The present invention includes long-day onion plants comprising bulbs having low pungency and methods for obtaining such onions. The present invention also provides reagents and materials that can be used in the methods for obtaining such onions.

Onions belong to the lily family, Amaryllidaceae, and the genus, Allium. Alliums comprise a group of perennial herbs having bulbous, onion-scented underground leaves, including such commonly cultivated crops as garlic, chives, and shallots. It also includes ornamental species grown for their flowers.
Onions are an important vegetable world-wide, ranking second among all vegetables in economic importance with an estimated value of $6 billion dollars annually. The onion is also one of the oldest cultivated vegetables in history. The common garden onions are in the species Allium cepa. Onions are classified in numerous ways, by basic use, flavor, color, shape of the bulb, and day length. Onions come in white, yellow, and red colors. The bulb may be rounded, flattened, or torpedo shaped.
Commercial onions include "storage onions", "fresh onions", "pearl or mini onions", and "green onions". "Fresh onions" tend to have a lighter color with a thin skin, a milder, sweeter flavor, and must be eaten fresh as they do not store well. These onions are available in red, yellow, and white colors, and are often sold under the name of their region, e.g., Sweet Imperials, Vidalias, Walla Walla Sweets and Texas Sweets. Perhaps the best known of the fresh onions is the Bermuda onion. Fresh onions are available beginning in March or early April and can be purchased until August.
Storage onions are available from harvest, which is at the beginning of August, and are stored and available throughout the winter months up to about March. Storage onions have a darker skin that is thicker than that of a fresh onion. They are also known for intense, pungent flavor, higher percentage of solids and desirable cooking characteristics. These onions are also available in red, yellow and white colors. Not all long day length type (long day type) onions are suitable for storage. A true storage onion is one that can be harvested in late summer or fall, and stored, under proper conditions, until the spring, when the fresh onion crop is again available.
"Spanish onion", "Spanish onions", or "Spanish type" are terms applied to various long-day onions, generally yellow, though some white, and generally varieties that are large and globe-shaped. Spanish onion is commonly applied to various long day type onions of the type grown in western states of the United States (California, Idaho, Oregon, Washington, Colorado) with a bulb size averaging 300-700 grams (g) (typically over 3 inches up to 4 inches but also up to 5 inches in diameter for bulbs classified as "colossal").
Onion varieties initiate bulbing when both the temperature and a minimum number of daylight hours reach certain levels. When onions are first planted, they initially develop their vegetative growth, with no sign of bulb formation until the proper day length for that onion variety triggers the signal to the plant to stop producing above ground vegetative growth and start forming a bulb. Onions are thus sensitive to the hours of daylight and darkness they receive, and for most varieties it is only when the specific combination of daylight and darkness is reached, that the bulb starts to form. Onions are therefore classified by the degree of day length that will initiate bulb formation. Onions are described as short-, intermediate-, and long-day length types. Short day means that bulbing will initiate at 11 to 12 hours of daylight. Intermediate day is used for onions bulbing at 12 to about 14 hours of daylight. Long day onions require about 14 or more hours of daylight for bulb formation to start.
Growers producing onions in more northerly climates plant long-day length onions. Daylight length varies greatly with latitude, and at higher latitudes long-day onions will produce sufficient top growth before the day length triggers bulbing to produce a large bulb. A short-day onion grown in the North (higher latitudes) will bulb too early and produce relatively small bulbs.
Short day onions are preferred for southern areas such as southern Texas, southern California and Mexico. If a long day type onion is planted in such a short day climate, it may never experience enough day length to trigger the bulbing process.
Onions are also classified on flavor, with the common designations of sweet, mild, and pungent. The flavor of the onion is a result of both the type of onion and the growing conditions. For instance, soils containing a high amount of sulfur result in more pungent flavored onions. Sweetness in onions is caused by the sugars glucose, fructose and sucrose. Onions also contain polymers of fructose called fructans. Onion cultivars differ quite markedly in the relative amounts of sucrose, glucose, fructose and fructans which they contain. They also differ in sugars according to length of storage and location in the bulb. Short day cultivars, which are poor storers, tend to have higher levels of sucrose, fructose and glucose, but hardly any of the fructans. In contrast, long day type cultivars and intermediate storage cultivars such as Pukekohe Longkeeper have less sucrose, glucose and fructose and higher amounts of fructans.
The fructans do not play a role in sweetness. The balance between levels of pungency and levels of sugars determines the perception of pungency in an onion. High levels of pungency can mask high levels of sugars so that the onion is not perceived as sweet. Onions with low levels of pungency but low levels of sugars can be perceived as bland. Ideally a low pungency onion would have high levels of sugars and lower levels of pungency.
It is believed that sunlight strongly influences the development of pungent flavors. While compounds such as sugars and organic acids contribute to the flavor of onions, it is a special class of biologically active organosulfur compounds which give onions their distinctive flavor and aroma. Pungency in onions is caused by these volatile sulfur compounds, some of which affect the eyes when onions are fast cut and induce tearing (often called lachrymatory effect). There are 3 different flavor precursors in onions: 1-propenyl cysteine sulfoxide, which is usually found in the highest concentration; methyl-cysteine sulfoxide, which is normally found in lesser concentration; and propyl cysteine sulfoxide, which is found in the lowest concentration.
Storage conditions may also affect pungency, and though the research is conflicting, most studies show an increase in pungency for most long day type onions during storage. See Shock, C. C., E. B. G. Feibert, and L. D. Saunders. 2004. Pungency of Selected Onion Varieties Before and After Storage. Oregon State University, Malheur Experiment Station Special Report 1055: 45-46.
Within intact cells the enzyme allinase is compartmentalized in the cell vacuole and the flavor precursors are found in the cytoplasm. A reaction, therefore, only occurs when onion tissues are damaged and the enzyme and substrate are brought together as organelles are disrupted. The kinetics of decomposition are different for each specific flavor precursor. The decomposition of 1-propenyl cysteine sulfoxide is almost instantaneous, while the methyl and propyl cysteine sulfoxide decomposition occurs in several minutes. Primary products produced from flavor precursor decomposition include pyruvate, ammonia and chemically unstable sulfenic acids. Among the sulfenic acids is the lachrymator, or tear producing compound, characteristic of onions. The sulfenic acids undergo further rearrangement to form thiosulfinates, which are responsible for the characteristic flavor of onions.
Flavor precursor formation begins with the uptake of sulfate (SO4−2) by the onion, its reduction to sulfide, and subsequent assimilation into cysteine by light-dependent reactions in the leaves of the plant. Glutathione, a tripeptide of cysteine is then synthesized. This the starting point of the flavor precursor biosynthetic pathway. The pathways leading to the synthesis of each flavor precursor are not fully understood, although sulfur is known to be transformed through several identifiable peptide intermediates, each unique to a specific flavor precursor.
Researchers have recently developed a tool for documenting differences among onion flavor using a laboratory analysis of pyruvic acid development (PAD). Pyruvic acid has been shown to correlate well with consumer flavor perception. The PAD measurements are gaining acceptance within the industry as a clearer index of onion mildness, even though pungency is assessed solely by the amount of enzymatic pyruvic acid. For most commercial onions, pyruvic acid levels fall between about 1 and about 18 micromoles per a gram fresh weight. PAD units are given in micromoles pyruvic acid per gram, fresh weight (μM/g FW). Short day onions marketed as low pungency onions will typically have PAD values of 5.5 μM/g FW or less. Onion bulbs having a PAD of 5.5 μM/g FW or less are considered sweet according to Vidalia Labs sweet onion certification specifications (Shock, C. C., E. B. G. Feibert, and L. D. Saunders. 2004. Onion Production from Transplants in the Treasure Valley. Oregon State University, Malheur Experiment Station Special Report 1055: 4752).
Long day onions are generally grown in the northern states, because of their requirement for long days to initiate bulb production. For this reason, long day type storage varieties do extremely well in the northern states of the United States and Canada, regions that have the required 14-16 hours of day-length during the summer. There are no long day type onions that have low pungency. Some of the commonly planted long day type yellow onion cultivars are Daytona, Ranchero, Granero, Sabroso, Tamara, Hamlet, Fortress, Norstar, Teton, and Vaquero.
Short day varieties do not keep well in storage conditions, and the pungency of short day varieties can climb considerably during storage. Present production in North America and Europe allows harvest of short day onions from mild winter regions from November through April. Long day onions are available fresh in the late summer and as storage onions from September through March, or even year round, have not been available in low pungency varieties. Sweet onions must be imported from the southern hemisphere to fill the gap in sweet onion production (November-February). In the United States, regions like Georgia and Texas produce short day onions from March to June, while low pungency onions available from November to February are short day onions, produced in the southern hemisphere.
There is a need in the art for the development of onions having low pungency, particularly, long-day varieties having low pungency. There is also a need for storage onions in which pungency does not substantially increase during storage.


Provided is a fusion protein comprising, at its carboxy terminal of human erythropoietin (EPO), a mutant having one to four amino acid substitutions in the carboxy terminal peptide (CTP) fragment of a human chorionic gonadotropin (HCG) β subunit, for increasing an in vivo half-life activity of EPO. The in vivo half-life can be greatly elongated while retaining the intrinsic activity of the EPO, without increasing the sugar chain content.

1. Field of the Invention
The present invention relates to a fusion protein having an enhanced in vivo activity of an anti-pernicious anemia drug, erythropoietin (hereinafter, it is also referred to as "EPO"). More particularly, the present invention relates to a fusion protein having an enhanced EPO activity by increasing its in vivo half-life with its own amino acid sequences, that is, without increasing the glycosylation content, wherein the fusion protein contains an EPO molecule fused to a particular peptide naturally occurring in vivo.
2. Description of the Related Art
EPO is a glycoprotein having a molecular weight in the range of 30,000 to 34,000 Da, and is a hematopoietic factor promoting production and differentiation of red blood cells. The glycoprotein binds to a receptor of precursor cells of red blood cells to initiate its hematopoietic activity and causes an increase in the amounts of intracellular calcium ions, an enhancement of DNA biosynthesis and stimulation of hemoglobin formation. Also, recombinant human EPO(rhEPO) has been approved for the treatment of anemia associated with kidney failure, prematurity, hypothyroidism, malnutrition and so forth, and clinical use of rhEPO is continuously increasing. However, extensive use of rhEPO could be limited by inconvenience and high costs because rhEPO should be administered about three times a week due to its short half-life. Thus, the frequency of rhEPO administration for treatment could be reduced by maintaining an in vivo activity of EPO for a longer time.
In vivo biological activity of EPO is proportional to its in vivo half-life which has been known to be related with the content of sialic acid located at the terminus of sugar chains in EPO. Thus, the in vivo biological activity of EPO is greatly dependent upon the presence or absence of sugar chains. The types of sugar chains vary depending on cell types. Thus, when the same glycoprotein is expressed in different cells, the types of sugar chains of the protein are characteristically different depending on the cell types. It is known that bacterial cells, for example, E. coli could not attach sugar chains to its proteins. Since it is known that proteins expressed in E. coli do not have any sugar chains, EPO expressed in E. coli does not contain sugar chains. In this case, EPO is confirmed to be biologically active in vitro but not active at all in vivo. This is because EPO without sugar chains is more rapidly removed from the body, compared to EPO with sugar chains, resulting in an extremely short half-life. Consequently, the presence or absence of sugar chains in EPO plays an important role in the biological activity of EPO.
To date, a lot of researches have been vigorously carried out to increase the biological activity of EPO. Most of these researches focus on substitution of some amino acids by inducing mutation of EPO genes using mutagenesis techniques. For example, PCT/US94/09257 entitled "Erythropoietin Analogs", filed by Amgen Inc., disclosed a method of increasing an in vivo half-life by increasing the sugar chain content in EPO through mutagenesis. Increasing an in vivo half-life through EPO dimer formation has been also attempted (A. J. Sytkowski et al., J.B.C. vol. 274, No. 35, pp 24773–24778). Other methods for increasing the in vivo biological activity of EPO include fusing a novel amino acid, peptide or protein fragment to EPO molecules using genetic engineering, and to increase the sugar chain content in EPO, specifically the amounts of sialic acids. However, the kinds of amino acids, peptides or protein fragments used in this method are very limited. In most cases, such genetic modifications may result in a decrease or loss in specific activity of protein or cause antigenicity problems frequently occurring when those substances are used in vivo.
Researches into fusion proteins or chimeric proteins, rather than EPO, have been carried out, and one of the examples thereof is a follicle stimulating hormone, which is a sex hormone (Furuhashi et al., 1995, Mol. Endocrinol). However, such proteins have not yet been applied in the field because genetically modified proteins using genetic engineering pose several problems. It is not easy to obtain a modified target protein itself, requiring highly professional skills. Also, in most cases, the activities of proteins may be undesirably decreased or removed by addition of or substitution by new amino acids.
Under the circumstances, the present inventors began extensive studies into the development of a new method of increasing the in vivo activity of EPO by fusing new amino acids, peptides or proteins to EPO molecules. In the course of carrying out these studies, it was found that a fusion protein obtained by fusing carboxy terminal peptide (hereinafter, it is also referred to as "CTP") fragments of the β subunit of a human chorionic gonadotropin (hereinafter, it is also referred to as "HCG") which is a protein naturally occurring in vivo, to EPO, dramatically increases the in vivo half-life of the EPO. Also, the EPO contains amino acids having the function of increasing glycosylation sites while retaining the intrinsic activity of the EPO (see Korean Patent Application No. 10-2000-0075230).

Fusion protein having enhanced in vivo erythropoietin activity


Determining a touch contact object type is disclosed. A signal detected due to a touch input object contacting a touch input surface is received. At least a portion of the received signal is compared with one or more signatures of one or more touch input object types. A type of the touch input object contacting the surface is determined based at least in part on the comparison.

Popularity of devices such as tablet computers and smartphones has spawned an ecosystem of software applications utilizing touch input detection. The ability to reliably and efficiently detect touch input location on a display surface has enabled applications to take advantage of new user interface interaction patterns to offer enhanced application usability across a wide range of inexpensive devices. Further enhanced usability may be enabled if it is possible to detect a type of object that is providing the touch input. For example, the ability to distinguish between a human finger and a stylus contacting a touchscreen may be utilized by an application to provide different functionality based on the type of object used to provide the touch input. It has been difficult for prior touch input devices to reliably and inexpensively detect a type of object contacting the touch input surface of a device. Therefore, there exists a need for a way to more efficiently detect a type of object used to provide a touch input.

Detection of type of object used to provide a touch contact input


A method of maintaining a data store is disclosed. The data store is distributed across a plurality of storage provider instances, including a master storage provider instance and a plurality of additional storage provider instances. A master data log is updated to reflect a change to the data store. The master data log is synchronized with a plurality of replicas of the master data log. The change is propagated across the plurality of additional storage provider instances based on an analysis of the replicas.

For consumer-facing websites, having a scalable system to handle increasing user traffic is often important. Traditionally, data is stored persistently in a relational database system (RDMS) and cached in a multi-tier or multi-layer software system for fast serving. Scaling the multi-tier software system is frequently a challenging and expensive proposition. For example, traditional systems may partition data over a set of nodes, allowing scalability to be achieved by adding nodes. Examples of such traditional systems include Amazon Dynamo and Platform for Nimble Universal Table Storage (PNUTS) of Yahoo!'s Sherpa data services platformi. Although distributing data over multiple nodes may simplify the data layer, this solution places additional responsibility on the application layer. Additionally, some traditional solutions sacrifice one or more properties that guarantee database transactions are processed reliably (e.g., atomicity, consistency, isolation, or durability) in favor of scalability. Furthermore, some traditional solutions depend on distributing the data across nodes that are homogenous, particularly in terms of the underlying storage technologies used by the nodes.


The present invention provides a method of achieving the time-specific delivery of a pharmaceutically active agent to a patient in need of the therapeutic effects of the pharmaceutically active agent. The method includes administering a pharmaceutical formulation comprising (a) a core including the pharmaceutically active agent to be delivered, and (b) a swellable polymeric coating layer substantially surrounding the core. The swellable polymeric coating layer delays the release of the pharmaceutically active agent from the core for a predetermined period of time dependent upon the thickness of the swellable polymeric coating layer. The swellable polymeric coating layer surrounding the core is provided by a new method which includes alternately (i) wetting the core with a binder solution, and (ii) coating the core with powdered polymeric particles a sufficient number of times to produce a time-specific dosage formulation having the desired thickness of swellable polymeric coating layer.

Pharmaceutical formulations for oral administration have employed various coatings for the purpose of preserving the integrity of the formulation while passing through the gastric tract. The high acidity, and presence of proteolytic and other enzymes generates a highly digestive environment which readily disintegrates pharmaceutical formulations which do not possess some type of gastro-resistance protection.
In recent years, a need has arisen for formulations which are capable of passing over the entire tract of the small intestine, including the duodenum, jejunum, and ileum, so that the active ingredients are released directly in the colon. For example, European Patent Application No. 366 621 provides a formulation for delivery in the colon which includes a core containing the active ingredient and three protective layers having differing solubilities around the core. As another example, our European Application No. 572 942, the disclosure of which is hereby incorporated by reference in its entirety, provides an oral pharmaceutical composition including a core containing the active ingredient, an intermediate coating layer which delays the release of the active ingredient contained in the core for a programmed time period, and an outer layer, the dissolution of which activates the process of swelling/dissolution/erosion of the intermediate layer. In the composition described in European Application No. 572 942, the coating layers are applied sequentially by watery or organic film coating or by press coating techniques, such as double press coating. A primary disadvantage of these coating methods is that these methods employ solutions of the coating polymers, which coating polymers have very high viscosities in water-based environments. The use of high viscosity polymer is advantageous because a small amount of film is sufficient to provide protection to the core. However, high viscosity polymers present an obstacle to film coating of water-based solutions because of the high viscosity. Typically, these polymers require organic solvents, or slow application procedures of very dilute water-based solutions to overcome the obstacle presented by the high viscosity of the polymers in order to successfully apply the coating agents. The use of organic solvents is not preferred because of the potential health hazards associated therewith. The use of dilute solutions also is not preferred because of the extended manufacturing times required to achieve the same degree of coating application.
Double press coating techniques have mechanical disadvantages in that the core of the formulation may not be properly centered within the coating.
It is therefore an object of the present invention to provide a method of preparing a time-specific release pharmaceutical formulation which does not require the use of organic solvents, or very dilute solutions of coating materials, and which is faster than conventional coating techniques.
There also remains a need in the art for pharmaceutical formulations which release active ingredient after a predetermined latency or lag time period in the body, i.e., time-specific release formulations.

Time-specific controlled release dosage formulations and method of preparing same


A multilayer microporous membrane containing a thermoplastic resin, comprising a coarse structure layer with a higher open pore ratio and a fine structure layer with a lower open pore ratio, wherein said coarse structure layer is present at least in one membrane surface having a thickness of not less than 5.0 μm, a thickness of said fine structure layer is not less than 50% of the whole membrane thickness, and said coarse structure layer and said fine structure layer are formed in one-piece.

Recently, problems with pathogens such as viruses and pathogenic proteins, which may possibly exist as contaminants in a solution for injection, have been highlighted as a critical situation. This is especially true when a liquid preparation containing a physiologically active substance such as plasma derivatives, biopharmaceuticals or plasma for transfusion is administered into a human body. A method for removing or inactivating such pathogens is required.
Methods for inactivating viruses include heating processes and treatments using chemical agents (for example solvent/detergent (S/D) treatment). However, these methods are limited in their inactivation effects depending on types of viruses. For example, a heating process is less effective for thermostable viruses such as hepatitis A virus. Further, an S/D treatment has virtually no effect on viruses such as parvovirus which have no lipid membrane. In a treatment using chemical agents, since there is a possibility that the chemical agent used may be administered into a human body, a process for removing the chemical agent may be required.
Membrane filtration is known as a method for physically removing viruses. Since a procedure for separation is performed using a membrane filtration system which is dependent on a size of virus particles, it is effective for all viruses regardless of chemical or thermal natures of viruses.
A type of virus ranges from the smallest viruses such as parvovirus having a diameter of about 18–24 nm or poliovirus having a diameter of about 25–30 nm to a relatively large virus such as HIV having a diameter of 80–100 nm. In order to remove such groups of viruses by physical means using the membrane filtration, a microporous membrane having a maximum pore diameter of 100 nm or less is required. The need for a system for removing small viruses such as parvovirus has been increased recently.
Virus removal membrans, which can be used for purification of plasma derivatives and biopharmaceuticals by removing viruses, must have not only viral removal ability but also a high permeability for physiologically active substances such as albumin and globulin. For such purposes, ultrafiltration membranes having a pore diameter of several nm and reverse osmotic membranes having a smaller size of pore diameter are not suitable as a virus removal membrane.
Even if microporous membranes have a pore diameter suitable for the viral removal, the microporous membranes, such as an ultrafiltration membrane, having large voids inside the membrane and carrying appropriate filtration characteristics in a surface skin layer, have a low reliability for viral removal. The reason is that there are always significant deficiencies such as pinholes or cracks in the skin layer and large voids inside the membrane. The skin layer herein means an extremely thin layer existing on one side or both sides of the membrane, and having a dencer structure as compared with an inner region of the membrane.
A membrane constructed with a gradient structure with continuously increasing pore diameter from one side of the membrane surface to the other is not suitable for viral removal. In order to perform the viral removal completely, the membrane must have a structure in which a homogeneous structural region having no large internal void as well as having extremely few or almost no continuous change in a pore diameter along a thickness direction, is present with a certain thickness. In such a structure, a mechanism of filtration generally called "depth filtration" is generated. As a result, a highly reliable viral removal capability can be obtained as a sum of the viral removal in each minute region of a membrane thickness.
During a final process of manufacturing, a microporous membrane to be used for the viral removal is treated with some sterilization treatment in order to guarantee safety of the product. Sterilization procedures used include: a method using chemical agents, a method using ultraviolet irradiation or γ-ray irradiation, a method using steam sterilization and the like. Use of chemical agents may exert harmful effects on a human body caused by residual trace chemical agents remaining in a microporous membrane. A sterilization method using ultraviolet irradiation is not suitable for sterilization in the final process due to a low transmissivity of ultraviolet rays. A sterilization method using γ-ray irradiation is unreliable due to irradiation damage caused in a microporous membrane. It seems that use of steam is the most secure, reliable and preferable method. In this case, materials used in a microporous membrane are required to have a thermal stability, since the membrane should be treated by the steam sterilization at high temperature.
In order to prevent adsorption of protein, a component of a preparation, to a microporous membrane, the membrane should preferably be hydrophilic. Consequently, it is preferable to use membrane materials that are originally hydrophilic or to introduce hydrophilic nature into the membrane by a post-treatment. However, when hydrophilic materials are used, there is a possibility of remarkable deterioration in mechanical properties of the membrane due to swelling of the membrane with water. Consequently, it is preferable to prepare a hydrophilic microporous membrane firstly by constructing a physical structure of the membrane with hydrophobic materials, and thereafter hydrophilizing the surface of micropore of the constructed membrane.
In a case of industrial production of plasma derivatives and biopharmaceuticals, it is preferable to use a membrane having a high permeation rate for a solution containing physiologically active substances in order to increase productivity. However, a solution containing physiologically active substances such as globulin contains large amounts of suspended substances as polymers such as dimers or more. These suspended substances cause clogging of pores of a microporous membrane. As a result, filtration rate is rapidly decreased. The smaller the size of the micropore diameter, the more this tendency is significantly increased. As a result, filtration resistance is sometimes rapidly increased due to an accumulation of the suspended materials on a membrane surface. In order to reduce the inconvenience, a pre-filter with larger pore diameter is conventionally used to remove the suspended substances. However, it is difficult to remove the suspended substances completely by using a pre-filter. In addition, since use of two types of filters results in an increased cost, a membrane which does not result in clogging in the presence of the suspended substances, is eagerly demanded.
JP-A-7-265674 discloses a polyvinylidene fluoride membrane which can be used for the viral removal from a solution, and a term "isotropic" is used in the claims thereof. However, the "isotropic" membrane often had a problem of drastic decrease in treatment amount due to clogging or accumulation of the suspended substances onto a membrane surface, because a liquid for which the microporous membrane is used for the purpose of viral removal generally contains physiologically active substances and thus a variety of suspended substances.
WO 99/47593 discloses a polyvinylidene fluoride membrane which has a surface layer with improved open pore ratio by using a specified cooling medium, and describes that said surface layer can have a pre-filtering function. However, the thickness of said surface layer is not greater than 3 μm, resulting in the problem of not exhibiting a sufficient pre-filtering effect during filtration of a liquid containing a variety of suspended substances such as protein solutions.
JP-A-7-173323 discloses a polyvinylidene fluoride microporous membrane manufactured by making a difference between cooling rates at both membrane surfaces from each other in a cooling process. Under this condition, a pore diameter at the surface cooled at slower rates becomes larger, and thus providing a difference between pore diameters on each surface of the membrane. A pore diameter ratio of both membrane surfaces is specified as 4–10 in the claims of said publication. In the method according to said publication, cooling speed varies continuously along a membrane thickness direction, providing a continuous change in a membrane structure along a membrane thickness direction, and further a noticeable gradient structure having a pore diameter difference of over four times between both membrane surfaces. In such a manufacturing method, a fine structure layer which has a highly accurate homogeneity to realize a depth filtration required for the viral removal, cannot be obtained.
WO 91/16968 discloses, as a polyvinylidene fluoride membrane to be used for the viral removal from a solution, a microporous membrane comprising a supporting body, a surface skin and an intermediate porous region present between the supporting body and the skin, produced by coating and coagulating a polymer solution on the supporting body having pores and thus forming the skin layer and the intermediate porous layer onto said supporting body. However, said microporous membrane does not have a one-piece structure nor a fine structure layer of the present invention.


A package is composed of an inner box accommodating an inner content and an outer packing member essentially formed of a plastic film layer and adapted to wrap the inner box so as to have end portions to be bonded in a projecting manner through a heat sealing process. A pair of notches are formed to an end edge portion of the bonded end portions of the outer packing member and the packing member is provided with an easily opening portion at a portion near a base portion of one of the projected bonded end portions so as to correspond to the paired notches. In another aspect, a carton package comprises a carton body having an opened end, a pair of lid pieces formed integrally with the carton body and a carton tape applied to mating end edge portions of the lid pieces when closed, the carton tape having a tearing portion, from which the carton tape is easily torn, formed so as to extend in a longitudinal direction of the carton tape at a central portion in a width direction thereof.

The present invention relates to easily openable packages each in the shape of a box, and more particularly, packages each comprising an inner box or case and an outer plastic film packing an outer periphery of the inner box and containing an inner content which is easily taken out by opening the plastic film along the outer periphery thereof, and the present invention also relates to a carton tape which is easily torn at its intermediate portion in a width direction thereof without using any cutting device and relates to a carton package using such carton tape.
For example, foods such as chewing gum, sweet jelly beans or the like have been commercially sold in a package in which the food is accommodated in an inner box such as paper and packed or wrapped by an outer packing film formed of such as plastic film. However, a outer packing film is generally formed of the plastic film which cannot be easily torn, and hence, it is difficult for a user to take out the inner content contained in the inner box by easily tearing the outer packing film of the package.
For example, in one aspect, for a package of cigarettes or cigars, in order to easily tear or break an outer packing of the package, a plastic film forming the outer packing is composed of two plastic films and a tear(tearable) tape disposed between these plastic films, and the outer packing is opened by tearing the outer packing along the tear tape.
As mentioned above, the package provided with such tear tape is openable by tearing the outer packing along the tear tape to take out the inner content accommodated in the inner box. However, it is required for the outer packing to have two plastic films having both-surface heat sealable structure to interpose the tear tape therebetween, that is, the outer packing is required to have at least three-layer structure of the plastic films. In addition, positioning of the tear tape is troublesome process. Thus, the plastic film manufacturing process is made complicated, which will increase the manufacturing cost of the package.
The box-shaped package will further include a carton package in another aspect. The carton package is generally composed of a carton body formed by bending or folding a carton so as to provide a box-shaped carton body having an opening which is covered by a pair of lid members integrally formed with the carton body. The lid members entirely cover the opening of the carton body by bending at both side edge portions of the opening so that front end edge portions thereof are mated when bent. When both end edge portions of the lid members are mated at a closed position on the carton body, they are tied to each other by means of a carton tape, thereby fastening the lid members to the closed position. The opening of such carton package is performed by opening the lid members, and when the lid members are opened, it is required to tear the carton tape stuck to the mated end edge portions of the lid members or peel off the carton tape from the lid members.
The carton tape is generally composed of a tape body formed of a paper or synthetic resin film, a binder layer on one surface of a tape body and a release agent layer on the other one surface thereof. The carton tape is wound up around a core member and is cut into a piece having a predetermined width when used. Such carton tapes have relatively large tearing (i.e. rupture) strength, which differ from each other due to the difference of the tape materials, and hence, the carton tapes have structure not to be easily torn or cut.
The tearing strength of the carton tape is determined by the tension strength of the tape material itself, and accordingly, when the tension strength is made small for easily tearing the carton tape, it is impossible to sufficiently function as the carton tape, and on the contrary, when the tension strength thereof is made strong for eliminating such defect, it will be required to use a certain cutting means for cutting the carton tape.


A micro-oscillation element includes an oscillation section and a frame. The oscillation section is provided with a mirror surface and is connected to the frame via trapezoidal first and second springs. The oscillation section is located between the first spring and the second spring. Each of the first spring and the second spring is deformable along with the oscillation of the oscillation section.

1. Field of the Invention
The present invention relates to a micro-oscillation element that has an oscillating section for which rotary displacement is possible. More particularly, the present invention relates to a micro-oscillation element which can be applied to a micro-mirror element, which is built into such optical devices as optical measurement devices for performing precision measurement using light waves, optical disk devices for recording and reproducing data for optical disks, and optical switching devices for switching the optical paths between a plurality of optical fibers, so as to change the traveling direction of the light.
2. Description of the Related Art
Recently the application of MEMS (Micro-Electro-Mechanical-System) devices, which have a microstructure created by micro-machining technology, are being attempted in various technical fields. For example, in the field of optical communication technology, micro-mirror elements having light reflecting functions are receiving attention.
A micro-mirror element has a mirror face for reflecting light, and can change the reflecting direction of the light by the oscillation of this mirror face. Electrostatic driving type micro-mirror elements, which use electrostatic force for oscillating the mirror face, are used for many optical devices. Electrostatic drive type micro-mirror elements can roughly be classified into two: micro-mirror elements manufactured by so called surface micro-machining technology, and micro-mirror elements manufactured by so called bulk micro-machining technology.
In surface micro-machining technology, material thin films corresponding to each composing region are processed into a desired pattern on the substrate, and by layering such patterns sequentially, each region of constructing elements, such as a support, mirror face and electrode, and a sacrifice layer to be the removed layer, are created. An electrostatic driving type micro-mirror element by such a surface micro-machining technology is disclosed, for example, in Japanese Patent Application Laid-Open No. H7-287177. In bulk micro-machining technology, on the other hand, the support and mirror section are formed into a desired shape by etching the material substrate itself, and the mirror face and electrode are created with a thin film when necessary. A bulk micro-machining technology is disclosed, for example, in Japanese Patent Application Laid-Open No. H9-146032, No. H9-146034, No. H10-62709 and No. 2001-13443.
One technical issue which is required for micro-mirror element is the high flatness of the mirror face which reflects light. However, according to surface micro-machining technology, where a mirror face to be finally created is thin, the mirror face tends to warp, and it is difficult to implement high flatness on the entire mirror face over a wide area. Whereas in bulk micro-machining technology, where a mirror face is disposed on the mirror section which is created by etching a relatively thick material substrate itself using etching technology, the rigidity of the mirror section can be more easily insured over a wide area of the mirror face. Therefore bulk micro-machining technology is preferable for creating a mirror face which has a sufficiently high optical flatness.
FIG. 24 and FIG. 25 show a conventional electrostatic driving type micro-mirror element X6 fabricated by bulk micro-machining technology. FIG. 24 is an exploded perspective view of the micro-mirror element X6, and FIG. 25 is a cross-sectional view along the XXV-XXV line in FIG. 24, of an assembled micro-mirror element X6.
The micro-mirror element X6 has a structure where the mirror substrate 60 and the base substrate 66 are layered. The mirror substrate 60 is comprised of a mirror section 61, a frame 62 and a pair of torsion bars 63 connected to these. The external forms of the mirror section 61, frame 62 and the pair of torsion bars 63 can be formed by etching one side of a predetermined material substrate, such as a silicon substrate which has conductivity. On the front face of the mirror section 61, the mirror face 64 is created. On the rear face of the mirror section 61, a pair of electrodes 65a and 65b are disposed. The pair of torsion bars 63 specifies the rotation axis A6 in the later mentioned oscillation operation of the mirror section 61. On the base substrate 66, the electrode 67a, which faces the electrode 65a of the mirror section 61, and the electrode 67b, which faces the electrode 65b thereof, are disposed.
In the micro-mirror element X6, when potential is applied to the frame 62 of the mirror substrate 60, the potential is transferred to the electrode 65a and the electrode 65b via the pair of torsion bars 63 and the mirror section 61, which are integrated with the frame 62 using a same conductive material. Therefore by applying a predetermined potential to the frame 62, the electrodes 65a and 65b can be charged to positive, for example. If the electrode 67a of the base substrate 66 is charged to negative in this status, electrostatic attraction is generated between the electrode 65a and the electrode 67a, and the mirror section 61 oscillates in the direction of the arrow M6 with twisting the pair of torsion bars 63, as shown in FIG. 25. The mirror section 61 can oscillate to the angle at which the electrostatic attraction between the electrodes and the total of the torsional resistance of the torsion bars 63 balance. If the electrode 67b is charged to negative in the status where the electrodes 65a and 65b of the mirror section 61 are charged to positive, on the other hand, electrostatic attraction is generated between the electrode 65b and the electrode 67b, and the mirror section 61 can oscillate to a direction opposite of the arrow M6. By such an oscillation driving of the mirror section 61, the reflection direction of the light, which is reflected by the mirror face 64, can be switched.
In order to increase the resonance frequency of the mirror section 61 (e.g. several hundred kHz or more), to meet the demand for high-speed operation in the micro-mirror element X6, a method of increasing the rigidity of the torsional direction (torsional rigidity) of the torsion bar 63 to increase the rotational rigidity of the mirror section 61, or a method of decreasing the mass of the mirror section 61 so as to decrease the moment of inertia thereof (polar moment of inertia of area with respect to the axis A6) may be used in prior art. Generally the resonance frequency of the mirror section (region which performs the rotary operation) of the element is given by the following formula (1). In formula (1), f0 is a resonance frequency of the mirror section, K is a rotational rigidity of the mirror section, and I is a moment of inertia of the mirror section (polar moment of inertia of area with respect to the axis).
                              f          0                =                              K            I                                              (        1        )
According to formula (1), for the mirror section 61 of the micro-mirror element X6, a higher resonance frequency can be obtained as the rotational rigidity thereof is higher, or as the moment of inertia thereof is lower. As the torsional rigidity of the torsion bar 63 is higher, the rotational rigidity of the mirror section 61 becomes higher, and the potential energy to be stored in this torsion bar 63, when the mirror section 61 oscillates in one direction, increases, and therefore the quantity of potential energy, which is released from the torsion bar 63 when the mirror section 61 oscillates to the opposite direction after this oscillation in one direction, and is converted into kinetic energy, increases, which is suitable for obtaining a high resonance frequency. As the moment of inertia of the mirror section 61 decreases, the driving force required for a predetermined oscillation operation of the mirror section 61 is smaller, so this is suitable for obtaining a high resonance frequency.
A known method of increasing the torsional rigidity of the torsion bar 63 is increasing the thickness and width of the torsion bar 63 so as to increase the cross-section area thereof. However, the thickness of the torsion bar 63 must be set to the thickness of the mirror section 61 or less, for practical reasons. If the thickness of the torsion bar 63 exceeds the thickness of the mirror section 61, then the torsional rigidity of the torsion bar 63 increases excessively, and in this case even if a driving force of the mirror section 61 is generated, this torsion bar 63 cannot be appropriately twisted, and the mirror section 61 tends to deform. If the width of the torsion bar 63 is inappropriately increased, this too increases excessively the torsional rigidity of the torsion bar 63, and in this case, even if a drive forcing of the mirror section 61 is generated, this torsion bar 63 cannot be appropriately twisted, and the mirror section 61 tends to deform.
A known method for decreasing the moment of inertia of the mirror section 61 by decreasing the weight thereof is decreasing the thickness of the mirror section 61. However, as the mirror section 61 becomes thinner, the mirror section 61 itself tends to deflect, and assuring the flatness of the mirror face 64 tends to become difficult. If the flatness of the mirror face 64 cannot be sufficiently assured, an appropriate light reflection function cannot be implemented in the micro-mirror element X6.
In this way, prior art has difficulty to operate a micro-mirror element or a micro-oscillation element at a high resonance frequency.

Micro-oscillation element incorporating springs


A component for use in a gas turbine engine includes a channel configured to port a gas from an inlet along a flow path. The component further includes a wall defining an outlet configured to receive the gas, the wall forming an angle with the flow path that is between 60 degrees and 120 degrees, the outlet having a first portion with a first diameter and a second portion with a second diameter, the first portion configured to receive the gas before the second portion, and the first diameter being greater than the second diameter.

Gas turbine engines include compressor sections to compress an airflow, combustor sections that combine the airflow with fuel for combustion and generate exhaust, and turbine sections that convert the exhaust into torque to drive the compressor sections. The turbine sections may include rotating turbine blades that may be exposed to relatively high temperatures. The turbine blades include cooling features that port a cooling airflow therethrough in order to offset some effects of heat. In response to contact between debris within the cooling airflow and an internal surface of the turbine blade, the debris may undesirably bond to the internal surface of the turbine blades.


An automatically traveling floor cleaning appliance during travel is capable of traveling over low obstacles extending lengthwise, typically represented by a carpet border, having an upwardly inclined obstructing surface, with a direction of travel at a right or acute angle with respect to a longitudinal extent of the obstacle. The appliance also has an obstacle detector. The appliance is formed so that the obstacle or an area adjoining same may be cleaned using a procedure in which the appliance assumes a direction of travel based on the extent of the obstacle, and with regard to the obstructing surface includes traveling on a floor area in front of the obstacle, and at a lateral distance of an associated boundary edge of the appliance in the direction of travel from the obstructing surface which is smaller than that corresponding to a width of the appliance perpendicular to the direction of travel.

1. Field of the Invention
The invention relates in first instance to an automatically traveling floor cleaning appliance, the floor cleaning appliance during travel being capable of traveling over low obstacles extending lengthwise, typically represented by a carpet border, having an upwardly inclined obstructing surface, with a direction of travel at a right angle or acute angle with respect to a longitudinal extent of the obstacle, and in addition the floor cleaning appliance having a means for detecting the obstacle.
In the same way, the invention relates to a method for operating an automatically traveling floor cleaning appliance which has the above-mentioned capabilities and means.
2. Description of the Related Art
These types of floor cleaning appliances are already known in many respects. Reference is made to DE 102011000536 A1, DE 102008014912 A1, DE 102011000250 A1, and DE 102010036772 A1, for example.
Such automatically traveling floor cleaning appliances are also able to overcome fairly small obstacles having an edge that is upwardly inclined, i.e., raised or elevated with respect to the surface on which the appliance is traveling just before reaching the obstacle, such as carpet borders in particular, but also possibly floor thresholds.
The cleaning strategy of these types of floor cleaning appliances is designed, for example, such that a certain space that is selected for cleaning, which may be the same as a room of a building or also may pertain to (only) a portion of a room of a building, is traveled over in a certain regular sequence, so that the action of a cleaning brush and/or suction of dirt with regard to the surface traveled over is provided over the most complete area coverage possible. The mentioned obstacles, which may be traveled over, possibly present within this cleaning strategy, are in each case traveled over in the direction of the pattern internally predefined in the robotic cleaner or in a certain orientation with respect to a given wall of a room. The obstacles may also be traveled over multiple times.

Automatically traveling floor cleaning appliance and method for operating a floor cleaning appliance


A bone harvesting tool includes an elongate hollow collection cannula with a lumen for receiving harvested bone tissue. Holes are formed through the collection cannula to permit visual observation of the volume of bone tissue that has been collected. Cutting blades are mounted to the distal end of the collection cannula and are configured for cutting into bone tissue. The cutting blades are aligned so that the harvested bone tissue advances proximally into the lumen of the collection cannula. A guide pin is telescoped into the collection cannula and through the blades. The guide pin is employed for initial positioning of the tool on the bone. A plug near the distal end of the guide pin enables the guide pin to be used for expelling the collected bone tissue from the collection cannula.

1. Field of the Invention
The invention relates to a bone harvesting device for collecting bone tissue that can be used in orthopedic procedures.
2. Description of the Related Art
Many orthopedic procedures require bone tissue to be harvested at one location on a patient for use at another location on the patient. For example, some patients experience a deterioration of the discs between vertebrae due to disease or injury. The deterioration of the discs causes the vertebrae to impinge upon nerves in and near the spine. The condition is extremely painful and debilitating. One procedure for addressing this problem is to fuse vertebrae together on opposite sides of the damaged disc. Spinal fusion surgery may include implantation of harvested bone tissue in the region between the vertebrae that are to be fused.
Bone tissue also may be harvested from one location to help heal a broken bone at a different location. For example, a severe fracture may completely sever a bone and may produce bone fragments in areas near the fracture. A severe break of this type often requires surgical intervention to remove some of the bone fragments. Additionally, a plate or rod may be implanted to provide structural support for the broken bone. Bone tissue harvested from one location may be implanted across the fracture and adjacent to the bone plate or rod. The harvested bone tissue will regenerate and contribute to structural support across the fracture.
Many patients experience disease or injury at joints. Diseased or damaged joints may require implantation of a prosthetic joint to supplement a portion of the diseased or damaged natural joint or to completely replace the natural joint. For example, total hip replacement requires the head of the natural femur to be removed and replaced by a prosthetic component. The prosthetic component includes a stem that must be inserted into a hole bored in the intramedullary cavity of the femur. Harvested bone tissue may be implanted around the stem of the femoral component of the prosthetic joint to enhance the support of the joint in the natural femur. Similarly, a socket may be implanted in a cavity prepared in the hip of the patient. Harvested bone tissue may be implanted around the prosthetic socket to provide the necessary support for the socket.
Many tools and techniques are employed for harvesting bone tissue. For example, some surgeons employ a reamer that is structurally and functionally similar to a cheese grater. The reamer may be generally cylindrical or spherical and may be formed from a thin stainless steel material. A plurality of openings are formed through the wall of the reamer and at least one side of each opening is sharpened and bulged to define a cutting edge that can cut into the bone tissue. The reamer is rubbed against or rotated against a targeted area for bone harvesting. As a result, bone tissue is cut from the bone and accumulates inside the reamer. The surgeon then must collect the accumulated bone tissue from the inside of the reamer in much the same way that grated cheese is accumulated from the inside of a cheese grater. Some reamers have worked well. However, it often is difficult to precisely target a location from which bone will be harvested with a reamer. Additionally, it is difficult for a surgeon to accurately determine how much bone tissue has been harvested. In some instances, too much bone tissue is accumulated in the reamer, thereby creating unnecessary trauma at the site of the bone harvesting. In other instances, too little bone tissue is harvested and the surgeon must revisit the site of the harvesting to collect additional tissue.
Some surgeons employ an auger-type tool to bore a hole in the bone at the site where the bone tissue is to be harvested. The auger is a rotating tool that produces bone debris in much the same way that a conventional drill produces sawdust when drilling into a piece of wood. This bone harvesting technique also requires the surgeon to guess about the volume of bone tissue that is being collected. Furthermore, the harvested bone tissue is not collected conveniently by the anger.
In view of the above, it is an object of the subject invention to provide a tool for harvesting bone tissue from specified locations and in clearly definable amounts.
It is another object of the subject invention to provide a bone harvesting tool that can be utilized easily by a surgeon.


A microprocessor that executes a repeat prefetch instruction (REP PREFETCH). The REP PREFETCH prefetches multiple cache lines, wherein the number of cache lines is specifiable in the instruction. The instruction is specified by the Pentium III PREFETCH opcode preceded by the REP string instruction prefix. The programmer specifies the count of cache lines to be prefetched in the ECX register, similarly to the repeat count of a REP string instruction. The effective address of the first cache line is specified similar to the conventional PREFETCH instruction. The REP PREFETCH instruction stops if the address of the current prefetch cache line misses in the TLB, or if the current processor level changes. Additionally, a line is prefetched only if the number of free response buffers is above a programmable threshold. The prefetches are performed at a lower priority than other activities needing access to the cache or TLB.

Modern microprocessors include a cache memory. The cache memory, or cache, stores a subset of data stored in other memories of the computer system. When the processor executes an instruction that references data, the processor first checks to see if the data is present in the cache. If so, the instruction can be executed immediately since the data is already present in the cache. Otherwise, the instruction must wait to be executed while the data is fetched from the other memory into the cache. The fetching of the data may take a relatively long time—in some cases an order of magnitude or more longer than the time needed for the processor to execute the instruction to process the data.
Many software programs executing on a microprocessor require the program to manipulate a large linear chunk of data. For example, the linear chunk of data might be between 100 to 1,000,000 bytes. Examples of such programs are multimedia-related audio or video programs that process a large chunk of data, such as video data or wave file data. Typically, the large chunk of data is present in an external memory, such as in system memory or a video frame buffer. In order for the processor to manipulate the data, it must be fetched from the external memory into the processor.
If a needed piece of data is not present in the cache, the disparity in data fetching and data processing time may create a situation where the processor is ready to execute another instruction to manipulate the data, but is stalled, i.e., sitting idle waiting for the data to be fetched into the processor. This is an inefficient use of the processor, and may result in reduced multimedia system performance, for example.
In addressing this problem, modern microprocessors have recognized that many times the programmer knows he will need the data ahead of the time for execution of the instructions that actually process the data, such as arithmetic instructions. Consequently, modern microprocessors have added to or included in their instruction sets prefetch instructions to fetch a cache line of the data into a cache of the processor before the data is needed. A cache line is the smallest unit of data than can be transferred between the cache and other memories. An example of a modern microprocessor with a prefetch instruction is the Intel Pentium III® processor. The Pentium III includes a PREFETCH instruction in its Streaming SIMD Extensions (SSE) to its instruction set.
In many software applications, a programmer knows he will be manipulating a large linear chunk of data, i.e., many cache lines. Consequently, programmers insert prefetch instructions, such as the Pentium III PREFETCH, into their programs to prefetch a cache line. The programmer inserts the prefetch instructions multiple instructions ahead of the actual instructions that will perform the arithmetic or logical operations on the data in the cache line. Hence, a program may have many prefetch instructions sprinkled into it. These added prefetch instructions increase the size of the program code as well as the number of instructions that must be executed.
Furthermore, under the conventional method, not only does the programmer have to sprinkle prefetch instructions into the code, but he also has to try to place them in the code so as to optimize their execution. That is, the programmer has to try to determine the timing of the execution of the prefetch instructions so that the data is in the cache when it is needed. In particular, the programmer attempts to place the prefetch instructions in the code so they do not clobber one another. That is, in conventional processors if a prefetch instruction is currently executing and a subsequent prefetch instruction comes along, one of the prefetch instructions may be treated as a no-op instruction and not executed. This does not accomplish what the programmer wanted, and likely results in lower performance.
One problem a programmer faces when hand-placing prefetch instructions is the variability of core/bus clock ratio. In many modern microprocessors, the clock frequency of the processor bus that connects the processor to the rest of the system is not the same as the clock frequency at which the logic inside the processor operates, which is commonly referred to as the core clock frequency. The core/bus clock ratio is the ratio of the processor core clock frequency to the processor bus clock frequency.
The difference in core clock and processor bus clock frequency is attributed in part to the fact that it is common to sort processors as they are produced according to the core clock frequency that a given integrated circuit will reliably sustain. Hence, it may be that a given processor design will sort into batches of four different core clock frequencies, such as 800 MHz, 900, MHz, 1 GHz, and 1.2 GHz. However, all of these batches of processors must operate in motherboards that are designed to run at one or two fixed bus clock frequencies, such as 100 MHz or 133 MHz. Hence, in the example above, eight different combinations of core/bus clock ratios may occur. Consequently, there may be eight different numbers of core clocks that are required for a typical prefetch to complete.
The fact that a range exists of core clocks required for a typical prefetch to complete makes it very difficult for a programmer to effectively hand-place conventional prefetch instructions. This may be shown by the following example. Assume the highest core/bus clock ratio is 12, and assume a typical prefetch instruction takes about 10 bus clocks or about 120 core clocks. Assume the programmer is programming a loop that processes a single cache line of data, and the loop takes approximately 60 core clocks to execute and is not dependent upon bus activity other than the bus activity generated by the prefetch instruction.
In this case, the programmer may choose to execute a prefetch instruction every other iteration of the loop, i.e., every 120 core clocks, to accommodate the highest core/bus ratio. The programmer's choice may work well if the ratio is 12. However, if the user has a system in which the ratio is 6, a typical prefetch instruction only takes about 60 core clocks, which is only one iteration through the loop. In this scenario, a prefetch instruction will be active only half the time, which may result in stalls of the processor waiting for the data to be fetched into the cache.
Therefore, what is needed is a microprocessor that supports a prefetch instruction that facilitates efficient prefetching. What is also needed is for the prefetch instruction to efficiently fit into the Pentium III opcode space.

This patent is subject to a terminal disclaimer.

Microprocessor with repeat prefetch instruction


A method and apparatus for clock signal noise shaping are described. Embodiments of a clock circuit include a filter coupled to receive an input clock signal and to provide an output clock signal. The filter filters noise of the input clock signal to shape the noise to provide the output clock signal. In a method for adjustment of phase noise, input clock signaling having the phase noise is obtained, and the input clock signal is filtered to adjust the phase noise to provide output clock signaling.

Conventionally, an input clock signal is provided to a phase lock loop ("PLL") for locking to such input clock signal to provide an output clock signal. However, as data rates have increased, such as a gigabit per second or more for example for serial links, phase noise associated with the input clock signal is more of a problem.
Accordingly, it would be desirable and useful to address phase noise in a clock signal. More particularly, it would be both desirable and useful to address phase noise in a clock signal for serial links having at least a gigabit-per-second bit rate.


An apparatus includes a touch interface that includes a plurality of electrodes and a shield device. The shield device is configured to establish a first mutual capacitive coupling with a first electrode of the plurality of electrodes. The shield device is further configured to establish a second mutual capacitive coupling with a second electrode of the plurality of electrodes. The apparatus further includes a controller coupled to the touch interface. The controller is configured to detect a touch based on a detected first capacitance value of the first mutual capacitive coupling and a detected second capacitance value of the second mutual capacitive coupling.

Capacitive touch detection techniques are used many touch driven devices, such as touch screens and keypads. Such a touch driven device includes a plurality of sensors and detects a tooth location based on measured changes in capacitance of the sensors. For example, a user's finger near a sensor may cause the capacitance of one of the plurality of sensors to increase or decrease resulting in the touch driven device detecting a touch at the location of the sensor. However, liquid present on a surface of a capacitive touch sensor may interfere with touch detection. For example, liquid present on the surface of the capacitive touch sensor may establish an electrical connection between a first sensor and a second sensor such that a user touching the first sensor may affect capacitance of both the first sensor and the second sensor. In addition, liquid present on the capacitive touch sensor may establish an electrical connection between a sensor and a surrounding ground component of the capacitive touch sensor system causing the sensor to change capacitance and the touch device to incorrectly detect a user touch.

Using driven shield and touch elements lock algorithm for achieving liquid tolerant capacitive touch solution


Apparatus configured to be foldable from an unfolded configuration into an in-use folded configuration. The apparatus, when in the unfolded configuration, comprising: a flexible substrate having first and second opposing ends with respective first and second connectors located at respective first and second opposing ends; and a third connector located on the flexible substrate between the first and second opposing ends. The apparatus is configured to be folded from the unfolded configuration into the in-use folded configuration to bring the first and second connectors together.

Slide-type electronic devices, such as mobile telephones, are known. Such electronic devices use flexible printed circuit boards (FPCs) to connect between the modules that move relative to each other during sliding. Typically, an FPC is designed as a flat cable with connectors at each end. When installed into the electronic device, the FPC forms a U-shape that allows it to follow the sliding motion by rolling along its longitudinal axis.
In systems where space is limited, the FPC is provided with wires on each side of the flexible substrate so as to reduce the width of the FPC.
Flexible printed circuit boards are known that use two parallel substrates between two connectors, wherein each of the substrates carries a layer of wires between the connectors. In such examples, the substrates are joined together at their two ends, near the connectors so as to provide a gap between the two substrates between the two ends of the FPC. Such an example may be known as an air gap FPC.
However, the use of air gaps in slide application devices can create some challenges to the dynamic performance. Due to the FPC manufacturing process, both conductor layers/substrates in the FPC are the same length. This means that when the FPC is folded in use, a "kink" (also known as "flex buckling") can appear in the inner layer when the FPC is assembled in the electronic device. The kink can severely affect the dynamic durability of the flexible printed circuit board, and can also generate an unwanted clicking sound during movement of the slide.
A known way to resolve the "kink" problem is to create a permanent kink in a strategic position of the inner conductor layer using a pre-bend technique. This pre-bend/kink effectively shortens the inner radius layer to eliminate or reduce problems created by using an air gap flexible printed circuit board. However, the crimping process that is required to create the permanent kink can damage the flex, and special machinery may be required for semi-automatic pre-bend application to ensure the pre-bend is made in the same way every time.
A conventional two-layer build-up may not withstand the rolling motion often enough to be suitable for use in some devices, such as mobile telephones.
The listing or discussion of a prior-published document or any background in this specification should not necessarily be taken as an acknowledgement that the document or background is part of the state of the art or is common general knowledge. One or more aspects/embodiments of the present disclosure may or may not address one or more of the background issues.


A method and apparatus are described including selecting a first route between a source node and a destination node using a bandwidth-aware routing protocol, determining if the selected first route satisfies a bandwidth requirement of an application of the source node, initiating a switch to a new channel selected from a back-up channel list if the bandwidth requirement of the application is not satisfied by the selected route, selecting a second route over the new channel using the bandwidth-aware routing protocol, determining if the selected second route over the new channel satisfies the bandwidth requirement of the application of the source node and streaming data from the source node to the destination node if the selected first route satisfies the bandwidth requirement of the application or if the selected second route over the new channel satisfies the bandwidth requirement of the application.

In multicast and broadcast applications, data are transmitted from a server to multiple receivers over wired and/or wireless networks. A multicast system as used herein is a system in which a server transmits the same data to multiple receivers simultaneously, where the multiple receivers form a subset of all the receivers up to and including all of the receivers. A broadcast system is a system in which a server transmits the same data to all of the receivers simultaneously. That is, a multicast system by definition can include a broadcast system.
Wireless networks, given their low deployment cost and flexibility, have increasingly been used as the last hop extension of wired networks. Emerging technologies such as Orthogonal Frequency Division Multiplexing (OFDM) and Multiple-In-Multiple-Out (MIMO) have effectively significantly increased the bandwidth of a wireless channel. A potential application of these technologies is to distribute video content over wireless links in a home environment. Distribution of video content such as by video streaming is bandwidth demanding. In most homes, a one hop wireless local area network (WLAN) is sufficient for network access. When a playback device (TV or computer) is far away from a access point (AP) and/or gateway, a multi-hop wireless network may be necessary for a certain level (quality) of viewing experience. A multi-hop wireless network uses a routing protocol to select the best path (route) from a source to destination. Some protocols such as Automatic On-demand Distance Vector (AODV) find the shortest path (route). An earlier filed application PCT/US05/039597 filed Nov. 2, 2005 extended AODV to take bandwidth into consideration. In some cases, when there are one or more interfering wireless devices, even the best route cannot provide enough bandwidth for video distribution, switching to a less interfering channel may solve the problem.
A great deal of study has been devoted to combining packet scheduling, routing and channel selection to support multi-radio and multi-channel wireless ad-hoc or mesh networks, such as Kyasanur and Vaidya, "Routing and Link-layer Protocols for Multi-Channel Multi-Interface Ad Hoc Wireless Networks," SIGMOBILE Mobile Computing and Communication Review, vol. 10, no. 1, pp. 31-43, January 2006; Alicherry et al "Joint Channel Assignment and Routing for Throughput Optimization in Multi-radio Wireless Mesh Networks," in ACM Mobicom, Cologne, Germany, August 2005; Bahl et al. "SSCH:Slotted Seeded Channel Hopping for Capacity Improvement in IEEE 802.11 Ad-Hoc Wireless Networks," In Proceedings of ACM Mobicom, Philadelphia, Pa., September 2004. These studies, however, propose modifications to the current IEEE 802.11 MAC layer, and assume that all the devices in the wireless network are synchronized and that channel switching can be performed on a per packet basis. In "Centralized Algorithms for Multi-channel Wireless Mesh networks," in ACM Mobile Computing and Communication Review, April 2004, Raniwala et. al proposed a scheme for relatively long term channel assignment for a multi-radio mesh network, the goal was to increase the total capacity of a mesh work. Raniwala et. al does not combine routing with the channel assignment protocol. Other proposals, such as Nelson and Kleinrock, "Spatial TDMA: A Collision Free Multihop Channel Access Protocol," IEEE transactions on communications, vol. com-33, No. 9, pp. 934-944, September 1985 and Cidon, Moshe Sidi, "Distributed Assignment Algorithms for Multihop Packet Radio Networks," IEEE transactions on computer, vol. 38, no. 10, pp. 1353-1361, October, 1989 advocate the use of TDMA MAC layer to increase the spatial reuse of wireless channels. These proposals, again, require modification of the IEEE 802.11 MAC layer. In an earlier filed application PCT/US05/039597 filed Nov. 2, 2005, a bandwidth aware routing protocol was proposed, which selected a path that had the best bandwidth instead of the shortest hop. This was better for video streaming, which is bandwidth demanding. However, when there are one or more interfering devices in the neighborhood, even this protocol may still fail to find a path that can meet the requirements of a video streaming, In the case of an interfering channel, switching to a less interfering channel may solve the problem.
Bandwidth aware routing protocol needs information about available bandwidth between a node and its neighbors in a wireless network. The available bandwidth maybe estimated using information from IEEE 802.11k, but currently IEEE 802.11k is not implemented in most of the wireless cards. In Shah et al "Available Bandwidth Estimation in IEEE 802.11-based Wireless Networks," In Proceedings of 1st ISMA/CAIDA workshop on Bandwidth Estimation (BEst 2003), a MAC layer available bandwidth estimation method was proposed. In an Ad-hoc or mesh wireless network, each node may have multiple neighbors. The method in Shah et al requires the MAC layer to maintain neighboring nodes status.
A method that combines bandwidth aware routing and channel selection for video distribution in a multi-hop wireless home network would be useful. New application layer methods to estimate available bandwidth between neighboring nodes in a wireless network that do not require maintaining the status of neighboring nodes would also be useful.

Combining bandwidth aware routing with channel selection and switching in a multi-hop wireless home network


A method of predicting whether an MDS patient has a good or poor prognosis uses a general purpose computer configured as a classifier and mass-spectrometry data obtained from a blood-based sample. The classifier assigns a classification label of either Early or Late (or the equivalent) to the patient's sample. Patients classified as Early are predicted to have a poor prognosis or worse survival whereas those patients classified as Late are predicted to have a relatively better prognosis and longer survival time. The groupings demonstrated a large effect size between groups in Kaplan-Meier analysis of survival. Most importantly, while the classifications generated were correlated with other prognostic factors, such as IPSS score and genetic category, multivariate and subgroup analysis showed that they had significant independent prognostic power complementary to the existing prognostic factors.

Myelodysplastic syndrome (MDS) comprises a heterogeneous group of myeloid hemopathies, characterized by ineffective bone marrow production of the myeloid class of blood cells. While the incidence of MDS in the general population is only about 4.5 per 100,000 people, the incidence of MDS rises steeply with age, such that the incidence rate exceeds 50 per 100,000 people over 80 years of age. MDS can arise de novo or occur after chemotherapy or radiation for prior malignancies. The major clinical problems facing patients with MDS are morbidities due to cytopenias (low blood counts) and the progression of MDS into acute myeloid leukemia (AML). National Comprehensive Cancer Network (NCCN) Guidelines, Version 1 Myelodysplastic Syndromes (2015).
MDS can be subdivided into several categories. Until recently, the French-American-British (FAB) categorization was used. This schema divided the syndrome into the five categories outlined in table 1. This categorization has now been superseded by the World Health Organization (WHO) classification, also described in Table 1.
TABLE 1French-American-British and WHO categories of MDSFABWHODescriptionRefractoryRefractory Blasts < 5% in bone marrow, anemia (RA)anemia (RA)median survival from 2-5 years, progression to AML rare, 20%-30% of MDS patients.RefractoryBlasts < 5% in bone marrow, cytopenia withmultiple or single cytopenia multilineage orpresent, median survival 33 unilineagemonths, 11% progression to dysplasia.AML, 15% of MDS patients.RefractoryRefractory anemiaRing sideroblasts > 15% of anemia withwith ringmarrow red cell precursors, ring sideroblastssideroblasts1%-2% progress to AML, (RARS)(RARS)prognosis as for RA, 10%-12% of MDS patients.RefractoryRefractory anemiaRAEB-1: 5%-9% blasts in bone anemia withwith excess blastsmarrow and < 5% blasts in excess blasts−1 and −2blood, median survival 18 (RAEB)months, 25% of patients progress to AML.RAEB-2: 10%-19% blasts in bone marrow, median survival 10 months, 33% of patients progress to AML.RAEB-1+RAEB-2 accounts for 40% of MDS patients.MDS,unclassifiableMDS associatedBlasts in blood < 5%, associated with del(5q)with isolated del(5q) cytogenetic abnormality. Long survival,RefractoryReclassified fromMultiple cytopenias, 5%-19% anemia withMDS to AMLblasts in blood, 20%-30%excess blasts infollowing MDSblasts in bone marrow.transformation(RAEB-t)ChronicReclassified from<20% blasts in bone marrow myelomonocyticMDS toand > 109 monocytes/L in bloodleukemiamyelodysplastic(CMML)andmyeloprofilerativediseasesSources: NCCN MDS Guidelines, available from the cancer.gov website, see link in our prior provisional application, specification.
Several prognostic scoring systems have been developed to help to stratify MDS for appropriate treatment regimens. These include the International Prognostic Scoring System (IPSS), the revised IPSS (IPSS-R), and the WHO-based Prognostic Scoring System (WPSS). The original IPSS score ranges from 0 (low risk) to over 2.5 (high risk) and is based on the percentage of blasts in marrow, the karyotype and presence and multiplicity of cytopenias. This scoring system proved inadequate for accurate patient stratification, resulting in the development of the IPSS-R (ranging from 0 (very good prognosis) to over 4 (very poor prognosis)), which uses a combination of cytogenetic status, percentage of marrow blasts, hemoglobin level, platelet level, and ANC level, and the WPSS (ranging from 0 (very low risk) to 6 (very high risk)), which combines WHO MDS category, karyotype, and presence of severe anemia.
In addition to these commonly used prognostic scores, there have been some investigations into blood-based biomarkers that might be able to improve patient stratification. One particular study, using the same samples that were made available to us for this project, studied serum CD44 (sCD44) and showed that it had potential to add information to the existing IPSS scoring system. Loeffler-Ragg J. et al., Serum CD44 levels predict survival in patients with low-risk myelodysplastic syndromes Crit. Rev. Oncol. Hematol. vol. 78 no. 2 pp. 150-61 (2011) In addition, attempts have been made to refine risk stratification or identify patients most likely to develop secondary acute myelogenous leukemia using circulating microRNAs (see Zuo Z., et al., Circulating microRNAs let-7a and miR-16 predict progression free survival and overall survival in patients with myelodysplastic syndrome, Blood vol. 118 no. 2 pp. 413-5 (2011)) or gene expression profile by microarrays (see Mills K. I., et al., Microarray-based classifiers and prognosis models identify subgroups with distinct clinical outcomes and high risk of AML transformation of myelodysplastic syndrome Blood vol. 114 no. 5 pp. 1063-72 (2009)). These potential biomarkers remain to be validated in independent datasets.
Other prior art of interest includes Garcia-Manero, G., Myelodysplastic syndromes: 2014 update on diagnosis, risk stratification, and management, Am. J. Hemat., Vol. 89. No. 1, pp. 98-18 Jan. 2014); Bejar, R., Prognostic models in myelodisplatic syndromes, Am. Soc. Of Hematology, p. 504-510 (2013); Ades, L. et al., Myelodysplastic Syndromes, The Lancet, vol. 383 pp. 2239-52 (Jun. 26, 2014); and Westers, T. M., et al., Aberrant immunophenotype of blasts in myelodysplastic syndromes is a clinically relevant biomarker in predicting response to growth factor treatment Blood vol. 115 pp. 1779-1784 (2010).
Treatment for MDS patients is determined by risk category. High and some intermediate risk patients, if considered candidates for intensive therapy, will receive hematopoietic stem cell transplants (HSCTs) or high intensity chemotherapy. Patients in this risk group unsuitable for intensive therapy receive azacitidine or decitabine and/or supportive care. Treatment for these high-risk, very poor prognosis patients is relatively well determined and there is little unmet need for additional tests in this patient subgroup. On the other hand, treatment alternatives for low risk and other intermediate risk patients are more varied, including lenalidomide, immunosuppressive therapy, or possibly azacitidine or supportive therapy, and here better tools for patient stratification would be beneficial. In particular it would be clinically useful to improve on the prognostic scoring systems to determine which patients might have significantly worse than average prognosis, as such systems can guide treatment of MDS patients. This invention meets that need.

Predictive test for prognosis of myelodysplastic syndrome patients using mass spectrometry of blood-based sample


Disclosed is a phase change ink composition including an ink carrier and a colorant, said ink being suitable for use in an indirect printing process wherein the ink is jetted from a printhead onto a heated intermediate transfer member and subsequently transferred from the intermediate transfer member to a final recording substrate, wherein: (a) the ink exhibits the characteristic of being jetted from the printhead onto the intermediate transfer member when the ink at a temperature of about 125° C. or lower; (b) the ink exhibits the characteristic of being jetted without purging from a printer maintained at a standby temperature of about 100° C. or lower; and (c) the ink has a cohesive failure temperature of at least about 56° C.

Disclosed herein are hot melt or phase change inks and methods for the use thereof. More specifically, disclosed herein are hot melt or phase change inks particularly suitable for use in phase change ink jet printing processes with reduced energy requirements. One embodiment is directed to a phase change ink composition comprising an ink carrier and a colorant, said ink being suitable for use in an indirect printing process wherein the ink is jetted from a printhead onto a heated intermediate transfer member and subsequently transferred from the intermediate transfer member to a final recording substrate, wherein: (a) the ink can be jetted from the printhead onto the intermediate transfer member when the ink is maintained at a temperature of about 125° C. or lower; (b) the ink can be jetted without purging from a printer maintained at a standby temperature of about 100° C. or lower; and (c) the ink has a cohesive failure temperature of at least about 56° C.
In general, phase change inks (sometimes referred to as "hot melt inks") are in the solid phase at ambient temperature, but exist in the liquid phase at the elevated operating temperature of an ink jet printing device. At the jet operating temperature, droplets of liquid ink are ejected from the printing device and, when the ink droplets contact the surface of the recording substrate, either directly or via an intermediate heated transfer belt or drum, they quickly solidify to form a predetermined pattern of solidified ink drops. Phase change inks have also been used in other printing technologies, such as gravure printing, as disclosed in, for example, U.S. Pat. No. 5,496,879 and German Patent Publications DE 4205636AL and DE 4205713AL, the disclosures of each of which are totally incorporated herein by reference.
Phase change inks for color printing typically comprise a phase change ink carrier composition which is combined with a phase change ink compatible colorant. In a specific embodiment, a series of colored phase change inks can be formed by combining ink carrier compositions with compatible subtractive primary colorants. The subtractive primary colored phase change inks can comprise four component dyes, namely, cyan, magenta, yellow and black, although the inks are not limited to these four colors. These subtractive primary colored inks can be formed by using a single dye or a mixture of dyes. For example, magenta can be obtained by using a mixture of Solvent Red Dyes or a composite black can be obtained by mixing several dyes. U.S. Pat. No. 4,889,560, U.S. Pat. No. 4,889,761, and U.S. Pat. No. 5,372,852, the disclosures of each of which are totally incorporated herein by reference, teach that the subtractive primary colorants employed can comprise dyes from the classes of Color Index (C.I.) Solvent Dyes, Disperse Dyes, modified Acid and Direct Dyes, and Basic Dyes. U.S. Pat. No. 5,621,022, the disclosure of which is totally incorporated herein by reference, discloses the use of a specific class of polymeric dyes in phase change ink compositions.
Phase change inks have also been used for applications such as postal marking, industrial marking, and labelling.
Phase change inks are desirable for ink jet printers because they remain in a solid phase at room temperature during shipping, long term storage, and the like. In addition, the problems associated with nozzle clogging as a result of ink evaporation with liquid ink jet inks are largely eliminated, thereby improving the reliability of the ink jet printing. Further, in phase change ink jet printers wherein the ink droplets are applied directly onto the final recording substrate (for example, paper, transparency material, and the like), the droplets solidify immediately upon contact with the substrate, so that migration of ink along the printing medium is prevented and dot quality is improved.
Compositions suitable for use as phase change ink carrier compositions are known. Some representative examples of references disclosing such materials include U.S. Pat. No. 3,653,932, U.S. Pat. No. 4,390,369, U.S. Pat. No. 4,484,948, U.S. Pat. No. 4,684,956, U.S. Pat. No. 4,851,045, U.S. Pat. No. 4,889,560, U.S. Pat. No. 5,006,170, U.S. Pat. No. 5,151,120, U.S. Pat. No. 5,372,852, U.S. Pat. No. 5,496,879, European Patent Publication 0187352, European Patent Publication 0206286, German Patent Publication DE 4205636AL, German Patent Publication DE 4205713AL, and PCT Patent Application WO 94/04619, the disclosures of each of which are totally incorporated herein by reference. Suitable carrier materials can include paraffins, microcrystalline waxes, polyethylene waxes, ester waxes, fatty acids and other waxy materials, fatty amide containing materials, sulfonamide materials, resinous materials made from different natural sources (tall oil rosins and rosin esters, for example), and many synthetic resins, oligomers, polymers, and copolymers.
U.S. Pat. No. 6,860,930 (Wu et al.), the disclosure of which is totally incorporated herein by reference, discloses a phase change ink composition comprising (a) a colorant and (b) a carrier comprising a polyamide, wherein the polyamide component of the carrier contains at least about 10 percent by weight of a branched triamide.
U.S. Patent Publication 2005/0130054 (Yuan et al.), the disclosure of which is totally incorporated herein by reference, discloses wax based inks for phase change/hot melt inkjet printing or thermal transfer printing applications. Also disclosed are waxes useful for toners for use in electrostatographic printing applications. Both materials are prepared using a wax having a narrow melting range. The narrow melting range of the wax reduces energy requirements in printing applications. The use of the waxes also promotes release for high speed printing and especially promotes fast drying in wax based ink applications.
U.S. Pat. No. 6,001,904 (Matzinger et al.), the disclosure of which is totally incorporated herein by reference, discloses phase change (hot melt) ink compositions for use in a phase change (hot melt) ink jet recording device in which recording is conducted by thermally melting the ink at a temperature above ambient temperature (20° C.) to provide prints that possess high quality images, scratch resistance, abrasion resistance, low-temperature storage stability and flexibility, offset and pick resistance, adhesion, and other desired properties to comprise: (a) from about 0.1% to about 30% of one or more colorants; and (b) from about 0.1 to about 99.9% of one or more reversibly-crosslinked-polymers. Components other than those listed above may be included in the ink compositions to achieve specific printer, substrate, or end use requirements. Furthermore, the invention also includes methods for the preparation of reversibly-crosslinked-polymers and for their use in the above-described inks.
U.S. Pat. No. 6,923,853 (Kremers et al.), the disclosure of which is totally incorporated herein by reference, discloses a meltable ink which is solid at room temperature, which ink is suitable for use in an indirect printing process, in which printing process the ink is transferred, by the use of an inkjet printhead, to a transfer element, whereafter the ink is transferred to a receiving material under pressure from the transfer element, the ink having a composition such that it is pressure-transferable at a temperature between a bottom temperature limit and a top temperature limit, wherein the ink has a deformation energy of less than 20×105 Pa·s at a temperature equal to said top temperature limit.
While known compositions and processes are suitable for their intended purposes, a need remains for improved phase change ink compositions. In addition, a need remains for phase change inks that can be jetted at temperatures below about 125° C. Further, a need remains for phase change inks that can be jetted with reduced energy requirements. Additionally, a need remains for phase change inks that can be jetted with less expensive printheads. There is also a need for phase change inks that enable improved thermal stability of the inks manifested as the color's stability over time when heated in printers. In addition, there is a need for phase change inks that enable improved printer reliability. Further, there is a need for phase change inks that enable quick recovery times from standby mode. Additionally, there is a need for phase change inks that enable printing with "instant-on" mode. A need also remains for phase change inks that exhibit desirable viscosity values at reduced printing temperatures. In addition, a need remains for phase change inks that enable the aforementioned advantages and also exhibit good printing characteristics, such as transfixing properties (including dither and solid fill dropout performance), acceptable jetting reliability, folding and creasing performance, color intensity, recovery after standby mode, and the like. Further, a need remains for phase change inks that generate images with improved hardness. Additionally, a need remains for phase change inks that generate images with improved gloss. There is also a need for phase change inks that exhibit reduced sweating; sweating is a problem wherein some ink ingredients migrate to the surface of solid ink sticks and aggregate at the ink stick surface inside the printer; the sticky "sweat" gradually drains down to the bottom and can cause the ink sticks to be difficult to slide in the ink load racks in the printers. In addition, there is a need for phase change inks that generate images with reduced showthrough when printed on paper substrates. Further, there is a need for phase change inks that exhibit reduced clogging of printheads while exhibiting all of the aforementioned advantages. Additionally, there is a need for phase change inks that enable reduced standby temperatures of phase change ink jet printheads without leading to clogging of the printhead or the need for a purge upon recovery to the operational jetting temperature. A need also remains for phase change inks with desirably low freezing points. In addition, a need remains for phase change inks that transfer efficiently from an intermediate transfer member to a final recording substrate when the intermediate transfer member is at a desirably high temperature to enable efficient transfer member cooling, which allows for efficient heat transfer and avoids automatic printer shutoff or slowdown from overheating of the intermediate transfer member by the ink, while also enabling jetting of the ink at a desirably low temperature. Further, a need remains for phase change inks that exhibit desirably high smudge temperatures when still-hot prints pass along guidance tracks in the printer, thereby reducing accumulation of ink along these guidance tracks that could later be transferred to blank paper.