursty traffic pattern. Indeed, a high priority QoS characteristic may even permit the bearer to take priority over already established bearers. One of the benefits of the signaling QoS profile being already configured in the nodes in an access network is the quality of service for such a bearer requesting that signaling QoS profile need not be negotiated during the setup of the session, as is typically the case. Although it may be desirable for signaling bearers to have such a signaling bearer quality of service profile, if the signaling QoS indicator is not set in the bearer request message, a signaling bearer may be established with some other quality of service class/profile.
In order to control access to and use of the signaling quality of service profile, a further aspect of the present invention permits restricting use of a bearer with the pre-established signaling QoS profile. Such restriction may ensure that only signaling packets are transported over the signaling bearer, and that traffic packets are blocked from transport over the signaling bearer. This restriction may be indicated/activated using a signaling usage indicator included in the bearer request/setup message (or in some other message) that may be separate from the signaling QoS indicator. Restrictions may be implemented using packet filters at the access point node. Another example restriction is to identify a bearer source and a bearer destination of packets for the bearer established with the signaling QoS profile. Only those packets from the identified source to the identified destination are transported over the bearer. One example of source and destination includes the mobile terminal and a multimedia system server. Other restrictions and options may also be implemented/associated with the signaling usage indicator. In one non-limiting, example embodiment, the signaling usage indicator may be included in a protocol configuration options (PCO) parameter associated with the PDP context setup message.
A preferred example application is to a UMTS/GPRS access network. The UMTS/GPRS access network is coupled to an IP network such as the Internet. The session bearer request is in the form of a PDP context request message. A PDP context extends from a mobile terminal across the UMTS/GPRS access network to a GGSN node that is coupled to the Internet. The signaling QoS indicator included in such a PDP context request message may be detected in an SGSN node as well as a radio network controller (RNC). Each of RNC, SGSN, and GGSN nodes may store the pre-established signaling QoS profile before any sessions are requested. In addition, each of these nodes may be configured with a standard set of bearer capabilities associated with the signaling QoS profile.

Signaling quality of service class for use in multimedia communicatations


A multiaxial hinge assembly that enables rotation about a first axis between a clockwise limit and a counterclockwise limit and also enables rotation about a second axis that is orthogonal to the first includes a rotational direction indicator to provide an indication of a direction of rotation about the first axis to reduce the likelihood of rotation against the clockwise or counterclockwise limits and possible damage to the hinge assembly, or connected apparatus, or both. In one example, the multiaxial hinge assembly may be used for mounting the display of a hybrid notebook/tablet PC to provide an indication to a user of the direction in which the display may be counter-rotated when the hinge is positioned at either the clockwise or counterclockwise limits.

A notebook PC generally includes a main body portion that houses a processor, motherboard, associated peripheral components, rechargeable batteries, disk drives, cursor controls and a keyboard, and a display portion that is pivotably joined to the main body. The display of a notebook PC typically is joined to the main body by a pair of spaced, single-axis hinges positioned on a common horizontal axis at or near a back edge of the main body. The hinges enable the display to pivot in clamshell fashion from a closed position in which the display is folded face down over the keyboard and secured in place, through a range of working positions in which the display faces the keyboard, to a fully open position in which the display can lie in a face up, 180 degree position next to the main body, or, in some examples, can be pivoted beyond 180 degrees to a position behind the main body.
A tablet PC is modeled after an ordinary pen and pad of paper and integrates a sensor array, which generates signals according to where it has been touched, such as by a specialized digital stylus, together with a flat panel display to form a digital writing tablet. The display screen/writing tablet essentially covers the entire top surface of the main body of the tablet PC where traditional keyboard and cursor controls are located on a notebook PC. With a suitable handwriting recognition software platform, users can interact with the tablet PC and input a wide variety of data including text and graphics, simply by writing on the display surface with the digital stylus or pen. Although the tablet PC represents a significant advance, many users find that a keyboard is still necessary for some applications. Thus, a hybrid or convertible notebook/tablet PC has been developed that enables a tablet PC to be converted back and forth between a notebook mode in which the display faces the keyboard and a tablet mode in which the display/writing slate overlies the keyboard.
A variety of hybrid notebook/tablet PCs mount the display to the main body on joint or hinge assemblies that enable the display to be maneuvered from a notebook to a writing tablet mode without being detached or disconnected electrically. For example, the display of a notebook/tablet hybrid PC can be mounted to the main body on a single multiaxial hinge assembly positioned at or near the center of a back edge of the main body. Such a multiaxial hinge assembly enables the display to be pivoted open and closed about a pivot axis in a manner similar to the typical notebook PC described above, and also enables the display to be rotated about a second "center" or vertical axis that is orthogonal to the pivot axis. Rotation about the center or vertical axis allows the display to be oriented facing toward or away from the keyboard side of the PC at a variety of angles. When the display is rotated 180 degrees to face away from the keyboard, it can then be closed face up over the keyboard to provide a writing tablet. When the display is rotated back to face the keyboard the PC can be used as a notebook and the display can be closed face down to cover the keyboard and display for storage.
While a number of different hinge and joint assemblies can be employed to mount the display of a hybrid notebook/tablet PC, such as universal joints, saddle joints, ball and socket joints, and the like, essentially, any such hinge or joint assembly will have at least two orthogonal axes of rotation and provide sufficient rotational freedom thereabout to convert the hybrid tablet/notebook PC between notebook and tablet modes. Such a mechanism, referred to herein as a multiaxial hinge assembly, is a hinge or joint assembly that enables rotation about at least two orthogonal axes (i.e., axes that are mutually perpendicular).
Although a hybrid notebook/tablet PC with a multiaxial hinge that limits rotation about the center axis to 180 degrees can easily be converted between notebook and tablet modes, unfortunately, it is often difficult for users to remember which way the display must be rotated to change from one mode to another. The hinge mechanism does not provide any external indication of the correct direction of rotation and often provides inadequate sensory feedback when an incorrect rotation is attempted. For example, a hinge stop mechanism may prevent rotation of the hinge beyond its predetermined limits but the flexibility inherent in a portable PC display panel, which will act as a lever against the hinge, makes it difficult for users to sense that the hinge is at a rotational limit, particularly so if torque detents are also used to help hold the display in place at 0 and 180 degrees. Considerable torque can be applied to the hinge in the wrong direction before the user senses the hinge is against a stop, rather than a detent (soft) stop. Repeated attempts to rotate the hinge against the stop mechanism may cause the hinge or stop to loosen up, rendering it even more difficult to determine when the hinge is at the limit. Excessive play in the stop mechanism may also cause failure of the latch that secures the display to the main body and which depends on the hinge stop mechanism for proper alignment. Thus, there is a need for a hybrid notebook/tablet multiaxial hinge assembly that provides a reliable, easy to interpret indication to a user of the correct direction to rotate the display to reduce the likelihood of damage to the hinge assembly and/or display from attempts to rotate the hinge beyond a rotational limit.

Multiaxial hinge assembly with rotational direction indicator


The present invention discloses an improved DRAM of semiconductor device and method for manufacturing the same wherein an ONO (oxide-nitride-oxide) structure for trapping electrons or holes used in a non-volatile memory is employed in a gate insulating film of the DRAM to reduce impurity concentrations of a channel region and a well region.

1. Field of the Invention
The present invention relates to DRAM (Dynamic Random Access Memory) of semiconductor device and method for manufacturing the same, and in particular to an improved DRAM of semiconductor device and method for manufacturing the same wherein a gate insulating film having an ONO (oxide-nitride-oxide) structure is employed to reduce impurity concentrations of a channel region and a well region and improve a leakage current and a refresh characteristics of the device.
2. Description of the Related Art
FIG. 1 is a cross-sectional view illustrating a structure of a conventional DRAM of semiconductor device.
Referring to FIG. 1, the conventional DRAM comprises a device isolation film 20, a deep n-well 15 and a p-well 25 disposed on a semiconductor substrate 10. The conventional DRAM also comprises a stacked structure of a gate oxide film 40 and a gate electrode 45, and a channel region 45 disposed in the semiconductor substrate 10 below the gate electrode 45. A source/drain region 30 is disposed in the semiconductor substrate 10 at both sides of the gate electrode 45.
In the conventional DRAM, a channel length and a channel width decrease as the dimension of the DRAM cell is reduced. The drawbacks of the shrinkage are that a threshold voltage of a cell transistor is decreased and a punch-through phenomenon is easily induced. In order to overcome these problems, a method for increasing impurity concentrations of a channel region and a well region has been proposed.
Generally, the threshold voltage of a cell transistor is defined in Equation 1.
                                                        V              TH                        =                                          Φ                MS                            -                                                Q                  EFF                                                  C                  OX                                            +                              2                ·                                                                        Φ                    F                                                                                -                                                Q                  B                                                  C                  OX                                                              =                                    Φ              MS                        -                                          Q                EFF                                            C                OX                                      +                          2              ·                                                                Φ                  F                                                                      +                          2              ·                                                                                ɛ                      S                                        ·                    q                    ·                                          N                      A                                        ·                                                                                        Φ                        F                                                                                                                            C                  OX                                                                    ,                            [                  Equation                                                              1                ]
where ΦMS is work function difference between the gate electrode and the semiconductor substrate, QEFF is effective charge per unit area of the gate oxide when VG=VTH, COX is capacitance per unit area of the gate oxide, ΦF is Fermi level of the semiconductor substrate, ΦB is charge per unit area of the depletion region, εS is permittivity constant of the semiconductor substrate, q is charge of one electron, and NA is impurity concentration of the semiconductor substrate.
QEFF is defined in Equation 2 below.
                                          Q            EFF                    =                                    Q              SS                        +                          Q                              it                                                  (                                                            Φ                      S                                        =                                          2                      ·                                              Φ                        F                                                                              )                                                      +                                          ∫                0                                  T                  OX                                                                                x                    ·                                          ρ                                                                    (                        x                        )                                                                                T                    OX                                                  ·                                                                                ⅆ                  x                                                                    ,                            [                  Equation                                                              2                ]
where QSS is surface state fixed charge at the interface between the gate oxide film and the semiconductor substrate, Qit is interface state charge between the gate oxide film and the semiconductor substrate, ΦS is surface potential of the semiconductor substrate, ρ(χ) is oxide charge density within the gate oxide, and TOX is thickness of the gate oxide.
Therefore, the threshold voltage of the cell transistor can be obtained from Equation 3.
                              V          TH                =                              Φ            MS                    -                                    1                              C                OX                                                                [                                                Q                  SS                                +                                  Q                                      it                                                              (                                                                        Φ                          S                                                =                                                  2                          ·                                                      Φ                            F                                                                                )                                                                      +                                                      ∫                    0                                          T                      OX                                                                                x                        ·                                                  ρ                                                                                (                            x                            )                                                                                T                        OX                                                              ·                                                                                ⅆ                      x                                                                                ]                                +                      2            ·                                                        Φ                F                                                            +                      2            ·                                                                                ɛ                    S                                    ·                  q                  ·                                      N                    A                                    ·                                                                                Φ                      F                                                                                                                      C                OX                                                                        [                  Equation                                                              3                ]
When the impurity concentrations of a channel region and a well region are increased, NA is increased. As a result, the threshold voltage and the punch-through voltage are increased, thereby overcoming the problems of the conventional art. However, as shown in FIGS. 2a and 2b, the increases in the threshold voltage and the punch-through voltage increase an electric field of a source/drain region, resulting in an increase in a leakage current and degrading a refresh characteristic of the DRAM. Therefore, the proposed method shows its limitation, and a leakage current characteristic and a refresh characteristic are considered when determining a proper impurity concentration.
However, it is very difficult to manufacture a DRAM of semiconductor device wherein the threshold voltage, the punch-through voltage and the refresh characteristic all meet desired level as the dimension of the DRAM is reduced to below 100 nm.
FIG. 3 is a cross-sectional view illustrating a conventional non-volatile memory cell.
Referring to FIG. 3, the conventional non-volatile memory cell comprises a device isolation film 60, a deep n-well 55 and a p-well 65 disposed on a semiconductor substrate 50. The conventional non-volatile memory also comprises a stacked structure of a lower gate oxide film 80 and an intermediate gate nitride film 85, an upper gate oxide film 90 and a gate electrode 95, and a channel region 75 disposed in the semiconductor substrate 50 below the gate electrode 95. A source/drain region 70 is disposed in the semiconductor substrate 50 at both sides of the gate electrode 95.
The conventional non-volatile memory cell stores data by trapping electrons or holes in the intermediate gate nitride film. A threshold voltage changes in case whether electrons or holes are trapped or not. That is, when electrons are trapped in the intermediate gate nitride film, the threshold voltage is increased and when holes are trapped, the threshold voltage is decreased. '1' or '0' can be stored in the non-volatile memory cell using this principle.
For example, when in case of trapping electrons are defined as '1' and trapping holes as '0' (or vice versa), the operation of the non-volatile memory cell is shown in Table 1 below.
TABLE 1GateDrainSourceBulk (p-Operation[V](V)[V]well) [V]ERASEVP000Write '1'PROGRAM0VPVPVPWrite '0'READVRGVRD00VRG, VRD < VP
During an ERASE operation, VP is applied to the gate electrode and 0V is applied to the drain, the source, the bulk so that the voltage difference between the gate electrode and other contacts is VP(>0), whereby electrons flow from the drain, the source, the bulk into the ONO gate insulating film to be trapped in the ONO gate insulating film. Therefore, the threshold voltage is increased according to Equation 3 and '1' is stored.
During a PROGRAM operation, 0V is applied to the gate electrode and VP is applied to the drain, the source, the bulk so that the voltage difference between the gate electrode and other contacts is −VP(<0), whereby holes flow from the drain, the source, the bulk into the ONO gate insulating film to be trapped in the ONO gate insulating film. Therefore, the threshold voltage is decreased according to Equation 3 and '0' is stored.
During a READ operation, when VRD is applied to the drain, the threshold voltage is greater than VRG in case that '1' is stored and the threshold voltage is smaller than VRG in case that '0' is stored. Therefore, '1' or '0' can be read out when VRG is applied to the gate electrode since the transistor is turned off or on according to the threshold voltage.
In case of a non-volatile memory cell, since the state of the electrons or holes trapped in the intermediate gate nitride film are maintained even when power is cut off, the data can be read out from the transistor when power is again applied to the transistor.
However, a non-volatile memory cell requires a high VP in order to trap electrons or holes during the ERASE or the PROGRAM operation, which is a write operation. Such a write operation also requires 1000 times longer time period compared to the READ operation. Moreover, the amount of electrons or holes trapped in the intermediate gate nitride film decreases as READ or PROGRAM operations are repeatedly performed. Therefore, non-volatile memory cells cannot be used in a DRAM of semiconductor device having frequent read/write operations.
As described above, in accordance with the conventional DRAM of semiconductor device and method for manufacturing the same, wherein a gate insulating film having an ONO (oxide-nitride-oxide) structure is employed to reduce impurity concentrations of a channel region and a well region and improve a leakage current and a refresh characteristics of the device.

Dynamic random access memory of semiconductor device and method for manufacturing the same


A protein derived from a strain of methylotrophic yeast which has a protein disulfide isomerase activity having the amino acid sequence as set forth in SEQ ID No. 1, or protein in which the amino acid sequence has been modified by deletion or addition of one or a few amino acids, or substitution with other amino acid(s) and which has a protein disulfide isomerase activity; and a process for production thereof.

1. Field of Invention
The present invention relates to protein disulfide isomerase, an enzyme which promotes formation of protein conformation by catalyzing formation of disulfide bonds in a protein, and to a gene thereof. The present invention relates, among the protein disulfide isomerases, to protein disulfide isomerase derived from a strain of methylotrophic yeast, a microorganism suitable for industrial production of valuable proteins due to its high efficiency of expression of heterologous genes and secretion of the expression products, and to a gene thereof.
2. Related Art
Protein disulfide isomerase (PDI) is a major protein present in the lumen of the endoplasmic reticulum (referred to hereinafter as ER) and it was first discovered as having an activity which effects oxidative refolding of a reduced RNase (Goldberger, R. F. et al. (1963) J. Biol. Chem. 238: 628-635). PDI is believed to be an enzyme which catalyzes formation of stable conformation by recombining disulfide bonds of secretory proteins.
It has been pointed out that, in the case of heterologous proteins, in particular secretory proteins, which often have disulfide bonds, recombination of disulfide bonds by PDI as well as protein folding by peptidyl-prolyl-cis-trans isomerase (PPI) represent the rate-limiting step in the secretory process of proteins (Gething, M. J. and Sambrook, J. (1992) Nature 355: 33-45). It has also been demonstrated that PDI promotes folding of proteins consisting of a single domain such as RNase in vitro as well (Jaenicke, R. (1993) Curr. Opin. Struct. Biol. 3: 104-102).
On the other hand, because strain of methylotrophic yeasts grow using methanol as the sole carbon source and they have high yields of cells, they have been used for the production of materials for use in the synthetic chemical industry including, for example, aldehydes such as formaldehyde, epoxides, methylethylketone, and formic acid. Research has been conducted on the possible utilization of the cells per se as a protein source, and the utilization for production of cell components such as amino acids, vitamins, and the like, and some have been put into practical use. In recent years, furthermore, an expression system of heterologous genes using strain of methylotrophic yeasts as the host has been developed and it has been shown that said system has a higher productivity than Saccharomyces yeasts (Japanese Unexamined Patent Publication (Kokai) No. 5-344895).
Its productivity is high especially for secretory proteins. For example, the productivity of glucoamylase derived from filamentous fungi of the genus Rhizopus was 3.4 g/l, which is about 10 times higher than the productivity by Saccharomyces yeasts (Sakai, Y., et al. (1996) Biochim. Biophys. Acta 1308: 81-87). As the strain of methylotrophic yeast, there are known Candida boidinii, Pichia pastoris, Hansenula polymorpha, and the like.
When heterologous proteins are produced by secretory production using recombinant DNA technology, the efficiency of the secretion is thought to be increased by enhancing the speed of folding proteins. Based on such an idea, an example has been disclosed in which the amount secreted of human albumin was increased by about 60% on the average by coexpressing a human PDI gene with the desired gene in a Saccharomyces yeast (Japanese Unexamined Patent Publication (Kokai) No. 5-38771).
Formation or exchange of disulfide bonds which are necessary for appropriate folding of proteins requires environments suitable therefor. For that purpose, eukaryotic cells have intracellular compartments such as the ER or the Golgi apparatus, etc. While passing through the compartments, secretory proteins are subjected to suitable folding or addition of sugar chains and then are secreted out of the cell by means of exocytosis. Many of the secretory proteins of eukaryotic origin have intramolecular disulfide bonds, and formation and exchange of these disulfide bonds taking place in the ER are essential for formation of protein conformation and its secretion.
Accordingly, the PDI which catalyzes reactions for formation and/or exchange of disulfide bonds must be localized or stay in the ER. For this purpose the PDI has a unique amino acid sequence called an ER retention signal sequence at the C-terminal. As ER retention signal sequences there are known Lys-Asp-Glu-Leu (SEQ ID No. 2) for animals and His-Asp-Glu-Leu (SEQ ID No. 3) for Saccharomyces yeasts. When the human PDI gene as described above was expressed in a Saccharomyces yeast, the ER retention signal sequence of the human PDI did not fully function, which was possibly due to inadequate localization of the PDI in the ER. Thus, it is believed that even the highly expressed PDI gene did not cause enhancement in the PDI activity commensurate with the expression in the ER, and accordingly the increment of the amount secreted of the coexpressed secretory protein remained at a value of 60%.
In order for the PDI expressed in a strain of methylotrophic yeast to fully perform its functions, it is preferred to use the PDI derived from a strain of methylotrophic yeast. The reason why the strain of methylotrophic yeast has a high ability of secreting protein as described above is that recombination of disulfide bonds by the PDI which is the rate-limiting step of the protein secretion process takes place efficiently and that the PDI derived from the strain of methylotrophic yeast has a higher specific activity than the PDI derived from other sources or has a higher activity in the ER. However, the PDI of the strain of methylotrophic yeast or the gene thereof was unknown. Accordingly, no studies had been carried out on enhancement of productivity in the expression system of the strain of methylotrophic yeast by using the above PDI or the gene thereof.

Protein disulfide isomerase gene derived from strain of methylotrophic yeast


A tire manufacturing apparatus for precisely mounting an annular tread on a base tire with the width center of the base tire aligned with the width center of the annular tread. The tire manufacturing apparatus includes a drum to which a base tire is secured, a holding means for holding the annular tread by its inner periphery, and a moving means for having the holding means approach or separate from the drum along the rotation axis of the drum. The holding means is provided with a conveying means to have the annular tread, which is held by the holding means, approach or separate from the base tire. And the conveying means mounts the annular tread on the outer periphery of the base tire by conveying the annular tread in the approaching direction at a conveyance speed which is equal to the travel speed of the holding means in the separating direction.

An apparatus for mounting a tread on the outer periphery of abase tire is known among tire manufacturing apparatuses. On this apparatus, a separately manufactured base tire, which serves as the base of a tire, and an annular tread, which has been cured in advance, are joined together as they are brought closer to each other by a plurality of units holding them separately.
Specifically, such a tire manufacturing apparatus consists of a drum shaft, a rim assembly, a tread expanding means, a tread pressing unit, and a moving mechanism. The drum shaft, extending horizontally from the machine body, rotates as it is driven by a motor. The rim assembly provided on the drum shaft holds a base tire in such a manner as to allow air to be injected into the base tire. The tread expanding means has a plurality of bar members (fingers) for synchronized expansion or contraction, the bar members, which have each a plurality of rollers protruding and disposed in two upper and lower rows, arranged at equal distances on a circumference. And the moving mechanism moves the tread expanding means and the tread holder toward the rim assembly. On this apparatus, an annular tread is first held on the plurality of bar members such that the inner periphery of the annular tread is radially expanded, and a base tire is secured to the rim assembly. Then the tread radially expanded by the tread expanding means is moved to a predetermined position relative to the base tire, and then the tread is brought closer as the bar members come in contact with the outer periphery of the base tire. Finally the tread is held down to the base tire by the tread pressing unit and then the bar members are pulled out, thus accomplishing the integration of a base tire and a tread.
Also, another tire manufacturing apparatus is of such a structure that the bar members are advanced and retracted individually. Since the bar members can be freely advanced or retracted relative to the support member supporting the bar members, pulling the bar members out from between the base tire and the tread will accomplish the integration of a base tire and a tread.
Further, its tread expanding unit is provided with a sensor to control the advance and retraction of the bar members. And when the tread is placed on the bar members, both the edge portions of the tread are detected as they pass along the sensor, and the width center of the tread is calculated therefrom. Then the positions at which the tread is held on the respective bar members are detected. Now the bar members are advanced or retracted individually according to these detections so that the edge of the tread comes in contact with a positioning member provided at a predetermined position on each bar member. Thus the tread is aligned with respect to the tread expanding unit.
However, in the former case, the tread radially expanded by the tread expanding means may not often be mounted on the base tire in a correctly aligned condition. Therefore, there may be cases where the tread is defectively mounted on the base tire with waves in the width direction or in an oblique orientation. Also, in the latter case, the tread may be held aligned on the bar members of the tread expanding unit, but the alignment of the tread is accomplished with the edges of the tread brought into contact with the positioning members. When, for example, the tread is a wing type, that is, when both edges of the tread are molded thin-walled, the thin tread edges tend to get turned up or deformed when they are brought into contact with the positioning members. Thus, when the tread is mounted on the base tire, the turned-up or deformed portions, which remain on the tread on the base tire, may affect the tire performance negatively. Furthermore, in both the former and latter cases, the bar members are pulled out with the tread pressing unit holding down the annular tread to the base tire. This may cause a friction between the annular tread and the bar members and thus lead to a defective mounting of the tread on the base tire with waves in the width direction

This patent is subject to a terminal disclaimer.


An altimeter having a magnifying element configured to magnify a barometric scale for use in setting the altimeter to a local barometric pressure. The magnifying element can be a plano-convex lens positioned on a transparent cover of the altimeter over the barometric scale. The lens can be adhered to the transparent cover with an adhesive or can be formed as part of the transparent cover. In one embodiment, the magnifying element is included as part of a cover that can be secured to an altimeter.

General aviation aircraft are typically equipped with one or more altimeters that determine altitude by measuring changes in barometric pressure. Changes in barometric pressure are determined by a diaphragm that is responsive to atmospheric pressure. The response of the diaphragm to changes in barometric pressure is used to drive an indicator, such as a needle, relative to a scale on a dial face to thereby indicate altitude.
In order to provide accurate altitude readings, an altimeter must be adjusted to the local barometric pressure on the ground at a given location. To adjust the altimeter to the local barometric pressure, a small window in the dial face, referred to as a Kolsman window, exposes a barometric pressure scale. A knob is provided for adjusting the barometric pressure scale to the desired setting. By turning the knob one way or the other, the desired barometric pressure can be aligned with a mark on the dial face thereby setting the altimeter.
The altimeter should be adjusted to the local barometric pressure at takeoff and landing. For example, prior to takeoff a pilot will typically receive an altimeter setting (the local barometric pressure) over the radio from a ground controller and adjust the altimeter accordingly. Once set to the local barometric pressure, the altimeter should indicate the elevation of the airfield provided that the aircraft is at the same reference level used to establish the altimeter setting. Once in flight, the pilot will periodically obtain current altimeter settings en route, and adjust the altimeter accordingly. Periodically adjusting the altimeter is important, for example, when flying from an area of high pressure into an area of low pressure. If the altimeter is not adjusted to the new lower local barometric pressure, the aircraft will be closer to the surface than the altimeter indicates. In this regards, an inch change in the altimeter setting equals approximately 1,000 feet of altitude. When approaching an airfield for landing, the pilot will again receive a local altimeter setting and adjust the altimeter to the local barometric pressure at the landing airfield.
Adjusting an altimeter to the local barometric pressure is critical to ensuring the most accurate altitude reading possible. Indeed, in the history of aviation, many mishaps have occurred due to inaccurate and/or improperly adjusted altimeters. Many factors can contribute to a pilot setting an altimeter inaccurately. For example, the pilot may misunderstand the altimeter setting dictated by the ground controller over the radio and thereby set the altimeter to an incorrect barometric pressure. The pilot may inadvertently adjust the altimeter to a inaccurate barometric pressure by misreading the barometric pressure scale through the Kolsman window. Further, while in flight, turbulence may prevent the pilot from accurately reading and/or adjusting the altimeter to the proper pressure.
For pilots with any visual impairment due to age, such as myopia or cycloplegia, difficulty adjusting the altimeter is further compounded, particularly in turbulence or in low light conditions. As a large percentage of general aviation pilots are over the age of 40, the age at which cyclopegia commonly starts occurring, difficulty in viewing the Kolsman window is a prevalent problem. As such, a long felt yet unresolved need exists for an altimeter having a Kolsman window that is easy to read.


Certain aspects of the present disclosure relate to precise position determination for the downhole placement and position of the tubing-side portion of a behind-casing measurement system. The position determination can be used to establish precise alignment of the system and thus prevent signal loss. A system according to some aspects includes a casing-side antenna mountable between a well casing and a formation wall and a processing device connected to the casing-side antenna. The processing device is operable to measure signal intensities for a signal received from at least one tubing-side antenna, calculate a position of the tubing-side antenna relative to the casing-side antenna based on the signal intensities, and transmit the position to the surface.

For penetration-free behind casing measurements, electronic systems sometimes use antennas for power transfer and communication through the casing. The casing is normally fixed to the formation by cementing. Electronics in or on a tubing string can couple to and communicate with electronics outside the casing through the antennas. The electronics outside the casing are part of the casing assembly during run-in-hole ("RIH") and cementing and its position is fixed in the well when cemented. The electronics on the tubing string are moved as RIH operations progress, and can also move unintentionally during measurement operations due to temperature changes, or pressure variations. In order to make behind-casing measurements, alignment between the tubing-side antenna or antennas and the antenna or antennas outside the casing must be maintained. This alignment is typically maintained by trial and error adjustment when an operator notices signal loss or degradation.

Position sensing for downhole electronics


A cylinder apparatus comprises a body having a flat rectangular parallelepiped shape, a cylinder unit for accommodating a piston which is reciprocatable along a cylinder chamber, a toggle link mechanism for converting linear motion of a piston rod into rotational motion, and an arm for making rotation by a predetermined angle in accordance with a driving action of the cylinder unit, wherein reaction force-receiving plates for absorbing reaction force applied when a workpiece is clamped are detachably provided in the body.

1. Field of the Invention
The present invention relates to a cylinder apparatus capable of clamping a workpiece by the aid of an arm which is rotatable by a predetermined angle in accordance with a displacing action of a piston.
2. Description of the Related Art
When components of an automobile are welded, for example, a cylinder apparatus has been hitherto used to clamp such a component. The cylinder apparatus is disclosed, for example, in U.S. Pat. No. 4,905,973 and DE 29504267 U1.
The cylinder apparatus disclosed in U.S. Pat. No. 4,905,973 and DE 29504267 U1 comprises a main body which is constructed by integrally assembling a pair of casings formed to be substantially symmetrical to one another, a cylinder unit which is connected to the main body, and an arm which is rotatable by a predetermined angle in accordance with a driving action of the cylinder unit by the aid of a toggle link mechanism provided in the main body.
The cylinder unit is provided with a piston which is reciprocatively accommodated in a cylinder tube, and a piston rod which is connected to the piston. The toggle link mechanism, which comprises a bearing member for rotating the arm, is connected to a free end of the piston rod. A guide groove is formed on an inner wall surface of the casing, which functions to guide the linearly movable piston and absorb the reaction force applied when a workpiece is clamped by the arm.
A desired welding operation is performed for the workpiece while clamping the workpiece by the aid of the arm which is rotatable by a predetermined angle in accordance with the driving action of the cylinder unit.
However, the cylinder apparatus disclosed in U.S. Pat. No. 4,905,973 and DE 29504267 U1 adopts an arrangement in which the reaction force is applied to the arm when the workpiece is clamped by the arm, and the reaction force is received by the guide groove formed on the inner wall surface of the casing. In this arrangement, the wall surface for constructing the guide groove wears out due to sliding friction of the piston rod which is reciprocated integrally with the piston. Therefore, backlash or looseness occurs resulting from a gap between the piston rod and the guide groove, and it becomes difficult to rotate the arm in a stable manner. Further, a disadvantage arises in that the occurrence of backlash decreases the clamping force of the arm for the workpiece.


A through-wall flashing device includes a metal exterior surrounding a polymeric core, wherein the metal exterior is substantially non-continuous or otherwise interrupted by thermal breaks disposed about the metal exterior. In assembly, the thermal breaks help to reduce or all together eliminate thermal bridging from an exterior of a building construction to the interior of a building or building wall. The through-wall flashing device is adapted for use with a variety of wall constructions and is specifically configured to provide insulation and moisture sheeting properties around doors, windows and other architectural apertures which may be found in a wall construction.

Through-wall flashing systems generally comprise a membrane used in a wall construction for the purpose of preventing the passage of water into a structure from a joint in the wall. Flashing devices can be used anywhere in a building where it is necessary to deflect water away from seams or joints or other areas where water runoff is concentrated. In the past, flashing devices have been comprised of sheet metal such as lead, aluminum, copper, galvanized steel, stainless steel and other architectural metals. These sheet metal components have been primarily used in flashing constructions due to their strength, workability and durability. However, these metal components, when used to connect exterior components of a building directly to interior frame, are at least partially exposed to external conditions and provide direct paths for thermal conductivity from the exterior of a building to an inside portion of a wall construction, or into the interior of the building itself. Such thermal conductivity is known as thermal bridging. Particularly, these metal substances provide negligible thermal resistance, such that hot and cold temperatures from the external environment are easily transferred through these metallic flashing devices. Thus, a need exists for a through-wall flashing system having flashing members with the structural rigidity of continuous metallic flashing members, while greatly reducing, if not eliminating, thermal bridging from exposed portions of the flashing members to internally disposed portions of the flashing members.

Through-wall metal flashing having thermal breaks


A client signal received at an ingress interface is adapted to a higher-rate transport signal. Clock frequency acceleration is achieved by an M/N-multiplying PLL where the magnitude of M and N can be restricted without causing the rate of the resulting transport signal rate to deviate unacceptably from a nominal transport signal rate. Each frame of the transport signal has a payload section with a fixed number of transport payload bytes, each of which is either a dummy byte or a client byte. The number of client bytes per transport frame is within one byte of the number of client bytes actually received at the ingress interface during the duration of the frame. The designation of each frame as a low-fill frame or a high-fill frame is automatically regulated by checking the fill level of a memory element and is redundantly encoded by the ingress interface and transmitted to an egress interface as part of the frame.

High-capacity transport networks such as optical transport networks (OTNs) have heretofore been successfully used for providing end-to-end connectivity between customer sites adapted to transmit and receive certain types of client signals. In a typical scenario, shown in FIG. 1, a customer site 105 transmits a client signal having a certain client signal format to an ingress interface 100 such as a hub or central office (CO). The ingress interface 100 is connected to the OTN 110 by a high-capacity link 120 such as an optical fiber. The client signal received by the ingress interface 100 is intended to be transmitted to another customer site 125 connected to the OTN 110 via an egress interface 130 (such as another hub or central office) and a corresponding high-capacity link 140.
The ingress interface 100 typically encapsulates the client signal within a transport signal that adheres to a format known as a transport signal format. In most existing OTNs, the transport signal format and the client signal format are not independent. Rather, when setting up the OTN to service a group of large or medium-sized customers, the transport signal format is carefully chosen to simplify encapsulation of client signals having a client signal format commonly used by those customers. An example of a popular client signal format is the SONET OC-48 client signal format which refers to a frame-based Synchronous Optical NETwork Optical Carrier signal having a bit rate of 48 times the basic OC-1 rate of 51.84 Mbps.
By way of example, a transport signal format which was specifically designed to simplify the encapsulation of client signals in the OC-48 format is the so-called G.975 format as defined in ITU Recommendation G.975 "Series G: Transmission Systems and Media; Digital System and Networks; Digital Transmission Systems—Digital Sections and Digital Line System—Optical Fibre Submarine Cable Systems; Forward Error Correction for Submarine Systems" and incorporated by reference herein in its entirety.
There exist other transport signal formats which provide simplified encapsulation of client signals having a limited number of other client signal formats used by large and medium-sized "legacy" customers. As a result, most OTNs in use today are able to accommodate transport signals having a transport signal format that facilitates the encapsulation of client signals adhering to one or another of a limited number of client signal formats.
However, as the thirst for seamless end user connectivity grows, so does the diversity of customers desirous of reaping the benefits of a high-capacity OTN. Thus, a new generation of customer has appeared alongside the more traditional large and medium-sized legacy customer. Many of these newer customers utilize equipment which produces client signals in a format which is not easily encapsulated by the transport signal formats currently used in most existing OTNs. As a result of the incompatibility existing between today's OTNs and many of the "nontraditional" client signal formats employed by an emerging customer base, end-to-end connectivity and its myriad potential benefits are seldom realized.
A possible solution would be to change the transport signal format used within an existing OTN in order to accommodate encapsulation of client signals having new, nontraditional formats. However, a large investment in OTN infrastructure depends on the chosen transport signal format and thus any change to the transport signal format would lead to a prohibitively expensive overhaul of many backbone networks in use today. Moreover, the legacy customers around which existing OTNs were built have not disappeared from the scene. This raises a complexity issue since access to existing OTNs must not only be provided to a new breed of customer but such access must continue to be provided to customers who employ the more traditional client signal formats.

Processing of arbitrarily formatted client signals to achieve compatibility with existing transport networks


A new and distinct cultivar of Thuja plant named ‘Art Boe’, characterized by its upright and narrowly conical plant habit; vigorous growth habit; freely branching habit; green-colored leaves that do not winter burn; and good winter hardiness.

The present invention relates to a new and distinct cultivar of Thuja plant, botanically known as Thuja occidentalis, and hereinafter referred to by the name 'Art Boe'.
The new Thuja plant is a product of a planned breeding program conducted by the Inventor in Faribault, Mich. The objective of the breeding program is to create new narrowly conical Thuja plants with good winter hardiness.
The new Thuja plant originated from an open-pollination in 1998 in Faribault, Mich. of Thuja occidentalis 'Hetz Wintergreen', not patented, as the female, or seed, parent with an unknown selection of Thuja occidentalis, as the male, or pollen, parent. The new Thuja plant was discovered and selected by the Inventor as a single plant within the progeny of the stated open-pollination in a controlled environment in Faribault, Mich. in 2001.
Asexual reproduction of the new Thuja plant by hardwood cuttings in a controlled environment in Faribault, Mich. since 2001, has shown that the unique features of this new Thuja plant are stable and reproduced true to type in successive generations.


For identifying a fault in an electrical machine vibration is measured in a plurality of radial directions of the stator. On the basis of the vibration measurements a vibration frequency and a mode shape of the vibration at this frequency is determined. Characteristics of the vibration in terms of both the vibration frequency and the mode shape are used to identify a fault condition of the electrical machine.

Like any technical device, electrical machines may suffer from different kind of faults, either of mechanical or electrical character. Since electrical machines have a moving element in form of a rotor, many of the most common fault conditions cause vibrations to the machine. It is known that different fault conditions cause different kind of vibrations. In turn, it follows that by knowing what kind of vibration a certain fault condition causes, it is possible to detect the fault by monitoring the vibration characteristics of the machine.
Vibration monitoring has been conventionally used to detect mechanical faults in electrical machines. This monitoring method has been successful e.g. in detecting bearing defects. However, one has not been able to detect electrical faults in a satisfactory way by means of vibration monitoring, even if attempts into this direction have been taken. For example, the conference paper "An analytical approach to solving motor vibration problems" from Finley, W. R. et al. 1999 (D1) discloses a table (Table I) with indicators for identifying both mechanical and electrical faults in an induction motor. The main fault indicators are the frequencies of the vibrations and their sidebands. It requires a lot of empirical interpretation to determine the root source of the vibration with the help of D1, and it is not possible to distinguish between different fault conditions in a satisfactory manner.

Method for identifying a fault in an electrical machine


A reliable semiconductor device including support bumps so as to adequately seal the region between the chips is to be provided. The semiconductor device includes a semiconductor chip; a bump formed on an upper face of the semiconductor chip; and a plurality of support bumps formed along a circumference of the region where the bump is provided, formed on the upper face of the semiconductor chip; and a flow path for a sealing resin is provided between the plurality of support bumps, so as to connect the region where the bump is provided and a periphery region of the semiconductor chip.

1. Field of the Invention
The present invention relates to a semiconductor device, a semiconductor device module and a method of manufacturing the semiconductor device.
2. Related Art
In accordance with the ongoing reduction in dimensions and weight of electronic devices, demand for micronization of the electronic components to be employed is continuously increasing. On the other hand, the demand for higher performance, such as a high speed operation and larger memory capacity, has also been increasing. Accordingly, an SiP (System in Package) in which a plurality of semiconductor chips electrically connected to one another is integrated has been developed, as a method for system integration at the device level that can satisfy both of the micronization in dimensions and higher performance.
A primary part of the SiP technique is a Chip-On-Chip combination technique, which includes disposing so as to oppose each main face of devices having a different optimum designing parameter in a wafer process, such as a CMOS logic and a DRAM, or devices that are difficult to integrate in a wafer process, such as a silicon device and a compound semiconductor device, and electrically connecting the devices via bump electrodes in a shortest distance. Such a Chip-On-Chip technique is expected to achieve a SiP that offers a higher performance and a higher operation speed.
However, some issues to be addressed have already been discovered in such a technique, such as deterioration in strength of each individual bump due to a reduction in size, or difficulty in injecting a sealing resin required for protection from an external environment, which are supposed to come up when still further micronization and improvement in performance are required in future and the bump electrode are compelled to be made smaller.
Therefore, a related art such as JP-A No. 2002-26238 proposes employing a bump for preventing a chip from bending backward, to thereby protect an electrode bump formed according to the chip-on-chip technique. In JP-A No. 2002-26238, an upper chip includes upper bumps arranged along a periphery region of an interconnect forming surface, and a lower chip has lower bumps located at positions corresponding to the upper bumps.
In addition, the lower chip and the upper chip both include, apart from the lower bumps and the upper bumps, a reaction force blocking lower bump and a reaction force blocking upper bump respectively, designed to sustain a reaction force generated by the chip in a direction of bending backward, located at a central portion of the chip or inside the periphery region thereof. When stacking the lower bumps and the upper bumps so as to put the bumps in contact, the reaction force blocking lower bump and the reaction force blocking upper bump are also put into mutual contact.

Semiconductor device, semiconductor device module and method of manufacturing the semiconductor device