Methods and apparatus are disclosed for: 1) the gentle, controlled mixing of solid and liquid botanical components during fermentation; and 2) the regulation of parameters in cap material and juice during primary fermentation to optimize attributes such as expressive organoleptic characteristics including bouquet, texture and flavor, while simultaneously and selectively monitoring and mitigating the deleterious effects of reduced sulfur compounds, harmful bacteria, multicellular fungi, and/or biogenic amines during the artisan creation of ultra-premium fine wines and other alcoholic libations according to a customized schedule.

For over seven millennia, fermented beverages have been a popular and common drink. Today, wine alone is estimated to contribute over a hundred billion dollars to the American economy. There are more than five thousand wineries in the United States including at least one winery in each state.
Many problems associated with the preparation of alcoholic beverages, including wine and beer, occur during primary fermentation when yeasts anaerobically convert sugar into carbon dioxide and ethyl alcohol by way of the following chemical reaction:C6H12O6(sugar)→2C2H5OH(alcohol)+2CO2(carbon dioxide)
One of the most critical steps required to ensure a successful fermentation is the careful extraction of desirable components including phenols, for example. Phenolic compounds, both natural phenol and polyphenols, include a large group of several hundred chemical compounds that affect the taste, color and mouthfeel of wine. Natural phenols can be broadly separated into two categories: flavonoids and non-flavonoids. The flavonoids include anthocyanin and tannins which contribute to the color and mouthfeel of the wine or other fermented botanical components. The non-flavonoids include the stilbenoids such as resveratrol and phenolic acids such as benzoic, caffeic and cinnamic acids.
High quality (i.e. ultra-premium) wine grapes weigh a mere tenth of an ounce or about one-fifth the weight of common table grapes. The skin to pulp ratio for wine grapes determines the actual concentration of polyphenols. During fermentation, oxygen (O2), hydrogen (H2), and other molecules polymerize new molecular combinations, ultimately imparting an evocative array of complex organoleptic attributes to the finished wine.
The extraction of desirable components can be accomplished via good cap management. Nowhere is this more prophetic than during the production of fine red wine (from grapes) or fruit wine (from other fruit sources), although alcoholic fermentation using any botanical component(s) will undoubtedly benefit from diligent cap management.
Residual sugar (RS) caused by sluggish or stuck fermentations and volatile acidity caused by distillable acids like acetic, lactic, butyric, propionic, and formic acids, are common examples of erroneous ferments; however, the presence of undesirable matter, including chemical and bacterial contaminants, can also be problematic. Most fermentation troubles can be specifically attributed to poor cap management.
On average, about 75 percent of the fermentation activity will occur during primary fermentation. As fermentation proceeds, each yeast cell produces carbon dioxide (CO2) beyond the capacity of the juice to keep it in solution Skins and seeds are less dense than the fermenting liquid and tend to form a solid cap of material which is usually about 33% by volume when fermenting grapes. Carbon dioxide gas bubbles rise and adhere to the solid material causing it to float upward, rise above the juice, and dry out to form a cap as the juice slowly drains away.
Cap Management
Cap management generally relates to the control of physical, chemical and biological interactions between solid cap material (or pomace) and juice (or must) during primary fermentation. The word "pomace" is considered a subset of solid cap material that specifically includes grape skins, grape seeds (i.e. pips) and/or grape stems. The word "marc" refers to only the grape skins and seeds. As used herewith, the word "juice" refers to any liquid component before or during fermentation and the word "must" refers specifically to grape juice before or during fermentation. The word "ferment" refers to any fermenting substance. The word "wine" is generally used to describe the liquid component post-fermentation using grapes. Primary fermentation is used synonymously with alcoholic fermentation and secondary fermentation is used synonymously with malolactic fermentation for purposes of this disclosure and general discussion. The following terms are used interchangeably throughout this document: aroma/bouquet/essence; mouthfeel/texture/smoothness; and taste/flavor/savor.
The formation of a cap (or chapeau) is a potentially dangerous situation. Left unchecked, the dry cap material, oxygen, and warmth provide an ideal environment for harmful strains of bacteria. If a cap isn't properly managed, several other deleterious events can occur: 1) the cap temperature overheats and kills the yeast before enough sugar is consumed; 2) acetic acid bacteria (e.g. Acetobacter aceti, A. cerevisiae, A. liquefaciens and others) proliferate and begin converting ethanol to acetic acid in the presence of oxygen which, in turn, forms acetaldehyde which ultimately spoils the wine; and 3) the fermentation can stratify and/or stick. A stratified fermentation includes the establishment of two or more distinct micro-environments. This is usually due to insufficient mixing. A stuck fermentation occurs when yeasts become dormant before the fermentation is complete. Poorly managed caps contribute to large quantities of ruined wine each year.
Therefore, it's prudent to manage a fermentation cap to accomplish at least these goals: 1) keep the cap moist enough for the yeast to remain active; 2) keep the cap cool enough for the yeast to remain active; 3) redistribute sugar and nutrients so that they remain accessible to the yeast; 4) keep cap solids in anaerobic conditions to prevent volatile acidity and other issues; and 5) extract desirable components, including phenols.
Historically, a number of enological techniques have been used to accomplish one or more of the above-identified goals. The main categories generally include: 1) pump over; 2) submerged cap; 3) rotary tank; 4) rack and return (i.e. délestage); 5) timed gas-pressure release; 6) pneumatage; and 7) punch down (i.e. pigeage).
Pump over systems remove a volume of juice from the bottom of the vessel and pump it back over the top of the floating cap to keep the cap moist. These systems are one of the more oxidative cap management techniques. Even though carbon dioxide (CO2) quickly displaces almost all the oxygen (O2) out of the headspace in the fermentation vessel, the physical motion of the juice falling through the headspace from the irrigator to the top of the cap will tend to cause excessive O2 from the outside atmosphere to be brought into the headspace. Introduction of too much O2 and aggressive mixing are major drawbacks of this approach.
Submerged cap systems use a grate or other partition in the fermentation vessel to keep the skins submerged throughout the fermentation. Unfortunately, this type of cap management system often causes stratification unless a pump over system is also employed.
Rotary tanks are rotated on their horizontal axis which leads to mixing the pomace (i.e. grape skins, seeds and stems) with the must (i.e. grape juice) during winemaking. This assures regular contact of the cap and ethanol produced by the yeasts and also creates a more uniform temperature during the fermentation. Stationary mixing tanks provide a vertical impeller for mixing. These types of systems allow for maximum extraction in a minimum amount of time. This is not necessarily an advantage because aggressive mixing often results in an imbalance of tannin and fruit and/or excessive oxygenation which can age wine prematurely. In fact, with the exception of Sherry, Port, Madeira and white wines from the Jura region of France, oxidation is considered a technical fault. Wines lacking the protective benefits of tannins are more susceptible to oxygen exposure during the winemaking process.
Rack and return (délestage) is a common cap management protocol used in winemaking that first removes of all the must from the fermentation vessel. The must is then poured back onto the cap to fully submerse the cap. When used with ripe fruit, this regime can lead to a wine with less structure. Therefore, this approach should be reserved for wines showing excessive tannins.
Timed gas-pressure and release systems, including those produced by Ganimede®, capture CO2 as it is produced during fermentation. The gas displaces some of the must and lifts it upward in the fermentation vessel. A solenoid periodically releases the gas to allow the cap to fall back in the vessel. This action is designed to break up and irrigate the cap.
Pneumatage employs plates to trap gas bubbles until the resulting bubble is large enough to overcome the surface tension of the liquid at which point the growing bubble escapes from under the plate and ascends through the must. The movement of the bubble through the column of must breaks up the cap when it reaches the surface. Pneumatage, as well as the previously described gas-pressure and release systems, are not economical methods for small (i.e. boutique) wineries and it's sometimes difficult to control the mixing as the bubbles randomly ascend.
The term "punch down" (i.e. pigeage) describes the process of breaking up the cap by randomly pushing it back down into the juice. While pigeage doesn't require any pumping, it aggressively mixes the cap by disintegrating the cap material to disassociate the pulverized cap material into the juice. Pigeage is also somewhat limited by the size of the fermentation vessel. Fermenters larger than five tons tend to generate caps that are too thick for manual pigeage and thus benefit from a semi-automatic system. Fully-automated industrial pigeage systems can get as large as 35 to 50 tons in capacity.
Regardless of the mixing technique or fermentation vessel chosen, the duration of time the solid components are in contact with the juice is the controlling factor for extraction of phenolic compounds. Excessive extraction and the accompanying bitterness and astringency that follow can cause yet another set of problems. Red wines are typically aged longer than white wines so excessive extraction may be tempered by extended aging of red wines, in particular. However, additional aging may not be an option due to controlling economic factors or limited long term storage capacity, for example.
Extraction can be difficult to control. Microwave irradiation and thermovinification are two extraction techniques that have been used. Thermovinification heats up the entire cap material. This method favors extractions but can reduce the desirable characteristics and compromises color stabilization to ultimately lower the quality of the finished wine. Irradiation can be expensive to implement and may destroy a large amount of important phytochemicals and nutrients.
Traditional pigeage tools, such as the example shown in FIG. 1, can cause seeds to be inadvertently crushed between the disk and the bottom of the vessel which exacerbates the release of harsh tannins into the wine. This is a particular concern when using shallow open top fermentation vessels. Conventional tools are also difficult to push downward and lift upward due to the lack of hydrodynamic design and the strong resistance created by the disk as it is moved through viscous juice. The solid components also adhere to the top of the disk making it difficult to lift the tool out of the vessel and move it to other locations around the fermentation vessel when mixing the components. Solid components are sometimes dislodged from the disk by banging the tool on the edge of the vessel. This can be messy and unsanitary as must and/or pomace randomly splatter.
Manual cap punch down requires significant strength and can cause back pain and physical injury, particularly if the worker is standing alongside the fermentation vessel and must lean over the vessel to punch down the cap. Alternatively, punching down a cap may require balancing on the edge of a fermentation vessel or catwalk to position the worker directly above the vessel. In these days of health and safety awareness it is somewhat surprising that this operation is still permitted, as a number of people have fallen into vessels of fermenting wine while punching down the cap, several with fatal results.
Automated punch down units have eliminated the physical strength required during pigeage and are routinely used in industrial bulk wine production; however, the expense and maintenance of specialized machinery eliminates automation as a viable option for boutique commercial wineries and hobbyists. Furthermore, automation of traditional mixing techniques does not solve other cap management issues such as mitigating reduced sulfur compounds, harmful bacteria, multicellular fungi and/or biogenic amines. Nevertheless, some embodiments of the invention are suitable for automated punch down units, commercial wineries, or wherever cap management can be improved.
Reduced Sulfur Compounds
Sulfur (S) is difficult to avoid during fermentation because relatively small amounts are naturally present on many fruits. Larger amounts of sulfur may arrive on harvested grapes sprayed in the vineyard to protect the crop from disease. The chemically related sulfites are reported by some consumers to be a significant cause of headaches and perhaps other maladies. Small amounts (about 10 parts per million) of hydrogen sulfide (H2S) and other reduced sulfur compounds are formed when yeasts convert sulfur to H2S during fermentation in an oxidation-reduction reaction as shown below with net electron transfer indicated:S0(sulfur)+H20(hydrogen)→S2−H2+(hydrogen sulfide)
Hydrogen sulfide formation is a chronic problem in the wine industry worldwide. Under normal conditions, some H2S is volatilized from the wine or other ferment along with CO2; however, the residual H2S may pose a serious problem due to its low sensory threshold and its potential reactivity. Hydrogen sulfide smells of rotten eggs and is generally considered to be a fatal flaw in finished wine. Amounts of H2S over 1.0 parts per billion (ppb) are readily detectable by human olfaction. Even amounts below this threshold can react with ethanol or acetaldehyde to form mono- and di-mercaptans, which radiate strong garlic and petroleum aromas, respectively, both before and/or after bottling as generally depicted below:H2S(volatile)→mono-mercaptans(becoming bound)→poly-mercaptans(bound)
Removal of H2S, particularly bound mercaptans produced near the end of fermentation, can be extremely difficult if not technically challenging. This process is not discrete. While H2S is present, it is likely that mono-mercaptans are forming; and poly-mercaptans may be forming before the H2S in its volatile form disappears. Research shows that mercaptan formation occurs within a few days after the beginning of fermentation and is at its peak at about two months after which the poly-mercaptans become dominant.
One traditional "solution" used to eliminate H2S has included aeration; however, mono- and di-mercaptans are formed by aggressive aeration. Therefore, aeration may actually compound the problem or at least require subsequent protocols to remove the mercaptans. Even gently splashing wine to eliminate sulfide aromas can encourage the formation of disulfides which can serve as a reservoir from which sulfides can be re-formed under reductive conditions such as after bottling.
In more severe or advanced cases, solutions of, or filters impregnated with, copper sulfate (CuSO4), have been used to remove H2S and mono-mercaptans. However, copper sulfate is poisonous and, therefore, requires further steps of fining with bentonite (or another absorbent aluminum phyllosilicate) or Sparkolloid® in order to remove it from the ferment. The fining agent must then be removed by filtering which, unfortunately, also removes many of the desirable components of the wine. Other methods use radiation to remove harmful gasses from wine but this approach prematurely ages the wine and is expensive to employ in small scale winemaking operations.
Another way to manage cap micro-environments and prevent reduced sulfur compounds includes using yeasts that are genetically modified not to catalyze the conversion of sulfite to sulfide. However, the use of altered organisms remains controversial and this approach does nothing to address control of reduced sulfur compounds in non-inoculated fermentations (e.g. using only wild or natural yeasts), for example.
Harmful Bacteria
Harmful bacteria are another potential inhabitant of the cap and surrounding material. Although some forms of lactic acid bacteria (principally Oenococcus oeni) play a positive role during malolactic fermentation (MLF), bacteria can prove detrimental during primary fermentation, particularly if the pH rises above about 3-4 as this range encourages bacterial proliferation. Most recalcitrant bacteria belong to the genera: Leuconostoc (rancid butter flavor); Pediococcus (bitter flavor); and Lactobacillus (sauerkraut aroma). These organisms are gram positive and can grow well throughout various depths in the ferment because they are microerophilic (i.e. they do not require much oxygen). Both lactic acid bacteria (LAB) and acetic acid bacteria (AAB) routinely exist on the surface of grapes prior to crushing. The subsequent crushing process increases the propagation and colonization potentials of these microbes. In addition, harmful bacteria can also contaminate the grape juice via winemaking equipment and spoilage biofilms formed inside hoses and pipes. Some species or strains of lactic acid bacteria acidify wine and give it an undesirable bitter palate and/or musty odor. Harmful lactic acid bacteria can also form biogenic amines in the wine. Acetic acid bacteria can spoil wine by literally turning it into vinegar.
If harmful bacterial cells are identified early, their numbers may be kept to a safe level. Attempts to control harmful bacteria have included, for example, treatment with sulfur dioxide (SO2) gas, potassium metabisulphite (K2S2O5) and/or filtration. As previously discussed, adding forms of sulfur and/or filtering have their own unique drawbacks. Potassium metabisulphite is also an allergen for some individuals.
Multicellular Fungi
Multicellular fungi may also find a suitable home in cap material, especially when spores are inadvertently transferred into the winery from the vineyard during harvest. Mold and mildew are two common examples of fungi that can spoil wine or other liquids during primary fermentation. Spores of mold and mildew, like bacteria and yeasts, naturally exist on most surfaces. Too much head space in a covered fermentation vessel or tank or unsanitary equipment contribute to their growth and potential ecological succession. A musty odor, wet wood odor, or an oily/rainbow appearance on the surface of the liquid are usually initial indications of a fungus problem.
A common "solution" in wine tainted by mold and/or mildew is to rack the wine into a sanitized container. This step is followed by the addition of campden tablets to remove the additional oxygen introduced by racking Campden tablets are a sulfur-based product, usually in the form of sodium metabisulfite, that suffer from the same limitations as previously described.
Biogenic Amines
Biogenic amines can be formed by a wide range of yeasts and some (mostly malolactic) bacteria. Most important among the amines found in wine are histamine and tyramine. The presence of histamine, like sulfites, has been implicated as a potential cause of headaches that some people experience after imbibing alcoholic beverages. Biogenic amines may cause allergic reactions and changes in blood pressure as well. Other biogenic amines such as cadaverine and putrescine, as their names suggest, have extremely foul odors which mask fruit flavors (and turn stomachs). Preventive techniques include cold soaking combined with flash pasteurization. Curative reduction of biogenic amines by bentonite absorption and yeast cell hull preparations have been attempted albeit with mixed results. Separation columns or filters have been used but these methods fail to adequately select only the undesirable matter and, therefore, inevitably also remove attributes which make a positive contribution to the quality of the wine.
Information related to attempts to address these problems can be found in U.S. Pat. Nos. 4,473,001; 4,479,721; 4,745,068; 4,474,890; 4,934,828; 5,472,278; 5,744,183; 5,972,402; 6,125,736; 6,703,055 B1; 6,905,601 B2; 7,198,809 B2; 7,353,750 B2; 7,571,673 B2; 8,216,803 B2; and United States Patent Application Publication Numbers: 2005/0147776 A1; 2006/0156929 A1; 2006/0240146 A1; 2008/0175951 A1; 2010/0143536 A1; 2011/0024418 A1; 2011/0305794 A1; 2012/0064610 A1; 2012/0190386 A1; and 2012/0269925 A1 as well as European Patent Numbers: EP 0089225 A2; EP 0871699 B1; EP 1049764 B1 and International Patent Publication Numbers: PCT/WO 97/14781 A1; and PCT/WO 03/011440 A1, for example. Various types of cap management equipment and technologies, including some embodiments of the invention, can mitigate or reduce the effect of, or even take advantage of, some or all of these potential problems.
For the foregoing reasons, there's a legitimate need for effective and efficient ways to facilitate cap management including selectively mitigating undesirable matter during fermentation. It would be particularly beneficial and desirable to provide methods and apparatus for cap management to facilitate some or all of the following: regulate fermentation parameters; optimize organoleptic attributes; and/or selectively and simultaneously mitigate (or eliminate) undesirable matter including reduced sulfur compounds, harmful bacteria, multicellular fungi and/or biogenic amines.

Methods and apparatus for cap management and mitigation of selected undesirable matter during fermentation


A method and system for transparent timing of an Ethernet signal over an optical transport network are disclosed. In one embodiment, a transceiver includes a first clock recovery circuit, a first synchronizer and an asynchronous mapper. The first clock recovery circuit recovers a first clock from a first signal received from an Ethernet network. The first synchronizer multiplies the first clock by a ratio M/N to produce a second clock to time a second signal transmitted over the optical transport network. M and N are integers. The asynchronous mapper maps frames of the first signal to produce frames of the second signal.

Telecommunication networks increasingly use the Optical Transport Network (OTN) standards for aggregation and transport of Ethernet data traffic. The standard method of mapping Ethernet frames to optical transport unit (OTUk) frames involves terminating the packets and mapping them using generic framing protocol frames (GFP-F). However, GFP-F does not provide synchronization between the timing of the Ethernet network and the timing of the OTN. Consequently, telecommunications providers must add extra equipment to add stratum timing at the egress of the telecommunications network, resulting in increased equipment and operating costs. Further, adding stratum synchronized timing from an external source requires meeting stringent timing wander requirements. Addressing these wander requirements requires complicated and expensive stratum synchronization circuits.
For synchronous 10 Gigabit Ethernet (10GBE), there are transparent timing mappings to over-clocked OTU2x, (such as, for example, OTU1e, at 11.05 Gigabits per second (Gb/s) and OTU2e at 11.09 Gb/s.) These over-clocked signals cannot be passed over a standard OTU2 link or multiplexed into a standard OTU3 link.
Therefore, there is a need for synchronization between an Ethernet link and an OTN link that provides a transparent timing change at a boundary node between the links.

Transparent timing of a stratum synchronized ethernet signal using standard optical transport network rates


A method performed by a User Equipment (UE) for handing a Radio Link Failure (RLF) on a first group of cells in a wireless communication network is provided. The UE is engaged in an ongoing communication with the wireless communication network via a first group of cells and a second group of cells. The UE detects (501) that an RLF is on one or more out of the first group of cells. The further UE sends (502) a report to a network node in the wireless communication network. The report is sent via one or more out of the second group of cells while continuing the communication with the wireless communication network. The report comprises radio link information about the RLF on one or more out of the first group of cells.

In a typical wireless communication network, wireless devices, also known as wireless communication devices, mobile stations, stations (STA) and/or User Equipments (UE), communicate via a Local Area Network such as a Wi-Fi network or a Radio Access Network (RAN) to one or more core networks (CN). The RAN covers a geographical area which is divided into service areas or cell areas, which may also be referred to as a beam or a beam group, with each service area or cell area being served by a radio network node such as a radio access node e.g., a Wi-Fi access point or a radio base station (RBS), which in some networks may also be denoted, for example, a NodeB, eNodeB (eNB), or gNB as denoted in 5G. A service area or cell area is a geographical area where radio coverage is provided by the radio network node. The radio network node communicates over an air interface operating on radio frequencies with the wireless device within range of the radio network node.
Specifications for the Evolved Packet System (EPS), also called a Fourth Generation (4G) network, have been completed within the 3rd Generation Partnership Project (3GPP) and this work continues in the coming 3GPP releases, for example to specify a Fifth Generation (5G) network also referred to as 5G New Radio (NR). The EPS comprises the Evolved Universal Terrestrial Radio Access Network (E-UTRAN), also known as the Long Term Evolution (LTE) radio access network, and the Evolved Packet Core (EPC), also known as System Architecture Evolution (SAE) core network. E-UTRANILTE is a variant of a 3GPP radio access network wherein the radio network nodes are directly connected to the EPC core network rather than to RNCs used in 3G networks. In general, in E-UTRAN/LTE the a 3G RNC are distributed between the radio network nodes, e.g. eNodeBs LTE, and the core network. As such, the RAN of an EPS has an essentially "flat" architecture comprising radio network nodes connected directly to one or more core networks, i.e. they are not connected to RNCs. To compensate for that, the E-UTRAN specification defines a direct interface between the radio network nodes, this interface being denoted the X2 interface.
Multi-antenna techniques can significantly increase the data rates and reliability of a wireless communication system. The performance is in particular improved if both the transmitter and the receiver are equipped with multiple antennas, which results in a Multiple-Input Multiple-Output (MIMO) communication channel. Such systems and/or related techniques are commonly referred to as MIMO.
NR Standalone
in NR non-standalone a 5G networks will be supported by existing 4G infrastructure or 5G infrastructure and in NR standalone a 5G networks will be supported by only a 5G infrastructure.
In NR standalone, but more in general in NR, an NG-RAN node is a gNB providing NR user plane and control plane protocol terminations towards a UE. Alternatively, in case of LTE connected 5GC core network, an NG-RAN node is a ng-eNB, providing E-UTRA user plane and control plane protocol terminations towards the UE.
FIG. 1 shows the User Plane Protocol Stack for the NR user plane, with Service Data Adaptation Protocol (SLAP), Packet Data Convergence Protocol (PDCP), Radio link control (RLC) and Medium Access Control (MAC), and Physical Layer (PHY) sublayers, terminated in gNB on the network side. PHY in FIG. 1 stands for Physical Layer.
The NR control plane architecture is shown in FIG. 2 with a UE, a gNB, a Mobility Management Function (AMF), and the layers: Non Access Stratum (NAS), Radio Resource Control (RRC), PDCP, RLC, MAC and PHY.
Carrier Aggregation (CA)
When CA is configured, a UE only has one RRC connection with the network. Further, at RRC connection establishment, re-establishment and/or handover, one serving cell provides the NAS mobility information, and at RRC connection re-establishment and/or handover, one serving cell provides the security input. This cell is referred to as the Primary Cell (P Cell). In addition, depending on UE capabilities, Secondary Cells (SCells) may be configured to form together with the PCell a set of serving cells. The configured set of serving cells for a UE therefore comprises one PCell and one or more SCells. Further, when dual connectivity is configured, it may be the case that one carrier under the Secondary Cell Group (SCG) is used as the Primary SCell (PSCell). Hence, in this case there may be one PCell and one or more SCell(s) over a Master Cell Group (MCG) and one PSCell and one or more SCell(s) over the SCG.
The reconfiguration, addition and removal of SCells may be performed by RRC. At intra-RAT handover, RRC may also add, remove, or reconfigure SCells for usage with the target PCell. When adding a new SCell, dedicated RRC signalling is used for sending all required system information of the SCell i.e. while in connected mode, UEs need not acquire broadcasted system information directly from the SCells.
The configured set of serving cells for a UE therefore comprises one PCell and one or more SCells:                For each SCell the usage of uplink resources by the UE in addition to the downlink ones is configurable, the number of DL Secondary Component Carrier (SCC)s configured is therefore always larger than or equal to the number of UL SCCs and no SCell can be configured for usage of uplink resources only:        From a UE viewpoint, each uplink resource only belongs to one serving cell,        The number of serving cells that can be configured depends on the aggregation capability of the UE;        The PCell can only be changed with handover procedure, i.e. with security key change and, unless a Random Access Channel (RACH)-less Handover (HO) is configured, with RACH procedure;        The PCell is used for transmission of a Physical Uplink Control CHannel (PUCCH);        If Dual Connectivity (DC) is not configured, one additional PUCCH can be configured on an SCell, the PUCCH SCell;        Unlike SCells, a PCell cannot be de-activated:        Re-establishment is triggered when a PCell experiences radio Link Failure (RLF), not when an SCells experience RLF;        NAS information is taken from PCell.
Radio Link Failure
In LTE, a UE considers a RLF to be detected when:                i. Upon detecting, a certain number of out of sync indications from the lower layers associated with the PCell within a given time, or        ii. upon random access problem indication from MAC, or        iii. UI upon indication from RLC that the maximum number of retransmissions has been reached for a Signaling Radio Bearer (SRB) or for a Data Radio Bearer (DRB).
When RLF is detected, the UE prepares an RLF report, which includes, among other information, the measurement status of the serving and neighbor cells at the moment when RLF was detected, goes o IDLE mode, select cell following LE mode cell selection procedure, the selected cell may be the same serving node and/or cell or another node and/or cell, and start the RRC re-e n procedure, with a cause value set to rlf-cause.
In particular, when the RLF failure happens on PCell, a RRC connection establishment procedure is triggered. On the other side, when the failure happens on the SCell, RLF is triggered.
Duplication in NR
It has been agreed to in duplication of packets for the sake of enhancing reliability. Duplication may be applied at either the DC level or CA level. Usually, in case of CA level duplication, two RLC entities are mapped to the same PDCP entity, i.e., one RLC entity for the PCell and another one for the SCell. With CA level duplication, logical channel, also referred to carrier, restriction is made so that one RLC entity is mapped only to one of the carriers comprising the CA tuple, so that diversity can be ensured, i.e. the original and the duplicate will not be sent over the same carrier. CA duplication may be enabled both for DRBs and SRBs. In the following, if the CA level duplication was setup for a DRB(s), then it is assumed that there is also CA level duplication on SRBs.
Therefore, differently from LTE, where the PCell and SCell where mapped to one RLC and one PDCP entity, as shown in FIG. 3, in NR there one RLC entity for each PCell and SCell(s) linked with one PDCP entity that take care of the duplication. FIG. 3 depicts a CA duplication in standalone NR.

User equipment, network node and methods in a wireless communications network


A method of making a NAND string includes forming a tunnel dielectric over a semiconductor channel, forming a charge storage layer over the tunnel dielectric, forming a blocking dielectric over the charge storage layer, and forming a control gate layer over the blocking dielectric. The method also includes patterning the control gate layer to form a plurality of control gates separated by trenches, and reacting a first material with exposed sidewalls of the plurality of control gates to form self aligned metal-first material compound sidewall spacers on the exposed sidewalls of the plurality of control gates.

In most integrated circuit applications, the substrate area allocated to implement the various integrated circuit functions continues to decrease. Semiconductor memory devices, for example, and their fabrication processes are continuously evolving to meet demands for increases in the amount of data that can be stored in a given area of the silicon substrate. These demands seek to increase the storage capacity of a given size of memory card or other type of package and/or decrease their size.
Electrical Erasable Programmable Read Only Memory (EEPROM), including flash EEPROM, and Electronically Programmable Read Only Memory (EPROM) are among the most popular non-volatile semiconductor memories. One popular flash EEPROM architecture utilizes a NAND array having a large number of strings of memory cells connected through one or more select transistors between individual bit lines and common source lines. FIG. 1 is a top view showing a single NAND string and FIG. 2 is an equivalent circuit thereof. The NAND string depicted in FIGS. 1 and 2 includes four transistors 100, 102, 104 and 106 in series between a first select gate 120 and a second select gate 122. Select gate 120 connects the NAND string to a bit line via bit line contact 126. Select gate 122 connects the NAND string to a common source line via source line contact 128. Each of the transistors 100, 102, 104 and 106 is an individual storage element and includes a control gate and a floating gate. For example, transistor 100 includes control gate 100CG and floating gate 100FG, transistor 102 includes control gate 102CG and floating gate 102FG, transistor 104 includes control gate 104CG and floating gate 104FG, and transistor 106 includes control gate 106CG and floating gate 106FG. Control gate 100CG is connected to word line WL3, control gate 102CG is connected to word line WL2, control gate 104CG is connected to word line WL1, and control gate 106CG is connected to word line WL0.
Note that although FIGS. 1 and 2 show four memory cells in the NAND string, the use of four transistors is only provided as an example. A NAND string can have less than four memory cells or more than four memory cells. For example, some NAND strings will include eight memory cells, 16 memory cells, 32 memory cells, or more.
The charge storage elements of current flash EEPROM arrays are most commonly electrically conductive floating gates, typically formed from a doped polysilicon material. Another type of memory cell useful in flash EEPROM systems utilizes a non-conductive dielectric material in place of a conductive floating gate to form a charge storage element capable of storing charge in a non-volatile manner. Such a cell is described in an article by Chan et al., "A True Single-Transistor Oxide-Nitride-Oxide EEPROM Device," IEEE Electron Device Letters, Vol. EDL-8, No. 3, March 1987, pp. 93-95. A triple layer dielectric formed of silicon oxide, silicon nitride and silicon oxide ("ONO") is sandwiched between a conductive control gate and a surface of a semi-conductive substrate above the memory cell channel. The cell is programmed by injecting electrons from the cell channel into the nitride, where they are trapped and stored in a limited region. This stored charge then changes the threshold voltage of a portion of the channel of the cell in a manner that is detectable. The cell is erased by injecting hot holes into the nitride. See also Nozaki et al., "A 1-Mb EEPROM with MONOS Memory Cell for Semiconductor Disk Application," EEE Journal of Solid-State Circuits, Vol. 26, No. 4, April 1991, pp. 497-501, which describes a similar cell in a split-gate configuration where a doped polysilicon gate extends over a portion of the memory cell channel to form a separate select transistor.

NAND string containing self-aligned control gate sidewall cladding


Apparatus for the continuous heating and melting of a solid mixed waste bearing radioactive and hazardous materials to form separate metallic, slag and gaseous phases for producing compact forms of the waste material to facilitate disposal includes a copper split water-cooled (cold) crucible as a reaction vessel for receiving the waste material. The waste material is heated by means of the combination oaf plasma torch directed into the open upper portion of the cold crucible and an electromagnetic flux produced by induction coils disposed about the crucible which is transparent to electromagnetic fields. A metallic phase of the waste material is formed in a lower portion of the crucible and is removed in the form of a compact ingot suitable for recycling and further processing. A glass-like, non-metallic slag phase containing radioactive elements is also formed in the crucible and flows out of the open upper portion of the crucible into a slag ingot mold for disposal. The decomposition products of the organic and toxic materials are incinerated and converted to environmentally safe gases in the melter.

The processing and disposal of radioactive and hazardous waste materials is one of the most pressing environmental remediation problems. In most cases, such waste materials have a wide range of compositions that include metals, ceramics, and organic materials. It is generally desirable that prior to disposal, such waste materials are reduced to a compact form. Compaction of the waste materials is typically achieved by melting the waste and cooling the molten mass to crystallized or vitreous (slag) materials.
One approach to the melting and reducing of waste materials is disclosed in U.S. Pat. Nos. 4,770,109 issued Sep. 13, 1988, and 5,136,137 issued Aug. 4, 1992. This approach employs a rotating drum adapted to receive a hot plasma from a plasma torch for melting the mixed waste and discharging the molten mass into an ingot mold. The thus produced and cooled waste products are poured into containers together with the ingot molds for final disposal. Emitted toxic gases given off by the thermal decomposition of organic and hazardous materials are partially incinerated in the reactor vessel, with the remainder further incinerated in a secondary burner and, after transiting an off-gas system, released into the environment. The rotating drum is comprised of a ceramic material which offers only limited heat resistance and corrosion resistance to metals or to the slag molten mass generated during reduction of the waste materials. As a result, the rotating drum must be periodically replaced, which procedure is complicated by the high level of radioactive contamination of the drum. Also in the rotating drum approach, the radioactive materials are spread out throughout the entire volume of the thus produced solid waste product, limiting the compaction of the radioactive waste and requiring the entire product to be handled and disposed of as radioactive waste, substantially increasing the complexity and cost of such disposal.
Currently, the most promising radioactive waste form for handling and disposal involves the incorporation of the radioactive waste into a glasslike matrix of a special composition which is not subject to destruction during long-term storage. It would therefore be highly desirable to be able to separate the radioactive waste material from the nonradioactive waste and to incorporate the radioactive waste into a glasslike matrix having a very durable and stable composition and structure for long-term storage. Prior art approaches do not provide for the separation of radioactive materials from the remaining hazardous waste materials, and do not account for the generation and discharge into the atmosphere of hazardous gases generated during the waste melting process. Thus, toxic gases given off during the high temperature decomposition of organic and toxic materials are discharged from the reactor vessel into the atmosphere.
The present invention addresses the aforementioned limitations of the prior art by providing apparatus and a method for the processing of solid mixed waste which allows for the discharge of a radioactive slag molten mass directly into a waste tank intended for final disposal, while a non-radioactive molten metal mass is crystallized into a compact ingot which could be recycled into radioactive waste storage containers. The present invention allows for the continuous processing of solid mixed waste material over an extended period of time without requiring the replacement of, maintenance to, or cleaning of the reaction vessel. The high temperatures achieved in the reaction vessel convert the toxic gases given off from the decomposition of organic and toxic materials to environmentally safe gases which can be discharged to the atmosphere.

Apparatus for the processing of solid mixed waste containing radioactive and hazardous materials

Institute of Chemical Technology (PlasTech)


A biscarbazole derivative represented by formula (1):

Organic electroluminescence (EL) devices utilizing organic substances are much expected to be useful as inexpensive, large-sized full color display devices of solid state emission type and many developments have been made thereon. An organic EL device is generally constructed from a light emitting layer and a pair of opposite electrodes sandwiching the light emitting layer. When an electric field is applied between the electrodes, electrons are injected from a cathode and holes are injected from an anode. The injected electrons recombine with the injected holes in the light emitting layer to form excited states. When the excited states return to the ground state, the energy is released as light.
A phosphorescent organic EL device wherein a phosphorescent organic material is used in the light emitting layer has been proposed. Utilizing the singlet excited state and the triplet excited state of the phosphorescent organic material, a high emission efficiency can be obtained by the phosphorescent organic EL device. When electrons and holes are recombined in an organic EL device, singlet excitons and triplet excitons may generate in a ratio of 1:3 in accordance with their difference in the spin multiplicity. Therefore, an organic EL device employing the phosphorescent emitting material would achieve an emission efficiency three to four times higher than that of an organic EL device employing only the fluorescent emitting material.
The early organic EL device requires a high driving voltage and is insufficient in the emission efficiency and durability. To eliminate these problems, various technical improvements have been made.
The improved emission efficiency and the prolonged lifetime are very important for reducing the power consumption of displays and improving the durability. Therefore, further improvements have been still required. In addition, many studies have been made in order to improve the emission efficiency and the device lifetime of organic EL devices employing a phosphorescent emitting material.
To solve the above problems, Patent Document 1 discloses a derivative having a 3,3′-biscarbazole skeleton as the phosphorescent host material. Patent Document 2 discloses a derivative having a 6,6′-bis(9-carbazolyl)-N,N′-disubstituted-3,3′-biscarbazole skeleton as the hole transporting material. Patent Document 3 discloses a compound having a carbazole, dibenzofuran, or dibenzothiophene skeleton as the phosphorescent host material, for example, 6,6′-bis(9-carbazolyl)-N,N′-diphenyl-3,3′-biscarbazole (Compound 32).
Patent Document 1 describes the use of the 3,3′-biscarbazole derivative in the phosphorescent light emitting layer, but describes nothing about the use in the hole transporting layer.
Patent Document 2 describes the use of the derivative having a 6,6′-bis(9-carbazolyl)-N,N′-disubstituted-3,3′-biscarbazole skeleton as the hole transporting material and a high heat stability of the derivative. However, since the derivative having such a skeleton has a large ionization potential, the driving voltage unfavorably increases if the derivative is used in the hole transporting layer adjacent to the light emitting layer.
Patent Document 3 merely describes the derivative having a carbazole, dibenzofuran, or dibenzothiophene skeleton as the phosphorescent host material, and suggests nothing about its function as the hole transporting material.
Patent Document 4 describes a compound having a biscarbazole skeleton wherein two carbazole structures are directly bonded to each other by a carbon-carbon bond (formulae (1a) and (1b)). A (hetero)arylamino group is bonded to the nitrogen atom of one carbazole skeleton through a 4,4′-biphenyldiyl group or a 9,9-dimethylfluorene-2,7-diyl group. Only in the compound 76, two aryl groups of the amino group are bonded to each other via a single bond.
Patent Document 5 describes a compound having a biscarbazole skeleton wherein two carbazole structures are directly bonded to each other by a carbon-to-carbon bond and a carbazolyl group is bonded to the nitrogen atom of the carbazole structure. The carbazolyl group bonded to the nitrogen atom must have a heterocyclic group selected from a dibenzofuranyl group, a dibenzothiophenyl group, and a carbazolyl group.

Bis-carbazole derivative and organic electroluminescent element using same

Abstract: wherein A1, A2, L1, L2, R1 to R4, and a to d are as defined in the specification, is useful as a material for forming organic EL devices and the organic EL devices including the derivative is capable of driving at a low voltage and has a long lifetime.


A process is disclosed wherein whole blood or a blood fraction, such as platelets or leukocytes are stored within a modulated electrical field, such as a capacitive field, to extend the shelf life of the blood or fraction.

Blood is the medium which carries everything needed by ever every cell in the body. The shelf life of most blood fractions is measured within a span of only a few days. Therefore, it is highly desirable to find methods by which the shelf life and quality of whole blood and of blood fractions especially of platelets, leukocytes and red cells can be extended.
As used herein, reference to "quality" of whole blood or blood fractions treated in accordance with the present invention means that at the limits of the normal shelf life of like but untreated blood or fraction, the treated blood or fraction better retains the inherent components of the individual cells for a layer time to support normal and necessary physiological functions.
The various component fractions of the blood tissue are of cellular and fluid (plasma) types. Plasma comprises about 60% by vol. of whole blood and the cells comprise about 40% vol. The cellular components include erythrocytes (red blood cells), platelets, and leukocytes (white blood cells). Leukocytes comprise granulocytes (about 55% vol.), lymphocytes (about 40% vol.) and monocytes (about 5% vol.). Granulocytes have the shortest shelf life. The shelf life of lymphocytes and monocytes is somewhat better. The fluid components of blood include those carbohydrates, lipids, salt, minerals, and proteins which contain albumins, globulins, antibodies, and enzymes. The differing fractions can be used for various purposes and, therefore, the same unit of whole blood can yield components which can each find separate applications.
Whole blood is most often fractionated, because its fractions have different shelf lives and one or more fractions in whole blood which lose their viability may contaminate the rest. Furthermore, red cells will retain their shelf life for relatively long periods in the frozen state. Other blood fractions cannot tolerate freezing. The improvement of shelf life is most important for platelets and to a lesser extent for leukocytes. Platelets are in great demand, and extending their shelf life is of great importance. The platelet fraction, or platelets are given to patients in hemorrhagic disorders. Their principal function is to patch small defects in the endothelial lining of blood vessels and to limit hemorrhage by promoting local coagulation of the blood. Currently platelets have an in vitro shelf life of about five days.
Lymphocytes are comprised of two major subclasses, T-lymphocytes and B-lymphocytes. Their primary function is to regulate the immune system to produce antibodies. The antibodies can be effective against bacteria, viruses, or particulate matter. AIDS and AIDS related syndromes are a direct result of improper functioning of T & B cell systems. Therefore, any product which has a positive effect on regulating their shelf life to preserve them for longer periods of usefulness will have a beneficial effect also upon combating AIDS.
White blood cells, particularly T-cells are also used in the biotechnology industry to produce monoclonal antibodies. Such antibodies have an ever increasing application in therapy and have achieved some advances as diagnostic agents, such as in viral or bacterial diagnostic kits and to enhance the development and yield of the antiviral agents.
Platelets generally become unstable after about five days, and even during this period they have to be agitated or gently rotated to keep them from clumping. The number of blood donors has been declining primarily due to the AIDS scare and there appears to be a constant shortage in the available amount of platelets. For example, between 1984 and 1985 the total number of plateletpheresis procedures increased by over 24%. During the same period the total number of blood transfers increased only by merely 3%. This indicates that platelet requirements are significantly increased over the total number of transfusions and this suggests an increase in the proportion of clinical usage of platelets. An increase in shelf life of about two days of the platelets would increase the supply by about 40%. Such an extended supply would mean that the increased present need for platelets would be achieved by fewer blood donors. Hence, the most important need is for the extension of the shelf life of the platelets.

Process for improving the shelf life of whole blood


The present invention provides a fixing apparatus having a cleaning member for removing offset toner without damaging a roller surface, to thereby permit formation of a good image having no contamination and stripes for a long time. The cleaning member includes a base material, Al.sub.2 O.sub.3 particles and polyester resin, and the Al.sub.2 O.sub.3 particles are dispersed in the polyester resin and the base material is coated by the polyester resin dispersing therein the Al.sub.2 O.sub.3 particles. The polyester resin dispersing therein the Al.sub.2 O.sub.3 particles and coating the base material is contacted with the roller surface to thereby remove offset toner from the roller surface.

1. Field of the Invention
The present invention relates to a fixing apparatus used in an image forming apparatus such as an electrophotographic copying machine, and more particularly, it relates to a fixing apparatus having an improved cleaning member for cleaning a fixing rotary member of the fixing apparatus.
2. Related Background Art
In image forming apparatuses such as electrophotographic copying machines, as a last finishing step of an image forming process, a non-fixed image transferred to a recording material (for example, a paper sheet or an OHP sheet) is permanently fixed to the recording material. To this end, a fixing apparatus of a heat roll fixing type is generally used.
As shown in FIG. 7, a conventional fixing apparatus of a heat roll fixing type comprises a fixing device 10 of a heat roll fixing type and a cleaning device 20. The fixing device 10 includes a fixing roller 1 formed of a silicone rubber layer 3 having a predetermined thickness coated on an aluminium core cylinder 2, a pressure roller 4 constituted by a silicone rubber layer 6 having a predetermined thickness coated on an aluminium core cylinder 5 and a resin coating layer 6a disposed on the silicone rubber layers and heat sources 7 disposed within the fixing roller 1 and the pressure roller 4. A surface temperature of the fixing roller 1 is maintained at about 170.degree. C. by heat from its heat source 7 and transmission of heat from the pressure roller 4.
According to the fixing apparatus having the above-mentioned construction, when a recording material 13 to which a non-fixed toner image 12 was transferred is sent to the fixing apparatus by a convey means (not shown), while the recording material is being passed through a nip between the fixing roller 1 and pressure roller 4 of the fixing device 10, the non-fixed toner image 12 is thermally fixed onto the recording material 13 by the fixing roller 1. In this case, a small amount of toner forming the non-fixed toner image on the recording material 13 is transferred (offset) to the surface of the fixing roller 1. When the toner is offset to the fixing roller 1, since there is a danger of smudging an electrophotographic image (i.e., worsening image quality) due to the offset toner, the surface of the fixing roller 1 is cleaned by the cleaning device 20.
Although various kinds of cleaning devices can be used as the cleaning device 20 shown in FIG. 7, a cleaning device in which a web 15 formed from fibers is contacted with the surface of the fixing roller 1 and the cleaning of the fixing roller 1 is effected by shifting the web 15 while contacting with the fixing roller is known (for example, refer to Japanese Patent Laid-Open Application No. 50-57237). Explaining in more detail, the cleaning device 20 comprises a web supply shaft 21, a web take-up shaft 22 and a hold-dowry roller 23. The web 15 is supplied from the supply shaft 21 and is wound around the take-up shaft 22; meanwhile, the web 15 is urged against the surface of the fixing roller 1 by the hold-down roller 23, thereby cleaning the fixing roller. An urging force of the hold-down roller 23 for urging the web 15 against the fixing roller 1 is adjusted by a pressurizing means such as a spring 24. The web 15 is shifted in a direction shown by the arrow C and is wound around the take-up shaft 22 by means of a driving device (not shown) for driving the take-up shaft 22. Incidentally, in FIG. 7, the reference numeral 16 denotes a mold releasing agent coating device for coating mold releasing agent such as silicone oil on the surface of the fixing roller 1 by means of a coating member 18
In the above web 15 formed from the fibers, since the toner scraped from the surface of the fixing roller 1 is absorbed between the fibers, the toner can be removed from the fixing roller efficiently, thereby providing high cleaning ability. However, since the fiber cloth of the web 15 is formed from Nomex (tradename: manufactured by Du Pont) there are the following disadvantages.
Nomex is obtained by weaving aramid fibers made of aromatic polyamide with polyester fibers and binding the aramid fibers and the polyester fibers to each other by heat. In the cleaning operation, due to the heat from the fixing roller 1 contacting with the web 15, the aramid fibers are softened to lose rigidity. Consequently, toner scraping ability (obtained by "fiber rigidity") of the aramid fibers is worsened, so that the toner offset on the fixing roller 1 passes through the softened aramid fibers in the web 15 not to clean the fixing roller 1 adequately.
Of course, even when the rigidity of the aramid fibers in the web 15 is lost to worsen the scraping ability, if an amount of the offset toner is small, the toner can be cleaned from the fixing roller 1 by the web 15. However, as the amount of offset toner is increased due to degradation of the fixing roller 1, the influence of the reduction of the scraping ability of the aramid fibers becomes noticeable, so that the toner cannot be removed from the fixing roller 1 adequately by the web 15, to thereby cause poor cleaning. Consequently, as the fixing roller 1 is further rotated, the offset toner still remaining on the fixing roller 1 is contacted with and transferred to the pressure roller 4 and/or the succeeding recording material, to thereby smudge the pressure roller and/or the recording material.
To avoid this, in the conventional techniques, PPS fibers which are not softened by heat were used as shown in Japanese Patent Laid-Open Application No. 3-183284, or, a web was metal-plated to increase rigidity of the web itself as shown in Japanese Patent Laid-Open Application No. 2-83691. These proposals increase the toner scraping ability. However, fundamentally, the fixing roller is constructed mainly in consideration of its mold releasing ability. Thus, since the surface of the fixing roller is constructed by relatively soft silicone rubber and the like, when the web having great rigidity is slidingly contacted with the fixing roller, the roller surface is damaged. That is to say, due to unevenness In fibers of the web itself and/or the plated metal foils on the web, a large number of scratches are formed on the surface of the fixing roller along its circumferential direction, which cause deterioration of image quality and shorten the service life of the fixing roller.


A data processing apparatus transmits and receives moving image data to and from an external device through a transmission path. A first pipe used for transferring the moving image data and a second pipe used for transferring timing information relating to the processing timing of the moving image data are provided on the transmission path. The moving image data is being transferred to the external device through the first pipe in parallel with the timing information relating to the moving image data being transferred through to the external device through the second pipe.

1. Field of the Invention
The present invention relates to a data processing apparatus and, more particularly, to an apparatus that transmits and receives data to and from an external device.
2. Description of the Related Art
A data communication system used in data transmission and reception between different media in accordance with sampling rates based on different system clocks is disclosed in, for example, Japanese Patent Laid-Open No. 2003-179662. In this data communication system, the difference between the clock of a master and the clock of a slave is calculated based on the received packet timestamp, and a transfer-rate change message having the calculated value as the data for changing the transfer rate is generated and the generated message is transmitted to the slave. The slave absorbs the difference in clock between the master and the slave by changing the transfer rate in accordance with the transfer-rate change message in order to avoid buffer over-run and buffer under-run.
However, known transfer interfaces in which the slave responds to a transfer request from the master, as in a universal serial bus (USB) interface, and in which the packet size cannot be arbitrarily reset for every packet cannot completely avoid the buffer over-run and under-run.

Data processing apparatus that transmits and receives moving image data to and from an external device through a transmission path


An occupant propelled device having at least one hydraulic cylinder, a platform and a housing. The at least one hydraulic cylinder has at least two chambers in fluid communication. The platform is attachable to the at least one hydraulic cylinder, such that upon movement of the platform a hydraulic fluid is displaced from one chamber to the other chamber. The housing is attachable to the platform at a pivot point and has at least one axle adapted to receive at least one wheel.

Skateboarding is a popular sport and for some is even a means of transportation. One typical problem a skateboarder encounters is the need to propel the skateboard forward for example, when the slope of the terrain is too shallow and does not allow gravity to pull the skateboard and rider down the slope. Typically, the skateboarder will place one foot on the skateboard and utilize the other foot to push or propel the skateboard forward. This pushing motion, however, can become tiresome and may detract from the more pleasurable experience of riding the board with both feet on it.
In addition, skateboards often do not provide a sensation for the rider that is similar to the gains and losses in speed encountered when turning, curving, and straightening ones path when snowboarding downhill or surfing ocean waves due to the requirement to periodically remove one foot from the board to propel the skateboard. Many geographic areas do not have the terrain required to allow gravity to do some or all the work of propelling the skateboard.
Furthermore, many skateboards suffer from distracting wobbles and vibration at higher rates of speed. Thus, the use of the hydraulic system will tend to dampen the vibrations and provide for a much more stable and controlled feeling for the occupant.
Although, there have been innovations in the self-powered skateboard, none of the innovations have utilized a hydraulic system and method of converting linear motion into rotational motion to propel the skateboard forward.
Accordingly, what is needed is a system and method utilizing a hydraulic system to convert linear motion into rotational motion to propel a skateboard forward and provide a sensation similar to snowboarding or surfing without having to put one foot on the ground to propel the skateboard and without the need for gravity or inclined surfaces.

Occupant-propelled fluid powered rotary device, truck, wheeled platform, or vehicle


A method of automatically starting and stopping an engine of a truck to conserve fuel while maintaining the engine in a ready-to-start condition, and while controlling the temperature of a truck sleeper unit. The method includes the steps of selecting predetermined system parameters via a password accessible interactive program, providing a first switch for selecting an automatic engine start-stop operating mode, providing a second switch for selecting an automatic temperature control mode for the truck sleeper unit, and providing safety apparatus which indicates when the truck engine may be safely operated in the automatic engine start-stop operating mode. The method further includes the step of overriding the ignition switch control of the engine in response to a predetermined condition when the first switch selects the automatic operating mode and the safety apparatus indicates the truck engine may be safely operated in the automatic operating mode. The engine is started and stopped automatically while the ignition switch control of the engine is being overridden by the overriding step, to maintain the engine in a ready-to-start condition, regardless of the selection of the second switch, and additionally controlling the temperature of the sleeper unit, when the second switching means selects automatic temperature control. The overriding step is terminated in response to a predetermined condition, restoring ignition switch control of the engine, and preventing automatic re-starting of the engine while the ignition switch is in control of the engine.

U.S. Pat. No. 5,072,703 teaches apparatus for automatically starting and stopping a truck engine to conserve fuel while providing temperature control of a truck sleeper unit, and maintaining the engine in a ready-to-start condition. The apparatus of this patent works well in carrying out the required functions, but requires the expense of tailoring each such apparatus for the specific truck it is to be used with, and for accommodating the different needs and desires of different truck owners. For example, some truck engines are electronically controlled fuel injected engines, and some are not; and different truck engines have different numbers of teeth in the ring gear used for engine speed (RPM) detection, requiring each apparatus to be calibrated for the number of teeth in the ring gear of the truck it is to be used with. Some truck owners have different desires related to how an automatic engine control should operate relative to the position of the ignition switch, requiring the apparatus to be built in different models for different owners to accommodate the different options which are available. Some drivers do not like the engine starting and stopping during the sleeper unit temperature control mode, and will try to "fool" an engine start-stop system into operating all of the time, which thus defeats the fuel saving purpose of the apparatus. Further, the apparatus cannot detect and interpret different operating conditions and adapt to certain changing conditions in a way to more effectively carry out the purposes and functions of the apparatus.
Thus, it is an object of the present invention to provide new and improved methods for operating a truck engine in an automatic start-stop mode, when it is safe to do so, to conserve fuel while maintaining the truck engine in a ready-to-start condition, and while controlling the temperature of a truck sleeper unit when such temperature control is desired. The new methods should improve the flexibility of apparatus constructed according to the methods, accommodating different truck engine designs as well as different control options which may be desired by truck owners. The new methods should further sense when the system is being "fooled" into continuous operation, and should take appropriate action to maintain the desired start-stop fuel saving operation. Finally, the new methods and apparatus should sense when different operating conditions make the parameters being used inefficient, and should further be able to change or modify the parameters, at least until the operating conditions change back to where the parameters being used are effective.

Method of monitoring a truck engine and for controlling the temperature of a truck sleeper unit


A leveling system (10 and 50) with adjustable light beams (38, 53, 55, 59 and 61) is provided for photolithography processes used in manufacturing integrated circuits. The beams (38, 53, 55, 59 and 61) used to assist with positioning wafer (12) relative to the projection camera lens (90) of the step and repeat camera (92) are adjusted for the exposure field (22 and 70) and the desired chip size. For large beam systems (10), the beam width is modified to match the exposure field (22) dimensions which correspond to the desired chip dimensions. For multiple beam systems (50), the geometric relationship of the beams (53, 55, 57, 59 and 61) relative to each other and the desired exposure field (70) are adjusted to provide optimum leveling of the wafer (12) with respect to the projection camera lens (90).

Various techniques have previously been used to manufacture integrated circuits on semiconductor wafers. Optical projection lithography using ultra-violet light is one of the more common techniques. Projection lithography techniques use a mask which is several times larger than the integrated circuit which the process will create. The pattern or circuit is projected from some distance onto a photoresist on a semiconductor wafer.
A step-and-repeat camera system (sometimes referred to as a "stepper") operates by projecting an image containing a portion of an integrated circuit onto one or more chips in a reticle or exposure field on a semiconductor wafer. The stepper then moves to the next exposure site on the wafer and repeats the process. As the line width for integrated circuits on semiconductor devices becomes smaller and smaller, step-and-repeat camera systems with higher aperture numbers or larger lens are used to improve the performance of the lithography process.
As higher number aperture lenses are used to project the integrated circuit onto the wafer, improved resolution is required to meet shrinking line width needs. Increasing the numerical aperture to improve resolution has a negative effect by reducing the depth of focus of the system. At the same time, integrated circuits on semiconductor devices are becoming more complex requiring several more process steps (more topography), which increases the difficulty of maintaining focus across the entire exposure field on a wafer. These requirements increase the demand on the lithography process for greater depth of focus to improve production. Several techniques are being applied to improve depth of focus, such as planarization, the use of smaller wave lengths of light for exposure, and chip leveling on the exposure tools.
A common practice used to compensate for wafer taper and bow, is tilting the wafer before each exposure to match the wafer plane in the exposure field to the step and repeat camera lens plane. This tilting is accomplished by measuring where the surface of the wafer is located, and then tilting the wafer to obtain an optimized plane to lens alignment. Current state-of-the-art steppers often have an alignment system with a fixed beam size which covers a large portion of the exposure field. The beam is reflected from the selected exposure field onto a four-quadrant detector to determine optimum tilting of the wafer. An alternative alignment system used by other steppers is to project multiple (5 to 20) small focus beams which locate at specific distances from each other on the exposure fields. For example, the four corners and the center of a chip might be a typical multiple beam pattern. Based on information from the beam detectors, the wafer is tilted and then exposed.
While prior leveling systems have worked satisfactorily in the past, the patterns for complex integrated circuits are becoming smaller. At the same time, there is increased variation in the size of semiconductor devices which are placed on a wafer. This results in the leveling beam sometimes being larger than the actual exposure field or the multiple beam system projecting onto chips outside the desired exposure field. When a fixed size leveling beam collects data from areas larger than the exposure field, inclination errors may occur between the plane of the exposure field and the plane of the stepper camera lens. This problem is most pronounced around the edge of a wafer. Steppers with multiple leveling beams distributed over the exposure field will have leveling errors if one or more beams fall outside the desired exposure field.
A need has thus arisen for improved leveling of the wafer and the exposure field on the wafer prior to initiating the lithography process.

System and method for leveling semiconductor wafers


A method of installing an asymmetric heat pipe in a heat sink includes providing an asymmetric heat pipe with additional material on one side; forming a cavity in a base of the heat sink leaving additional base material on the component side of the heat sink; inserting the asymmetric heat pipe in the cavity; and removing the additional material on the asymmetric heat pipe and the additional base material on the heat sink to form a smooth and substantially uniform contact surface on the component side. An apparatus includes a component; a heat sink with a cavity; and a flattened heat pipe inserted into the cavity; wherein the heat sink and the heat pipe have a smooth and substantially uniform surface on the side proximal to the component and the heat pipe has a thickness which is substantially the same size on a component side and an opposite side.

Heat sinks are used to cool high power components in many different electronic assemblies, e.g., computers, networking equipment, optical modems, lasers, transceivers, switch circuitry, etc. Heat sinks rely on a flat contact surface with the component to ensure good thermal contact and efficient heat transmission. To improve heat sink performance, one or more heat pipes (with a higher thermal conductivity than solid materials) may be added to the system. Heat pipes may be used to improve the conduction of heat within the base of a single heat sink or to bring the heat out to a secondary device where it is dissipated. A heat pipe is a heat-transfer device that combines the principles of both thermal conductivity and phase transition to effectively transfer heat between two solid interfaces. At the hot interface of a heat pipe, a liquid in contact with a thermally conductive solid surface turns into a vapor by absorbing heat from that surface. The vapor then travels along the heat pipe to the cold interface and condenses back into a liquid—releasing the latent heat. The liquid then returns to the hot interface through either capillary action, centrifugal force, or gravity, and the cycle repeats. Due to the very high heat transfer coefficients for boiling and condensation, heat pipes are highly effective thermal conductors.
Heat pipes began to be used in computer systems in the late 1990s when increased power requirements and subsequent increases in heat emission resulted in greater demands on cooling systems. They are now extensively used in many modern computer systems and networking systems, typically to move heat away from components to heat sinks where thermal energy may be dissipated into the environment.
Heat pipes may be installed from the fin side or the component side of the heat sink. Installation from the fin side typically requires the removal/replacement of fins, adding cost and reducing performance. Installation from the component side eliminates this drawback, but the formed surface of the heat pipe is difficult to align with the machined surface on the heat sink, again reducing performance due to poor thermal contact with the component. It is possible to use a heat pipe with a thicker wall than is normally required. When combined with a base that is also thicker, the subsequent assembly may be machined down, removing any surface irregularities and creating a smooth, high performing contact surface with the component. However, this results in a base that is thicker than may be desirable and/or reduces the internal volume in the heat pipe. In the case where additional height is not available, shorter fins must be used, also reducing performance.

Asymmetric heat pipe coupled to a heat sink


The present invention is an enhanced fresh meat composition and method of making the same. The fresh processed meat composition is made from post-rigor meat and includes a bicarbonate additive.

1. Technical Field
The present invention relates to improved enhanced fresh meat products and methods of making the enhanced fresh processed meat products. More specifically, it relates to processed and injected fresh meat products made from post-rigor meat with the addition of a bicarbonate.
2. Background
Meat is a highly perishable food product that becomes unfit for consumption as a result of microbial growth, chemical change, or breakdown by endogenous enzymes. Enhanced meat products include processed meat products and meat products having an added brine or flavoring. One method for extending the shelf life of enhanced fresh meat products is the addition of chemicals during processing. These chemical additives can slow the microbial growth and chemical changes.
Typically, meat used in enhanced fresh meat products is processed before the onset of rigor mortis Rigor mortis ("rigor") is the stiffening and loss of extensibility of the muscles that occurs in animals soon after death. Processing meat prior to the onset of rigor ("pre-rigor processing") is commonly believed to provide superior color appearance, color stability, and shelf life. The disadvantages associated with pre-rigor processing include the time constraints of processing all meats prior to the onset of rigor, which typically occurs about twenty-four hours post-mortem. As a result of these time constraints, a substantial portion of meat is often unavailable for pre-rigor processing.
There is a need in the art for enhanced meat products made from post-rigor meat and methods of making these enhanced meat products.


An image system dynamically updates drive sequences in an image system. Drive sequences are image display settings or display driving characteristics with which a display is operated. The image system may determine the drive sequence at least partially based on input from one or more sensors. For example, the image system may include sensors such as an inertial measurement unit, a light sensor, a camera, a temperature sensor, or other sensors from which sensor data may be collected. The image system may analyze the sensor data to calculate drive sequence settings or to select a drive sequence from a number of predetermined drive sequences. Displaying image content on a display includes providing the display with image data and includes operating the display with various drive sequences.

Common image display-related characteristics include frame rate of the image data, color durations for pixels in a display, and brightness of the display, among others, which may be controlled via drive circuitry and/or software that drives a display. These display characteristics can be used to control brightness, resolution, depth perception, and other visual effects of a displayed images.
When some existing image rendering technologies are employed to reconfigure display characteristics (e.g., frame rate, brightness of the display, etc.), these existing image rendering technologies involve turning off the display or otherwise interrupting the rendering of content for display to reconfigure or update the display characteristics. Sometimes, these changes may consume an amount of time that is on the order of seconds and often require image rendering to be temporarily terminated. As result, existing techniques for reconfiguring display characteristics in an image system may not enable real-time and/or dynamic reconfiguration of display characteristics, e.g., while image data is being rendered.
Although the following Detailed Description will proceed with reference being made to illustrative embodiments, many alternatives, modifications and variations thereof will be apparent to those skilled in the art.

Systems and methods for driving a display


A method, medical imaging workstation (300) and a hybrid medical imaging scanner (400) are provided for the analysis of images obtained during medical scans. The extent of a first region of interest (ROI-1) in a first scan image (120) is defined. A second region (ROI-2), in a second scan image (130), is identified. The second region (ROI-2) in the second scan image (130) corresponds to the first region of interest (ROI-1) in the first scan image. Each of the spatial locations of the second region (ROI-2) is classified, in order to identify the spatial locations of the second region (ROI-2) that comprise at least one tissue type. The invention may improve the recognition of lesions in medical scan images, and may reduce the incidence of false positives.

A variety of technologies can be used to investigate biological processes and anatomy. The following examples are types of scan that may be used to provide medical images: X-Ray; Computed Tomography (CT); Ultrasound (US); Magnetic Resonance Imaging (MRI); Single Photon Emission Tomography (SPECT); and Positron Emission Tomography (PET). Each type of scan is referred to as an 'imaging modality'.
In medical imaging, typically, digital 3-dimensional images are produced. Medical imaging workstations are commonly used to allow the viewing and manipulation of these images. Medical images are read, analysed and reviewed by specialists, for example radiologists.
Typically, a scan provides a 'dataset'. The dataset comprises digital information about the value of a variable at each of many points. The points are different spatial locations that are spread throughout 3 physical dimensions, i.e. each point is at a particular location on a three dimensional grid. The variable may typically be an intensity measurement. The intensity may be, for example, an indication of the X-Ray attenuation of the tissue at each particular point.
In such a three dimensional dataset, the element of the scan image located at a particular spatial location may be referred to as a 'voxel'. A voxel is therefore analogous to a 'pixel' of a conventional 2-Dimensional image.
Although the dataset of the medical scan is 3-Dimensional, it is typically displayed as a two dimensional image to a user on a medical imaging workstation. The 3-D scan may be divided up into tens or hundreds of parallel, 2-D images. The user of a workstation can then flick through the images in sequence, for example, thereby allowing a view of successive cross sections of the tissue that was scanned.
Typical workstations allow the 2-D slices to be viewed individually or sequentially in successive steps along a selected one of three perpendicular directions. For a human subject lying down, the axes of the three perpendicular directions may, for example, be along the 'long axis' of the body, 'across' the body from one side to the other, and through the body from top to bottom. These axes are conventionally referred to as: 'axial' (for cross-sections that lie along the long axis of the body), coronal (for cross-sections that lie along an axis running from the front to back) and sagittal (cross-sections that lie along an axis that runs from side to side.)
Henceforth, the term 'scan image' should be construed as meaning a three dimensional dataset that results from performing a medical scan. However, when the scan image is displayed, only a two dimensional slice of the dataset may be on view at any one time. Medical images usually have as their subject humans. However, images may also be obtained of non-human animals, particularly as part of medical research projects.
Medical images may include information about a wide variety of anatomical features and structures. For example, an image may show various types of healthy tissue, such as bone and organs within the body. An image may also show abnormal tissues. The term 'lesion' is often used to describe various types of abnormal tissue. One common example of a lesion is a tumour. However, an image may also show other types of lesions, such as cysts or swollen glands. The word 'lesion' should henceforth be construed to include both tumours and other types of abnormal tissues.
The purpose of obtaining a medical image is often to detect abnormal tissue. So, a typical example of an application of medical imaging is in the identification and 'staging' of cancerous tumours. Images may also be required for assessing the efficacy of any administered treatment. Images from scans may however not lead unambiguously to an identification of whether or not a given part of the scan shows abnormal tissue. The identification of the pathology of tissue observed in a scan is still not possible with 100% certainty. As a consequence, for example, patients may subsequently need to be subjected to biopsies, in order to obtain a sample of tissues whose nature is not clear on a scan.
'Multiple modalities' may be used to provide medical images. This approach involves obtaining images of the same region of tissue by more than one modality. For example, the same region of tissue may be imaged using both a PET scan and a CT scan. Another important example of a multiple mode scan is a SPECT/CT scan. Both PET/CT and SPECT/CT scans combine the predominantly anatomical and structural information obtained from a CT scan with a scan which measures the biological function.
Scanners that can carry out multiple mode scans are referred to as 'hybrid scanners'. Typically, a hybrid scanner allows the subject to be scanned by both modalities in the same sitting.
A multimodal scan such as a PET/CT or SPECT/CT scan may provide the following advantages:    1) It provides the reader with both anatomical and structural information, as well as functional information.    2) The CT scan can be used to correct for the attenuation to which the SPECT or PET signal is subjected, as it travels through the body.    3) It allows the reader to localise areas of PET or SPECT signal to particular regions of the body.    4) The patient benefits from fewer examinations.    5) A given scanning machine will provide more information for any given number of patients who are scanned, than a single mode scanner, thereby delivering enhanced 'utilisation' for a hospital.
The precise biological signal measured by a PET or SPECT scan is dependent on the radiotracer used. For PET, the most widespread radiotracer is fluorodeoxyglucose (FDG), which is a sugar. FDG acts as a surrogate for glucose, thereby facilitating the measurement of metabolic activity within a region of tissue.
Malignant tumours are highly metabolically active. They therefore tend to appear as bright areas in a PET image. Such active tissues are often referred to as being 'FDG avid'.
A problem may arise due to the fact that there are many normal physiological processes that are also FDG avid. For example, the brain also consumes large amounts of energy. So the brain appears as a bright region on a PET image. The same applies to the heart, the bladder and parts of the kidneys.
Normally, such well localised anatomical regions can be identified by experienced personnel. This identification usually just requires examination of the PET image alone, and rarely requires examination of the corresponding CT image of any multimodal scan, to allow these regions to be categorically ruled out in any search for abnormal tissue. However, some lesions that are near the edges of FDG avid organs may be less clearly differentiated. In these cases, the normal way to decide the likely cause of a bright region in the PET image is by looking at the CT scan.
Other, more subtle sources of apparently FDG avid regions may be seen in images. Examples include:    (i) The larynx, which may exhibit some FDG activity if the subject spoke after injection of the radiotracer.    (ii) Artificial implants. In a PET/CT multimodal scan, the CT can be used to correct for the photon attenuation observed when the photons travel through different parts of the body. This correction process relies on a correct estimation of the attenuation that a photon undergoes. However, the presence of implants and mis-alignment of the two scans may cause errors in the estimation. The errors lead to 'artefacts' in the PET post attenuation correction.    (iii) Inflammation processes.    (iv) Metabolically active brown-fat.
These sources (i)-(iv) are more problematic than areas such as the brain, and may lead to 'false positive' diagnoses. A 'false positive' is a case where a normal area of tissue is mistakenly classified as abnormal.
In summary, a key problem in the interpretation of medical image scans is the determination of the underlying cause of apparent activity. This problem arises particularly when considering radiotracer activity in a PET or SPECT image.
Three more detailed prior art systems are listed under points 1-3 below. The 'Computer Aided Detection/Diagnosis systems' and 'Basic histogram' approach are essentially techniques for interpreting information obtained in scans. The 'MR spectroscopy' approach is a different type of scan, which provides different data to those described above.
1. Computer Aided Detection/Diagnosis Systems
Many computerised approaches have been proposed to aid the clinician in detecting and diagnosing disease. So-called 'Computer Aided Detection and Diagnosis' systems aim to do this by indicating to the user locations in the image that are likely to correspond to disease. However, such systems are designed to indicate the presence or absence of disease. They operate by examining patterns in the image, and categorising them as 'disease' or 'non-disease'. Such systems have been proposed mostly for single image, single modality applications like X-ray mammography, lung CT and colon CT. Furthermore, such systems do not integrate well into the clinical work-flow, because they tend only to show limited information about the images.
2. Basic Histogram
Medical image workstations may include functionality that enables them to display a histogram of the distribution of intensities within a user defined region of interest in a scan. Such histograms are typically 'binned' according to some uniform bin width, for example every 100 units of intensity. Alternatively, they may be specified to have a certain number of bins. Information may be provided to the user on e.g. the mean of the values in a region of interest, or the maximum.
3. Spectroscopy
MR spectroscopy is a particular type of MR scan, in which the chemical composition of regions of tissue in a patient can be identified in vivo. The method relies on the different nuclear magnetic resonance signal of different chemical compounds. The result is often displayed to the user as a graphical plot, which shows the proportion of different compounds. MR spectroscopy leads directly to an identification of the chemical composition of a region of tissue.

Processing system for medical scan images


Technologies for determining a root of congestion include a network switch. The network switch is to operate arbiter units in at least one upstream stage at a packet transfer rate that is greater than a packet transfer rate of an arbiter unit in an output stage, determine whether an input buffer of a remote network switch in communication with the output stage has sustained congestion over a first predefined time period, determine whether an output buffer of the arbiter unit in the output stage has sustained congestion over a second predefined time period, and determine, as a function of whether the input buffer of the remote network switch has sustained congestion and whether the output buffer of the arbiter unit in the output stage has sustained congestion, whether the network switch is a root of congestion.

To manage congestion in a fabric, some network switches include mechanisms to detect traffic flows that cause sustained incast congestion (e.g., a large influx of packets that build up faster than the network switch can output the packets). A network switch experiencing sustained incast condition is sometimes referred to as "the root of congestion" because the network switch becomes the cause of a decrease in overall throughput in a fabric. Once identified, the network switch may deploy a mechanism to mark all of the packets associated with the incast to notify an endpoint device to reduce the speed at which the packets are sent to the network switch, to prevent continual build-up of packets in the network switch.
Some high-radix switches with multiple levels of arbitration, which are sometimes referred to as "stages," may include a detection mechanism at each stage of the network switch, to detect whether and which input streams of packets to the corresponding stage are experiencing an incast. However, equipping each stage with a detection mechanism adds cost and complexity to the multi-stage network switch. Additionally, in some multi-stage network switches, the stages may have shallow buffers. As such, when a large packet encounters any form of congestion, the packet can fill the shallow buffer relatively quickly, causing the detection mechanism associated with the corresponding stage to have difficulty distinguishing between temporary and sustained congestion.

Technologies for efficiently determining a root of congestion with a multi-stage network switch


The present invention relates to compounds according to Formula I:

Cellular proliferative disorders such as cancer are among the most common causes of death in developed countries. That said, many cellular proliferative disorders have no available cures or few, if any, treatment options to slow the progression of the disease. For cellular proliferative diseases for which treatments exist, undesirable side effects and limited efficacy often call into question the utility of a given treatment. This is particularly true when the available treatment option(s) may not appreciably prolong life, but have a definitive adverse effect on the quality of time remaining. Thus, identifying new effective drugs for cellular proliferative disorders, and in particular cancer, is a continuing focus of medical research.
Pim-1
Pim-1 is a proto-oncogene which encodes for a serine/threonine. Pim-1 over-expression has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies. Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors and is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways (Bachmann and Möröy, Int. J. Biochem. Cell Biol. 37(4):726-30 (2005)). Compounds that inhibit the activity of Pim-1 have potential as anticancer agents.
CK2 and CDK9
Casein Kinase 2 (CK2) is a ubiquitously expressed serine threonine protein kinase, whose activity and expression levels are elevated in a variety of tumor types (St-Denis and Litchfield, Cell. Mol. Life Sci., 66:1817-1829 (2009); Trembley et al., Cell. Mol. Life Sci., 66:1858-1867 (2009)). CK2 is unusual among protein kinases in that it can use both ATP and GTP as phosphate donors (St-Denis and Litchfield, supra). CK2 is also unique in that it is constitutively active and does not appear to require phosphorylation or other post-translational alterations to activate its kinase activity. As a result, the catalytic activity of CK2 is roughly proportional to its cellular concentration (Guerra and Issinger, Curr. Med. Chemistry, 15: 1870-1886 (2008)). CK2 is a tetrameric complexes consisting of two catalytic (α and/or α′) subunits and two regulatory β subunits (Litchfield, Biochem. J. (2003) 369:1-15).
CK2 phosphorylates a large number of substrates, many of which regulate signal transduction pathways that in turn mediate cell growth, cell death, DNA replication and transcription (St-Denis and Litchfield, supra; Trembley et al., supra; Guerra and Issinger, supra). CK2 has also been shown to regulate the activity of tumor suppressors, cell cycle regulatory proteins, apoptotic proteins and oncogenes thus making it a key player in the development and maintenance of cancer progression (Ahmed et al., Cellular and Molecular Life Sciences, 66: 1858-1867 (2009)).
Elevated CK2 activity has been associated with the malignant transformation of several tissues and higher levels of CK2 are found to correlate with aggressive behavior of head and neck cancer and poor prognosis of prostate cancer (Gapany et al., Mol. Med. 1: 659-666 (1995); Laramas et al., Eur. J. Cancer. 43(5):928-34 (2007)). The ability of CK2 to phosphorylate (and activate) PTEN and AKT, two key components of tumor cell survival pathway, suggests an important role of CK2 in suppressing apoptosis in cancer cells (Di Maira et al., Cell Death Differ. 12: 668-677 (2005)). Downregulation of CK2 by various approaches results in induction of apoptosis in cultured cell and xenograft cancer models, further suggesting its potential as a therapeutic target (Guerra and Issinger, supra; Ruzzene and Pinna, Biochim Biophys Acta, 1804(3): 499-504 (2010)).
Normal cells, which express low levels of CK2, do not appear to have such undue reliance on the activity of this kinase and hence are unaffected by reduction in the levels of this kinase activity, suggesting that development of potent and selective CK2 inhibitors may not exhibit undesirable side effects seen with traditional chemotherapeutic agents.
CDK9 is a cyclin-dependent kinase, which forms a complex with and is regulated by two different regulatory cyclins known as cyclin T and cyclin K (Wang and Fischer, Trends Pharmacol. Sci. 29(6):302-13 (2008)). CDK9 accumulates on chromatin and limits the amount of single-stranded DNA in response to replication stress. CDK9/Cyclin K complex was found to play direct role in maintaining genome integrity (Yu and Cortez, Cell Cycle 10:1, 28-32 (2011)).
Depletion of CDK9 or its cyclin K (but not cyclin T) was found to impair cell cycle recovery in response to replication stress, resulting in spontaneous DNA damage in replicating cells (Wang et al., supra; Yu et al., EMBO Rep. 11(11):876-82 (2010)).
CDK9 is over-expressed in several cancers, including leukemias and lymphomas suggesting that inhibitors might be useful in cancers involving high levels of replication stress, or in combination with replication stress-inducing chemotherapies (Wang and Fischer, supra).

Substituted 2-benzylidene-2H-benzo[b][1,4]thiazin-3(4H)-ones, derivatives thereof, and therapeutic uses thereof

Abstract: and salts thereof, wherein R1, R2, R3, R4, Ar, and n are as defined herein. Methods for preparing compounds of Formula I are also provided. The present invention further includes methods of treating cellular proliferative disorders, such as cancer, with the compounds of Formula I.

TEMPLE UNIVERSITY—OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION