The present invention relates to methods for detecting the presence of ribonuclease enzymes, more specifically to methods that provide for a visual detection assay. The methods entail contacting a test sample suspected of containing ribonuclease activity with a substrate containing a ribonuclease-sensitive internucleotide linkage flanked directly or indirectly by a fluorescence reporter group and a dark quencher, such that if a ribonuclease activity is present in the sample, the ribonuclease-sensitive internucleotide linkage is cleaved and the fluorescence reporter group emits a visually detectable signal. The present invention further provides novel nucleic acid compositions used as substrates for such assays and encompasses kits for performing the methods of the invention.

Ribonuclease (RNase) enzymes degrade polymeric ribonucleic acids (RNA) into shorter fragments or component nucleotides. All organisms produce ribonucleases and these enzymes are found in most environments. The properties of a number of ribonucleases are described by D'Alessio and Riordan (1997. As a group, most ribonucleases are specific for single-stranded RNA and will not cleave RNA in duplex form. Further, ribonucleases generally cleave at the 3′-end of a ribonucleic acid phosphodiester linkage. Many different RNase enzymes exist, some of which have little or no substrate preference while others are sequence specific. For example, ribonuclease I, from E. coli, is a non-specific endoribonuclease that degrades RNA by cleavage at any base. Ribonuclease A, from mammalian pancreas, is a base-specific endoribonuclease that degrades RNA by cleavage following a pyrimidine (uridine or cytosine) base. Ribonuclease T1, from Aspergillus oryzae, is a base-specific endoribonuclease that degrades RNA by cleavage following a guanosine residue. These three RNase enzymes are noteworthy in that they are routinely employed in standard molecular biology protocols to remove unwanted RNA from samples or as a component in certain assay procedures.
Single-strand specific RNases are the primary nuclease activity encountered in research laboratories as an unwanted contaminant. Double-strand specific RNases have been described, however these are rare and not routinely found in most laboratory settings. RNase H cleaves RNA only when complexed as a heteroduplex with DNA and is not of concern as a laboratory contaminant.
Ribonucleases are present in all laboratories as ubiquitous environmental contaminants. RNases are also found in most molecular biology laboratories as purified enzyme stocks. In laboratories that study RNA, careful attention to experimental protocol is needed to avoid contamination of reagents with RNases; for example, gloves must be worn at all times to prevent contact with the RNases that are universally present on human skin. Regardless of source, the presence of a contaminant RNase will degrade any RNA that comes in contact with that reagent, resulting in the loss of valuable samples or interfering with time-consuming experiments. Once present, removing RNase activity from a laboratory reagent is difficult. Most RNase enzymes are remarkably stable and survive harsh treatments that are routinely used to eliminate other unwanted biologic activities, such as autoclaving. Methods that remove RNase activity range from baking glassware at very high temperature to treating reagent stocks with the highly toxic chemical diethylpyrocarbonate (Sambrook et al., 1989). In spite of such attention, RNase contamination remains a chronic problem and monitoring for the presence of RNase activity is a routine quality control (QC) step in most research and industrial laboratories. As such, methods are needed that would detect the presence of RNase activities commonly encountered in the laboratory setting and that are suitable for routine, frequent use.
Many methods have been devised attempting to measure RNase activity. RNase assays can be grossly divided into methods that detect degradation of heterogeneous RNA obtained from biological sources and methods that detect specific cleavage of a well-defined synthetic substrate, such as an oligonucleotide. In general, use of a synthetic substrate affords both increased sensitivity and improved specificity. Many different detection modalities have been incorporated into these assays, including direct staining, spectrophotometric and colorimetric readouts, chromogenic cascade, radioactive tracer, fluorescence polarization, and fluorescence quenching methods.
Choice of detection method will affect assay sensitivity and ease of use. For use in determining the presence or absence of RNase contamination in laboratory reagents, the method should be sufficiently sensitive to detect the presence of RNase enzymes at the lowest level that will degrade experimental samples in actual use. An insensitive assay would "pass" reagents that are contaminated, which is undesirable. Conversely, an assay could be too sensitive and might "fail" reagents that, from a practical standpoint, are not contaminated and would therefore also be undesirable.
A detection limit within the range of 1-100 picogram/ml (pg/ml) of RNase A is ideal for a reagent QC assay. Commercial assays currently available are sensitive in the 10-100 pg/ml range (Ambion Catalog, 1999). Since such an assay would be used repeatedly, it is also desirable that the method be rapid and easy to perform. Preferably, such an assay could be done at the site of suspected contamination and offer a rapid visual readout.
The original unit definition of ribonuclease activity is based upon the method of Kunitz (1946) which employs a spectrophotometric assay to measure the decrease in absorbance at 300 nm that occurs with degradation of heterogeneous RNA. While the method has been improved (Oshima, 1976), it is insensitive and therefore of little use as a quality control (QC) assay.
Another method to detect RNase activity involves separation and assay of component enzyme activities within a sample using polyacrylamide gel electrophoresis (Wilson, 1969). RNase enzymes can be detected in the acrylamide matrix by direct staining or by incubation with a heterogeneous substrate RNA and an RNA staining dye, such as toluidine blue. While conceptually simple, this approach is time-consuming and relatively insensitive, having a lower limit of detection of about 1 unit of RNase I. In an improvement of this technique, Karpetsky (1980) describes a polynucleotide/polyacrylamide-gel electrophoresis method that improves sensitivity to below 100 pg of RNase A. However, even the improved method remains slow and cumbersome and is better suited to the analysis of ribonuclease activities in biologic specimens than to the QC of laboratory reagents.
Another approach to detect RNase activity is described by Egly and Kempf (1976). This procedure detects release of soluble 125Iodine-labeled RNA from an insoluble RNA-agarose matrix in the presence of ribonuclease. The method is capable of detecting the presence of RNase A at levels as low as 0.01 pg/ml and is actually too sensitive for use as a routine QC assay. Furthermore, this method employs a hazardous radioactive isotope as reporter that is not desirable for use in most laboratory or industrial settings.
Another approach to detect RNase activity is described by Wagner (1983). RNA forms a complex with Pyronine-Y that has an optical absorbance maximum at 572 nm. Degradation of high molecular weight RNA by ribonuclease activity results in loss of absorbance at 572 nm in a linear and quantitative fashion. The method, however, is only capable of detecting about 2 ng/ml RNase A in a test sample and has insufficient sensitivity for use as a QC assay.
Another approach to detect RNase activity was described by Greiner-Stoeffele (1996). The dye methylene blue intercalates into high molecular weight ribonucleic acid forming a dye-RNA complex. Upon degradation by ribonuclease action, methylene blue is released and absorbance at 688 nm decreases. This method, however, is also relatively insensitive and can detect ribonuclease activity only down to about 25 ng/ml, which is inadequate for use as a QC assay.
Another approach to detect RNase activity is described by Karn (1979). Ribonuclease A-mediated cleavage of a synthetic ribonucleotide dimer substrate was detected by a cascade of enzymatic reactions involving adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase that ultimately forms a detectable blue tetrazolium salt. The method can detect the presence of 0.066 units of RNase A (about 100 ng), insufficient for use as a QC assay. Furthermore, the procedure is lengthy, complex and requires modification to detect the presence of ribonucleases other than RNase A.
Another approach to detect RNase activity is described by Witmer (1991). A synthetic ribonucleotide substrate, U-3′-BCIP, was synthesized that releases a reporter group in the presence of RNase A that could be detected spectrophotometrically by absorbance at 650 nm. While this chromogenic method is simple to use, it is insensitive and is better suited for applications such as the in vivo bacterial colony assays taught by Witmer than for use as a reagent QC assay.
Fluorescence-quenching detection is used in many applications in the biological sciences; representative examples include methods to detect proteolytic enzyme activity (Yaron, 1979), methods to detect DNA restriction endonuclease activity (Ghosh, 1994), methods to detect the 5′-nuclease activity of DNA polymerase (Gelfand, 1993), methods to detect nucleic acid sequence identity (Gelfand, 1993; Tyagi, 1999; Livak, 1999; Nazarenko, 1999; Nadeau, 1999), and methods to detect bimolecular protein interactions in an immunoassay (Maggio, 1980). A synthetic oligoribonucleotide having a Fam reporter group and a Tamra quencher group has been used as a FRET probe to detect hammerhead ribozyme activity (Hanne, 1998). Fluorescence Resonance Energy Transfer (FRET) and fluorescence quenching methods are reviewed by Morrison (1992).
Zelenko (1994) describes synthesis of a dinucleotide substrate uridylyl-3′5′-deoxyadenosine that is conjugated to a fluorophore (O-aminobenzoic acid) on one end and a fluorescence quencher (2,4-nitroaniline) on the opposite end of the molecule. Cleavage by RNase A separates the fluorophore and quencher, leading to a detectable increase in fluorescence. The substrate was designed specifically for use in kinetic studies of RNase A activity and will react only with the subset of ribonuclease enzymes that cleave at a uracil residue. Having a limited spectrum of sensitivity, this reagent is not suitable for use as a single substrate in an RNase QC assay.
James (1998) describe an alternative substrate for kinetic studies of RNase A in which a 9-mer chimeric oligonucleotide that contains a single ribonucleotide uracil base flanked by deoxyadenosine residues was modified with a 5′ fluorescein reporter group and a 3′ rhodamine quencher group. The utility of the substrate is limited in that it can detect only those ribonucleases that cleave at a uracil residue. Further, assay results must be detected using a fluorometer due to background fluorescence of the rhodamine quencher group.
Kelemen (1999) describes a similar substrate having somewhat greater sensitivity measuring RNase A kinetics with the following composition: SEQ ID. NO:2: 5′ Fluorescein-AuAA-Tamra 3′. Like the James reagent, the Kelemen substrate is limited to detecting ribonucleases that cleave at a uracil residue and requires the use of a fluorometer.
James (1998) and Kelemen (1999), therefore, have described use of fluorescent-labeled oligonucleotide probes with FRET/quenching to study the catalytic properties of RNase A. Both compositions are chimeric DNA-RNA oligonucleotides that contain a single internal uridine base, use a fluorescein dye as reporter group, and use a quencher group that is a fluorophore that itself emits light in the visible spectrum, so methods that use these substrates require availability of a fluorometer for detection. These probes were optimized for kinetic studies of RNase A and cannot be used to detect the presence of RNase enzymes that do not cleave at a uridine residue. In addition, both compositions include DNA residues, which are subject to cleavage by DNase enzymes, so cleavage is not RNase specific. They are, therefore, not useful as a tool to assay for the presence of contaminating RNase activity.
Burke (1998) describes a method that utilizes fluorescence polarization detection techniques to measure cleavage of short, synthetic nucleic acid probes. A commercial kit for performing RNase detection of Burke is available (Pan Vera Catalog, 2000). Wilson (2000) describes a variant of this technique that examines real-time degradation of a long, synthetic RNA species (made by in vitro transcription) using fluorescence anisotropy. The fluorescence polarization-based techniques that must be employed, however, cannot be performed without a specialized fluorescence polarization fluorometer, which is not available in most laboratories.
Another commercial kit for the detection of RNase activity measures the release of soluble fluorescent dye from a precipitated (i.e., insoluble) fluorescent RNA substrate (Pan Vera Catalog, 2000). This method is less sensitive than the fluorescence polarization method and also requires availability of a fluorometer, thereby limiting the utility of the assay.
A commercial kit is available that uses a biotin-labeled RNA substrate immobilized on dipsticks to test for the presence of RNase activity (Ambion Catalog, 1999). Detection is achieved using a visual colorimetric method. In the absence of RNase, the substrate remains intact and the calorimetric assay develops a blue spot on the dipstick while in the presence of RNase the label is cleaved and no color develops. This assay is labor intensive, takes over 3 hours to perform, and is not well suited for high-throughput QC use.
Another commercial RNase detection kit employs gel electrophoresis to visualize degradation of a high molecular weight RNA in the presence of ribonuclease activity (Mo Bio, Web Catalog, 2000). The method is a multi-step, labor intensive protocol that is very expensive, making it unsuitable for routine QC use.
It is apparent from the above discussion that, while progress has been made in methodology to detect ribonuclease activity, existing assays have significant limitations. None are suitable for use as a universal ribonuclease detection system (i.e., a QC assay). A ribonuclease detection method suitable for use in a QC assay should meet the following 7 criteria:                1) The assay will be highly sensitive.        2) The assay will be highly specific.        3) The assay will detect a broad spectrum of ribonuclease activities.        4) The assay reagent(s) will be inexpensive and suitable for commercial manufacture.        5) The assay method will be both simple and rapid.        6) The assay method will allow for visual detection and will not require the use of highly specialized equipment.        7) The assay will not employ any hazardous compounds.
Clearly new methods, or improvements in earlier methods, are needed. In particular, a need exists for an RNase assay that is rapid, sensitive, within the desired range and allows for visual detection.

This patent is subject to a terminal disclaimer.

Compositions and methods for visual ribonuclease detection assays


An input device and an input method for a data processing device are provided. The input device includes a touch-sensitive module, an operation prompt interface and a controller. According to the input method, the input device issues a first input signal to the data processing device when a first electrical property change resulting from the keystroke or the tap is sensed in a first operation state. The input device is switched from the first operation state to a second operation state in response to a switching operation. The input device issues a second input signal to the data processing device when a second electrical property change resulting from a touch action is sensed in the second operation state.

Please refer to FIG. 1 illustrating a structure of a resistive membrane keyboard. The resistive membrane keyboard has a triple layer structure. In the triple layer structure, an intermediate insulating layer 13 is interposed between a top membrane layer 11 and a bottom membrane layer 12. There are conductive traces 110 and 120 mounted on the membrane layers 11 and 12. The intermediate insulating layer 13 has holes corresponding to positions of keys (not shown). When the user presses the key, the conductive traces 110 and 120 are in electrical contact to allow current flow and an input corresponding to the keystroke is sent to a data processing device, e.g. a computer. However, frequent contacts between the conductive traces 110 and 120 cause abrasion which reduces the lifetime of the resistive membrane keyboard. Furthermore, the conventional keyboard can only receive keystroke inputs, but can not accept other inputs such as multi-touch gesture which becomes very popular recently. Therefore, the limited input function of the conventional resistive membrane keyboard is not satisfied for controlling modern electronic apparatus, and a novel input device and method accepting various types of inputs is desired.


This application discloses a resource location determining method and apparatus, and a resource determining method and apparatus, which are used by a terminal in 5G NR to determine an SR resource location. The resource location determining method includes: receiving, by the terminal. SR resource indication information from a base station, where the SR resource indication information is used to indicate an SR resource; and determining, by the terminal, an SR resource location on a first time domain resource based on the SR resource indication information and information about an OCC multiplexing multiple of the first time domain resource, where the SR resource includes a code domain resource and a frequency domain resource.

During discussion of a 5th generation (fifth-generation, 5G for short) wireless communications technology, there are currently two research directions in the 3rd generation partnership project (3rd generation partnership project, 3GPP for short) organization: a research direction with consideration of backward compatibility and a research direction without consideration of backward compatibility. The research direction without consideration of backward compatibility is referred to as 5G new radio (new radio, NR for short). Currently, there is no SR resource location determining solution in 5G NR.

Resource location determining method and apparatus, and resource determining method and apparatus


An automated storage and retrieval system includes at least one relay module for relaying storage containers between a port column and an access station. The relay module is arranged below a port column. The relay module includes a port station, a first conveyor, a second conveyor, each arranged at a side of the port station, and a lateral displacement device. The port station receives storage containers dropped off from and to be picked up through the port column. The first conveyor is adapted to transport storage containers to an access station. The second conveyor is adapted for transporting storage containers from the access station. The lateral displacement device is arranged to transport storage containers between the port station and the first conveyor, and between the second conveyor and the port station.

FIG. 1 discloses a framework structure 1 of a typical prior art automated storage and retrieval system and FIGS. 2A-2C disclose different container handling vehicles 9 of such a system.
The framework structure 1 comprises a plurality of upright members 2 and a plurality of horizontal members 3, which are supported by the upright members 2. The members 2, 3 may typically be made of metal, e.g. extruded aluminium profiles.
The framework structure 1 defines a storage grid 4 comprising storage columns 5 arranged in rows, in which storage columns 5 store storage containers 6, also known as bins, stacked one on top of another to form stacks 7. Each storage container 6 may typically hold a plurality of product items (not shown), and the product items within a storage container 6 may be identical, or may be of different product types depending on the application. The framework structure 1 guards against horizontal movement of the containers 6 in the stacks 7, and guides vertical movement of the containers 6, but does normally not otherwise support the storage containers 6 when stacked.
A track system 8 is arranged in a grid pattern across the top of the storage columns 5. On this track system 8 a plurality of container handling vehicles 9 are operated to raise storage containers 6 from and lower storage containers 6 into the storage columns 5, and also to transport the storage containers 6 above the storage columns 5. The track system 8 comprises a first set of parallel tracks 10 arranged to guide movement of the container handling vehicles 9 in a first direction X across the top of the frame structure 1, and a second set of parallel tracks 11 arranged perpendicular to the first set of tracks 10 to guide movement of the container handling vehicles 9 in a second direction Y, which is perpendicular to the first direction X. In this way, the track system 8 defines grid columns 12 above which the container handling vehicles 9 can move laterally above the storage columns 5, i.e. in a plane which is parallel to the horizontal X-Y plane.
Each container handling vehicle 9 comprises a vehicle body 13 and first and second sets of wheels 14, 15 which enable the lateral movement of the container handling vehicle 9, i.e. the movement in the X and Y directions. In FIG. 2A two wheels in each of the sets 14, 15 are visible, while in FIGS. 2B and 2C only two wheels in one of the set of wheels 14 are visible. The first set of wheels 14 is arranged to engage with two adjacent tracks of the first set 10 of tracks, and the second set of wheels 15 arranged to engage with two adjacent tracks of the second set 11 of tracks. Each set of wheels 14, 15 can be lifted and lowered, so that the first set of wheels 14 and/or the second set of wheels 15 can be engaged with the respective set of tracks 10, 11 at any one time.
Each container handling vehicle 9 also comprises a lifting device 16 (see FIGS. 2B and 2C) for vertical transportation of storage containers 6, e.g. raising a storage container 6 from and lowering a storage container 6 into a storage column 5. The lifting device may be arranged inside the body 13 (as in FIG. 2A) or outside the body 13 (as disclosed in FIGS. 2B and 2C). The lifting device 16 may comprise a lifting frame 18 which is adapted to engage a storage container 6. The lifting frame 18 can be lowered from the vehicle body 13 so that the position of the lifting frame with respect to the vehicle body 13 can be adjusted in a third direction Z, which is orthogonal the first direction X and the second direction Y.
Conventionally, and also for the purpose of this application, Z=1 identifies the uppermost layer of the grid 4, i.e. the layer immediately below the track system 8, Z=2 the second layer below the track system 8, Z=3 the third layer etc. In the exemplary prior art grid 4 disclosed in FIG. 1, Z=8 identifies the lowermost, bottom layer of the grid 4.
Consequently, as an example and using the Cartesian coordinate system X, Y, Z indicated in FIG. 1, the storage container identified as 7′ in FIG. 1 can be said to occupy grid location or cell X=10, Y=2, Z=3. The container handling vehicles 9 can be said to travel in layer Z=0 and each grid column can be identified by its X and Y coordinates.
Each container handling vehicle 9 comprises a storage compartment or space for receiving and stowing a storage container 6 when transporting the storage container 6 across the top of the grid 4. The storage space may comprise a cavity arranged centrally within the vehicle body 13 (FIG. 2A), e.g. as is described in WO2014/090684A1, the contents of which are incorporated herein by reference. Alternatively, the storage compartment or space can be arranged on the side of the body as disclosed in FIGS. 2B and 2C, i.e. the container handling vehicles 9 may have a cantilever construction, as is described in NO317366, the contents of which are also incorporated herein by reference.
The container handling vehicles 9 may have a footprint 22 (see FIG. 4) which is generally equal to the extension of a grid column 12 in the X and Y directions, e.g. as is described in WO2015/193278A1, the contents of which are incorporated herein by reference. Alternatively, the container handling vehicles 9 may have a footprint which is larger than the extension of a grid column 12 in the X and Y directions, e.g. as is disclosed in WO2014/090684A1.
The track system 8 may be a single track system, as is shown in FIG. 3. Alternatively, the track system 8 may be a double track system, as is shown in FIG. 4, thus allowing a container handling vehicle 9 having a footprint 22 generally corresponding to the lateral area defined by the extension of a grid column 12 to travel along a row of grid columns 12 even if another container handling vehicle 9 is positioned above a grid column 12 neighbouring that row.
In a storage grid, a majority of the grid columns 12 are storage columns 5, i.e. grid columns where storage containers 6 are stored in stacks. However, a grid normally has at least one grid column which is used not for storing storage containers, but which comprises a location where the container handling vehicles can drop off and/or pick up storage containers so that they can be transported to an access station where the storage containers can be accessed from outside of the grid or transferred out of or into the grid. Within the art, such a location is normally referred to as a "port" and the grid column in which the port is located may be referred to as a "port column".
The grid 4 in FIG. 1 comprises two port columns 19 and 20. The first port column 19 may for example be a dedicated drop-off port column where the container handling vehicles 9 can drop off storage containers to be transported to an access or a transfer station (not shown), and the second port column 20 may be a dedicated pick-up port column where the container handling vehicles 9 can pick up storage containers that have been transported to the grid 4 from an access or a transfer station.
The access station may typically be a picking or a stocking station where product items are removed from or positioned into the storage containers. In a picking or a stocking station, the storage containers are normally never removed from the automated storage and retrieval system, but are returned back into the grid once accessed. A port can also be used for transferring storage containers out of or into the grid, e.g. for transferring storage containers to another storage facility (e.g. to another grid or to another automated storage and retrieval system), to a transport vehicle (e.g. a train or a lorry), or to a production facility.
A conveyor system comprising conveyors is normally employed to transport the storage containers between the ports and the access station.
If the port and the access station are located at different levels, the conveyor system may comprise a lift device for transporting the storage containers vertically between the port and the access station.
The conveyor system may be arranged to transfer storage containers between different grids, e.g. as is described in WO2014/075937A1, the contents of which are incorporated herein by reference.
WO2016/198467A1, the contents of which are incorporated herein by reference, discloses an example of a prior art access system having conveyor belts (FIGS. 5a and 5b in WO2016/198467A1) and a frame mounted track (FIGS. 6a and 6b in WO2016/198467A1) for transporting storage containers between ports and work stations where operators can access the storage containers.
When a storage container 6 stored in the grid 4 disclosed in FIG. 1 is to be accessed, one of the container handling vehicles 9 is instructed to retrieve the target storage container from its position in the grid 4 and transport it to the drop-off port 19. This operation involves moving the container handling vehicle 9 to a grid location above the storage column in which the target storage container is positioned, retrieving the storage container from the storage column using the container handling vehicle's lifting device (not shown), and transporting the storage container to the drop-off port 19. If the target storage container 6 is located deep within a stack 7, i.e. with one or a plurality of other storage containers positioned above the target storage container, the operation also involves temporarily moving the above-positioned storage containers prior to lifting the target storage container from the storage column. This step, which is sometimes referred to as "digging" within the art, may be performed with the same container handling vehicle 9 that is subsequently used for transporting the target storage container to the drop-off port 19, or with one or a plurality of other cooperating container handling vehicles 9. Alternatively, or in addition, the automated storage and retrieval system may have container handling vehicles 9 specifically dedicated to the task of temporarily removing storage containers 6 from a storage column. Once the target storage container has been removed from the storage column, the temporarily removed storage containers 6 can be repositioned into the original storage column. However, the removed storage containers 6 may alternatively be relocated to other storage columns.
When a storage container 6 is to be stored in the grid 4, one of the container handling vehicles 9 is instructed to pick up the storage container from the pick-up port 20 and transport it to a grid location above the storage column where it is to be stored. After any storage containers 6 positioned at or above the target position within the storage column stack have been removed, the container handling vehicle 9 positions the storage container 6 at the desired position. The removed storage containers may then be lowered back into the storage column, or relocated to other storage columns.
For monitoring and controlling the automated storage and retrieval system, e.g. monitoring and controlling the location of respective storage containers within the grid 4, the content of each storage container 6, and the movement of the container handling vehicles 9 so that a desired storage container can be delivered to the desired location at the desired time without the container handling vehicles 9 colliding with each other, the automated storage and retrieval system comprises a control system, which typically is computerised and comprises a database for keeping track of the storage containers.
A problem associated with known automated storage and retrieval systems is that the area surrounding the pick-up and drop-off ports may become congested with container handling vehicles instructed to drop off or pick up storage containers. This may seriously impede the operation of the automated storage and retrieval system. In small systems this situation may possibly be alleviated by adding ports to the grid, as this will allow the container handling vehicles to be distributed among a larger number of ports in order to avoid congestion. However, if ports are added, the conveyor system infrastructure must normally be increased. This requires space, which may not necessarily be available. Also, adding conveyor system infrastructure is costly.
Another problem with prior art automated storage and retrieval systems is that the separate drop-off ports 19 and pick-up ports 20 require the container handling vehicles 9 to move to a storage column after drop-off to retrieve a new storage container 6. Likewise, the container handling vehicles 9 have to be empty of a storage container 6 when they are sent to a pick-up port 20 to pick up a storage container. This results in an inefficiency and causes increased congestion around the ports, as container handling vehicles 9 are moving around on the grid without a storage container 6 as payload. In addition, the drop-off 19 and pick-up 20 ports may take up space on the grid which could be used for other purposes such as the movement of container handling vehicles 9.
In view of the above, it is desirable to provide an automated storage and retrieval system, and a method for operating such a system, that solve or at least mitigate one or more of the aforementioned problems related to the use of prior art storage and retrieval systems.
In addition to the above, US 2018/086573 describes a port column for vertical transport of containers by a clamping system, and a conveyor for transporting the container from an access station.

Automated storage and retrieval system comprising a relay module and a method of operating such a system


An envoy device for performing transactions with a further device in proximity to the envoy device, the envoy device comprising: a first communication device configured to communicate with the further device that is located within a predetermined distance of the envoy device using a local short range communication link; at least one further communication device configured to communicate with the further device using at least one longer range communication link. The envoy device is configured to respond to detecting the further device within the predetermined distance of the envoy device to: establish communication with the further device using the local short range communication link; receive information from the further device regarding any further communication links that the further device has access to; transmit to the further device information regarding the at least one longer range communication link; and to commence a transaction with the further device using the local short range communication link.

There are ever increasing numbers of devices within our environment that have processing and communication capabilities, which allows them to interact with other processing devices. However, connecting to these different devices and maintaining the connection during a transaction has its own challenges related to security. Furthermore, the use of different protocols and the need for authentication keys to access many communication links makes the establishment of communication between devices a challenge.
It would be desirable to be able to connect to and maintain a connection with these different devices in a straight forward user-friendly and yet secure manner.

Establishing communication links automatically with local devices


The present invention provides a nanocarbon-iron composite system which is a composite structure formed by interaction of acid-treated nanocarbon serving as a carrier, with and ferrous ions and/or ferric ions in an iron salt. In an in-vitro experiment and an animal experiment, the nanocarbon-iron composite system of the present invention shows a very efficient inhibition effect on solid tumors containing liver cancer, breast cancer and cervical cancer and has an excellent targeting property. Accordingly, the present invention further provides a preparation method of the nanocarbon-iron composite system, use of the nanocarbon-iron composite system in preparation of a drug for treating solid tumors, and a suspension for injection based on the nanocarbon-iron composite system.

Cancer is the number one killer that threatens human life at present. 8 million new cases of cancer are diagnosed annually, with 3 million new cases of cancer in China. For solid tumors, a main treatment means at present is surgical resection of cancerous tissues, or chemotherapy to kill cancerous cells, or a combination thereof. Generally, both surgical resection and chemotherapy are relatively effective cancer-treatment procedures. However, there are dilemmas in cancer treatment at present that after surgical resection, tumor cells may metastasize to other parts to cause relapse; and after adoption of chemotherapy, chemotherapeutic drugs attack normal cells and tumor cells without differences, and thus severe toxic and side effects, and even multidrug resistance (MDR) of the tumor cells to chemotherapeutic drugs will be caused.
One method to solve the above dilemmas is cell immunotherapy represented by PD-1, CAR-T and the like, of which the clinical research is developing in full swing around the world and which is expected to be an ultimate solution to conquer certain type of tumors. However, so far it is proved that because of its accuracy at the level of genes, the cell immunotherapy has extraordinary clinical efficacy on some genes, but has no efficacy on other genes. Consequently, it is necessary for global scientists to perform more research and exploration to obtain a more universal tumor treatment scheme.
Besides the cell immunotherapy, in 2012, Dixon et al. discovered a new iron-dependent form of cell apoptosis when researching an action mechanism for killing tumor cells containing mutated oncogenes RAS by small molecule erastin. RAS is the most common oncogene, and RAS protein encoded by RAS is small G protein, whose activity depends on the binding with GTP. The mutated RAS protein loses the activity of hydrolyzing GTP, and thus activates related genes at the downstream of an RAS pathway, leading to cell canceration. RAS-mutated tumor cells can increase the content of iron in cells through up-regulation of a transferrin receptor 1 and down-regulation of ferritin. The use of such a small molecule to treat cells expressing RAS causes cell death through an "oxidative and nonapoptotic" mechanism. Based on lots of research, Dixon et al. appreciated that this cell death form is a new form different from apoptosis, necrosis and autophagy, and named this iron-dependent death form as "ferroptosis" (reference document 1).
Through further research, it was found that the transferrin receptor on the cell surface and the glutamine-fueled intracellular metabolic pathway played crucial roles in the death process. Inhibition of glutamine is an essential part of ferroptosis and can reduce heart damage caused by ischemia reperfusion, which suggests that ferroptosis is a potential method for treating related diseases (reference document 2).
On the basis of the above research, after the action mechanism of "ferroptosis" is confirmed, in 2016, a tumor laboratory in America uses ultrasmall (<10 nm in diameter) polyethylene glycol-coated silica nanoparticles functionalized with melanoma-targeting polypeptides. These silica nanoparticles can induce a form of programmed cell death known as "ferroptosis" in starved cancer cells and tumor-bearing mice. In the further research, through the lipid reactive oxygen species (ROS) assay and experiments using an iron chelator (DFO), it was demonstrated that the silica nanoparticles induce apoptosis by means of ferroptosis (reference document 3).
Furthermore, the review literature Ferroptosis: process and function published in the subsidiary journal of Nature in 2016 comprehensively reviewed and summarized research conclusions about ferroptosis since ferroptosis was proposed in 2012. It pointed out that ferroptosis is characterized morphologically in that mitochondria become small, the density of a mitochondrial membrane is increased, a mitochondrial crista is reduced or vanished and an outer mitochondrial membrane ruptures. Ferroptosis can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, up-regulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter are involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton).
For generation of ROS in ferroptosis that is directly caused apoptosis, the relatively reasonable explanation at present is that due to an increase of intracellular iron concentration, an intracellular Fenton reaction is promoted and thus ROS with extremely high oxidizability is formed and accumulated in cells to cause apoptosis (reference document 5).
The current research shows that iron is the trace element with the highest content in human bodies, is widely distributed in various organs and tissues of the human bodies, and plays an important role in processes of DNA synthesis, electron transfer, oxygen transport and the like. The phenomenon that iron involves in cell death when brain damage and neurodegenerative diseases occur has long been noted. Iron sedimentation has been found in the brains of patients with Parkinson's disease and alzheimer's disease, and iron chelators may protect models of neurotoxicity caused by 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPP+) or β-amyloid (Aβ). As the research on ferroptosis is conducted, it is clear that whether ferroptosis exists in various neurodegenerative diseases, and then ferroptosis of nerve cells is regulated through drugs, thereby controlling the occurrence and development of these nervous system diseases. Under the action of various inducers, induction of ferroptosis to act on cells to cause apoptosis may be a bran-new tumor treatment concept.
In addition, the research also discovered that cell iron can also induce functional selection of macrophages. The macrophage is a cell population with relatively high plasticity and pluripotency, shows an obvious functional difference under the influence of different in-vitro and in-vivo micro-environments and is mainly characterized by transformation of anti-inflammatory subspecific M2 macrophages to pro-inflammatory subspecific M1 macrophages. The co-culture of ferumoxytol and macrophages demonstrated an 11-fold increase in hydrogen peroxide and a 16-fold increase in hydroxyl radicals. This indicates that ferumoxytol enhances the production of ROS by macrophages, which increases cancer cell cytotoxicity. To further determine whether ferumoxytol induces M1 macrophages, macrophages are separated from the co-cultures. It was found that mRNA related to pro-inflammatory M1-type response is increased, M1-related TNFα and CD86 markers are up-regulated significantly, and M2-related CD206 and IL10 markers are significantly decreased. In vivo, ferumoxytol significantly inhibits growth of subcutaneous adenocarcinomas in mice. In addition, intravenous ferumoxytol before intravenous tumor cell prevents liver metastasis. Fluorescence-activated cell sorting (FACS) and histopathology research showed that the observed tumor growth inhibition is accompanied by an increase of pro-inflammatory M1 macrophages in the tumor tissues (reference document 6).
In the research on regulation of functional selection of macrophages by iron, it was found that iron in super-paramagnetic iron-oxide nanoparticles (SPION) induces a phenotypic shift of THP1 cell-derived M2 macrophages towards high CD86+ and tumor necrosis factors (TNF-α+). This phenotypic shift of M2 macrophages was accompanied by up-regulated levels of ferritin and cathepsin L in the cells, which is a characteristic mark of M1 macrophages (reference document 7).
Currently, some iron-related drugs that have been approved for market comprise iron sucrose such as Venofer®, ferric sodium gluconate complexes such as Ferrlecit and ferridextran, which are absorbed parenterally by injection for solving the problems of severe iron deficiency, iron-deficiency anemia and enteral iron absorption. These drugs, even newer ferumoxytol and the like all aim to supplement the trace element iron in the bodies of patients with iron deficiency, thereby solving the problem of anemia. Such products directly enter blood through intravenous injection to adjust the content of the iron element in blood of a human body for solving the problem of iron deficiency. However, due to existence of cell transferrin, such iron cannot enter cells to induce ferroptosis.
In addition, regarding some clinical developments of nano-iron, the latest patent application WO2015/007730A1 by German scientists proposes an inhibitor for inhibiting ferroptosis, for example, which is expected to treat the ROS stress neurofunctional disorder disease caused by ferroptosis.
It can be seen therefrom that an iron-containing preparation is of great significance for development of antitumor drugs.
At present, research on tumor treatment is developing towards two directions, One is intelligentization, namely, intelligent identification for normal cells and tumor cells; and the other is reduction of toxic and side effects of antitumor drugs, reduction and even elimination of tolerance, and reduction of the dosage of chemotherapeutic drugs, Years of research has shown that nanoparticles can cross cell membranes and directly enter cell nucleuses to act on tumor cells. The accurate drug administration is achieved by taking nanoparticles, such as graphene, magnetic nanoparticles and carbon nanotubes, as a drug carrier, as disclosed in Chinese patent CN105944110A. In this patent, disclosed is a nanocarbon quantum dot-assisted drug-administration carrier system, in which a targeted nanocarrier is formed through covalent coupling of polyethylene glycol (PEG) which is used as a crosslinking agent, and transferrin (TF) which is used as a targeting molecule.
However, for general targeted nanocarrier drugs, there is a very frustrating problem in preparation and animal experiments: how to increase the carrying amount of the drugs and release the drugs at targets accurately. To achieve targeted drug-administration through nanocarrier drugs, the carrying amount of drugs must be increased firstly, namely, a nanocarrier must be associated with a certain number of drug molecules. Secondly, after the nanocarrier drug enter a body to reach a target location through the nanocarrier, the drug molecules carried by the nanocarrier drop off automatically and reach certain concentration, thereby achieving clinical treatment effects.
In addition, the cells have a mechanism to actively excrete iron, so that it is impossible to produce high enough iron concentration in the cells, and thus ferroptosis and cancer cell death that is induced by the polarization of pro-inflammatory macrophages cannot be caused effectively. Therefore, there is an urgent need to find a suitable targeted drug-loaded nano preparation to cooperate with a Fe preparation of appropriate concentration so as to prepare a drug-loaded system, thereby improving the efficiency of iron entering cells. Thus, the cells reach relatively high iron concentration within a short time to induce ferroptosis and the polarization of pro-inflammatory macrophages. In these two action mechanisms, a main action mechanism to induce cancer cell death is polarization of pro-inflammatory macrophages, which produces a series of inflammatory factors and ROS, thus activates the activity of caspase-3 and finally causes cancer cell death in the form of apoptosis.
Reference document 1: Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death, Cell 149, 1060-1072, May 25, 2012;
Reference document 2: Glutaminolysis and Transferrin Regulate Ferroptosis, Molecular Cell 59, 298-308, Jul. 16, 2015;
Reference document 3: Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumor growth, Nature Technology, 26 Sep. 2016;
Reference document 4: Ferroptosis: process and function, Cell Death and Differentiation 23, 369-379, 2016;
Reference document 5: Generation of hydrogenperoxide primarily contributes to the induction of Fe(II)-dependentapoptosis in Jurkat cells by (−)-epigallocatechin gallate, Carcinogenesis, 25(9), 1567-1574, 2004;
Reference document 6: Iron oxide nanoparticles inhibit tumor growth by inducing pro-inflammatory macrophage polarization in tumor tissues, Nature NanoTechnology, Sep. 26, 2016; and
Reference document 7: SPION primes THP1 derived M2 macrophages towards M1-like macrophages, Biochemical and Biophysical Research Communications 441, 737-742, 2013.

Nanocarbon-iron composite system as well as composition, preparation method and use thereof

SICHUAN YINGRUI PHARMACEUTICAL TECHNOLOGY COMPANY


Dialysis machines comprising a feed arrangement (170) to supply a dialysis fluid to a dialyzer (150) during dialysis treatment and a return arrangement (171) to remove the dialysis fluid from the dialyzer during dialysis treatment and forward it to an exit (129); a feed recirculation circuit (172) to allow a fluid of the feed arrangement to be re-circulated in a fluid loop path comprising, at least a portion of, the feed arrangement and the feed recirculation circuit and a return recirculation circuit (173) to allow a fluid of the return arrangement to re-circulate in an auxiliary fluid loop path comprising, at least a portion of, the return arrangement and the return recirculation circuit. A controller (160) configured to perform disinfection by re-circulating a disinfectant and/or a heated fluid through said fluid loop path and/or through said auxiliary fluid loop path. The dialysis machine (1) further comprises a feed forward arrangement (172) connected to the fluid loop path and arranged to enable a fluid of the feed arrangement (170) to be forwarded to the exit (129) by-passing the auxiliary fluid loop path.

There are several types of treatments in which blood is extracted in an extracorporeal blood circuit. Such treatments involve, for example, haemodialysis, haemofiltration, haemodiafiltration, plasmapheresis, etc. Normally, blood is removed from a blood vessel at an access site and returned to the same blood vessel or at another location.
In for example the cases of haemodialysis, haemofiltration, haemodiafiltration, and plasmapheres, but not limited to these cases, a treatment fluid (also referred to as a dialysis fluid) is made approximately isotonic with a patient's blood. In haemodialysis and haemodiafiltration, the treatment fluid and the patient's blood are made to flow on each side of a semi-permeable membrane of a membrane device (referred to as a dialyzer). Diffusive transfer is achieved from one side of the membrane to the other when the concentration of the substance on each side of the membrane differs. Such substances may be impurities in the blood (urea, creatinine, etc.) which thereby migrates from the blood to the treatment fluid. Since fluid normally has to be removed from the patient during haemodialysis, a convective transfer by ultrafiltration, resulting from a pressure difference created between the blood side and the treatment fluid side of the membrane, is added to the diffusive transfer.
An apparatus for extracorporeal blood treatment includes a dialysis machine which is connected to a disposable extracorporeal blood circuit. The disposable extracorporeal blood circuit includes blood transport lines (in general an arterial line for blood removal from the patient, and a venous line for blood return to the patient) and the membrane device for blood treatment.
The semi-permeable membrane of the membrane device divides a blood compartment, connected to the blood transport lines, and a fluid compartment, connected to treatment fluid supply and discharge circuits. The blood transport lines are further coupled to a sensor and actuator system equipped on the dialysis machine, which system normally comprises means for blood circulation, pressure sensors, air bubble sensor, one or more circuit blocking clamps, blood detector, etc.
The treatment fluid supply circuit receives purified water from a water supply system. The water supply system may be a small unit providing water to only a single treatment control machine, but may also be a large unit providing water by means of a water system loop arrangement to a significant number of treatment units in for example a hospital or a clinic.
Dialysis fluid, which may come into contact with the patients' blood, is often prepared from the purified water by means of a treatment fluid supply circuit. It is of paramount importance that the dialysis fluid used for the treatment is substantially free from virus, fungi, bacteria and their residue and degradation products, such as endotoxins.
Therefore, the treatment fluid path of a dialysis machine may be disinfected between dialysis treatments in order to reduce the presence of virus, fungi, bacteria, etc in the treatment fluid path. Chemical disinfection (e.g. using NaOCl or other chemical disinfection agents) is an efficient way to reduce the presence of bacteria, etc but it makes great demands on the following rinse procedure and requires very close measuring to assure that the treatment fluid path is free of chemical residual products before being used for subsequent treatments. The chemical process is not environmentally friendly and may have a negative effect on the life-length of the disinfected parts and components.
In an alternative disinfection process, thermal disinfection is achieved by letting hot water pass through the treatment fluid path. As a result, the problem of chemical residual products does not exist, the process puts less load on the environment, and often has comparatively less negative effect on the life-length of the disinfected parts and components compared to the use of biological aggressive solutions (as for example Chlorine).
In a further alternative disinfection process, the thermal disinfection is combined with chemical agents, such as citric acid, in order to achieve an efficient disinfection of the treatment fluid path.
WO96/09080 discloses a disinfection arrangement for a dialysis machine consisting of a clean side and dirty side. The clean side comprises an inlet for water, a heat exchanger as well as a water vessel containing a heater. A feed conduit leads from the water vessel to a tube which is normally connected to the clean side of the dialyser but, during disinfection, is connected to a recirculation conduit via a valve in order to perform a first recirculation circuit. A second recirculation circuit is constituted by a recirculation conduit, a valve, a tube, which is normally connected to the dirty side of a dialyser, a return conduit as well as a pump. A heat exchanger heats up the fluid in the second circuit with help of the fluid in the first circuit, which is heated up by the heater in the water vessel. A small amount of fluid is transferred from the first circuit to the second circuit via a shunt conduit.
Another example of disinfection arrangement of similar configuration is disclosed in WO96/40314.
Thermal disinfection of the treatment fluid path of a machine is preferably carried out after the treatment of each patient. As the number of dialysis patients increases there is a need to increase the available time for treatments in the clinics. Consequently, there is a desire to reduce the time spent on disinfection between treatments.
Before dialysis treatment can be commenced for a patient, the dialysis machine needs a certain time to start up the production of treatment fluid with the correct composition and at a set temperature. Again, as the number of dialysis patients increases there is a need to increase the available time for treatments in the clinics. Consequently, there is a need to reduce the time spent on the starting-up of the preparation of the treatment fluid before the dialysis treatment can be commenced on the patient.

Dialysis machines and methods of disinfecting a dialysis machine


An apparatus (10) for inflating a vehicle occupant restraint such as an air bag (32) includes a container (30). The container (30) includes a liner (96) and a composite material (100) encasing the liner (96). A gas (94) is stored under pressure in the container (30) and, when released from the container, inflates the vehicle occupant restraint (32). The apparatus (10) includes opener means (180) for opening the container (30) by rupturing the composite material (100) and the liner (96) to release the gas (94) from the container (30). The liner, when ruptured, produces liner fragments (200). The composite material (100) inhibits separation of the liner fragments (200) from the container (30).

1. Technical Field
The present invention relates to an apparatus for protecting an occupant of a vehicle in the event of a collision or the like. The present invention is directed particularly to an air bag inflator having a stored gas container made of a composite material.
2. Description of the Prior Art
It is known to use an inflatable air bag to protect an occupant of a vehicle in the event of a collision or the like. In some systems, the air bag is inflated by a gas stored under pressure in a container. In the event of sudden vehicle deceleration and/or a side impact to the vehicle, for example, the gas is released from the container and directed into the air bag to inflate the air bag to restrain movement of the vehicle occupant.
It is known to use a detonator to rupture a stored gas container to form an opening in a wall of the container. When this is done, the portion of the container wall which is broken open may be broken into small fragments. These fragments may undesirably be drawn into the gas flowing from the container. It is known to place filter material between a container and an air bag to trap such fragments.

Air bag inflator with composite stored gas container


A method and system are provided for integrating a streaming audio server application, an instant messaging client application, and a media player application. The instant messaging client application may be utilized to engage in an instant messaging session with other users. The instant messaging client application can notify participating users that an audio stream is available from the media player application. The streaming audio server obtains a selection via the instant messenger and then streams the audio track to the requestor. The streaming audio server may also be utilized to provide a streaming audio radio station at a client computer.

Audio player applications exist that allow users to manage and playback music on their computer. For instance, these applications typically allow a user to play compact discs, listen to audio tracks encoded in the Motion Picture Experts Group audio layer 3 format ("MP3"), listen to streaming audio available over the Internet, and to manage their collection of digital music. However, these types of programs do not allow a user to directly share their music collection with other users. Computer programs such as Napster™ and Gnutella™ have been developed that do allow users to share their music collections with other users. However, these programs do not allow sharing in real, or near real-time. Instead, these programs require users to download complete songs prior to listening to them. Depending upon the size of the file and the speed of each user's Internet connection, this process could take several minutes or longer before the user downloading the audio track is able to listen to music. Moreover, these programs do not provide any facility for two users to listen to a song at the same time. Sharing of music is a very common social activity. However, the currently available music playback applications provide no functionality for two or more remote Internet users to listen to a song at the same time.
Instant messaging applications also exist that allow two or more remote users to converse in real-time over a computing network, such as the Internet. Typically, an instant messaging server computer is utilized to facilitate instant messaging sessions. Instant messaging server computers will typically maintain a "buddy list" for each subscriber that identifies a number of users that a subscriber typically converses with. When a user identified in the buddy list signs onto the instant messaging server computer, the subscriber is notified that the user has signed on. The subscriber can then utilize an instant messaging client application to select the user from the buddy list and request an instant messaging session with the user. If the remote user accepts, a near real-time instant messaging session is initiated between the two users. Other users may also participate in the instant messaging session.
Through the use of such instant messaging applications, users may also transmit files to other users. For instance, one user may send another user an audio track. Again, however, the transfer of the audio track does not take place fast enough to listen to the music in real time. In fact, depending upon the bandwidth of each user's connection, such a transfer may take a long period of time to complete. Therefore, while instant messaging applications allow users to converse in near real-time, these types of applications also do not permit users to listen to music together in real-time.
Streaming audio server applications also exist that provide Internet-based streaming audio "radio stations." These applications typically provide a World Wide Web ("Web" or "WWW") front-end that a user may utilize to select and listen to the streaming audio radio station. Typically, a selection is made of the streaming audio radio station within the Web browser. In response to this selection, a streaming audio playback application is launched that connects to a streaming audio sever application, receives a stream of audio data, and plays the audio data. In this manner, streaming audio applications such as these provide the ability for users to listen to streaming audio in real-time. However, these applications allow no interactivity with other users while listening to the streaming audio radio station. Moreover, streaming audio server applications are typically difficult to setup and operate, and, therefore, are not utilized by individual users to share their music libraries.
Accordingly, in light of the above, there exists a need for a method and system for integrating instant messaging with streaming audio and audio playback that allows two or more users to listen to an audio track at the same time. Moreover, there exists a need for a method and system for integrating audio and instant messaging that allows users to easily share their music collections with other users while also interacting with those other users in real- or near real-time.

Method and system for integrating instant messaging, streaming audio and audio playback


A sensor has a die (with a working portion), a cap coupled with the die to at least partially cover the working portion, and a conductive pathway extending through the cap to the working portion. The pathway provides an electrical interface to the working portion.

Modern micromachining techniques have enabled designers to produce highly functional sensors in a minimum of space. For example, accelerometers have been widely produced as MEMS (microelectromechanical systems) to detect both positive and negative accelerations of an underlying system. One type of MEMS accelerometer converts the movement of a suspended mass into acceleration data.
To that end, the suspended mass typically has a plurality of movable fingers inter-digitated with a plurality of stationary fingers (on an underlying die) to form a variable capacitance. When subjected to an acceleration, the mass moves in an expected manner, thus changing the variable capacitance formed by the fingers. Detection circuitry detects this capacitance change and, consequently, converts it to a voltage or current signal that is proportional to the acceleration. Alternatively, the capacitance can be converted to a binary digital voltage or current signal that encodes the acceleration. Once determined, the acceleration data may be forwarded to another device, such as a computer, to perform some underlying function (e.g., deploy air bags).
The detection circuitry used to calculate acceleration can be either external or internal to the sensor. When external, the overall system has a number of problems. Among others, the interface between the sensor and interconnect circuitry (to the detection circuitry) can create a parasitic capacitance that can swamp the underlying signal being produced by the sensor. In other words, the variable capacitance produced by the inter-digitated fingers can be degraded by the parasitic capacitance produced by the sensor attach pads and circuitry. To overcome this problem, the sensor may be enlarged to produce a larger variable capacitance signal that can tolerate this parasitic capacitance. This solution, however, is contrary to one of the goals of MEMS devices—namely miniaturization.


A pegboard tray for retaining food items during transportation includes a base support surface on which a food container of a predetermined height can be disposed and retained in a manner to prevent lateral movement, the base support surface having a plurality of peg receiving surfaces and a plurality of pegs, wherein each peg is removably disposed one the peg receiving surface about the food container and wherein pegs cooperate with each other in a manner to prevent the food container from moving laterally on the base support surface.

1. Field of the Invention
The present invention relates to trays for food. More particularly, the invention relates to a pegboard tray for retaining food items during transportation.
2. Related Art
Food trays are commonly used at social functions where food is served, such as parties and receptions. At gatherings where family and friends are asked to bring a dish of food, these dishes vary in content of solids and liquids. In either case, the transportation of such foods in a vehicle to and from the gathering can be difficult. Dishes are commonly placed in the floor board of the vehicle and have a tendency to slide around during transport resulting many times in spilling of the contents into the vehicle. Attempts to prevent this from occurring include surrounding the food container with towels or other items to prevent the food container from sliding around on the floor board. This has not proven to be an acceptable solution. Still, others have created cargo retainers in the rear of vehicles, such as the trunk, which retain cargo within a predefined space within the retainer. Likewise, this has not proven to be an acceptable solution as the food container size varies in configuration which in many instances is not suitably fixed against movement within the cargo retainer's predefined retainer space. Moreover, many of the food items/containers are hot. Consequently, transporting these to and from the automobile requires handling with hot pads and/or mittens.
Some food trays of the prior art incorporate a flat surface portion and a cup-like portion formed in the upper surface of the plate for supporting both food and a drink container. Although the plates of this type are capable of supporting a drink container and some type of food container, they are not designed for transportation of various configured containers in a suitable manner to prevent spillage from occurring as a result of lateral G-forces acting on the transported food container.
There remains a need to aid one in transporting food items within a container from one's kitchen to a vehicle. Further, there is a need for a suitable transportation device for food containers which can be readily inserted and removed from one's vehicle. There is a further need that such a device be aesthetically pleasing. The present invention aims to solve these needs.

Pegboard tray for retaining food items during transportation


A triple stack NMOS integrated circuit structure protection circuit for a plurality of terminals operative at respective voltage levels is coupled between the plurality of terminals. First and second NMOS elements of the triple stack NMOS share a common active region. A third NMOS element, vertically positioned with respect to the first and second NMOS elements, has an active region separate from the active region of the first and second NMOS elements. The first, second and third NMOS elements are connected in series between two terminals of the plurality of terminals.

Fast-transient testing is a high noise event that can induce ESD clamp mis-triggering that results in chip function failure. End-products customers, concerned with ESD latchup, seek chips from chip-providers that provide a high electrical fast-transient specification but are reluctant to incur high cost of a printed circuit board (PCB) to solve ESD problems. Traditional attempts to overcome transient latch-up or static latch-up issues involve modification of ESD detection circuits that become more complex in design, requiring more area for a surface-type ESD clamp. FIGS. 1 and 2 illustrate the traditional RC-NMOS ESD clamp and feedback-type RC-NMOS ESD clamp. These circuits provide fast turn-on speed. However, a large chip area is allocated to R and C elements that are required to judge ESD event and normal function.
The IEC-like or transient latch-up testing impact on feedback-type RC-NMOS ESD clamp is shown in FIG. 3. The RC time constant of these circuits can induce false triggering. After Vcharge=−4V transient latch-up testing, the VDD drops and the IDD increases. This characteristic illustrates that latch-up like occurrences can happen on this ESD clamp during electrical fast-transient testing, such as transient latch-up testing IEC-like testing. Moreover, both the traditional RC-ESD clamp and feedback-type RC-NMOS ESD clamp can incur high noise damping or transient latch-up testing.
FIG. 4 is a modified RC-Clamp circuit. As in other type of RC-clamp circuits, it is the size of the clamping device that is usually large, in thousands of um width device. In a RC-Clamp circuit, the clamp device represents a high impedance to the circuit in normal operating condition or up to the clamp device trigger voltage (Vtl). The clamp device (or sometimes called ESD clamping device) in RC-clamp circuitry is an active device. The transient detection circuit controls the conduction of the active device. During an ESD event, the transient detection circuit will drive (bias the gate) of the active device and turn it on, i.e. become a low impedance acting as a discharge path in surface mode. The parasitic BJT (NPN in case of NMOS active device) can be further triggered on and provide another path, as the ESD signal pass/over the active device trigger voltage (Vtl).
RC-clamp circuit as an ESD device is a non-snapback device. However other ESD devices such as gate grounded NMOS, SCR and lateral NPN do have snapback characteristic.
The root cause inducing transient latch-up of RC-ESD clamp and false-triggering under electrical fast-transient testing is the RC elements. How to provide an ESD clamp with small size and high noise immunity such as transient latch-up, static latch-up free ESD clamp, becomes a more critical consideration in the development of high voltage technology.
An ESD snap-back device, once conducting current, will exhibit "snap-back" or negative resistance characteristics due to its structure. During normal operation, the ESD device represents a high impedance to the circuit up to the ESD device trigger voltage. During an ESD event, the trigger voltage will be exceeded and the ESD device will begin to conduct and enter a low impedance state. This point is defined on the curve, shown in FIG. 5, by the snap-back holding voltage (Vh) and snap-back holding current (Ih). To return to a non-conducting state, the current through the device must fall below the Ih and the voltage must fall below the Vh.
For the ESD device to be immune to static and transient latch-up, its snap-back holding voltage must be within the ESD protection windows, i.e., between supply rail voltage (VDD) and the core device breakdown voltage, as illustrated in FIG. 6. Static latch-up is an event that occurs when the clamp device becomes conductive due to lower snap-back holding voltage of the clamp device or fluctuation of the supply voltage rail (VDD). Transient latch-up is an event that occurs when the clamp device becomes conductive as a result of spikes, noise, or a start-up transient on the supply rail.
One general approach to overcome transient latch-up or static latch-up is to provide a non-snapback characteristic of ESD clamp, such as PMOS or lateral PNP. Such a device will impact on chip size due to low β compared to NMOS. In general, PMOS needs 2˜3 times the area compared to an NMOS device for a given ESD performance. Another approach is the use of PMOS or lateral PNP architecture to obtain a non-snapback characteristic. Such an arrangement encompasses a large size, approximately two to three times the area compared to NMOS architecture, and large on resistance (Ron). Surface mode PMOS with transient latch-up free ESD detection circuits is an attractive approach to solve transient or static latch-up issues, but incurs high area cost.
A need therefore exists for an improved ESD power clamp or I/O pad clamp that can be used as an electrical fast-transient whole-chip protection network. Such a device should be effective for application to maturing technology as such technology advances. An additional needed benefit would be a cost reduction of saved chip area.

High noise immunity with latch-up free ESD clamp


The invention provides a sealing gland capable of use in high-pressure environments and methods for the use thereof. One aspect of the invention provides a sealing gland including: a first sealing surface having a first groove and a second groove, a first O-ring received in the first groove, a second O-ring received in the second groove, and a pressure port located on the first sealing surface between the first groove and the second groove. The pressure port is configured to apply a fluid pressure intermediate to a first pressure applied to the first O-ring and a second pressure applied to the second O-ring.

Oil, gas, and water drilling applications involve both the use of high-pressure fluids, such as mud, and exposure to high-pressure drilling environments. The latter is particularly true in high-pressure, high-temperature (HPHT) environments such as North Sea oil reservoirs. Accordingly, there is a need for sealing devices capable of withstanding high-pressure environments.


A structure for a fuel lid section has a fuel lid supported on a vehicle body via a hinge, a vehicle body recess openably covered by the fuel lid, a fuel filling opening placed in the vehicle body recess, and a cap-less mechanism provided at the fuel filling opening and enabling fuel filling operation without requiring attachment/detachment of a fuel cap. The structure also has an electricity conduction path extending from the fuel lid to the vehicle body.

Conventionally, a fuel lid part structure is known in which a fuel cap attached to a filler opening is formed of conductive material and static electricity charged to a body of an oil-filling operator is discharged to a vehicle body during an operation for opening or closing the fuel cap (for example, see Patent Document 1).
Meanwhile, in a recent vehicle, in order to simplify the oil-filling operation, there is a case in which a capless mechanism which does not need attaching and detaching of the fuel cap is employed (for example, see Patent Document 2).    [Patent Document 1] Japanese Patent No. 3389850    [Patent Document 2] U.S. Pat. No. 7,011,121


In a method of controlling the power state of a peripheral device, the peripheral is changed from a first power state to a second power state in response to communications across a network connected to the peripheral indicating that a user is proximately located to the peripheral. A user may be determined to be proximately located to the peripheral by monitoring communications across the network to detect traffic that is associated with a user logging onto a computer that can utilize the peripheral, by discovering a wireless terminal that is associated with a user and which is proximately located to the peripheral, by receiving information from a cellular communication network across the network that indicates that a user of the peripheral is proximately located to the peripheral, and/or in response to a time of day and/or day of week/month schedule.

Continued technology advancements have provided an increasing proliferation of the various types and numbers of peripheral devices that can be networked to a computer. Such peripheral devices can include printers, photocopiers ("copiers"), video recording devices (e.g., digital video recorders), audio recording devices (e.g., MP3 recorders), televisions and other audio/video devices. Because of the number of peripherals that a user may utilize from time-to-time, the peripherals may be left powered-on between use and may even be left powered-on during long periods of non-use, such as overnight and throughout weekends. Because some peripherals consume relatively large amounts of power while operating and their operational life is reduced while powered-on, some peripheral devices automatically transition from a higher power operational state to a lower power sleep state after a defined duration of non-use.
For example, laser printers and copiers typically employ high temperature fuser assemblies to permanently adhere toner to paper. The heating elements that warm the fuser assemblies can consume substantial electrical energy and, therefore, powering the heater elements whenever a laser printer/copier is turned on but idle can be wasteful.
It has generally been known to cause some types of peripherals, such as printers and copiers, to enter a power save mode after a certain period of inactivity. For instance, after a period of about one hour of non-use, a printer or copier may transition from a higher power operational state to a lower power sleep state in which their fuser assemblies (heater elements) are powered-off. Depending on the particular printer/copier, the warm-up period for the fuser assembly may range from one to several minutes or more. This warm-up period may be considered unsatisfactory to a user who, for example, has sent a print job to a printer/copier and is now idly standing by the printer/copier awaiting completion of the print job.

Controlling power states of a peripheral device in response to user proximity


Disclosed are embodiments of an integrated circuit chip designed for reliability at low ambient temperatures. The chip substrate can be divided into zones, including at least one temperature-sensitive zone (TSZ) that contains one or more temperature-sensitive circuits. Temperature sensor(s) can be positioned in the semiconductor substrate adjacent to the TSZ. Thermal radiator(s) can be embedded in a metal wiring layer and aligned above the TSZ. The temperature sensor(s) can be operatively connected to the thermal radiator(s) and can trigger operation of the thermal radiator(s) when the temperature in the TSZ is below a predetermined threshold temperature. Additionally, an on-chip power control system can be operatively connected to the thermal radiator(s) so that operation of the thermal radiator(s) is only triggered when a circuit within the TSZ is about to be powered up. Also disclosed are associated embodiments of a system and method for designing such an integrated circuit chip.

1. Field of the Invention
The present invention relates to integrated circuit chips, and more specifically, to temperature control of integrated circuit chips particularly in low-temperature environments.
2. Description of the Related Art
Customers and, particularly, military and/or government customers often require integrated circuit chips to be operable at a specified very low ambient temperature (e.g., an ambient temperature of 0° C., −20° C., −55° C., −75° C., etc.). Many integrated circuit chips or components thereof are either non-functional or fail to meet specific performance requirements (i.e., fail to meet specific timing requirements) at very low temperatures. Unfortunately, circuits and/or circuit components designed to be functional and to meet specific performance requirements (i.e., timing requirements) at very low temperatures can be costly.

Integrated circuit chip incorporating embedded thermal radiators for localized, on-demand, heating and a system and method for designing such an integrated circuit chip

International Business Machines Corporation


A versatile system for producing channel letter coil of superior reflectivity and durability is described that includes providing a readily formable substrate. A first reflective material is disposed upon a first surface of the substrate. A second reflective material is disposed upon the first reflective material. An aesthetic material is disposed upon a second surface of the substrate. The entire substrate, with the reflective and aesthetic materials intact, is then rolled into a channel letter coil product, ready for immediate and efficient use in sign production.

Channel letter coil is used in the production of illuminated signs that are most often associated with commercial enterprises such as restaurants, stores, and other businesses. Channel letter coil usually comprises a roll of readily formable metal (e.g., thin aluminum). A sign manufacturer takes the channel letter coil and, using a number of tools and methods, forms it into troughs (or channels) disposed upon or within the sign. These channels generally have the shape of particular individual characters (e.g., letters, numbers, symbols). A specialized light source (e.g., neon tubing or LEDs) of a desired shape or configuration is typically then disposed within the channel, and the channel and light may then optionally be covered over by some sort of protective or decorative lens, such as acrylic or film.
Conventionally, the coil material is supplied with a protective coating pre-applied to its surfaces for primarily aesthetic purposes but also, in part, to improve durability during handling, processing, and use. Typically, however, this pre-applied coating comprises a single layer of nominal thickness. Such conventional pre-applied coatings often do not, and are not intended to, enhance the performance or usability of the coil material as used in a finished channel coil sign product.
Manufacturers of finished channel coil sign products therefore often must, or choose to, apply additional coatings to enhance the durability and reflectivity of the channel coil. In some instances (e.g., outdoor signs) additional coatings may also be added to protect the interior of the sign from damaging outdoor conditions. Most often, however, additional coatings are applied to the backside (i.e., inner surface) of the channel coil to increase the effective intensity of the light emitted from the sign, without increasing its required power usage. Otherwise, the sign manufacturer may have to position additional light sources within the channel to achieve the desired illumination.
Exterior coatings may also be applied—as or to the topcoat—to provide various aesthetic effects (e.g., color). Although rolled coil material is typically supplied with some basic pre-painting, as previously noted, these special additional coatings are usually not applied to the coil material until after it has been unrolled and formed into its desired shape. This conventional type of application adds cost and inefficiency into the production process.

Production of versatile channel letter coil


In a preferred embodiment, a windage tray assembly is mounted to crankshaft bearing caps which connect with oil passages in the windage tray. The passages carry the oil through nozzles directed toward the interior of associated pistons. The arrangement utilizes the windage tray and bearing caps as carriers for piston cooling oil obtained from the bearing caps, which are already supplied with oil for lubricating the bearings. Thus, modifications of an engine design to install a piston cooling system are limited to redesign of the windage tray to a sandwich-like assembly and modification of the bearing caps to conduct oil from the bearings to the windage tray passages. To limit oil pumping energy, oil distribution holes in the bearing caps connect intermittently with crankshaft journal feed passages so the oil is distributed in individually timed streams or sprays directed toward the pistons for a short interval once every revolution of the engine crankshaft.

This invention relates to piston engines and more particularly to piston cooling oil systems wherein oil is sprayed into the pistons from a crankcase mounted windage tray having internal oil delivery passages.
It is known in the engine art to provide piston cooling oil sprayed against the inside of the individual pistons of an engine to cool the pistons to obtain higher engine power output or increased piston life. Such systems have been commonly used on many models of diesel engines but have generally not been used in automotive gasoline powered engines. However, in high output gasoline engines and for other engines for the purpose of increased emission control, the possibility of further extension of piston cooling in spark ignition engines has been considered.
Conventionally, piston cooling systems have operated with piston cooling nozzles through which oil is continuously applied in a stream or a spray on the piston interiors. The provision of such a system generally requires internal engine modifications and equipment which make difficult its application to engines previously manufactured. In addition, the continuous delivery of oil for cooling requires increased oil pumping capacity which uses energy and thereby reduces engine efficiency. A system in which these problems may be reduced or overcome is accordingly desired.
The present invention provides a piston cooling system for an engine which may be relatively easily adapted to engines in current production as well as to new engine designs. The system modifies the windage tray, commonly used in engines to reduce oil aeration, to provide an assembly through which piston cooling oil may be delivered to the underside of the engine pistons.
Instead of a single stamped sheet, the windage tray may be made from a pair of sheets, of metal or a suitable non-metallic material, which are welded or bonded together to form an assembly. One or both sheets are embossed so as to provide internal oil passages between the sheets that are used to transport oil from individual inlet openings to outlet openings provided with nozzles for directing cooling oil to each of the pistons individually.
In a preferred embodiment, the windage tray assembly is mounted to lower ends of the crankshaft bearing caps that support the engine crankshaft. The bearing caps include oil passages that carry oil from the pressure lubricated bearings supporting the crankshaft to outlet connections that feed oil to the inlet openings in the windage tray. The internal passages in the tray carry the oil from the inlet openings to outlet openings positioned on the tray so as to direct oil through the nozzles toward the interiors of the respective pistons. The arrangement utilizes the windage tray and bearing caps as carriers for piston cooling oil obtained from the bearing caps which are already supplied with oil for lubricating the bearings. Thus, modifications of the engine required to install a piston cooling system are limited to redesign of the windage tray to a sandwich-like assembly with oil passages and modification of the bearing caps to conduct oil from the bearings to the windage tray passages.
In order to reduce the energy expended in pumping the piston cooling oil, the engine bearing caps and the bearings therein may be modified to connect with oil feed holes in the associated crankshaft bearing journals so that oil distribution holes in the bearing caps connect intermittently with the crankshaft journal feed passages. Thus, oil is distributed in individually timed streams or sprays directed toward the pistons for a short interval once every revolution of the engine crankshaft. In this way, the amount of cooling oil utilized is limited and the energy expended in pumping the cooling oil is reduced, allowing for increased efficiency of the engine.

Piston cooling oil system with windage tray