Water-soluble chelates represented by the formula: ##STR1## wherein R is H or alkyl (1-12C) and M is Ti or Zr. The above chelates can be prepared by reacting a Ti or Zr halide or alkoxide with between 1 & 2 molar equivalents of N,N-bix-(2-hydroxyethyl)-glycine, and used as cross-linking agents in hydraulic fracturing fluids and in gels that are used for selectively plugging permeable zones or leaks.

Reactions of titanium or zirconium compounds with amino compounds are known. For example, Yoshino et al., in the Bulletin of The Chemical Society of Japan, Vol. 46, 2899 (1973), have reported their observations in respect of certain mixtures of titanium and zirconium esters with nitrogen-containing compounds. Boiling a mixture of Zr isopropoxide and glycine dissolved in ethanol for 22 hours gave a white precipitate which was stated to be 2,5-piperazinedione. Substituting DL-alpha-alaline in that mixture, gave a white precipitate which was said to be 3,6-dimethyl-2,5-piperazinedione. When a mixture of glycine and Ti isopropoxide in isopropanol, and mixtures of glycine and Ti n-butoxide in ethanol and isopropanol, were heated to boiling, the glycine did not dissolve completely, but after 20 hours, light brown powders were obtained which were stated to be 2,5-piperazinedione. Moreover, in U.S. Pat. No. 2,824,114, Bostwick disclosed compounds prepared by reacting an alkyl titanium or zirconium ester with a monohydric, dihydric, or trihydric monoamino or diamino alcohol, e.g., di-hydroxyethyl-ethylene diamine, and suggested using his compounds as dispersing agents and as surface active agents for hydrocarbons and waxes. Similarly Beacham et al., in U.S. Pat. No. 2,824,115, disclosed combining organo titanium and organo zirconium compounds with polyhydroxyalkyl alkylene polyamines, and suggested using their compounds as dispersing agents, additives to paint and varnish formulations to improve durability, agents for the treatment of wool and animal fibers, and in various textile and cosmetic applications.
The use of zirconium compounds as cross-linking agents is described by Kucera in U. K. patent application GB 2 108 122 A. Kucera disclosed reacting a zirconium alkoxide with a dialkanol amine or trialkanol amine, and suggested using the resulting compounds as cross-linking agents in hydraulic fracturing of subterranean formations. The production of oil and gas can be stimulated by the hydraulic fracturing technique, in which a fluid composition is introduced into an oil or gas well at a flow rate and pressure which create and/or extend a fracture into the oil- or gas-containing formation. The fluid composition usually carries a proppant (e.g., sand, bauxite, etc.) which is forced into the fracture by the fluid composition and prevents closure of the formation after the fluid pressure is released. Tiner et al., in U.S. Pat. No. 3,888,312, provide an example of the use of titanium-containing cross-linking agents in fluid or hydraulic fracturing. They disclosed hydraulic fracturing of subterranean formations using aqueous gels prepared from a solvatable polysaccharide which had been cross-linked with ammonium tetralactotitanate(IV) or bis(triethanolamine)bis(isopropyl)-titanium.
Recovery of oil from subterranean formations frequently involves displacing crude oil with a driving fluid, e.g., gas, water, brine, steam, polymer solution, foam, or micellar solution. Ideally, such techniques (commonly called flooding techniques) would provide a bank of oil of substantial depth being driven to a producing well; in practice, that frequently is not the case. Oil-bearing strata are usually heterogeneous, some parts of them being more permeable to a driving fluid than others. As a consequence, channeling frequently occurs so that the driving fluid flows preferentially through zones depleted of oil (so-called "thief" zones) rather than through those parts of the strata which contain sufficient oil to make oil-recovery operations profitable. High permeability zones can also cause undesirable loss of drilling fluids when a well (e.g., water, oil or waste disposal) is being drilled. Misplaced casing perforations or casing leaks are another cause of channeling of the driving fluid through zones of high permeability in the subterranean formations. In addition, casing leaks sometimes occur in the annular region above the injection or production packer, and need to be dealt with whether the leaks occur in high or low permeability zones.
Hanlon et al., in U.S. Pat. No. 4,460,751, disclose a cross-linking composition and the use of the compositions in a method for reducing permeability of subterranean formations to water. They disclose preparing the composition by mixing (1) water, (2) a Zr salt (oxychloride, acetate, tetrachloride, o-sulfate, carbonate), (3) an acid having the formula HO-C(=O)-CH(OH)-R wherein R is H or alkyl (1-3 C) and (4) a amine having the formula R.sup.1 N(R.sup.2)R.sup.3 wherein R.sup.1 is hydroxyalkyl (1-3 C), R.sup.2 is alkyl (1-3 C) or R.sup.1, and R.sup.3 is H or R.sup.2.
The products of the present invention provide advantages over those of the prior art. For example, the titanium- and zirconium-containing compositions of the present invention have extremely slow rates of cross-linking. They can therefore be used at high temperatures and/or at high pH and still effect crosslinking at acceptable rates. Thus, for example, they can be used in a well completion fluid which contains a high level of brine. Consequently, the compositions of the present invention can be used in hotter geologic formations, including those at greater depths in oil and gas wells. In addition, the compositions of the present invention are better suited as cross-linkers than are those of the prior art in cross-linked gels used in hydraulic fracturing fluids and for plugging leaks and selectively plugging permeable zones.

Cross-linking titanum & zirconium; chelates & Their use


Provided is a high-capacity and highly-flexible electrode group for thin batteries, a thin battery including the electrode group, and an electronic device in which the thin battery is incorporated.

In recent years, there has been advancement in small-size portable electronic devices such as cellular phones and hearing aids. Besides, devices that operate in contact with human body have been increasingly commercially available. For example, biological information measuring devices that acquire biological information such as body temperature, blood pressure, and pulse, and automatically transmit the acquired information to a facility such as a hospital have been developed. For another example, body-attached devices that, upon application of a potential to the skin of human body, supply medicine etc. through the skin into the body have been developed.
Under these circumstances, the batteries for supplying electric power to the above-mentioned small-size electronic devices are required to be thinner and more flexible. Thin batteries that have been already developed include paper batteries, thin flat batteries and plate-like batteries. In these batteries, the strength of the housing is high, but it is difficult to make the battery more flexible and further thinner.
In order to make the thin batteries more flexible and further thinner, a technique of using a thin and flexible laminated film as the housing has been proposed (see, e.g., Patent Literatures 1 and 2). Specifically, as shown in FIG. 9, a thin battery includes an electrode group 101 and a housing 102. The electrode group 101 is formed by stacking flat plate-like positive electrode and negative electrode with a separator interposed therebetween. A positive electrode lead 103 and a negative electrode lead 104 are electrically connected to the positive electrode and the negative electrode, respectively. The housing 102 is made of a laminated film, and serves to cover the positive and negative electrodes, while allowing the end portions of the positive and negative electrode leads to be exposed outside the housing. The exposed end portions are used as positive and negative electrode terminals.
Another possible technique for making thin batteries more flexible and further thinner is to reduce the thickness of the electrode group. For example, one proposal suggests forming an active material layer of the positive or negative electrode by a vapor phase process, thereby to reduce the thickness of the active material layer (see, e.g., Patent Literature 3).

Electrode group for thin batteries, thin battery, and electronic device

Abstract: The electrode group for thin batteries includes: a sheet-like first electrode, a sheet-like second electrode being laminated on each of both surfaces of the first electrode, and an electrolyte layer interposed between the first electrode and the second electrode. The second electrode has a polarity opposite to that of the first electrode. The second electrode has a flexural modulus lower than that of the first electrode. The thin battery includes the electrode group, and a pouch-like housing accommodating the electrode group. The electronic device includes an electronic device main body with flexibility, and the thin battery is incorporated in the electronic device main body.

PANASONIC INTELLECTUAL PROPERTY MANAGEMENT CO., LTD.


The present invention provides a method and an apparatus for receiving reception acknowledgement for HARQ (Hybrid Automatic Repeat Request) in a wireless communication system. A terminal receives, from a base station, an uplink resource allocation that includes information on a plurality of allocated RBs (Resource Blocks) within a subframe that includes the plurality of RBs, and transmits uplink transmission blocks to a PUSCH (Physical Uplink Shared Channel) by using the plurality of allocated RBs on the subframe. The terminal receives, from the base station, ACk/NACK signals on a PHICH (Physical Hybrid-ARQ Indicator Channel). PHICH resources used on the PHICH are identified by the lowest index among indexes of the plurality of allocated RBs, and at least two of the indexes of the plurality of RBs are linked by being overlapped with the same PHICH resource.

3rd generation partnership project (3GPP) long term evolution (LTE) evolved from a universal mobile telecommunications system (UMTS) is introduced as the 3GPP release 8. The 3GPP LTE uses orthogonal frequency division multiple access (OFDMA) in a downlink, and uses single carrier-frequency division multiple access (SC-FDMA) in an uplink. The 3GPP LTE employs multiple input multiple output (MIMO) having up to four antennas.
In a hybrid automatic repeat request (HARQ) scheme, whether data received by a physical layer has an unrecoverable error is determined and retransmission is requested upon detecting the error, thereby improving performance.
If no error is detected from the received data, a receiver transmits a positive-acknowledgement (ACK) signal as a reception acknowledgment so that a transmitter is informed that the data is successfully received. Otherwise, if an error is detected from the received data, the receiver transmits a negative-acknowledgement (NACK) signal as a reception acknowledgment so that the transmitter is informed that the error is detected. When the NACK signal is received, the transmitter can retransmit data.
In recent years, there is an ongoing discussion on 3GPP LTE-advanced (LTE-A) evolved from the 3GPP LTE. The 3GPP LTE-A ensures backward compatibility with the 3GPP LTE, and supports a wideband by using carrier aggregation.
The 3GPP LTE-A has a basic frequency band supporting compatibility with the 3GPP LTE and an extended frequency band not supporting compatibility with the 3GPP LTE.
A physical channel used in the 3GPP LTE does not consider an extended frequency band supported by the 3GPP LTE-A. Therefore, a reception acknowledgment for HARQ may not be transmitted through the physical channel when data is transmitted in the extended frequency band.

Method and apparatus for receiving reception acknowledgement in wireless communication system


Networking systems and methods according to exemplary embodiments of the present invention can provide robust filtering to enable users to customize their networking environments. A networking system can comprise a plurality of interfaces, a request unit, a management unit, and a filter unit. Each interface can include a plurality of displayable objects, each of which can represent some user of the networking system. The request unit can receive from a client a request for one of the interfaces. The management unit can manage filters, where each active filter hides one or more users from one or more other users. When an interface is requested by a client associated with a first user, the filter unit can apply the active filters to the requested interface to exclude displayable objects that represent users hidden from the first user by one or more active filters.

Social networking environments generally provide search utilities that enable a user to search for other users by providing search criteria, thus filtering out those users that do not meet the provided search criteria. These search utilities are useful in that they enable users to identify friends, family, or other users meeting specific characteristics. After a user leaves the search page, however, users not meeting the search criteria are shown to the first user as part of the general networking environment.
Social networking environments also enable a user to block specific other users, so that the blocked users cannot interact with the user who did the blocking. A block must be applied individually to each user, so that blocking multiple people can become a chore.

This patent is subject to a terminal disclaimer.

Robust filters for social networking environments


Provided are compositions comprising a saponified product of an ethylene-vinyl acetate copolymer having an ethylene content of 20 to 80 mol % and a saponification degree of vinyl acetate component of at least 95 mol %, said composition containing 20 to 200 ppm as converted to alkali metal of an alkali metal acetate, 30 to 250 ppm of acetic acid, and 5 to 500 ppm as converted to phosphate ion of phosphoric acid or an alkali metal hydrogenphosphate, and having a content ratio of acetic acid/alkali metal acetate of 0.1 to 1 and the flow characteristic that the extrusion rate does not substantially increase for at least 10 hours in the relationship between the heating time and the extrusion rate with a capillary rheometer (Koka Flow Tester) at at least one temperature 10.degree. to 80.degree. C. above the melting point.. Also provided are multilayered containers comprising as the innermost layer a layer formed by the use of the above composition, and packages comprising such containers containing a liquid article or paste article.

1. FIELD OF THE INVENTION
The present invention relates to compositions which generate little odorous components and are excellent thermal stability, to multilayered containers which can pack and contain various foods, in particular various liquid foods and beverages, e.g. straight juices of citrus fruits, such as orange juice and lemon juice, as well as cosmetics, perfumes, etc., without impairing their good flavor and/or good odor, and further to packages, particularly food packages, comprising such containers containing various contents, with high quality and excellent keeping property.
2. DESCRIPTION OF THE PRIOR ART
Recently, as containers for liquid foods and the like, besides conventional glass bottles and metal cans, multilayered structures comprising thermoplastic resins and composite containers comprising paper and thermoplastic resin layers have been widely used.
In keeping with this movement, there has been a problem of deterioration of the contents, especially of foods. Particularly, when the contents are juices of citrus fruits or foods containing such fruits, terpene hydrocarbons such as d-limonene which constitute the flavor component tend to be absorbed in polyolefins such as polyethylene, which are widely used for the innermost layer of such containers. The reduction of the flavor components of a food during its storage necessarily leads to deterioration of the flavor, thereby minimizing its commercial value.
In the case where a saponified product of an ethylene-vinyl acetate copolymer (hereinafter referred to as EVOH) is used instead of polyolefin resins for the innermost layer, the absorption of the flavor components is, as described in Japanese Patent Application Laid-open No. 3950/1988, markedly reduced and the flavor does hence not deteriorate so much. However, conventional EVOH has still the following problem. Containers comprising conventional EVOH often produce an irritating odor due to isolation of residual acetic acid, or produce acetaldehyde, crotonaldehyde, aldol or the like as its pyrolysate, so that the containers cannot exhibit a sufficient preservability for food flavors. Even when the contents are good-smelling cosmetics or perfumes, which are non-foods, their odors deteriorate from the same reason, which is not preferred.
Japanese Patent Application Laid-open Nos. 955/1977, 49294/1976 and 143954/1987 disclose the incorporation into EVOH of metal salts and acetic acid for the purpose of providing the EVOH with thermal stability. The former two have not been able to succeed in suppressing generation of odorous components because of large incorporation of acetic acid, and the latter does not have sufficient thermal stability because of the use of the specific metal phosphates and further is not given consideration for suppressing generation of odorous components at all. Furthermore, none the above literature describes about the provision of the EVOH composition at the innermost layer of a multilayered container.


A method of establishing a multi-segment pseudowire (MS-PW) across domains executing different pseudowire signaling protocols augments a Label Distribution Protocol (LDP) label message to include a MS-PW Type-Length-Value (TLV). The MS-PW TLV carries pseudowire signal protocol information associated with signaling protocols of other segments of the MS-PW. As a result, a multi-segment pseudowire can be extended between domains that execute different pseudowire signaling protocols.

A Pseudowire (PW) is an emulation of a native service over a Packet Switched Network (PSN). The native service may be a layer 2 or Synchronous Optical Networking (SONET) connection, Asynchronous Transfer Mode (ATM), Frame Relay, Ethernet, low-rate Time-Division Multiplexing (TDM), or SONET/Synchronous Digital Hierarchy (SDH), while the PSN may be Multiprotocol Label Switching (MPLS), Internet Protocol (IP) (either IPv4 or IPv6), or Layer 2 Tunnel Protocol Version 3 (L2TPv3). More particularly, a pseudowire is a tunnel established between two provider-edge (PE) nodes to transport Layer 2 Protocol Data Units (PDUs) across a packet switched network (PSN).
A multi-segmented pseudowire (MS-PW) is one which traverses multiple PSN domains, i.e., one or more Service Provider (SP) networks, or multiple networks within the same SP network (e.g. an access and core network). More specifically a MS-PW is a static or dynamically configured set of two or more contiguous pseudowire segments that behave and function as a single point-to-point pseudowire. Each end of a MS-PW terminates at an Ultimate Provider Edge (U-PE) device.
Pseudowires may be established using a variety of processes including by static configuration (using MPLS or L2TPv3) or by Label Distribution Protocol (LDP). LDP defines two Forwarding Equivalency Class (FEC) elements which may be used to establish pseudowires; PWid FEC 128 and Generalized PWid FEC 129. As the standards for pseudowire signaling continues to evolve, deployed network devices may execute different LDP pseudowire signaling protocols. It is desirable to identify a method that enables MS-PW to extend between PSN domains that use different pseudowire signaling protocols.

Method for establishing multi segment pseudowire across domains having different pseudowire signaling protocol


A computing system includes an issue queue and a microprocessor. The issue queue receives a fused instruction, which includes a first instruction portion fused with a second instruction portion different from the first instruction portion. The microprocessor assigns a first instruction tag (ITAG) to the first instruction portion and a second ITAG to the second instruction portion. The microprocessor determines a first bit that represents the first ITAG, inverts the first bit to determine a second bit that represents the second ITAT, and determines an availability of one or more sources of a second instruction different from the fused instruction based at least in part on the first bit or the second bit.

The field of the invention is data processing, or, more specifically, methods, apparatus, and products for processing fused or fused instructions.
Computer systems typically include a combination of hardware and software components, application programs, operating systems, processors, buses, memory, input/output devices, and so on. As advances in semiconductor processing and computer architecture push the performance of the computer higher and higher, more sophisticated computer software has evolved to take advantage of the higher performance of the hardware, resulting in computer systems today that are much more powerful than just a few years ago.
One area of computer system technology that has advanced is computer processors. As the number of computer systems in data centers and the number of mobile computing devices has increased, the need for more efficient computer processors has also increased. The speed of operation and power consumption are just two areas of computer processor technology that affect the efficiency of computer processors.

Dual compare of least-significant-bit for dependency wake up from a fused instruction tag in a microprocessor

INTERNATIONAL BUSINESS MACHINES CORPORATION


A method and system which allows a remote monitoring and diagnostic computer or system to communicate using different communication protocols which are stored within a data base. After a communication is received, it is analyzed to determine if there is a protocol identifier. If the protocol identifier exists, a data base is searched to determine the format of the header of the communication. Once the format of the header is determined, the header of the received communication is read to determine the information contained therein. This information is utilized to determine the actual format of the data which follows. If the protocol identifier does not exist, the received communication is examined to determine if it is in a format which matches one of a plurality of previously defined format. Critical fields are defined which must have certain values and if the received communication matches these critical values, the record in a communication protocol data base matching the critical values will be utilized in order to determine the protocol of the data which has been received in the communication. The machine to which the remote monitoring and diagnostic system is connected is a business office device such as a copier, printer, or facsimile machine, a digital camera, or another type of device.

1. Field of the Invention
The present invention is related to communicating with, remote monitoring, diagnosis and control of machines using multiple communication formats. The invention is further related to the ability to upgrade and change the communication format which is to be utilized. The invention is still further related to a control/diagnostic system which has the ability to communicate with different machines such as copiers, printers, facsimile machines and digital cameras using different communication protocols.
2. Discussion of the Background
The communication between a remote diagnostic station and a machine such as a business office device which includes copiers, printers, facsimile machines and combinations thereof is known and disclosed in U.S. Pat. No. 5,412,779 issued to Motoyama and entitled "METHOD AND APPARATUS FOR CONTROLLING AND COMMUNICATING WITH BUSINESS OFFICE DEVICES", which is incorporated herein by reference. However, conventional diagnostic systems do not use varying communication protocols.
In order to have communication with, control of, or diagnostics of machines using different communication protocols, it is possible to have a dedicated control and monitoring system for each model. This would assure an ability to properly communicate using a different diagnostic computer for each type of machine. However, this could be expensive, an inefficient use of resources, and not allow or encourage a rapid development or improvement of communication protocols.

Method and system for controlling and communicating with machines using multiple communication formats


A method of simulating an enterprise computing management system is disclosed. The method includes receiving a simulated management infrastructure stack; and using the simulated management infrastructure stack and a user application to simulate the enterprise computing management system.

Computer systems running on distributed platforms can be managed remotely from a central location using a management infrastructure stack and a user application. Management of the systems includes gathering data on the hardware and software components, and testing various components and operating scenarios on the system. A computer system comprising a real distributed platform infrastructure is referred to herein as a real enterprise computing system.
A management infrastructure stack (202, 203, 204, 205), shown schematically in FIG. 2, comprises software and hardware components. The software component includes client application interface 202, server daemon 203, and server daemon plug-in 204. The hardware component includes service processor 205. In the stack, the components are in communication with each other and cooperate in managing the system either directly or through a computer network. An exemplary stack as shown in FIG. 2 is referred to herein as a real management infrastructure stack.
A user application 202, as shown schematically in FIG. 2, is software that functions with the management infrastructure stack (202, 203, 204, 205) to manage the enterprise computing management system. The user application 201 provides user functions, for example, a graphical user interface; functions for creating, modifying and deleting hardware partitions; functions for automatic detection of configuration and hardware problems; functions to view and print hardware inventory status; and a comprehensive on-line help.
In practice, the configuration of a user application 201 and a real management infrastructure stack in a real enterprise management computing system is flexible. For example, the user application 201 and the client application program interface 202 can reside on a Web server, while the server daemon 203 and the server daemon plug-in 204 can reside on the service processor 205; alternatively, the WEB server can be on one server, the server daemon 203 and daemon plug-in 204 can be on another server, and deamon-plugin 204 communicates with the service processor 205 in a third server.". In this exemplary configuration, communication between the user application 210 and the client application program interface 202 (residing on the web server), and the other portion of the real management information stack (residing on the service processor) can be direct or indirect via a network connection such as the Internet. Other configurations are possible and are well known in the art.
In the conventional art, to obtain data from on the enterprise management computing system and/or perform a test on the system, a user will log-on to the user application 210 and enter a request. The request is passed to the client application program interface 202 where it is converted to a format for transmission to the server daemon 203. The server daemon 203, on receiving the request, will invoke the server daemon plug-in 204 to handle the request. In handling the request, the server daemon plug-in 204 will make systems calls or the like to gather information to fulfill the request and provide a reply. The information is usually available from the service processor 205 which, typically, is the single point of contact for information on the system. The reply is returned to server daemon 203 for interpretation and integration, and thereafter passed to the client application interface 202 where it is converted to a format for presentation to the user at the user application 201. In this regard it should be noted that service processor 205, as the single point of contact in the hardware, allows for crossing of one or more operating systems boundaries to get information on the system.
In the conventional art, a pre-requisite for using or testing a real management infrastructure stack 202, 203,204,205 is that the stack must be complete and fully functional as a unit. That is, all the components of the stack, i.e., the client application program interface 202, the server daemon 203, the server daemon plug-in 204 and the service processor 205, must be integrated in the stack and functioning as a unit.
A problem with the fully functional requirement is that if it is desired to test a user application 201 or demonstrate a prototype of an enterprise computing system, while the stack is still being developed, the test or demonstration cannot be done until the real stack is available.
Another problem with the fully functional requirement is that, after the sack 202, 203,204, 205 is developed, since the software components are large and the hardware component is expensive, if it is desired to merely demonstrate features of the real stack on a small computer without investing in a service processor 205, the demonstration will not be possible without a connection to a real stack.
Accordingly, in view of these and other problems of the conventional art, it is an objective of the invention to provide for a simulated management infrastructure stack that will allow for testing the user application, or demonstrating an enterprise management system on a portable system, without requiring a connection to a real management infrastructure stack.
These and other objectives of the invention will no doubt become obvious to those of ordinary skill in the art on reading the following detailed description of preferred embodiments in conjunction with the various Figures.

Method of simulating an enterprise computing management system

Hewlett-Packard Development Company, L.P.


Apparatus including an ion trap, a controller connected to the ion trap, wherein the controller includes a memory containing computer readable instructions which, when executed, cause the controller to send control signals to the ion trap so that the ion trap produce and maintain a trapping field in the ion trap, a waveform generator to change the trapping field so that ions of a predetermined mass in the trapping chamber are selectively moved; a secondary waveform generator to change the orbits of the ions; an energy source to excite ions to emit photons, an optical detector to detect the emitted photons, and a processor which can apply fast-Fourier transform analysis of the time-domain signal of the detected emitted photons to generate a frequency or mass spectrum related to mass-to-charge ratio of the ions.

Many different mass analyzers are used in the field of mass spectrometry. The most common mass analyzers include ion-cyclotron resonance (ICR) or Fourier transform mass spectrometer ("FTMS"), ion traps, quadrupole, time-of-flight, orbitraps and magnetic sector instruments. All of the commercial versions of these instruments detect the ions by using an ionizing particle detector or by measuring an electrical image current as done when using the Fourier transform technique for FTMS and the orbitrap. Although there has been experimental work using photon emission to make ion measurements inside an ion trap, no known commercial instrument with any of the above mentioned mass analyzer types use optical detection of ions inside the mass analyzer to determine the m/z and/or the presence of select chromophores. In the pioneering work of, Wuerker, Shelton and Langmuir in 1959, they used a 3D-quadrupole field ion trap or what is often now called a "Paul" trap to teach how charged aluminum particles could be confined and photographed in dynamic equilibrium. They applied a voltage across the end caps of the ion trap to measure the resulting frequency of the charged particles at resonance and recorded interesting tell tale photographs of the charged particle trajectories. Holes were machined in the ion trap electrodes to make these observations and when the particles reached a stable orbit they noted the voltage and frequencies applied to the electrodes. They used a conventional 35 mm microscope camera and exposed the film for 0.1-0.2 seconds. They did not purposely move the ions to specific locations in the trap to image or photon count or count from specific regions of the ion trapping volume, but instead they scanned the RF or resonant frequency for mass analysis and recorded for the first time, the complete motion of the trapped charged particles in the ion trapping chamber. Others have since followed Wuerker, Shelton and Langmuir's work and have used improved light sources, such as lasers; detectors, such as photo multiplier tubes; different analyzers and optical techniques such as laser induced fluorescence (LIF) to make improved measurements. In 1975, LIF of a non trapped molecular ion was first reported for N2+ by Engelking and Smith. In 1977, Miller and Bondybey followed by showing the LIF of non-trapped CO+ and CO2+ and later with Sears, in 1978-81, of various fluorinated benzene cations. Between 1980-82 CD+ and BrCN+ and N2+ were trapped for the LIF measurements using a Paul trap by Grieman, Mahan and O'Keefe. There have also been reports of LIF in Penning ion traps by Drullinger and others. Welling, Thompson and Walther in 1996 [IJMSIP, 172, p95.] used a linear ion trap (LIT) to determine the absolute gas phase photo dissociation cross-section of the ionic molecular complexes. They made complexes of MgC60+ by in situ collisions inside the LIT and then dissociated them using a laser shot off-axis. The resultant signal was recorded using mass spectrometry or by using laser induced fluorescence (LIF) of the Mg+ product ion. Welling, Schuessles, Thompson and Walther followed those experiments in 1998 to study ion molecule reactions in the gas phase and again used optical spectroscopy on the trapped ions in a LIT. They used parametric excitation of the secular motion to generate the mass spectrum with ejection amplitudes of 1 Vpp and scan rates of 200 kHzs−1. They calculated that they trapped 106 ions in a 10 cm long trapping volume which facilitated the spectroscopy measurements even with an off-axis laser and detector. Co-linear excitation was not done. They measured total cross-sections of MgC60+ by LIF and photo-dissociation. Photons from the strong LIF transition from Mg+ were detected perpendicular to the ion axis in a pump probe approach. In these studies they did not do mass analysis using LIF. In 2001, Wang, Hendrickson and Marshall reported on LIF optical measurements of hexafluorobenzene from inside an ion cyclotron resonance mass spectrometer, but they did not use LIF for mass analysis.
Nakamura and coworkers [JAP 2001, 89, 2922], measured various resonances in a linear combined trap in 2001 and measured these frequencies by using a fast Fourier transform method.
In 2001, Schlemmer, Illemann, Wellert and Gerlich [JAP, 90, p5410] demonstrated mass spectrometry of 500 μm SiO2 particles in a Paul-like trap using a light scattering nondestructive method. Their ion trap used end caps, but the field in the r-dimension was generated by eight rods to allow for good penetration of the laser beam into the trap and thus they did not incorporate a ring electrode. In this experiment the particles were illuminated inhomogeneously so that the scattered light would be modulated at the secular frequency of the charged particles trajectories thus allowing the calculation of the m/z using a fast Fourier transform. The laser beam density was used to achieve this measurement and a photodiode detector was used to detect the photon emissions.
In 2002, Khoury, Rodriguez-Cruz and Parks used electrospray ionization (ESI) and a Paul trap to make pulsed fluorescence measurements of trapped molecular ions for rhodamine 640 and Alexa Fluor 350. For ion trapping during ion injection, the helium was pulsed to 2×104 Torr for 0.25 to 0.5 seconds. Their calculations showed that for 103 trapped ions, approximately 1% of these were detected by photon emissions through a hole in the ring electrode. The low percentage of ions detected per pulse was partially due to a maximum laser beam overlap of 3-15% of the ion cloud and the detection of the photons emitted through a 1.2 mm hole to the photomultiplier. They were able to eliminate background laser scattering during the pulse by delaying the measurement which greatly improved the signal-to-noise level. Measurements were taken over minute exposure times. They did not use the LIF signal to determine m/z. In 2003, Danell and Parks showed that fluorescence resonance energy transfers (FRET) measurement can be made on oligonucleotides duplexes in an ion trap using spectroscopy and a 3D-quadrupole field ion trap. They stressed that the elimination of background scattered radiation at the detector was essential to make their measurements.
Baba and Waki studied the sympathetic cooling rate of gas-phase ions in linear ion traps in 2002. In their experiment a laser beam was directed on-axis in the LIT. Marshal et al. determined fluorescence lifetimes of ions in a Penning trap and demonstrated the feasibility of resolving these ions from a heterogeneous mixture.
In 2003, Cai, Peng and Chang used a dual Paul trap to do LIF on labeled polystyrene particles. The first trap was used to trap all the charged particles while the second trap received select particles from the first and was used for LIF. They used a frequency scan from 0.5 Hz to 50 kHz for mass analysis. Particles up to 27 nm were analyzed by this method as well as fluorescently labeled IgG at 150 kDa. In 2005, Peng, Yang, Lin and Chang showed high precision mass determination for single polystyrene spheres using a Paul trap [Anal. Chem., 2005, 77, 7084.]. In these experiments they used a single trap and monitored the star like trajectory pattern to determine the mass following Hars and Tass [JAP 1995, 77 p4245.].
And finally, Iavarone, Meinen, Schulze and Parks made fluorescence measurements to probe peptide conformations in their Paul ion trap and did the mass analysis using conventional methods.

Mass spectrometer and method for using same


Cooling systems for high pressure compressor systems are provided. The cooling systems may comprise tangential on board injectors (“TOBIs”). The TOBIs may comprise one or more fluid channels configured to conduct cooling fluid flow to components of the compressor, including, for example, disk-hub portions of the compressor. In this regard, the TOBI may be configured to exhaust cooling air in a manner such that the exhausted air has a similar linear velocity of the disk-hub portion. The cooling air may also be exhausted in a manner that is substantially parallel to the disk-hub portion.

Modern turbofan engines have a modular design architecture consisting of the "cold section" and "hot section." Air drawn into the engine undergoes an increase in pressure through the cold section, followed by a decrease in pressure through the hot section, as work is extracted from the compressed air. Typically, the air temperature increases through each stage of the engine. These elevated temperatures may go beyond the current temperature limits of hub materials. To enhance the effectiveness of the cooling air on the rotating components, TOBIs may be employed.

Compressor injector apparatus and system


Disclosed is a gas-fired oven for heating food by steam and/or dry convection. The oven has a heating chamber; an atomizer for producing an atomized water spray; a source of a combustible gas mixture; and a burner-heat exchanger. The gas fired burner-heat exchanger receives and combusts the mixture and isolates hot combustion gases from the heating chamber so pure steam is furnished to the heating chamber. The heat exchanger receives hot combustion gases, and vaporizes atomized spray circulated over its external surface to produce steam for heating an article in the heating chamber. The amount of steam in the heating chamber is measured and controlled by monitoring a temperature in a drain.

The recent emphasis of health and its association with food has increased the use of steam cooking because of its unique capabilities. The flavor of many foods is retained when cooked with steam and is sometimes enhanced. Nutrients, such as vitamins, minerals, etc., are less prone to degradation when foods are cooked with steam. The appearance, texture, and color, especially of delicate foods such as vegetables, remain pleasing when cooked with steam. Of concern to the commerical food sector is time; applications of steam to commercial cooking can result in faster food preparation.
For browning of some foods, such as roasts for example, it is sometimes advantageous to maintain drier food surfaces at high temperatures by the use of dry air convection heating.
Oftentimes a combination of steam and convection heating is desired U.S. Pat. No. 4,700,685 to Miller issued Oct. 20, 1987, discloses an oven for cooking foodstuffs with either steam or convection hot air. A slinger cup atomizes water by centrifugal force which flows over an electrical heater to produce steam. The temperature of the cooking cavity is measured and used to control the electric heater.
European Patent No. EP277888 to Violi published Aug. 10, 1988, appears to disclose an oven that uses a small boiler to generate steam which is mixed with combustion gasses from a gas burner and introduced into the cooking chamber.
U.S. Pat. No. 4,722,321 to Meister issued Feb. 2, 1988, discloses an oven with a boiler for providing steam and a heating coil surrounding a blower for providing heated convection gases. A temperature sensor is positioned in a bypass line to a discharge pipe.

Gas fired combination convection-steam oven


A system and method, for identification of the user equipment with IMS PDN connectivity issues, and proactively recovering the PDN connectivity for said user equipment is disclosed. The disclosure provides triggering the System initiated detach with re-attach required request, to user equipment by checking the current IMS PDN state of said VoLTE user equipment to recover the IMS PDN connectivity. The present disclosure provides a novel automatic method for maintaining IMS PDN connection providing continuous voice call connectivity and improving the overall connectivity and user experience of the wireless network.

The following description of related art is intended to provide background information pertaining to the field of the disclosure. This section may include certain aspects of the art that may be related to various features of the present disclosure. However, it should be appreciated that this section be used only to enhance the understanding of the reader with respect to the present disclosure, and not as admissions of prior art.
A typical contemporary wireless network is deployed to provide various communication services including, but not limiting to, video, data, advertisement, content, messaging and broadcast. The network has usually multiple access networks to support communications for multiple users by sharing the available network resources. The earlier UTRAN (Universal Mobile Telecommunications System-Terrestrial Radio Access Network) is radio access network (RAN), which was defined as a part of the Universal Mobile Telecommunications System (UMTS), a third-generation (3G) mobile phone technology supported by the 3rd Generation Partnership Project (3GPP). The UMTS technology, which is the successor to Global System for Mobile Communications (GSM) technologies, currently supports various air interface standards, such as Wideband Code Division Multiple Access (W-CDMA), Time Division-Code Division Multiple Access (TD-SCDMA), and Time Division-Synchronous Code Division Multiple Access (TD-SCDMA). Also, the UMTS supports enhanced 3G data communications protocols such as the High-Speed Packet Access (HSPA) that provides higher data transfer speeds and capacity to associated UMTS networks. With increase in the demand for mobile data and voice access, these technologies are upgrading not only to meet the growing demand for access but also to enhance the user experience. One such advanced technology is Evolved Universal Terrestrial Radio Access (E-UTRA) which is a radio access network standard and is considered as a replacement of the UMTS and High-Speed Downlink Packet Access/High-Speed Uplink Packet Access (HSDPA/HSUPA) technologies covered under the 3GPP standards. The E-UTRA of the Long Term Evolution (LTE) is an entirely new air interface system, unlike the High-Speed Packet Access (HSPA), which is unrelated and incompatible with the wireless code division multiple access (W-CDMA). In addition, the E-UTRA not only provides higher data rate and lower latency but is also optimized for packet data. Thus, E-UTRA provides a single evolution path for providing enhancement in the data speeds, and spectral efficiency and allowing the provision of more functionality. LTE is a 4th generation cellular technology offering high-speed data and large capacity based on Orthogonal Frequency Division Multiple Access (OFDMA) technology. It was standardized by 3GPP in December 2008 and is specified in 3GPP Release 8 series, with continuous enhancements and further releases. The voice services over LTE is referred as Voice over LTE (VoLTE). The quality of voice through VoLTE is far superior compared to what is available today in legacy networks and is termed as High Definition (HD) voice.
The typical call flow of LTE and IMS PDN connection/disconnection with network is as follows:
Once the user equipment is powered ON, the UE will initiate the PDN connectivity procedure as per 3GPP TS 24.301 section 6.5.1. The purpose of UE request of PDN connectivity procedure is to setup a default EPS (Evolved Packet System) bearer for obtaining the services from network. The UE requests connectivity to a PDN by sending a PDN CONNECTIVITY REQUEST message to the network. If said request is accepted by the network, this procedure initiates the establishment of a default EPS bearer context. The procedure is used either to establish the first default bearer by including the PDN CONNECTIVITY REQUEST message into the initial attach message, or to establish subsequent default bearers to additional PDNs in order to allow the UE simultaneous access to multiple PDNs by sending the message stand-alone (PDN connectivity request with IMS APN for accessing VoLTE services simultaneously). If connectivity with the requested PDN is accepted by the network, a system shall initiate the default EPS bearer context activation procedure. Similarly when UE is powered OFF it will initiate detach request. The UE will initiate PDN disconnect procedure in some exceptional cases or optionally before initiating detach process as per 3GPP TS 24.301 6.5.2. The purpose of the UE requested PDN disconnection procedure is for the UE to request disconnection from one PDN. The UE can initiate this procedure to disconnect from any PDN as long as it is connected to at least one other PDN. With this procedure, all EPS bearer contexts established towards this PDN, including the default EPS bearer context, are released. In order to request PDN disconnection from a PDN, the UE shall send a PDN DISCONNECT REQUEST message to the system. The PDN DISCONNECT REQUEST message shall include the EPS bearer identity of the default bearer associated with the PDN to disconnect. Upon receipt of the PDN DISCONNECT REQUEST message, if it is accepted by the network, the system shall initiate the bearer context deactivation procedure by sending the DEACTIVATE EPS BEARER CONTEXT REQUEST message to disconnect default bearer associated with the PDN including the linked EPS bearer identity.
The detach procedure can be initiated either by the UE or from the network. In UE initiated detach procedure, the detach procedure is initiated by the UE by sending a DETACH REQUEST message. The Detach type IE included in the message indicates whether detach is due to a "switch off" or not. The Detach type IE also indicates whether the detach request is for EPS services only, for non-EPS services only, or for both. When the DETACH REQUEST message is received by the network, the network shall send a DETACH ACCEPT message to the UE and store the current EPS security context, if the Detach type IE does not indicate "switch off". Otherwise, if the UE is to be switched off, the UE shall try for a period of few seconds to send the DETACH REQUEST message. During this period, the UE may be switched off as soon as the DETACH REQUEST message has been sent. The detach procedure is completed when the network receives the DETACH REQUEST message. On reception of a DETACH REQUEST message indicating "switch off", the system shall delete the current EPS security context if it is a mapped EPS security context.
In the network-initiated detach procedure, the network initiates the detach procedure by sending a DETACH REQUEST message to the UE. The network may include an EPS Mobility Management (EMM) cause Information Element (IE) to specify the reason for the detach request. The Detach type IE in the message indicates "re-attach required" or "re-attach not required" or "IMSI detach". When receiving the DETACH REQUEST message and the detach type indicates "re-attach required", the UE shall deactivate the EPS bearer context(s) including the default EPS bearer context locally without peer-to-peer signalling between the UE and the system. The UE shall then send a DETACH ACCEPT message to the network and enter state EMM-DEREGISTERED. Furthermore, the UE shall initiate attach or combined attach procedure after the completion of the detach procedure. The UE may also re-establish any previously established PDN connection(s). Whenever the UE is powered-up, it initiates registration with the network on "Primary Internet" APN. After completion of initial attach with primary APN, the UE initiates PDN connectivity request with the network for "IMS" APN for voice service. Thus VoLTE devices have two APNs, Primary APN (operator specific) for data and "IMS" APN for voice with one default bearer for each APN. The device always maintains connections with both these APNs for both internet and voice services.
However, it is observed that the UE doesn't initiate IMS PDN connectivity request, though the UE successfully attaches with the network on Primary Internet APN. In such a scenario, the user will not be able to make or receive voice calls although the UE will be able to access High-Speed Internet (HSI) services. Also, the same UE will work on another operator, if another operator is on the 2G/3G CS Network. It is, therefore, difficult for the end-user to understand that the issue is of the device and not of the network for the interruption in voice call service. From a customer experience perspective, this behaviour is completely unacceptable since the user would not know if the IMS connection of the device has not been successfully attached and will miss incoming calls during this period of no connectivity. The user will realize something amiss only when he attempts an outgoing call which will fail and will not connect. This problem may be manually solved when UE would resume normal connectivity with IMS APN after the power-cycling of the UE or toggling the UE to airplane mode. This manual method is cumbersome and the user experience is not smooth.
Another challenge is the presence of multiple vendors for VoLTE UEs in open market which may exhibit this behaviour and since the operator do not exercise complete control over such devices, it will be very difficult to solve this problem from the UE perspective.
There are other several challenges in the existing arts for the VoLTE UE where the IMS PDN connectivity request is not initiated, thereby not able to connect to provide voice call hence not improving the overall connectivity and user experience of the wireless network. Therefore, there is a need for automatic novel method to provide solution for the IMS PDN connectivity request, to connect and provide continuous voice call connectivity for improving the overall connectivity and user experience.


A light detection and ranging (lidar) device includes: a lower base; an upper base; a laser emitting unit for emitting a laser in a form of a point light source; a nodding mirror for transforming the laser in the form of the point light source to a line beam pattern which is perpendicular to the lower base, wherein the nodding mirror reflects the laser emitted from the laser emitting unit; a polygonal mirror for transforming the line beam pattern to a plane beam pattern and receiving a laser reflected from an object; and a sensor unit for receiving the laser reflected from the object via the polygonal mirror.

Light detection and ranging (lidar) is a technology that measures a distance to an object by projecting a laser toward the object and receiving the reflected laser. As a method of measuring a distance in the lidar technology, a time of flight (TOF) which uses a flight time of laser light, a triangulation method which calculates a distance according to a position of a received laser according to a position of a received laser, and the like are used.
The triangulation method measures a distance with respect to a wide range at once mainly by using a flash laser, but has low accuracy, therefore lidar, to which the TOF method capable of performing relatively high definition/high resolution measurement with respect to a long distance, is used as a distance sensor for autonomous vehicles which have recently taken center stage as a significant application field for lidar.
Measurement distance, heat suppression, size reduction, and the like have emerged as main technical issues of lidar using the TOF method. To overcome the issues, a variety of research has been performed.


A vehicle includes an engine, a first motor generator, a second motor generator, a transmission, a differential device, and an electronic control unit. The transmission includes an input shaft, an output shaft, and a clutch. The electronic control unit is configured to detect a rotation speed difference between the input shaft and the output shaft when the clutch is controlled so as to be brought into a power transmission shut-off state. The electronic control unit is configured to, when the rotation speed difference detected by the electronic control unit is smaller than a target rotation speed difference between the input shaft and the output shaft that occurs in a case where the power transmission shut-off state of the clutch is established, suppress cranking of the engine by the first motor generator.

1. Technical Field
The disclosure relates to control for a vehicle in which are mounted a transmission having a clutch configured to be engaged at the time of starting and to be disengaged at the time of power shut-off and a motor generator coupled to an input shaft of the transmission.
2. Description of Related Art
For example, Japanese Patent Application Publication No. 2013-112335 (JP 2013-112335 A) discloses a hybrid vehicle in which the necessity of charging of an in-vehicle battery during stoppage of the vehicle is determined, and in a case where it is determined that charging of the battery is required, a motor brings a transmission coupled to an input shaft into a power shut-off state. JP 2013-112335 A discloses a technique which, after the transmission is brought into the power shut-off state, engages a clutch provided between an engine and the motor to start the engine, generates electric power with the power of the engine, and charges the in-vehicle battery with the generated electric power.


A system includes a turbine casing including a first hook configured to mate with a second hook to support a turbine shroud about a plurality of turbine blades. The turbine casing includes a coolant circuit configured to adjust clearance between the turbine shroud and the turbine blades based on coolant flow through the coolant circuit. The coolant circuit includes a first plurality of radial coolant passages extending into the first hook.

The subject matter disclosed herein relates to clearance control techniques, and more particularly to a system for adjusting the clearance between a stationary component and a rotary component of a rotary machine.
In certain applications, a clearance may exist between components that move relative to one another. For example, a clearance may exist between rotary and stationary components in a rotary machine, such as a compressor, a turbine, or the like. The clearance may increase or decrease during operation of the rotary machine due to temperature changes or other factors. As can be appreciated, a smaller clearance may improve performance and efficiency in a compressor or turbine, because less fluid leaks between blades and a surrounding shroud. However, a smaller clearance also increases the potential for a rub condition. The operating conditions also impact the potential for a rub condition. For example, the potential for a rub condition may increase during transient conditions and decrease during steady state conditions. Unfortunately, existing systems do not adequately control clearance in rotary machines.

System and method for clearance control in a rotary machine


A waistband for an article of apparel comprising at least one embroidery tunnel is provided. The waistband comprises at least one cord comprising a first and second end affixed to the waistband, and an intervening portion movably coupled to the waistband with stitches that form the embroidery tunnel, the embroidery tunnel configured to distribute a tensioning force applied to the cord across at least a portion of the waistband. The embroidery tunnel forms a series of parallel courses across the waistband, with the cord able to move freely within the embroidery tunnel.

A traditional waistband for an article of apparel such as board shorts often incorporates a drawstring waistband to secure the article to the wearer. Drawstring waistbands frequently utilize one or more cords traveling through and around the article. The cord can often be drawn or tightened to increase pressure on the waistband and reduce the circumference of the waistband, thereby securing the waistband to the wearer. A drawstring waistband is less bulky than a waistband featuring traditional securement components like snaps, hooks, or zippers. However, drawstring waistbands have a number of disadvantages including weak securement, minimal distribution of tensioning force across the waistband, strain on the waistband that weakens the waistband structures, and wearer discomfort.

Waistband for article of apparel featuring cord and embroidery tunnel


Disclosed herein is an all-digital phase and timing correction procedure for coherent averaging in dual-comb and multiheterodyne spectroscopy—applicable to any dual-comb spectroscopy setup. It can account for large frequency/phase instabilities of the used sources, yielding a significant reduction of the noise pedestal and an increase in signal-to-noise ratio (SNR) of the radio frequency (RF) beat notes. This technique is computationally efficient and can be conveniently implemented either as a post-processing algorithm or in a real-time data acquisition and processing platform without the necessity of adding any additional optical elements to the dual-comb spectroscopy system. By implementing this technique, the performance of any comb- or comb-like-source-based DCS system with a sufficient degree of mutual coherence between the optical modes can be improved in terms of SNR and number of spectroscopically-usable RF beat notes. The described technique is compatible with a DC-centered RF spectrum, where the negative frequencies are folded to the positive domain to double the number of beat notes within the detector bandwidth. The technique enables coherent averaging over extended time-scales even for free-running combs, thus increasing the sensitivity of absorption and dispersion DCS measurements.

The present invention relates generally to multiheterodyne spectroscopy or dual-comb spectroscopy and more particularly phase and timing correction procedure for the aforementioned techniques.
Multiheterodyne spectroscopy (MHS) or dual-comb spectroscopy (DCS) has attracted much attention in recent years due to its potential for small-footprint, moving-parts-free and fast acquisition (in the microsecond range) of high resolution spectra covering large optical bandwidths. The light sources used for MHS/DCS have historically been limited to femtosecond oscillators, micro-resonators, or electro-optic combs due to the strict requirements on frequency stability, but lately Fabry-Perot quantum cascade lasers (FP-QCLs) have also demonstrated broadband optical frequency comb generation with an unprecedented potential for miniaturization, although reliable operation is typically limited to a small range of temperatures and currents. Beyond the narrow comb regime, these lasers suffer from large oscillations of repetition rate and offset frequency, which hinders their ability to perform high resolution MHS/DCS due to increased phase noise.
Despite this, the spectroscopic information is still encoded in the beating signal (interferogram) even in the noisy operation regime, and it can be recovered by employing adaptive sampling techniques. Conventional adaptive sampling techniques are usually implemented by introducing additional continuous wave (CW) lasers as frequency references and electronic feedback, which unfortunately complicates the MHS/DCS configuration.
Several different phase correction methods have been suggested in order to perform coherent averaging in MHS/DCS systems by suppressing the unwanted measurement instabilities of free running frequency combs. One recent proposal was a computational phase and timing correction methodology based on Kalman filtering, which can handle extreme multiheterodyne beat note instabilities and RF spectrum congestion due to overlapping beat notes. Despite the excellent performance of this method, there are some practical limitations due to the computational complexity of the Kalman filter, as well as the requirement of a-priori knowledge of the number of modes, N, contributing to the RF spectrum, which may limit its real-time phase correction performance even in systems with a lower number of multiheterodyne beat notes.
Thus, there is a need for a less complex but equally effective computational procedure that can be implemented to perform the phase correction.

Fast computational phase and timing correction for multiheterodyne spectroscopy


A payload delivery apparatus comprised of a frangible hollow body for delivering a variety of payloads. The body is attached to a base having a threaded section for removable engagement with an arrow shaft. A plurality of equidistant spaced impact stanchions are attached around the perimeter of the body. A cap is fitted to an open end of the hollow body. Each impact stanchion is connected to the hollow body in such a way as to fracture upon impact with a target thus delivering the payload. In an alternate embodiment, a set of aerodynamic linear channels and annular indentions is included in the body so as to aid to fracturing upon impact.

This disclosure relates to hunting equipment, and more particularly to an arrow which is capable of disposably transporting a payload to a target.
In the sport of game hunting it is conventional for a hunter to select a spot believed to be in a path or other area where the game is likely to be and wait for the animal in a tree or other hiding place. Typically, a hunting stand is erected on a tree above the expected travel path of the animals where a hunter can stay without searing the animal and without leaving a human scent. To improve the hunter's odds, an attractant such as the scent of such animal may be left in the area so that other animals of the species would investigate it and while doing so, offer more target opportunities for the hunter.
Furthermore, the hunter hiding in a tree has to descend to the ground and spread the scent manually in the target area. A conventional alternative was to wet a rag or other absorbent material, tie the rag to an arrow and then fire the arrow from the tree stand. However, such approach suffers from major disadvantages. For example, the liquid can be spilled on the hunter or his clothes. Moreover, some of the scent is dispersed during the arrow flight and very little of the liquid reaches the ground.
My co-pending application discloses an improved scent dispersing arrowhead where a hollow body has a pair of opposing cutouts through which an animal attractant, such as liquid scent can exit the hollow body. The hollow body is configured to retain a frangible liquid-scent containing capsule. A plunger is configured to slide into the scent capsule enclosure and cause rapture the scent-containing capsule upon impact of the plunger with a solid surface, such as ground, rock or tree limb. While this arrowhead has distinct advantages over conventional scent dispersing arrows, it was discovered that a narrow forward tip of the arrowhead tends to at least slightly penetrate the soil and thus disperse a portion of the scent liquid into the soil.
For example, U.S. Pat. No. 6,450,905 to Edlund, discloses a scent dispersion arrow including an active arrow tip which uses a compression fitting to attach to an out shaft. A scent dispersion head, containing a sponge holding a liquid scent had a cavity in the arrow tip. The cavity is sealed against the compression fittings. When deployed, the arrow tip advances in the cavity dispersing the scent through openings in the arrowhead.
As another example, U.S. Pat. No. 5,836,842 to McLearan, discloses an arrow for dispersing a scent with an active arrowhead. The arrowhead is blunt and includes a deployment orifice connected to a rigid tube. A scent is contained in the arrow body in a container which is sealed around the tube. Upon impact, the arrow body drives the container along the tube thereby forcing the scent liquid through the tube and out of the orifice to be deployed at the target.
As another example, U.S. Pat. No. 4,726,584 to Bishop, discloses a scent releasing arrow which includes a hollow tubular metal shaft having a pad of absorbent material located within it. It's adjacent a group of openings. A cylindrical sleeve covers the openings until the arrow is deployed. Upon deployment the cover slides forward uncovering the holes and releasing the scent.
Similarly, United States Patent Publication No. 2008/0051231A1 to Everett, discloses a hollow scent arrow having a plurality of holes. The hollow arrow includes a wick stick adjacent the holes filled the scent liquid. Also within the hollow arrow is a heavy slug which is free to slide within the arrow compartment behind the wick stick. Upon deployment, the slug advances pressing the wick stick and releasing the scent out of the holes.


Methods for preparing cell lines that contain artificial chromosomes, methods for preparation of artificial chromosomes, methods for purification of artificial chromosomes, methods for targeted insertion of heterologous DNA into artificial chromosomes, and methods for delivery of the chromosomes to selected cells and tissues are provided. Also provided are cell lines for use in the methods, and cell lines and chromosomes produced by the methods. In particular, satellite artificial chromosomes that, except for inserted heterologous DNA, are substantially composed of heteroaromatic are provided. Methods for use of the artificial chromosomes, including for gene therapy, production of gene products and production of transgenic plants and animals are also provided.

The present invention relates to methods for preparing cell lines that contain artificial chromosomes, to methods for isolation of the artificial chromosomes, targeted insertion of heterologous DNA into the chromosomes, isolation of the chromosomes, and delivery of the chromosomes to selected cells and tissues. Also provided are cell lines for use in the methods, and cell lines and chromosomes produced by the methods.
Several viral vectors, non-viral, and physical delivery systems for gene therapy have been developed [see, e.g., Mitani et al. (1993) Trends Biotech. 11:162-166]. The presently available systems, however, have numerous limitations, particularly where persistent, stable, or controlled gene expression is required. These limitations include: (1) size limitations because there is a limit, generally on order of about ten kilobases [kB], at most, to the size of the DNA insert [gene] that can be accepted by viral vectors, whereas a number of mammalian genes of possible therapeutic importance are well above this limit, especially if all control elements are included; (2) the inability to specifically target integration so that random integration is required which carries a risk of disrupting vital genes or cancer suppressor genes; (3) the expression of randomly integrated therapeutic genes may be affected by the functional compartmentalization in the nucleus and are affected by chromatin-based position effects; (4) the copy number and consequently the expression of a given gene to be integrated into the genome cannot be controlled. Thus, improvements in gene delivery and stable expression systems are needed [see, e.g., Mulligan (1993) Science 260:926-932].
In addition, safe and effective gene therapy methods and vectors should have numerous features that are not assured by the presently available systems. For example, a safe vector should not contain DNA elements that can promote unwanted changes by recombination or mutation in the host genetic material, should not have the potential to initiate deleterious effects in cells, tissues, or organisms carrying the vector, and should not interfere with genomic functions. In addition, it would be advantageous for the vector to be non-integrative, or designed for site-specific integration. Also, the copy number of therapeutic gene(s) carried by the vector should be controlled and stable, the vector should secure the independent and controlled function of the introduced gene(s); and the vector should accept large (up to Mb size) inserts and ensure the functional stability of the insert.
The limitations of existing gene delivery technologies, however, argue for the development of alternative vector systems suitable for transferring large [up to Mb size or larger] genes and gene complexes together with regulatory elements that will provide a safe, controlled, and persistent expression of the therapeutic genetic material.
At the present time, none of the available vectors fulfill these requirements. Some of these characteristics, however, are possessed by chromosomes. Thus, an artificial chromosome would be an ideal vector for gene therapy, as well as for production of gene products that require coordination of expression of numerous genes or that are encoded by large genes, and other uses. Artificial chromosomes for expression of heterologous genes in yeast are available, but construction of a mammalian artificial chromosome has not been achieved. Such construction has been hindered by the lack of an isolated, functional, mammalian centromere and uncertainty regarding the requisites for its production and stable replication. Unlike in yeast, there are no selectable genes in close proximity to a mammalian centromere, and the presence of long runs of highly repetitive pericentric heterochromatic DNA makes the isolation of a mammalian centromere using presently available methods, such as chromosome walking, virtually impossible. Other strategies are required for production of mammalian artificial chromosomes, and some have been developed. For example, U.S. Pat. No. 5,288,625 provides a cell line that contains an artificial chromosome, a minichromosome, that is about 20 to 30 megabases. Methods provided for isolation of these chromosomes, however, provide preparations of only about 10-20% purity. Thus, development of alternative artificial chromosomes and perfection of isolation methods as well as development of more versatile chromosomes and further characterization of the minichromosomes is required to realize the potential of this technology.
Therefore, it is an object herein to provide mammalian artificial chromosomes and methods for introduction of foreign DNA into such chromosomes. It is also an object herein to provide methods for introduction of the artificial mammalian chromosome into selected cells, and to provide the resulting cells, as well as transgenic animals and plants that contain the artificial chromosomes. It is also an object herein to provide methods for gene therapy and expression of gene products using artificial chromosomes. It is a further object herein to provide methods for constructing species-specific artificial chromosomes.
Mammalian artificial chromosomes [MACs] are provided. Also provided are artificial chromosomes for other higher eukaryotic species, such as insects and fish, produced using the MACS are provided herein. Methods for generating and isolating such chromosomes. Methods using the MACs to construct artificial chromosomes from other species, such as insect and fish species are also provided. The artificial chromosomes are fully functional stable chromosomes. Two types of artificial chromosomes are provided. One type, herein referred to as SATACs [satellite artificial chromosomes] are stable heterochromatic chromosomes, and the another type are minichromosomes based on amplification of euchromatin.
Artificial chromosomes permit targeted integration of megabase pair size DNA fragments that contain single or multiple genes. Thus methods using the MACs to introduce the genes into cells, animals and tissues are also provided. The artificial chromosomes with integrated heterologous DNA are to be used in methods of gene therapy, in methods of production of gene products, particularly products that require expression of multigene biosynthetic pathways, and also are intended for delivery into the nuclei of germane cells, such as embryo-derived stem cells [ES cells] for production of transgenic animals.
Mammalian artificial chromosomes provide extra-genomic specific integration sites for introduction of genes encoding proteins of interest and permit megabase size DNA integration so that, for example, genes encoding an entire metabolic pathway or a very large gene, such as the cystic fibrosis [CF; xcx9c600 kb] gene, several genes, such as a series of antigens for preparation of a multivalent vaccine, can be stably introduced into a cell. Vectors for targeted introduction of such genes, including the tumor suppressor genes, such as p53, the cystic fibrosis transmembrane regulator gene [CFTR], anti-HIV ribozymes, such as an anti-HIV gag ribozyme, into the artificial chromosomes also provided.
The chromosomes provided herein are generated by introducing heterologous DNA that includes DNA encoding a selectable marker into cells, preferably a stable cell line, growing the cells under selective conditions, and identifying from among the resulting clones those that include chromosomes with more than one centromere or that have chromosomes that are fragments of chromosomes that had more than one centromere. The amplification that produces the additional centromere occurs in cells that contain chromosomes in which the heterologous DNA has integrated near the centromere in the pericentric region of the chromosome. The selected clonal cells are then used to generate artificial chromosomes.
In preferred embodiments, the DNA with the selectable marker that is introduced includes sequences that target it to the pericentric region of the chromosome. For example, vectors, such as pTEMPUD, which includes such DNA specific for mouse satellite DNA, are provided. Also provided are derivatives of pTEMPUD that specifically target human satellite sequences. Upon integration, these vectors can induce the amplification.
Artificial chromosomes are generated by culturing the cells with the dicentric chromosomes under conditions whereby the chromosome breaks to form a minichromosome and formerly dicentric chromosome. The artificial chromosomes [the SATACs] are generated, not from the minichromosome fragment as, for example, in U.S. Pat. No. 5,288,625, but from the fragment of the formerly dicentric chromosome.
Among the MACs provided herein are the SATACs, which are primarily made up of repeating units of short satellite DNA and are fully heterochromatic, so that absent insertion of heterologous or foreign DNA, the chromosomes do not contain genetic information. They can thus be used as xe2x80x9csafexe2x80x9d vectors for delivery of DNA to mammalian hosts because they do not contain any potentially harmful genes.
In addition to MACs methods for generating euchromatic minichromsomes and the use thereof are also provided herein. Methods for generating one type of MAC the minichromosome, previously described in U.S. Pat. No. 5,288,625, and the use thereof for expression of heterologous DNA are provided. Cell lines containing the minichromosome and the use thereof for cell fusion are also provided.
In one embodiment, a cell line containing the mammalian minichromosome is used as recipient cells for donor DNA encoding a selected gene or multiple genes. The donor DNA is linked to a second selectable marker and is targeted to and integrated into the minichromosome. The resulting chromosome is transferred by cell fusion into an appropriate recipient cell line, such as a Chinese hamster cell line [CHO]. After large scale production of the cells carrying the engineered chromosome, the chromosome is isolated. In particular, metaphase chromosomes are obtained, such as by addition of colchicine, and they are purified from the cell lysate. These chromosomes are used for cloning, sequencing and for delivery of heterologous DNA into cells.
Also provided are SATACs of various sizes that are formed by repeated culturing under selective conditions and subcloning of cells that contain chromosomes produced from the formerly dicentric chromosomes. These chromosomes are based on repeating units 7.5 to 10 Mb referred to herein as megareplicons, that are tandem blocks of satellite DNA flanked by heterologous non-satellite DNA. Amplification produces a tandem array of identical chromosome segments [each called an amplicon] that contain two inverted megareplicons bordered by heterologous [xe2x80x9cforeignxe2x80x9d] DNA. Repeated cell fusion, growth on selective medium and/or BrdU [5-bromodeoxyuridine] treatment or other genome destabilizing reagent or agent, such as ionizing radiation, including X-rays, and subcloning results in cell lines that carry stable heterochromatic or partially heterochromatic chromosomes, including a 150-200 Mb xe2x80x9csausagexe2x80x9d chromosome, a 500-1000 Mb gigachromosome, a stable 250-400 Mb megachromosome and various smaller stable chromosomes derived therefrom. These chromosomes are based on these repeating units and can include heterologous DNA that is expressed.
Thus methods for producing MACs of both types are provided. These methods are applicable to any higher eukaryotic cell, including mammals, insects and plants.
The resulting chromosomes can be purified by methods provided herein to provide vectors for introduction of the heterologous DNA into selected cells for production of the gene product encoded by the heterologous DNA, for production of transgenic animals and plants or for gene therapy. Vectors for chromosome fragmentation are provided. These vectors will be used to produce an artificial chromosome that contains a megareplicon, a centromere and two telomeres and will be between about 10 Mb and about 60 Mb, preferably between about 10 Mb-15 Mb and 30 Mb. Such artificial chromosomes may be produced by other methods. Isolation of the 7.5 Mb [or 15 Mb amplicon containing two 7.5 Mb inverted repeats] or a 30 Mb multimer thereof should provide a stable chromosomal vector that can be manipulated in vitro.
In addition, methods and vectors for fragmenting the minichromosomes and SATACs are provided. Such methods and vectors can be used for in vivo generation of smaller stable artificial chromosomes. Methods for reducing the size of the MACs to generate smaller stable self-replicating artificial chromosomes are also provided.
Methods and vectors for targeting heterologous DNA into the artificial chromosomes are also provided as are methods and vectors for fragmenting the chromosomes to produce smaller but stable and self-replicating artificial chromosomes. Vectors for targeted introduction of heterologous DNA into artificial chromosomes are provided.
The chromosomes are introduced into cells to produce stable transformed cell lines or cells, depending upon the source of the cells. Introduction is effected by any suitable method including, but not limited to electroporation, direct uptake, such as by calcium phosphate [see, e.g., Wigler et al. (1979) Proc. Natl. Acad. Sci. U.S.A. 76:1373-1376; and Current Protocols in Molecular Biolog, Vol. 1, Wiley Inter-Science, Supplement 14, Unit 9.1.1-9.1.9 (1990)]. precipitation, uptake of isolated chromosomes by lipofection, by microcell fusion [see, EXAMPLES, see, also Lambert (1991) Proc. Natl. Acad. Sci. U.S.A. 88:5907-5911, U.S. Pat. No. 5,396,767] or other suitable method. The resulting cells can be used for production of proteins in the cells. The chromosomes can be isolated and used for gene delivery.
Methods for isolation of the chromosomes based on the DNA content of the chromosomes, which differs from the authentic chromsomes are provided.
These artificial chromosomes can be used in gene therapy, gene product production systems, production of humanized organs, production of transgenic plants and animals, including invertebrates, vertebrate, reptiles and insects, any organism or device that would employ chromosomal elements as information storage vehicles, and also for analysis and study of centromere function, for the production of artificial chromosome vectors that can be constructed in vitro, and for the preparation of species- specific artificial chromosomes. The artificial chromosomes can be introduced into cells using microinjection, cell fusion, microcell fusion, electroporation, electrofusion, projectile bombardment, calcium phosphate precipitation, site-specific targeting and other such methods. Cells particularly suited for use with the artificial chromosomes include, but are not limited to plant cells, particularly tomato, arabidopsis, and others, insect cells, including silk worm cells, insect larvae, fish, reptiles, amphibians, arachnids, mammalian cells, embryonic stem cells, embryos and cells for use in methods of genetic therapy, such as lymphocytes that are used in methods of adoptive immunotherapy and nerve or neural cells. Thus methods of producing gene products and transgenic animals and plants are provided. Also provided are the resulting transgenic animals and plants.
Exemplary cell lines that contain these chromosomes are also provided.
Methods for preparing artificial chromosomes for particular species and for cloning centromeres are also provided. In particular, a method for cloning a centromere from an animal or plant by preparing a library of DNA fragments that contain the genome of the plant or animal, introducing the each of the fragments into a mammalian satellite artificial chromosome [SATAC] that contains a centromere from a different species, generally a mammal, from the selected plant or animal, generally a non-mammal, and a selectable marker. The selected plant or animal is one in which the mammalian species centromere does not function. Each of the SATACs is introduced into the cells, which are grown under selective conditions, and cells with SATACs are identified. Such SATACS should contain a centromere encoded by the DNA from the library.
Also provided are libraries in which the relatively large fragments of DNA are contained on artificial chromosomes.
Transgenic animals, invertebrates and vertebrates, plants and insects, fish, reptiles, amphibians, arachnids and mammals are also provided. Of particular interest are transgenic animals that express genes that confer resistance or reduce susceptibility to disease. Since multiple genes can be introduced on a MAC, a series of genes encoding an antigen can be introduced, which up expression will serve to immunize [in a manner similar to a multivalent vaccine] the host animal against the diseases for which exposure to the antigens provide immunity or some protection.
Methods for cloning centromeres, such as mammalian centromeres, are also provided. In particular, in one embodiment, a library composed of fragments of the SATACs are cloned into YACs [yeast artificial chromosomes] that include a detectable marker, such as DNA encoding tyrosinase and then introduced into mammalian cells, such as albino mouse embryos. Mice produced from YACs that include a centromere that functions in mammals will express the detectable marker. Thus, if albino mice will be pigmented or have regions of pigmentation.

Artificial chromosomes, uses thereof and methods for preparing artificial chromosomes

The Biological Research Center of the Hungarian Academy of Sciences


A column (1) for supporting a covering, comprising a core profiled section (2) having a plurality of fitting grooves in its periphery and a plurality of insertion profiled sections (3, 4, 5) which are each interchangeably fittable into each fitting groove, in such a way that the column (1) has a substantially rectangular cross section, each inserted insertion profiled section (3, 4, 5) in each fitting groove forms a corner (10) of the rectangular cross section of the column (1) and each side wall of the column (1) between the insertion profiled sections (3, 4, 5) is formed by the core profiled section (2). The present invention also relates to a screen construction comprising such a column (1).

Screen constructions of this type are usually erected in order to cover or to clear an outdoor area. Such screen constructions are thus often erected at residences, restaurants, shops and the like in order to protect an outdoor terrace or the like from the sun, precipitation and/or wind or to allow sunshine in temporarily. Said screen constructions may be configured in the form of awnings, pergolas, verandas, terrace coverings, carports, etc.
A screen construction of this type typically comprises a roof construction (covering) which is at least partially supported by columns. Said covering is typically supported on four (or more) columns or is also typically attached to a wall on one side for support and supported by two (or more) columns on the other side. Said covering may be configured in a permanent fashion, or may comprise a screen which can be rolled up and unrolled, or may comprise optionally rotatable slats, etc.
Screen constructions of this type are also often provided with electrical equipment, such as lighting and/or heating systems. Furthermore, said screen constructions are also often provided with screens at the side, in order to cover the opening between two columns. In this case, said opening may be covered, for example, by a screen which can be rolled up and unrolled. It is also possible for sliding walls or slatted walls or fixed wall elements, etc., to be provided.
A number of types of column have already been developed which also have other functions in addition to their function of supporting the covering. For instance, these columns may be adapted to comprise supply lines to the electrical equipment, or to comprise discharge pipes for drainage, or to comprise guide profiled sections for a screen, etc.
Preferably, it should be possible to use these columns in a multifunctional way, with it being possible to provide optional wall elements, such as screens or slatted walls or sliding walls or fixed wall elements, etc., adjoining said columns, optional drainage in said columns, optional lighting or heating systems, etc., as desired. For all of these options it is the aim for the finish of the exterior of the column to be as aesthetically appealing as possible.
BE 1 019 072 A5 describes a column system which closely corresponds to a column according to the present invention. In this case, said column system comprises a core profiled section and several insertion profiled sections. The core profiled section has a recess (fitting groove) in each of its four sides, into which recess in each case a filler profiled section, a screen guide or a slat guide and finishing profiled sections are fitted, as desired. After the filler profiled sections have been inserted into the fitting grooves, they extend substantially inside said fitting grooves. The slat guides, screen guides and finishing profiled sections extend partially inside and partially outside the fittings grooves after they have been inserted. Together, the profiled sections in each case form a column having a substantially rectangular cross section. The column as a whole, however, has a different cross section depending on which insertion profiled sections one wishes to attach to the core profiled section. Said column may become quite large. Depending on where one wishes to mount which insertion profiled sections, a number of types of profiled section may also be required. When it is desired to attach screen guides to two adjoining sides, the column will not have four attractively finished corners. A cavity will be present at the place where the sides to which the screen guides are attached meet.
FR 2 803 365 A1 and JP 50-27778 Y1 describe column systems, comprising a core profiled section and a plurality of insertion elements, with the core profiled section comprising a recess in its four side walls as well as in its four corners. The insertion elements for the recesses in the side walls are interchangeable and the insertion elements for the recesses in the four corners are interchangeable. It is possible to finish these columns in a simpler and more attractive way than the columns from BE 1 019 072 A5, but if it is desired that they have the same bearing power they will be even larger.

Column for supporting a covering and screen construction comprising such a column


Methods, computer-readable media, and apparatuses for determining the status of a clinical database in order to characterize the quality of the database. The status may be based on the proportion of outstanding items in relation to relative milestones. A database rating index for a database is determined from risk factors, where the database rating index is indicative of a status of the clinical database and may be determined from risk factors, where each risk factor includes an issue parameter and a subject parameter, the issue parameter equals the number of occurrences for the corresponding issue, and the subject parameter corresponds to the number of patients associated with the issue parameter. The database rating index may be determined from one of a set of functions that depend on an issue health score and a subject health score.

Clinical trials are often conducted to allow safety and efficacy data to be collected for new drugs or devices. Clinical trials can take place once satisfactory information has been gathered on the quality of the product and its non-clinical safety, and approval is granted in the country where the trial is taking place. Depending on the type of product and the stage of its development, investigators enroll healthy volunteers and/or patients into small pilot studies initially, followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment. As positive safety and efficacy data are gathered, the number of patients is typically increased. Clinical trials may vary in size from a single center in one country to multicenter trials in multiple countries. Although a sizable cost for a full series of clinical trials may be incurred, the burden of paying for all the necessary people and services is typically borne by the sponsor who may be a governmental organization, a pharmaceutical, or biotechnology company. Since the diversity of roles may exceed resources of the sponsor, often a clinical trial is managed by an outsourced partner such as a contract research organization.
Clinical trials involving new drugs are commonly classified into four phases with pharmaceutical studies. However, pre-clinical studies are often conducted in order to obtain preliminary efficacy, toxicity, and pharmacokinetic information before the clinical trials themselves. Pre-clinical studies assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug.
Phase I trials is the first stage of testing in human subjects. A small (20-50) group of healthy volunteers is typically selected. This phase includes trials designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff.
Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned or to have toxic effects.
Phase III studies are randomized controlled multicenter trials on large patient groups (300-3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is in comparison with current gold standard treatment. Because of the size and comparatively long duration, Phase III trials are typically the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the regulatory submission that is provided for review to the appropriate regulatory authorities in different countries. Regulatory authorities review the submission to determine whether to give the sponsor approval to market the drug. Most drugs undergoing Phase III clinical trials in the United States may be marketed under Federal Drug Administration (FDA) norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs may be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, many drugs undergo Phase III clinical trials in the market.
Phase IV trial is also known as the post marketing surveillance trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (e.g., the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials.
Each phase of the drug approval process is typically treated as a separate clinical trial. The drug-development process normally proceeds through all four phases over many years. If the drug successfully passes through Phases I, II, and III, the drug will usually be approved by the national regulatory authority for use in the general population. Phase IV involves post-approval studies. A clinical trial typically takes a number of years to complete. For example, about eight years passes from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. Drugs for other diseases often have similar timelines. Consequently, avoiding delays in collecting data during the clinical trial may reduce development costs while providing beneficial drugs to the public in a more expeditious manner.