Important design features and methods of launching a trailerable sailboat are described. The trailerable sailboat is designed to allow transportation on overland highways and to provide a simplified method of raising the mast without the need for a crane.

(1) Field of the Invention
This invention is directed toward trailerable sailboats in general and also to larger trailerable sailboats that can be transported over the public highway systems throughout the United States. Important features and methods are described which allow a sailboat to be trailerable with special considerations for convenience, operational simplicity, transportation, and expense.
(2) Description of Related Art
Historically, sailboats have provided important transportation and have more recently evolved into a significant recreation activity. As part of convenience, sailboats are commonly transported to desirable sailing locations on trailers over the US public roadway system. The trailer is used to launch the sailboat or a special crane is used to lift the boat into the water. Because sailboats always have a high sailing mast, the mast must be stored so the trailered boat will pass under bridges and fit with the US highway transportation specifications for dimensions and weight. How the mast is lowered, raised, and stored on a trailer becomes an important practical issue.
It is a distinct advantage to transport a sailboat on a trailer from the water to dry storage. This eliminates the need for an in water slip, which has the advantage of reducing cost to the owner for storage and handling. Being stored away from the harsh in-water environment also has the advantage of reducing maintenance expenses to the owner by reducing corrosion, fouling, mildew, organic growth, power use, and wear. Land storage of boats also has the advantage of releasing fewer toxins and other man made compounds into the water.
Others have considered the difficulties in raising and lowering a mast, including one that pivots. For example, U.S. Pat. Nos. 6,990,916, 6,526,901, 5,865,136, 4,718,370, and 4,624,204 all disclose various methods whereby a mast is raised and lowered. In these cases additional supporting structures, complicated mechanisms, or rigging that is not required for sailing the boat are needed to raise and lower the mast. The additional structures add weight, time, complexity, and expense to the boat operation.
A typical example of a mast raising system for a mast that pivots is U.S. Pat. No. 6,990,916 which discloses a mast stepping system with a vertical pole. The mechanism used to raise the mast is overly complicated and requires an operator to install the raising equipment. The mast support structure takes up a lot of deck space and has to be carried to, or stored on, the boat. It is very awkward for an operator to use.
Similarly, U.S. Pat. No. 5,865,136 discloses a portable crane with a winch and rigging that provides lifting force for a pivoting mast. However, the lifting mechanism is not required for sailing and must be installed and removed at each launching. The rail system described would need to be very heavy to contain the lifting and stability forces required making it unappealing for an operator to actually use.
U.S. Pat. No. 5,044,410 discloses a latching mechanism for a mast that pivots. However, no consideration is given to an easy method of raising the mast, in particular, for a mast that is too heavy for one operator to manually lift.
U.S. Pat. No. 4,934,295 discloses an unconventional A-shaped mast that is pivotally connected to the sailboat. The mast can be raised or lowered manually. However, as in other patents just described, no consideration is given to a simple method of raising the mast, in particular, for a mast that is too heavy for one operator to manually lift.
PCT publication number WO87002322 discloses a sailing boat with a separate 'boom,' which is more accurately described as an A-frame gin pole, that is added to the sailboat to aid in raising and lowering the mast. The so called boom is not actually used for sailing, and if placed aft of the main mast, would have to be removed for sailing. In actual use, this disclosure has serious practical limitations. The mast is prevented from tipping toward starboard or port by shrouds, or rigging. The tension in these lines must be continually adjusted when the mast is raised or lowered; otherwise even a light wind will place excessive torsion on the mast base. Another source of torsion may come from the boat being moderately tipped, such as may occur when the trailer is on a sloped surface. This is awkward and impractical and makes it difficult for a single operator to raise or lower the mast. A suggested spring adjustment is not well thought out and is illustrated non-symmetrically, without a practical explanation on how it would operate or be controlled. Finally, there are no descriptions of how the pivot points of the mast or boom should be designed to withstand any inadvertent twisting forces that will be likely be applied to the mast or boom in the raising operation.
U.S. Pat. No. 4,655,154 discloses a collapsible mast assembly for a sailboat that includes a deck mounted mast support. A pivoting mast is described but the patent does not disclose an easy method of raising the mast, in particular, for a mast that is too heavy for one operator to manually lift. The boom does not move the mast as the mast is folded over on top of the boom in the stored position.
On a conventional sailboat, the boom is mounted to the mast, above the mast base, on a universal joint. It is not practically possible to use the boom as a lever in raising the mast. The boom is unstable due to the freedom of motion provided by the universal joint.
Historically, and currently, trailerable sailboats are generally limited to sailboats having lengths of less than approximately thirty feet due to excessive width and weight of the boat, and due to the weight and complexity of the sailing rig in larger boats. The design of these relatively shorter boats does not consider important difficulties that arise in larger sailboats. Sailboats longer than approximately thirty feet, designed to customary industry proportions, have widths, drafts, or weights that exceed practical maximums for private trailers on most highways. Consequently, trailer, rigging, and launching challenges rise disproportionately as sailboats become longer than approximately thirty feet. Also, longer sailboats require special permits and/or commercial carriers for transport over land, due to their overall dimensions, and especially due to their width. These larger sailboats require substantial disassembly for transport requiring a crane to remove and position the mast.
Sailboats of the previously described patents often use hinged mast raising and lowering techniques suitable only for a smaller sailboat where the mast weight is about 25 pounds or less. When a mast is heavier than this, special tools, rigging, or mechanical leverage have become needed for a single operator to safely lift and install the mast.
A number of the previous trailerable sailboats utilize a mast that is completely removed from the sailboat and then stored horizontally on top of the sailboat during overland transport. Special mast supports are then used. This design is undesirable as modern masts for larger boats include numerous important rigging lines and electrical wiring to equipment used for sailing that must be disconnected. Also, longer trailerable sailboats have a commensurately heavier mast which makes the method of completely removing the mast from the sailboat highly undesirable. The storage of a heavy mast in this manner is very unappealing to an operator, requires a lot of time and care, makes an operator vulnerable to injury, and is likely to damage the sailboat. Sailboat operators are primarily interested in the amount of time in the water and not the amount of time needed for various preparations.
Longer, trailerable sailboats have a number of design problems that require a complete design encompassing important details due to the length and weight of the sailboat. The essential problems not previously considered as a whole are: the mast must be raised and lowered in a controlled and easy method, the overall dimensions must fit within normal overland transport requirements, and the position on a trailer must include considerations for the longer and heavier mast. The design must also consider that it is desirable to launch a sailboat within 10 to 15 minutes after arriving at a boat launch without use of a crane or other external equipment in typical weather conditions. It is especially desirable to launch the boat with only one operator. Further, it is also desired that existing equipment on the sailboat is used to the extent possible to accomplish these important functions.

Trailerable sailboat with mast raising method


There are disclosed various methods, apparatuses and computer program products for volumetric video encoding and decoding. In some embodiments of a method for encoding, obtaining one or more patches formed from a three-dimensional image information are obtained. The one or more patches represent projection data of at least a part of an object to a projection plane. Priority for at least one of the one or more patches is determined and the one or more patches are projected to a projection plane. Indication of the priority is encoded into or along a bitstream. In some embodiments of a method for decoding, one or more encoded patches formed from a three-dimensional image information are received. Also at least one indication of priority determined for at least one of the one or more patches is received and the patches are reconstructed in the order defined by the at least one indication of priority.

This section is intended to provide a background or context to the invention that is recited in the claims. The description herein may include concepts that could be pursued, but are not necessarily ones that have been previously conceived or pursued. Therefore, unless otherwise indicated herein, what is described in this section is not prior art to the description and claims in this application and is not admitted to be prior art by inclusion in this section.
A video coding system may comprise an encoder that transforms an input video into a compressed representation suited for storage/transmission and a decoder that can uncompress the compressed video representation back into a viewable form. The encoder may discard some information in the original video sequence in order to represent the video in a more compact form, for example, to enable the storage/transmission of the video information at a lower bitrate than otherwise might be needed.
Volumetric video data represents a three-dimensional scene or object and can be used as input for virtual reality (VR), augmented reality (AR) and mixed reality (MR) applications. Such data describes the geometry attribute, e.g. shape, size, position in three-dimensional (3D) space, and respective attributes, e.g. colour, opacity, reflectance and any possible temporal changes of the geometry attribute and other attributes at given time instances. Volumetric video is either generated from 3D models through computer-generated imagery (CGI), or captured from real-world scenes using a variety of capture solutions, e.g. multi-camera, laser scan, combination of video and dedicated depth sensors, and more. Also, a combination of CGI and real-world data is possible.
Typical representation formats for such volumetric data are triangle meshes, point clouds (PCs), or voxel arrays. Temporal information about the scene can be included in the form of individual capture instances, i.e. "frames" in 2D video, or other means, e.g. position of an object as a function of time.
Identifying correspondences for motion-compensation in 3D-space may be an ill-defined problem, as both the geometry and respective attributes may change. For example, temporal successive "frames" do not necessarily have the same number of meshes, points or voxel. Therefore, compression of dynamic 3D scenes may be inefficient. 2D-video based approaches for compressing volumetric data, i.e. multiview+depth, may have better compression efficiency, but rarely cover the full scene. Therefore, they provide only limited six degrees of freedom (6DOF) capabilities.
Because volumetric video describes a 3D scene (or object), such data can be viewed from any viewpoint. Therefore, volumetric video may be an important format for any AR, VR, or MR applications, especially for providing 6DOF viewing capabilities.
Increasing computational resources and advances in 3D data acquisition devices has enabled reconstruction of highly detailed volumetric video representations of natural scenes. Infrared, lasers, time-of-flight and structured light are all examples of devices that can be used to construct 3D video data. Representation of the 3D data depends on how the 3D data is used. Dense Voxel arrays have been used to represent volumetric medical data. In 3D graphics, polygonal meshes are extensively used. Point clouds on the other hand are well suited for applications such as capturing real world 3D scenes where the topology is not necessarily a 2D manifold. Another way to represent 3D data is coding this 3D data as set of texture and depth map as is the case in the multi-view plus depth. Closely related to the techniques used in multi-view plus depth is the use of elevation maps, and multi-level surface maps.
In dense point clouds or voxel arrays, the reconstructed 3D scene may contain tens or even hundreds of millions of points. If such representations are to be stored or interchanged between entities, then efficient compression may become essential.

Apparatus, a method and a computer program for volumetric video


A sensing delay circuit includes a logic element which responds to a test mode signal to transfer a start signal, a delay unit which is configured of a plurality of inverters having MOS transistors with controlled threshold voltage, and receives external voltage as bulk voltage and delays an output signal from the logic element by a predetermined period, and a buffer which responds to an output signal from the delay unit to buffer the output signal from the logic element and output it.

With the progress of a technology of a computer system or a telecommunication field, or the like, a demand for a low-cost, small-sized, and large-capacity semiconductor memory device used for storing information has been gradually increased. Further, since a demand for energy efficiency has also been increased, the technology development of the semiconductor memory device shows a tendency to suppress unnecessary current consumption.
Generally, a cell array storing data of a DRAM device has a structure that each of a plurality of cells configured of one NMOS transistor and one capacitor is connected to word lines and bit lines connected to each other in a net form.
An operation of a general DRAM device will be described briefly.
First, a /RAS signal, which is a main signal operating the DRAM device, is changed into an active state (low) and at the same time, an address signal input to a row address buffer is received. At this time, a row decoding operation selecting one of the word lines of the cell array by decoding the received row address signal is performed.
When the data of the cells connected to the selected word line are carried on a bit line pair BL, /BL configured of a bit line and a complementary bit line, a sense amplifier enable signal informing the operation timing of the sense amplifier is enabled to drive a bit line sense amplifier in a cell block selected by the row address. When the bit line sense amplifier is driven, the bit line pair BL, /BL maintaining predetermined potential difference ΔV by charge sharing is amplified at large potential difference. Thereafter, a column decoder selected by a column address turns-on a column transfer transistor transferring the data of the bit line to data bus lines to transfer the data transferred to the bit line pair BL, /BL to the data bus lines DB, DB/, which are then output to the outside of the device.
In the DRAM operation, the bit line sense amplifier should be driven after securing a sensing delay period shown in FIG. 1. In other words, the sense amplifier should be driven after securing sufficient potential difference ΔV between the bit line pair BL, /BL by the charge sharing, making it possible to prevent a phenomenon that the data of the bit line pair BL, /BL are reversed during the driving of the bit line sense amplifier.
Therefore, the bit line sense amplifier is controlled to be driven after securing sufficient potential difference ΔV between the bit line pair BL, /BL by controlling the enable start period of the sense amplifier enable signal using the delay circuit in the related art.
However, a core voltage VCORE level, which drives the delay circuit, rises when the external voltage VDD level is high or upon over driving so that the driving capability of the delay circuit is increased, thereby leading to a phenomenon that the delay period is short. When the delay period is short, the enable start period of the sense amplifier enable signal is early so that the sense amplifier is driven at a state where sufficient potential difference ΔV between the bit line pair BL, /BL is not secured, thereby leading to the phenomenon that the data of the bit line pair BL, /BL are reversed during the driving of the bit line sense amplifier.

Sensing delay circuit and semiconductor memory device using the same


A method and apparatus for accelerating the execution of an object oriented computer program having a plurality of objects. In one embodiment, each of the objects includes an object header and object data which are stored in a memory. Moreover, each of the objects is associated with a corresponding set of methods (or functions). A typical object oriented program only maintains one copy of a method which is accessed by more than one object. However, in the present invention, each method is copied and stored in a memory, such that each object has a dedicated set of methods stored in memory. For example, if a first object and a second object require access to the same method, then a first copy of this method is provided for the first object, and a second copy of this method is provided for the second object. Providing each object with a dedicated set of methods minimizes the levels of indirection required to access the methods, and thereby accelerates the execution of instructions which access the objects.

1. Field of the Invention
The present invention relates generally to computer systems, and in particular, to a computer system which executes object-oriented code.
2. Discussion of Related Art
Many individuals and organizations in the computer and communications industries tout the Internet as the fastest growing market on the planet. In the 1990s, the number of users of the Internet appears to be growing exponentially with no end in sight. In June of 1995, an estimated 6,642,000 hosts were connected to the Internet; this represented an increase from an estimated 4,852,000 hosts in January, 1995. The number of hosts appears to be growing at around 75% per year. Among the hosts, there were approximately 120,000 networks and over 27,000 web servers. The number of web servers appears to be approximately doubling every 53 days.
In July 1995, with over 1,000,000 active Internet users, over 12,505 usenet news groups, and over 10,000,000 usenet readers, the Internet appears to be destined to explode into a very large market for a wide variety of information and multimedia services.
In addition, to the public carrier network or Internet, many corporations and other businesses are shifting their internal information systems onto an intranet as a way of more effectively sharing information within a corporate or private network. The basic infrastructure for an intranet is an internal network connecting servers and desktops, which may or may not be connected to the Internet through a firewall. These intranets provide services to desktops via standard open network protocols which are well established in the industry. Intranets provide many benefits to the enterprises which employ them, such as simplified internal information management and improved internal communication using the browser paradigm. Integrating Internet technologies with a company's enterprise infrastructure and legacy systems also leverages existing technology investment for the party employing an intranet. As discussed above, intranets and the Internet are closely related, with intranets being used for internal and secure communications within the business and the Internet being used for external transactions between the business and the outside world. For the purposes of this document, the term "networks" includes both the Internet and intranets. However, the distinction between the Internet and an intranet should be born in mind where applicable.
In 1990, programmers at Sun Microsystems wrote a universal programming language. This language was eventually named the JAVA programming language. (JAVA is a trademark of Sun Microsystems of Mountain View, Calif.) The JAVA programming language resulted from programming efforts which initially were intended to be coded in the C++ programming language; therefore, the JAVA programming language has many commonalties with the C++ programming language. However, the JAVA programming language is a simple, object-oriented, distributed, interpreted yet high performance, robust yet safe, secure, dynamic, architecture neutral, portable, and multi-threaded language.
The JAVA programming language has emerged as the programming language of choice for the Internet as many large hardware and software companies have licensed it from Sun Microsystems. The JAVA programming language and environment is designed to solve a number of problems in modern programming practice. The JAVA programming language omits many rarely used, poorly understood, and confusing features of the C++ programming language. These omitted features primarily consist of operator overloading, multiple inheritance, and extensive automatic coercions. The JAVA programming language includes automatic garbage collection that simplifies the task of programming because it is no longer necessary to allocate and free memory as in the C programming language. The JAVA programming language restricts the use of pointers as defined in the C programming language, and instead has true arrays in which array bounds are explicitly checked, thereby eliminating vulnerability to many viruses and nasty bugs. The JAVA programming language includes objective-C interfaces and specific exception handlers.
The JAVA programming language has an extensive library of routines for coping easily with TCP/IP protocol (Transmission Control Protocol based on Internet protocol), HTTP (Hypertext Transfer Protocol) and FTP (File Transfer Protocol). The JAVA programming language is intended to be used in networked/distributed environments. The JAVA programming language enabled the construction of virus-free, tamper-free systems. The authentication techniques are based on public-key encryption.
As previously described, the JAVA programming language is an object oriented language. FIG. 1 is a block diagram which illustrates the processing of a conventional object oriented instruction, INSTRUCTION [METHOD.sub.-- NO, NO.sub.-- ARGS]. FIG. 1 illustrates operand stack 10, objects 20A and 20B, method vectors 30A and 30B and code vectors 40A and 40B. Objects 20A and 20b, method vectors 30A and 30B, and code vectors 40A and 40B are stored at predetermined addresses in a program memory (not shown). Object oriented computer programs, such as those programs written in the JAVA programming language, typically include a number of super classes and sub-classes. In the described example, object 20A forms a super class, while object 20B forms a sub-class.
The instruction, INSTRUCTION [METHOD.sub.-- NO, NO.sub.-- ARGS], is provided to an execution unit (not shown). This instruction is capable of accessing any one of four associated methods, METHOD 0, METHOD 1, METHOD 2 and METHOD 3. The variable, METHOD.sub.-- NO, has a value of 0, 1, 2 or 3 to identify the method to be accessed by the instruction. For example, when the variable METHOD.sub.-- NO has a value of 1, the execution unit accesses code associated with METHOD 1.
The instruction also includes a variable, NO.sub.-- ARGS, which identifies the number of arguments associated with the instruction. The arguments associated with the instruction are stored at the top of operand stack 10. In the described example, the variable NO.sub.-- ARGS has a value of 2 to indicate that there are two arguments (i.e., ARGUMENT #1 and ARGUMENT #2) associated with the instruction stored in operand stack 10. A pointer to an object header is stored immediately below the arguments in operand stack 10. This pointer identifies the address of an object which is associated with the instruction.
The execution unit determines the location of the pointer to the object header within operand stack 10 from the variable NO.sub.-- ARGS, and retrieves this pointer from operand stack 10. Thus, if the variable NO.sub.-- ARGS is equal to 2, the execution unit retrieves the pointer to the object header from the third entry down from the top of operand stack 10. In the described example, the pointer to the object header has a value of 1000. In response, the execution unit accesses address 1000 within the program memory. Address 1000 corresponds with object 20A. Object 20A includes an object header and object data which defines object 20A. In the present example, the object header of object 20A has a value of 2000. The object header is also referred to as a class pointer.
The execution unit accesses the value of the object header from address 1000 of the program memory. The execution unit then adds the value of the object header and the value of the variable METHOD.sub.-- NO. The resulting value is a method descriptor pointer (or method vector entry) which is used to access method vector 30A. That is, the execution unit accesses the address which is identified by the method descriptor pointer value. For example, if the variable METHOD.sub.-- NO has a value of 1, the execution unit generates a method descriptor pointer having a value of 2001. In this case, the execution unit accesses the method pointer stored at address 2001 of the program memory (i.e., METHOD POINTER 1). In the described example, METHOD POINTER 1 has a value of 6000.
The execution unit then accesses code which is stored at the address identified by the value of the accessed method pointer. For example, if METHOD POINTER 1 is accessed, the execution unit accesses code which is stored at address 6000 of the program memory (i.e., CODE FOR METHOD 1).
By selecting the variable METHOD.sub.-- NO to have values of 0, 2 and 3, the execution unit accesses CODE FOR METHOD 0 at address 3000, CODE FOR METHOD 2 at address 5000, and CODE FOR METHOD 3 at address 6000, respectively.
If the pointer to the object header stored in operand stack 10 has a value of 1500, then the execution unit accesses object 20B. The object header for object 20B has a value of 2500. Thus, if the METHOD.sub.-- NO has a value of 1, the method descriptor pointer has a value of 2501. As a result, the execution unit accesses METHOD POINTER 1 at address 2501 of the program memory. In the described example, METHOD POINTER 1 has a value of 4000. Consequently, the execution unit accesses the CODE FOR METHOD 1 at address 4000 of the program memory.
Thus, objects 20A and 20B are able to share the same code in the program memory. As is well known in the art, this is one of the advantages of an object oriented program. Objects 20A and 20B can also access unique code within the program memory. For example, object 20A can access code located at addresses 3000, 5000 and 6000 of the program memory, while object 20B can access code located at address 7000 of the program memory.
Although different objects can share the same code in the program memory, the execution unit must undergo two levels of indirection to accomplish this code sharing. That is, the execution unit must generate and use the method descriptor pointer to direct access to the appropriate method pointer, and the execution unit must retrieve and use the method pointer to direct access to the appropriate code. Yet another level of indirection may be introduced if the accessed code directs the execution unit to code which is located at another address in the program memory.
Each level of indirection requires additional processing time within the execution unit. Thus, as the levels of indirection increase, the time required for the execution unit to complete the execution of the instruction also increases. In certain object oriented programs, the time required to execute the code is relatively short. As a result, the additional processing time introduced by the levels of indirection can be as much as 40% of the entire time required to execute the instruction.
It would therefore be desirable to have a method for accessing object oriented code which reduces the levels of indirection required to execute an object oriented instruction.

Replicating code to eliminate a level of indirection during execution of an object oriented computer program


The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof:

Cystic fibrosis is an autosomal recessive genetic disorder caused by mutations of the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). The incidence of the disease among the Caucasian population is 1/2000-3000 newborns, whereas it is much lower among native Africans and Asians. Despite progress in the treatment of cystic fibrosis, there is no cure.
The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an epithelial ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues.
Specifically, CFTR is a 1480 amino acid plasma membrane protein that belongs to the superfamily of ATP-binding cassette (ABC) transporters. CFTR structure consists of a cytosolic N-terminus followed by six transmembrane helices, a nucleotide-binding domain (NBD1), aregulatory (R) domain, six additional transmembrane helices, a second nucleotide-binding domain (NBD2), and a cytosolic C-terminus (Riordan, Annu Rev Biochem 77:701-726, 2008). The transmembrane helices form a pore permeable to chloride, bicarbonate, iodide, and other anions. Opening of the pore requires the phosphorylation of the R domain by the cAMP-dependent protein kinase A as well as binding of two ATP molecules in two pockets formed by the assembly of NBD1 and NBD2.
CFTR is a cAMP/ATP-modulated anion channel that is expressed in a variety of cells types, and particularly in epithelial cells of various organs including lungs, pancreas, liver, and intestine (Mall and Hartl, Eur Respir J 44:1042-1054, 2014). Physiological signals that increase intracellular cAMP levels elicit CFTR activation. In most tissues, opening of CFTR pore leads to chloride and bicarbonate secretion. A notable exception is represented by the sweat gland duct in which CFTR mediates chloride absorption and not secretion.
In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissues.
The important role of CFTR is demonstrated by the severe pathological manifestations occurring in cystic fibrosis (CF), an inherited disease caused by mutations that lead to CFTR loss of function. In the lungs, lack of CFTR-dependent anion secretion impairs mucociliary clearance and innate antimicrobial mechanisms (Collawn and Matalon, Am J Physiol 307: L917-L923, 2014). Consequently, the airways become colonized by antibiotic-resistant bacteria that trigger a severe inflammatory response and a progressive loss of respiratory function.
The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362; Riordan, J. R. et al. (1989) Science 245:1066-1073). Defects in this gene cause mutations in CFTR protein resulting in cystic fibrosis, the most common fatal genetic disease in humans. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the cystic fibrosis associated gene suffer from the debilitating and fatal effects of cystic fibrosis, including chronic lung disease.
In addition to respiratory disease, cystic fibrosis patients typically suffer from gastrointestinal problems and pancreatic insufficiency. If left untreated, cystic fibrosis results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the cystic fibrosis associated gene, individuals with a single copy of the cystic fibrosis associated gene may exhibit increased resistance to dehydration resulting from diarrhea. This heterozygote advantage could explain the relatively high frequency of the cystic fibrosis gene within the population.
Sequence analysis of the CFTR gene of cystic fibrosis patients has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; Kerem, B-S. et al. (1989) Science 245: 1073-1080; Kerem, B-S. et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, more than 2000 CF-causing mutations in the cystic fibrosis gene have been identified, involving 6 classes of molecular defects of the protein (Class I: premature stop of CFTR protein synthesis; Class II: defective maturation and intracellular localization of the CFTR protein; Class III: impaired opening of CFTR pore; Class IV: reduced ability of CFTR pore to translocate anions; Class V: reduced CFTR protein synthesis due to altered RNA splicing; Class VI: reduced stability of CFTR at the plasma membrane leading to accelerated internalization and degradation).
A large majority of mutations have low or very low frequency (Bobadilla et al., Hum Mutat 19:575-606, 2002). However, a single mutation, F508del, is present in 50-90% of CF patients. F508del, i.e. loss of phenylalanine at position 508 within NBD1, causes multiple defects to CFTR protein (Okiyoneda et al., Nat Chem Biol 9:444-454, 2013). First of all, F508del-CFTR folding and stability are severely impaired. Such problems, which arise from the intrinsic instability of NBD1 and the altered interaction between NBD1 and the cytosolic loop 4, strongly reduce the trafficking of F508del-CFTR to the plasma membrane (trafficking defect). Indeed, mutant CFTR remains trapped in the endoplasmic reticulum (ER) where it is rapidly degraded by the ubiquitin-proteasome system (Lukacs and Verkman, Trends Mol Med 18:81-91, 2012). A second defect caused by F508del is the reduction of the open channel probability, i.e. the fraction of time spent by the channel in the open state (gating defect). Furthermore, if moved to the plasma membrane by rescue maneuvers, F508del-CFTR shows also a decreased half-time. Because of such defects, F508del mutation has combined class II, class III, and class VI characteristics.
The trafficking and gating defects can also be caused, often separately, by other CF mutations. For example, G85E, L1077P, A455E, and N1303K, defined as class II mutations, impair CFTR trafficking (Van Goor et al., J Cyst Fibros 13:29-36, 2014). Instead, G551D, G1349D, G178R, and G970R, defined as class III mutations, do not affect trafficking but strongly reduce CFTR open time (Yu et al., J Cyst Fibros 11:237-245, 2012).
The most prevalent mutation, i.e. the F508del, is associated with a severe disease.
The reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport.
As discussed above, it is believed that the deletion of residue 508 in CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced. This cellular phenomenon of defective ER processing of ABC transporters by the ER machinery has been shown to be the underlying basis not only for cystic fibrosis disease, but for other diseases (Loo et al., Journal of Bioenergetics and Biomembranes, 2005, 37, 501-507).
At present, the treatment of lung disorders in cystic fibrosis requires the development of innovative drugs aimed at the concomitant aspects of the disease and, consequently, modulators of the defective CFTR protein, new antibacterials and new anti-inflammatory agents, which can be used in parallel to obtain a synergistic action. Trafficking and gating defects caused by mutations in the CFTR protein are amenable to pharmacological treatment (Veit et al., Mol Biol Cell 27:424-433, 2016). Mistrafficking can be targeted with small molecules called correctors. Gating can be improved with so-called potentiators. There have been several attempts to identify potentiators and correctors (Galietta, Pediatr Drugs 15:393-402, 2013). The most advanced molecule is VX-770, also known as ivacaftor, developed by Vertex Pharmaceuticals (Van Goor et al., Proc Natl Acad Sci USA 106:18825-18830, 2009). Given its high efficacy in clinical trials (Ramsey et al., N Engl J Med 365:1663-1672, 2011), VX-770 has been approved for the treatment of patients with G551D and other eight mutations belonging to class III, who represent about 5% of all the cystic fibrosis patients. VX-770 has no significant therapeutic efficacy in patients who are homozygous for the F508del-CFTR mutation, confirming the need for customized treatments for sub-groups of patients suffering from cystic fibrosis depending on the specific CFTR protein molecular defect. For patients with the F508del-CFTR mutation, new molecules functioning as "correctors" of the mutated CFTR protein are under study. The VX-809 molecule, also known as lumacaftor, has been extensively characterized in cell models in vitro. In clinical trials on cystic fibrosis patients with F508del mutation, VX-809 did not show a clear therapeutic benefit (Clancy et al., Thorax 67:12-18, 2012). However, the combination of VX-809 and VX-770, commercially named Orkambi, elicited a significant although modest improvement in respiratory function (Wainwright et al., N Engl J Med 373: 220-231, 2015). Briefly, the treatment of cystic fibrosis patients requires different modulators of the mutated CFTR protein, namely "correctors" and/or "potentiators", depending on the mutations of the CFTR gene, which divide the patients into genetically distinct sub-groups, and complementary medicaments with an antibacterial action and an anti-inflammatory action.
Accordingly, there is a need for novel compounds to be used for the treatment of CFTR mediated diseases which involve CFTR modulator compounds.

This patent is subject to a terminal disclaimer.

Compounds and compositions for the treatment of cystic fibrosis

Abstract: It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses, in particular to modulate CFTR protein or ABC protein activities.


This disclosure concerns specific naturally-occurring mutant maize cad2 genes, which altered genes contribute to the bm1 maize phenotype in particular maize lines. In some embodiments, compositions and methods are provided that utilize a nucleic acid molecule comprising a mutant cad2 gene, and/or markers linked to a mutant cad2gene.

Lignins are universal components in plants that form cross-links with carbohydrates, such as hemicelluloses in the cell wall. Lignin and cellulose are the two predominant components of the plant cell wall. The plant cell wall provides a natural barrier against the extracellular environment. Many studies have demonstrated that one of the responses of plants to biotic stresses (e.g., pathogenic infection) or abiotic stresses (e.g., drought, mechanical stress, etc.) consists of reinforcement of the plant cell wall, in particular by increasing the lignin content in the plant cell wall. Many agronomical or industrial applications concern desired plant products (e.g., products used in paper production, silage production, and the production of energy, for example, in the form of biofuels), the yields of which are directly linked to the content and/or composition of lignin in the plant cell wall.
Lignin polymers limit the digestibility of the fiber in the corn plant. Lignin polymers lower fiber digestion in ruminants, and the degree of lignifications may be inversely proportional to forage crop digestibility. Cherney et al. (1991) Adv. Agron. 46:157-98. Modulation of lignin content and composition may be desirable to increase the digestibility of forage. Lignin content modulation may also be desirable, e.g., to reinforce plant walls, and thereby improve resistance to stresses; or conversely to weaken the plant wall in order to facilitate the extraction of cellulose or other chemical compounds. Baucher et al. (1998) Plant Mol. Biol. 39:437-47.
It is, however, difficult to know how to modify the lignin biosynthesis pathway, and to predict what the consequences of modifications will be. This is at least in part because the lignin biosynthesis pathway is a complex pathway involving a large number of enzymatic reactions. See, e.g., Dixon et al. (2001) Phytochemistry 57(7):1069-84. Possible mechanisms by which the pathway may be altered physiologically, for example, to compensate for a change introduced by a modification in the pathway, are not known.
Lignin is an insoluble polymer of 3 monomers of alcohols or monolignols: p-coumaryl alcohol (H subunits), coniferyl alcohol (G subunits), and sinapyl alcohol (S subunits), that are derived from the phenylpropanoid pathway. Neish (1968) Constitution and Biosynthesis of Lignin, eds. New York, Springer Verlag 1-43. Each type of subunit can form a variety of bonds with others, and thereby constitute lignin. Other bonds may also be established with other parietal compounds (e.g., polysaccharides and proteins) so as to form a complex three-dimensional network.
Steps in the complex lignin production pathway include hydroxylation, O-methylation of aromatic rings, and conversion of a carboxyl side chain to an alcohol function. The current hypothesis for the monolignol biosynthesis pathway includes successive hydroxylation and O-methylation reactions at various levels of oxidation of the side chains in a metabolic network, thereby resulting in the formation of S and G subunits. The enzymes of the network include caffeic acid 3-O-methyltransferase (COMT); hydroxyxinamate coenzyme A ligases (4CL); cytochrome P450-dependent ferulate 5-hydroxylases (F5Hs); and several isoforms of cinnamoyl CoA reductase (CCR) and of cinnamyl alcohol dehydrogenase (CAD).
For several years, attempts have been made to modify the lignin content and composition of plants by over-expressing or under-expressing one or more genes of the lignin biosynthesis pathway. Anterola and Lewis (2002) Phytochemistry 61:221-94. Though various strategies have been imagined, the over-expression or under-expression of one or more enzymes in the lignin biosynthesis pathway does not always give reliable and predictable results.
Another strategy consists of using, in selection schemes, mutants of a targeted gene in the lignin biosynthesis pathway. Plants containing a brown midrib (bmr) mutation exhibit altered lignin composition and digestibility. In corn, at least four independent brown midrib mutations have been identified. Kuc et al. (1968) Phytochemistry 7:1435-6. These mutations, termed "bm1, bm2, bm3, and bm4," all exhibit decreased lignin content when compared to control corn. Brown midrib corn plants are characterized by a brown pigmentation in the leaf midrib at the V4 to V6 stage and a light brown coloration of the pith after tasselling. One characterized bmr mutation is an insertion mutation in the COMT enzyme (bm3).
Mature bm1 maize plants have a lignin content that is reduced by 10-20%, a slight decrease in ferulic acid esters, and a substantially reduced content (˜40%) of p-coumaric esters and ferulic acid esters. Provan et al. (1997) J. Agric. Food 73:133-42; Barriére et al. (2004) Comptes Rendus Biologie 327:847-60. The frequency of p-hydroxyphenyl, guaiacyl, and syringyl thioacidolysis monomers is similar in bm1 and wild-type plants, showing that the bm1 mutation does not specifically affect a single type of lignin subunit. Guillaumie et al. (2007) Planta 226(1):235-50. Lignins of bm1 plants do appear to be substantially enriched in carbon-carbon inter-subunit linkages (Halpin et al. (1998) Plant J. 14(5):545-53; Barriére et al. (2004), supra), and bm1 lignins have substantial incorporation of coniferaldehyde and, to a lesser extent, of sinapaldehyde. Kim et al. (2002) J. Biol. Chem. 277:47412-9.
Agriculturally important uses of corn (maize) include silage. Silage is fermented, high-moisture fodder that can be fed to ruminants. It is fermented and stored in a process called ensilage or silaging, and is usually made from corn or other grass crops, including sorghum or other cereals, using the entire green plant. Bulk silage is commonly fed to dairy cattle, while baled silage tends to be used for beef cattle, sheep, and horses. Since silage goes through a fermentation process, energy is used by fermentative bacteria to produce volatile fatty acids, such as acetate, propionate, lactate, and butyrate, which preserve the forage. The result is that the silage is lower in energy than the original forage, since the fermentative bacteria use some of the carbohydrates to produce the volatile fatty acids. Corn silage is a popular forage for ruminant animals because it is high in energy and digestibility and is easily adapted to mechanization from the stand-crop to time of feeding. Corn silage generally is slightly brown to dark green in color, and has a light, pleasant smell.
The reduced lignin in brown midrib corn (bmr corn) results in silage with fiber that is more digestible than normal corn and exhibits an improved rate of biofuel conversion. Feeding bmr corn silage to lactating dairy cows has been shown to increase dry matter intake (DMI) and milk yield. Grant et al. (1995) J. Dairy Sci. 78:1970-80; Oba and Allen (2000) J. Dairy Sci. 83:1333-41; Oba and Allen (1999) J. Dairy Sci. 82:135-42. However, bmr corn silage reduced average daily gain and feed efficiency (G:F) in beef cows, compared to corn silage from a conventional corn variety. Tjardes et al. (2000) J. Anim. Sci. 78:2957-65. Brown midrib hybrid corn lines are also frequently found to be low yielding. Brown midrib hybrid corn has also typically been associated with forage lodging and lack of standability.

Gene and variations associate with BM1 phenotype, molecular markers, and their use


An arrangement of exchangers for marinization of a marine engine, including an engine block with in-line cylinders or cylinders in a V, cooled by a cooling fluid, at least one turbocompressor with a hot chamber connected to an outlet and a cold chamber connected to the cylinders of the engine block, a reverser including a housing and containing oil, wherein the arrangement includes:                a radiator hose for supplying cooling water,        a turbocompressor exchanger,        an engine exchanger,        a reverser exchanger,        a radiator hose for discharging cooling water toward an outlet of combustion gases, downstream from the hot chamber of the at least one turbocompressor,with these three exchangers being placed in this order and inserted in the circulation direction of the water between the radiator hose for supplying the cooling water and the radiator hose for discharging this same cooling water.

Marine power engines, namely internal combustion engines operating on diesel fuel and producing several hundred horsepower, are used on working craft, service vessels, fishing vessels, or else pleasure vessels. Such engines come, for the most part, from makers of ground vehicle engines, be they vehicles intended for road transport, construction machines, or else farm machinery.
To produce an engine base, the costs are extremely high because these engines are increasingly sophisticated, increasingly precise during their operation with, in particular, management of temperatures that are located in specific ranges.
In addition, reliability is increasingly important, and it is necessary for this purpose that all of the operating aspects are perfectly controlled.
These engine bases should be compatible with the maximum number of vehicles, engines, or machines to ensure the amortization of research efforts and manufacturing resources.
During operation, these engines should be cooled to discharge a residual portion of the calories generated by the operation, and a cooling liquid circulates in the engine block for this purpose.
This cooling liquid circulates through a cooling exchanger for its own cooling. In the case of ground machines, this exchanger is a water/air exchanger.
As for power engines, they are systematically equipped with turbocompressors that comprise the gases intended to be allowed into the engine using exhaust gases. For this purpose, a hot turbine is driven by the exhaust gases in a first chamber, and a cold turbine integral with the same shaft is driven in rotation in a cold chamber.
The exhaust gases are discharged at the outlet of the hot chamber toward the exhaust line, and the compressed gases are injected into the cylinders of the engine with the fuel mixture.
The problem is that a compressed gas heats up, or, to achieve the best operation with an internal combustion engine, it is necessary to use compressed gases but it is also necessary to cool them before mixing with the fuel to improve the yield. An exchanger is therefore inserted at the outlet of the cold chamber of the turbocompressor to cool the compressed air before its transfer toward the engine.
This exchanger is of the air/air type in ground vehicle engines.
In ground engines, the engines are coupled to manual or automatic transmissions whose operations and arrangements are complex and numerous. The oil from these transmissions is optionally cooled by an independent oil/air exchanger.
In marine engines, the arrangements of the cooling elements are necessarily different since it is impossible to provide air cooling. The cooling fluid is fresh water or sea water.

Arrangement of exchangers for marinization of a marine engine


A transfer case includes a two-speed range unit, a friction clutch, a power-operated actuation mechanism and a control system. The actuation mechanism includes an electric motor, a geartrain driven by the motor for controlling rotation of an actuator shaft, a range actuator assembly and a mode actuator assembly. The range actuator assembly functions to move a shift collar associated with the range unit in response to rotation of the actuator shaft. The mode actuator assembly includes a mode cam and a ballramp unit. The mode cam is rotatively driven by the actuator shaft for controlling the clutch engagement force exerted on the friction clutch by the ballramp unit.

Due to the popularity of four-wheel drive vehicles, a number of power transfer systems are currently being used in vehicular drivetrain applications for selectively directing power (i.e., drive torque) from the powertrain to all four wheels of the vehicle. In many power transfer systems, a transfer case is incorporated into the drivetrain and is operable in a four-wheel drive mode for delivering drive torque from the powertrain to both the front and rear wheels. Many conventional transfer cases are equipped with a mode shift mechanism having a dog-type mode clutch that can be selectively actuated to shift between a two-wheel drive mode and a part-time four-wheel drive mode. In addition, many transfer cases also include a two-speed range shift mechanism having a dog-type range clutch which can be selectively actuated by the vehicle operator for shifting between four-wheel high-range and low-range drive modes.
It is also known to use adaptive power transfer systems for automatically biasing power between the front and rear wheels, without any input or action on the part of the vehicle operator, when traction is lost at either the front or rear wheels. Modernly, it is known to incorporate such a torque "on-demand" feature into a transfer case by replacing the mechanically-actuated mode clutch with a multi-plate clutch assembly and a power-operated clutch actuator that is interactively associated with an electronic control system. During normal road conditions, the clutch assembly is typically maintained in a released condition such that drive torque is only delivered to the rear wheels. However, when sensors detect a low traction condition, the control system actuates the clutch actuator for engaging the clutch assembly to deliver drive torque to the front wheels. Moreover, the amount of drive torque transferred through the clutch assembly to the non-slipping wheels can be varied as a function of specific vehicle dynamics, as detected by the sensors. Such on-demand clutch control systems can also be used in full-time transfer cases to adaptively bias the torque distribution ratio across an interaxle differential.
In some two-speed transfer cases, actuation of the range shift mechanism and the clutch assembly are independently controlled by separate power-operated actuators. For example, U.S. Pat. No. 5,407,024 discloses a two-speed range shift mechanism actuated by an electric motor and a clutch assembly actuated by an electromagnetic ball ramp unit. In an effort to reduce cost and complexity, some transfer cases are equipped with a single power-operated actuator that is operable to coordinate actuation of both the range shift mechanism and the clutch assembly. In particular, U.S. Pat. Nos. 5,363,938 and 5,655,986 each illustrate a transfer case equipped with a motor-driven cam having a pair of cam surfaces adapted to coordinate actuation of the range shift mechanism and the clutch assembly for establishing a plurality of distinct two-wheel and four-wheel drive modes. Examples of other transfer cases equipped with a single power-operated actuator for controlling coordinated engagement of the range shift mechanism and the mode clutch assembly are disclosed in U.S. Pat. Nos. 6,645,109; 6,783,475; 6,802,794; 6,905,436 and 6,929,577.
While conventional transfer cases equipped with coordinated clutch actuation systems have been commercially successful, a need still exists to develop alternative clutch actuation systems which further reduce the cost and complexity of two-speed actively-controlled transfer cases.

Two-speed transfer case with adaptive torque transfer clutch


A system and method for determining and predicting a patient's susceptibility to neurological dysfunction based on measured electrophysiological parameters employs a self-contained implantable device with depth electrodes implanted in desired locations in the patient's brain. The patient's neurological tissue is stimulated to determine excitability and refractoriness (or inhibition period) parameters, which are employed to identify susceptibility to abnormal neurological activity, particularly epileptic seizures.

Epilepsy, a neurological disorder characterized by the occurrence of seizures (specifically episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or the perturbation of the autonomic nervous system), is debilitating to a great number of people. It is believed that as many as two to four million Americans may suffer from various forms of epilepsy. Research has found that its prevalence may be even greater worldwide, particularly in less economically developed nations, suggesting that the worldwide figure for epilepsy sufferers may be in excess of one hundred million.
Because epilepsy is characterized by seizures, its sufferers are frequently limited in the kinds of activities they may participate in. Epilepsy can prevent people from driving, working, or otherwise participating in much of what society has to offer. Some epilepsy sufferers have serious seizures so frequently that they are effectively incapacitated.
Furthermore, epilepsy is often progressive and can be associated with degenerative disorders and conditions. Over time, epileptic seizures often become more frequent and more serious, and in particularly severe cases, are likely to lead to deterioration of other brain functions (including cognitive function) as well as physical impairments.
The current state of the art in treating neurological disorders, particularly epilepsy, typically involves drug therapy and surgery. The first approach is usually drug therapy.
A number of drugs are approved and available for treating epilepsy, such as sodium valproate, phenobarbital/primidone, ethosuximide, gabapentin, phenyloin, and carbamazepine, as well as a number of others. Unfortunately, those drugs typically have serious side effects, especially toxicity, and it is extremely important in most cases to maintain a precise therapeutic serum level to avoid breakthrough seizures (if the dosage is too low) or toxic effects (if the dosage is too high). The need for patient discipline is high, especially when a patient's drug regimen causes unpleasant side effects the patient may wish to avoid.
Moreover, while many patients respond well to drug therapy alone, a significant number (at least 20–30%) do not. For those patients, surgery is presently the best-established and most viable alternative course of treatment.
Currently practiced surgical approaches include radical surgical resection such as hemispherectomy, corticectomy, lobectomy and partial lobectomy, and less-radical lesionectomy, transection, and stereotactic ablation. Besides being less than fully successful, these surgical approaches generally have a high risk of complications, and can often result in damage to eloquent (i.e., functionally important) brain regions and the consequent long-term impairment of various cognitive and other neurological functions. Furthermore, for a variety of reasons, such surgical treatments are contraindicated in a substantial number of patients. And unfortunately, even after radical brain surgery, many epilepsy patients are still not seizure-free.
Electrical stimulation is an emerging therapy for treating epilepsy. However, currently approved and available electrical stimulation devices apply continuous electrical stimulation to neural tissue surrounding or near implanted electrodes, and do not perform any detection—they are not responsive to relevant neurological conditions.
The NeuroCybernetic Prosthesis (NCP) from Cyberonics, for example, applies continuous electrical stimulation to the patient's vagus nerve. This approach has been found to reduce seizures by about 50% in about 50% of patients. Unfortunately, a much greater reduction in the incidence of seizures is needed to provide clinical benefit. The Activa device from Medtronic is a pectorally implanted continuous deep brain stimulator intended primarily to treat Parkinson's disease. In operation, it supplies a continuous electrical pulse stream to a selected deep brain structure where an electrode has been implanted.
Continuous stimulation of deep brain structures for the treatment of epilepsy has not met with consistent success. To be effective in terminating seizures, it is believed that one effective site where stimulation should be performed is near the focus of the epileptogenic region. The focus is often in the neocortex, where continuous stimulation may cause significant neurological deficit with clinical symptoms including loss of speech, sensory disorders, or involuntary motion. Accordingly, research has been directed toward automatic responsive epilepsy treatment based on a detection of imminent seizure.
A typical epilepsy patient experiences episodic attacks or seizures, which are generally defined as periods of abnormal neurological activity. As is traditional in the art, such periods shall be referred to herein as "ictal" (though it should be noted that "ictal" can refer to neurological phenomena other than epileptic seizures).
Most prior work on the detection and responsive treatment of seizures via electrical stimulation has focused on analysis of electroencephalogram (EEG) and electrocorticogram (ECoG) waveforms. In general, EEG signals represent aggregate neuronal activity potentials detectable via electrodes applied to a patient's scalp, and ECoGs use internal electrodes on or near the brain. ECoG signals, deep-brain counterparts to EEG signals, are detectable via electrodes implanted under the dura mater, and sometimes within the patient's brain. Unless the context clearly and expressly indicates otherwise, the term "EEG" shall be used generically herein to refer to both EEG and ECoG signals.
Much of the work on detection has focused on the use of time-domain analysis of EEG signals. See, e.g., J. Gotman, Automatic seizure detection: improvements and evaluation, Electroencephalogr. Clin. Neurophysiol. 1990; 76(4): 317–24. In a typical time-domain detection system, EEG signals are received by one or more implanted electrodes and then processed by a control module, which then is capable of performing an action (intervention, warning, recording, etc.) when an abnormal event is detected.
In the Gotman system, EEG waveforms are filtered and decomposed into "features" representing characteristics of interest in the waveforms. One such feature is characterized by the regular occurrence (i.e., density) of half-waves exceeding a threshold amplitude occurring in a specified frequency band between approximately 3 Hz and 20 Hz, especially in comparison to background (non-ictal) activity. When such half-waves are detected, the onset of a seizure is identified.
A more computationally demanding approach is to transform EEG signals into the frequency domain for rigorous spectrum analysis. See, e.g., U.S. Pat. No. 5,995,868 to Dorfineister et al., which analyzes the power spectral density of EEG signals in comparison to background characteristics. Although this approach is generally believed to achieve good results, for the most part, its computational expense renders it less than optimal for use in long-term implanted epilepsy monitor and treatment devices. With current technology, the battery life in an implantable device computationally capable of performing the Dorfineister method would be too short for it to be feasible.
Also representing an alternative and more complex approach is U.S. Pat. No. 5,857,978 to Hively et al., in which various non-linear and statistical characteristics of EEG signals are analyzed to identify the onset of ictal activity. Once more, the calculation of statistically relevant characteristics is not believed to be feasible in an implantable device.
U.S. Pat. No. 6,016,449 to Fischell, et al. (which is hereby incorporated by reference as though set forth in full herein), describes an implantable seizure detection and treatment system. In the Fischell system, various detection methods are possible, all of which essentially rely upon the analysis (either in the time domain or the frequency domain) of processed EEG signals. Fischell's controller is preferably implanted intracranially, but other approaches are also possible, including the use of an external controller. When a seizure is detected, the Fischell system applies responsive electrical stimulation to terminate the seizure, a capability that will be discussed in further detail below.
All of these approaches provide useful information, and in some cases may provide sufficient information for accurate detection and prediction of most imminent epileptic seizures.
However, none of the various implementations of the known approaches provide 100% seizure detection accuracy in a clinical environment.
Two types of detection errors are generally possible. A "false positive," as the term is used herein, refers to a detection of a seizure or ictal activity when no seizure or other abnormal event is actually occurring. Similarly, a "false negative" herein refers to the failure to detect a seizure or ictal activity that actually is occurring or shortly will occur.
In most cases, with all known implementations of the known approaches to detecting abnormal seizure activity solely by monitoring and analyzing EEG activity, when a seizure detection algorithm is tuned to catch all seizures, there will be a significant number of false positives. While it is currently believed that there are minimal or no side effects to over-stimulation (e.g., providing stimulation sufficient to terminate a seizure in response to a false positive), the possibility of accidentally initiating a seizure must be considered.
Known systems for detecting epileptic seizures are essentially passive in nature (i.e., they receive and process existing signals), and valuable information about the physiological state of the brain is typically not available. Although most or nearly all seizures may be detected by a well-tuned system passive system according to the art, there may be a significant number of false-positive detections, and some seizures may not be detected early enough to facilitate successful treatment.
As is well known, it has been suggested that it is possible to treat and terminate seizures by applying electrical stimulation to the brain. See, e.g., U.S. Pat. No. 6,016,449 to Fischell et al., and H. R. Wagner, et al., Suppression of cortical epileptiform activity by generalized and localized ECoG desynchronization, Electroencephalogr. Clin. Neurophysiol. 1975; 39(5): 499–506. And as stated above, it is believed to be beneficial to perform this stimulation only when a seizure (or other undesired neurological event) is occurring or about to occur, as inappropriate stimulation may result in the initiation of seizures.
Furthermore, it should be noted that a false negative (that is, a seizure that occurs without any warning or treatment from the device) will often cause the patient significant discomfort and detriment. Clearly, false negatives are to be avoided.
To generalize, it is presently believed there may not be sufficient information in EEG waveforms to permit accurate detection and prediction of seizures in all cases. And if the information is present, it may be manifested in a way that makes it computationally difficult, if not impossible, to extract it from other EEG contents, such as normal brain activity and noise.

Predicting susceptibility to neurological dysfunction based on measured neural electrophysiology


Process for preparing a human thrombin concentrate from the PPSB fraction of plasma that does not involve any addition of factors of animal origin to induce activation of the prothrombin to produce thrombin, and which includes a viral inactivation step using solvent-detergent and purification by cation exchange chromatography. The choice of a protective medium ensures the high specific activity of the final product. The thrombin concentrate obtained using this process is intended for therapeutic use, either alone, to serve as a local hemostatic agent, or in combination with a fibrinogen concentrate to form biological glue.

1. Field of the Invention
The present invention relates to a process for preparing a human thrombin concentrate intended for therapeutic use, purified on an industrial scale from an isolated fraction of human plasma.
Thrombin is a serine-protease generated in the blood stream through activation of its inactive precursor, prothrombin. It plays a fundamental part in the coagulation process: it cuts the fibrinogen into fibrin monomers and, through proteolytic cutting, it activates Factor XIII which stabilizes the fibrin network.
It also plays a part in other physiological processes: it initiates the secretion and platelet aggregation reactions, thus facilitating the formation of the white plug. It also activates the proteins of the complement system. It has a mitogenic effect on the fibroblasts, which accelerates the healing of the damaged blood vessels.
As a result of these different properties, thrombin has therapeutic applications as a local haemostatic agent. At the present time, animal thrombin, equine or bovine, is used clinically in said therapeutic applications. These preparations are not always perfectly purified and their application can be the cause of immunological reactions due to the overload of heterologous proteins. The use of bovine thrombin further carries the risk of transmitting infectious diseases recently diagnosed and as et controlled with difficulty, such as spongiform bovine encephalitis (or "mad cow disease").
Thrombin purification, like that of many enzymes, poses problems as regards maintaining its total enzymatic activity. Native .alpha.-thrombin is, in fact, generally unstable and, through autolysis or limited proteolysis, it yields derivatives, .beta.- and .gamma.- thrombins that have lost a substantial part of their coagulating activity on fibrinogen.
Thrombin purification processes also have the drawback of being unpredictable with regard to scale-up from the laboratory or bench scale to an industrial scale. Given the large amounts of blood involved in industrial scale processes, this drawback is significant.
2. Description of Related Art
Known purification techniques apply especially to bovine thrombin: the include chromatography on ion exchange resins such as DEAE-cellulose (Yin et al. J. Biol. Chem., 1968, 243 112), possibly associated with filtration on SEPHADEX G 100.RTM. (Baughman et al. J. Biol. Chem., 1967, 242, 5252-5259); certain methods can be used to separate the .beta. and .gamma. forms on a phosphocellulose column (Rosenberg et al., J. Biol.Chem. 1970,245,5049)and through the association of several types of ion exchange chromatography (Batt et al. J. Biol. Chem. 1970, 245, 4857).
New resins have also been used, such as sulphoethyl or sulphopropyl SEPHADEX (Lundblad-Biochemistry, 1971, 10, 2501) as well as affinity chromatographies on supports such as heparin-SEPHAROSE (Nordeman et al. Thromb. Res., 1977, 11, 799-888) and p-aminobenzamidine-agarose (Hixson et al. Arch. Biochem. Biophys., 1973, 154,501).
Two publications describe the purification of human thrombin, one on benzamidine-SPHERODEX (Lorne et al. Rev. Fr. Transf. Hemobiol., 1989, 32, 391-403), but the product only exhibits low activity (11 to 20 NIH U/ml), and the other on new polystyrenes (Fischer et al. J. Chromatography, 1986, 363, 95-100), but this Product contains bovine Factor V (see below).
To obtain thrombin, it is necessary to have at one's disposal not only a source of its precursor, prothrombin, but also, depending on the mode of activation chosen, a sufficient concentration of the other coagulation factors involved in the activation process. Various methods have been described permitting the activation of prothrombin to produce thrombin. Fenton et al. (Biochim Biophys. Acta, 1971, 229, 26-32 and J. Biol. Chem., 1977, 252, 3587-3598) describe the preparation of thrombin from Cohn's fraction III extracted on resin, through the addition of calcium chloride and tissue thromboplastin extracted from the human brain. The reaction can be accelerated by the addition of Factor V of bovine origin (Bernamon-Djiane-Coagulation, 1968, 1, 259).
Specific activators extracted from snake venoms can also be used (Gosh et al. Thromb. Res., 1980, 20, 281).
However, these different methods present major drawbacks when one contemplates preparing very large volumes of human thrombin intended for therapeutic use. For instance, thromboplastin from the human brain is difficult to obtain and represents a limiting factor when it comes to treating several hundred liters of plasma. It is difficult to make activation with viper venom compatible with use in man, unless there is a high-performance system available to enable it to be eliminated subsequently. The use of bovine Factor V has proven particularly dangerous because the residual quantities that may be injected into patients are the origin of serious immunological reactions.

Process for preparing a human thrombin concentrate intended for therapeutic use

Association pour l'Essor de la Transfusion Sanguine dans la Region du Nord


Systems and methods are provided for managing access to registers. A system may include a set of direct registers and a set of indirect registers. The indirect registers may be accessed through the direct registers, and the direct registers may provide various features to provide faster access to the indirect registers. One of the direct registers may indicate access modes for accessing the indirect registers. The access modes may include auto-increment, auto-decrement, auto-reset, and no change modes. Based on the access mode, the currently accessed address may be automatically modified after accessing the indirect register at the address.

1. Field of Invention
Embodiments of the invention relate generally to digital data processing, and, more specifically, in certain embodiments, to providing and managing registers.
2. Description of Related Art
In the field of computing, pattern recognition tasks are increasingly challenging. Ever larger volumes of data are transmitted between computers, and the number of patterns that users wish to identify is increasing. For example, spam or malware are often detected by searching for patterns in a data stream, e.g., particular phrases or pieces of code. The number of patterns increases with the variety of spam and malware, as new patterns may be implemented to search for new variants. Searching a data stream for each of these patterns can form a computing bottleneck. Often, as the data stream is received, it is searched for each pattern, one at a time. The delay before the system is ready to search the next portion of the data stream increases with the number of patterns. Thus, pattern recognition may slow the receipt of data.
Additionally, systems that perform the pattern recognition and the other associated processing may use multiple registers to store various data, such as search data, configuration parameters, status information, pattern-matching results, or the like. These "processor registers" may typically be directly available to a processing unit of the system, for example, in order to provide quick access as compared to other storage that may be accessible to the processing unit. It may be appreciated, however, that many systems include a finite addressing space for recording the physical location of various forms of memory, including main system memory (e.g., random access memory) as well as such registers. Further, certain systems, such as pattern-recognition systems, may include a large number of registers to enable configuration and operation of the system. If a system includes a large number of registers accessible by the processing unit, the remaining address space available for main system memory may be reduced and overall performance of the system may be impacted.

System and method of indirect register access via directly accessible registers


A cord lock includes various components used to slidably adjust a cord length, such as one or more housing components that releasably clamp around the cord. In one aspect, the cord lock includes an arrangement of magnets that bias the cord-lock housing components away from one another, in order to secure the cord between the housing components. The housing components can be pressed towards one another to slidably adjust the cord. In a further aspect, the cord lock may also include a magnetized excess-cord retainer that attaches to a portion of the cord and that releasably attaches to the cord lock in order to help gather excess cord pulled through the cord lock.

Drawcords or just "cords" (also sometimes referred to as laces, cables, drawstrings, and the like) are commonly integrated into various types of articles (e.g., bags, garments, etc.) to allow modification of a feature of the article, such as a size, dimension, or shape. Cord locks provide a mechanism to adjust, and set, a length of cord, and may utilize a biasing element to provide a force on the cord.


A mounting region is provided at an approximately center of one surface of an insulating layer. A conductive trace is formed so as to outwardly extend from inside of the mounting region. A cover insulating layer is formed in a periphery of the mounting region so as to cover the conductive trace. A terminal of the conductive trace is arranged in the mounting region, and a bump of an electronic component is bonded to the terminal. A metal layer made of copper, for example, is provided on the other surface of the insulating layer. A pair of slits is formed in the metal layer such that a region being opposite to the electronic component is sandwiched therebetween. Each slit is formed so as not to divide the metal layer into a plurality of regions.

1. Field of the Invention
The present invention relates to a printed circuit board and a method of manufacturing the same.
2. Description of the Background Art
Conventionally, a COF (Chip On Film) mounting technique has been known as a technique for mounting electronic components such as an LSI (Large Scale Integration) on a film-like substrate. In general, the substrate for COF (hereinafter referred to as the COF substrate) has a two-layer structure of an insulating layer made of polyimide and a conductive pattern made of copper. Terminals are formed on the conductive pattern. Terminals (bumps) of the electronic components are bonded to the terminals of the conductive pattern.
With a finer pitch of the COF substrate and higher performance of the electronic components, a heating value at the time of driving increases. This causes problems such as a malfunction of the electronic components in some cases; therefore, it is important to carry out sufficient heat dissipation. Thus, it is proposed to provide a metal layer for heat dissipation on a back surface (a surface to which the electronic components are not bonded) of the COF substrate.
In a tape circuit board disclosed in JP 2007-27682 A, for example, the metal layer is formed, below a chip mounting region, on a lower surface of a base film.
FIG. 7 is a schematic sectional view of a conventional COF substrate provided with the metal layer. In the COF substrate 200 of FIG. 7, conductive traces 32 are provided on one surface of the insulating layer 31 while the metal layer 33 is provided on the other surface. The bumps 35a of the electronic component 35 are bonded to terminals of the conductive traces 32.
Such a configuration causes heat of the electronic component 35 to be dissipated through the metal layer 33. When the electronic component 35 is mounted on the COF substrate 200, or when the COF substrate 200 is used being folded, however, a stress locally applied to part of the metal layer 33 is propagated to the entire COF substrate 200 through the metal layer 33. This causes the entire COF substrate 200 to be bent. Accordingly, part of the conductive traces 32 are detached from the insulating layer 31 to be disconnected, and the bumps 35a of the electronic component 35 are separated from the conductive traces 32 in some cases as shown in FIG. 7 (b). Thus, good connection between the electronic component 35 and the conductive traces 32 of the COF substrate 200 cannot be sustained.

Printed circuit board and method of manufacturing the same


An etching resist has a first heat-generating layer, a second heat-generating layer, and a metal compound layer including a metallic oxynitride layer containing a metallic oxynitride. The first heat-generating layer, the metallic oxynitride layer, and the second heat-generating layer are directly or indirectly laminated such that the metallic oxynitride layer is positioned between the first heat-generating layer and the second heat-generating layer.

Methods of working fine holes on a substrate surface are also applied in the working of optical members, and more high level working methods are demanded to meet the precise working of opto-electronic equipments of the recent years.
For example, Japanese Patent Laid-Open No. 2006-216220 discloses a method of forming fine holes on a substrate surface, using an etching resist worked to given patterns by irradiating a laser beam over an etching resist comprising a metal compound layer (electro-alloy layer) made of platinum oxide, silver oxide, or the like, and phase-change layers formed on both sides of the metal compound layer, thereby forming penetrating holes.

National Institute of Advanced Industrial Science and Technology


A high speed data transfer apparatus includes a data transfer controlling unit for outputting a signal to the standby mode system during the active mode system, and during the standby mode system, reading data and the data information stored in the second storing unit of the active mode system, storing the read contents in the second storing unit of the standby mode system, and transferring a right to a bus use through the local bus of the standby mode system, the signal being used for informing that there exists data to be transferred.

1. Field of the Invention
The present invention relates to a high speed data transfer apparatus for duplexing in an ATM (Asynchronous Transfer Mode) switching system.
2. Discussion of Related Art
In general, there should be provided a fault tolerance function and a real time process function in the electronic switching system, unlike conventional computer systems. Further, reliability and solubility are very necessary to the electronic switching system a down time of which should be less several minutes for 1 year. The solubility means a possibility of permitting the system to normally perform its original operation at any time. And, the fault tolerance function of the system is subjected to employ a duplex method. The duplex method is composed of the same systems, one of which is an active mode system and the other of which is a standby mode system. Therefore, under use, if a fault is found in the active mode system, the standby mode system is employed to perform a series of operations which have been executed by the active mode system. As a result, the duplex method does not permit the system to have such a fault.
FIG. 1 is a schematic construction diagram of a high speed data transfer channel capable of performing a concurrent writing in an electronic switching system TDX-10 according to the prior art.
Referring to FIG. 1, active/standby mode systems are shown therein and only the system which is under operation can be the active mode system. After the system is determined as the active or the standby mode system, only the processor of the active mode system can access resources of the standby mode system.
Main processor and memory management board assemblies 1 and 1' (hereinafter, called them MPMA) are used as main processors having the CPU (central processing unit) and a memory. Mass storage interface board assemblies 2 and 2' (hereinafter, called them MSIA) are used for managing auxiliary storage units like disk and MT. I/O interface board assemblies 5 and 5' (hereinafter, called them IOIA) are used as a kind of multiplexer to manage an input/output interface. Memory and error correction board assemblies 3 and 3' (hereinafter, called them MECA) are used as memory expansion boards. Duplication control channel board assemblies 4 and 4' (hereinafter, called them DCCA) are used for providing the high speed data transfer channel between the duplex processors.
The Duplex modes, i.e., the active and standby mode systems are subjected to each having their power and their buses separated from each other. And, in their operations, when the MPMA 1 of the active mode system writes data in its own local memory or the MECA 3, the high speed data transfer channel of the TDX-10 permits the DCCA board 4 of the active mode system to write corresponding data in the MECA 3' or the MPMA 1' of the standby mode system through the high speed data transfer channel UP-bus.
At this time, a response to the writing operation in the active mode system is delayed until another response is received from the standby mode system. Thereby, the high speed data transfer channel of the TDX-10 can not perform the next operation until one writing operation is completed in the standby mode system and its response is then received. This has caused reduction in the system's capability.

High speed data transfer apparatus for duplexing system

Electronics and Telecommunications Research Institute


A hinged closure including a lid hingedly connected to a base positioned upon a container for dispensing of the contents thereof. The base is formed with an upper wall including an angled deck surface. The lid has a peripheral wall with a portion thereof of reduced thickness to permit flexing thereof. When the lid is in closed position over the base, the reduced thickness portion of the lid is disposed adjacent to the angled deck surface. Upon exertion of a force against said reduced thickness portion of the lid, said portion flexes inwardly and a terminal edge thereof ramps upwardly on the angled deck surface to cause the lid to pivot into open position with respect to the base.

1. Field of the Invention
This invention relates generally to hinged dispensing closures for containers and more particularly, to snap-open type closures in which the lid snaps away from the base to permit product to be dispensed from such containers.
2. Description of the Prior Art
Hinged dispensing closures for containers are known, as represented in the prior art patents of record herein. Such closures commonly include a pivotally mounted lid hingedly connected to a base and capable of being moved between a closed and an open dispensing position. In the closed position, the lid covers a dispensing opening formed in the base, and in the open position, the lid is moved away from the opening to permit product to be dispensed from the container.
Prior art closures with pivotally mounted lids also are known to include hinge constructions to maintain the lid in open position away from the base without an outside restraining force, and also to maintain the lid in closed position over the base such as by friction fit of matingly engagable parts between the lid and the base. Representative illustrations of such closures are disclosed in U.S. Pat. Nos. 4,793,502 and 5,007,555 which are owned by the same assignee as the assignee of the present application. The disclosures of said commonly owned patents hereby are incorporated herein by reference.
It is desirable to provide a convenient and expedient structure for causing the lid of such closures to snap open with respect to the base to permit dispensing of the contents of the container on which such closure is mounted. Preferably, such structure is operable upon engagement of a single digit on a hand of the user so that a container is openable with minimal effort and inconvenience.


This invention has been made to cause a printing apparatus for conveying roll paper and performing printing to simultaneously attain a stable conveyance accuracy and prevent skewed conveyance independently of LF roller driving conditions and disturbance conditions that variously change as the roll paper state changes. For this purpose, a feed motor is used as a load generator for the roll paper. A section from a conveyance operation by the LF roller to the next conveyance operation is divided into a plurality of sub-sections. A feed mechanism is controlled by switching between a feeder load generation section and a feeder load zero section for each sub-section.

Field of the Invention
The present invention relates to a printing apparatus, a conveyance apparatus, and a conveyance control method. Particularly, the present invention relates to a printing apparatus that stabilizes a back tension variation during, for example, roll paper conveyance by a conveyance roller, a conveyance apparatus, and a roll paper conveyance control method in the apparatus.
Description of the Related Art
There are printing apparatuses that use large paper having a size of A2 or more. A printing apparatus of this type often uses roll paper (a rolled portion where a sheet is wound will be referred to as roll paper, and a portion pulled out from the roll paper will be referred to as a sheet portion hereinafter) in addition to sheets. The sheet portion is pulled out from the roll paper by rotating a conveyance roller. However, since the roll paper is heavy in weight, a large force is necessary for pulling out the sheet portion. When only the driving force of a conveyance motor for driving the conveyance roller is used, the end portion of the roll paper is pulled, but the roll paper itself does not rotate because of its weight. Hence, the sheet may be torn. An apparatus has been developed, which includes a roll paper motor independently of the conveyance motor. The roll paper motor is driven together with the conveyance motor, thereby pulling out the sheet portion.
As a printing apparatus of this type, an apparatus disclosed in Japanese Patent Laid-Open No. 2009-263044 is known. This printing apparatus is of a type that intermittently conveys roll paper, and includes a conveyance roller, a roll paper motor, a conveyance motor, a tension measurement unit that measures a tension generated in the roll paper, and a motor control unit that controls driving of at least one of the roll paper motor and the conveyance motor based on the tension measurement result. In this arrangement, the motors are feedback-controlled based on the tension accurately measured by the tension measurement unit so as to decide the conveyance amount of the roll paper. This makes it possible to appropriately control the tension acting on the roll paper and prevent variation in the tension caused by a change in the diameter of the roll paper.
As an arrangement different from that described above, a printing apparatus disclosed in Japanese Patent Laid-Open No. 2007-203564 is also known. This printing apparatus includes a conveyance roller, a conveyance motor, a wind-off roller arranged at a position contactable with the outer surface of roll paper, a wind-off motor that rotates the wind-off roller, and a control unit that rotates the wind-off roller using the printing time and the conveyance time. In this arrangement, the roll paper is rotated in the conveyance direction by an amount corresponding to the conveyance amount necessary for the conveyance operation of the conveyance roller during the time from the end of the conveyance operation of the conveyance roller to the start of the next conveyance operation. This allows the roll paper to always have a slack so that the conveyance accuracy can be improved without any influence of the inertia of the roll paper.
There is known a conveyance apparatus that pulls out a sheet (to be referred to as a rolled portion hereinafter) wound into a roll and sandwiches the pulled out sheet between a conveyance roller and its associated roller, thereby conveying the sheet. A load is given to the axis portion of the rolled portion using a torque limiter or the like. The load is applied to the sheet portion as a back tension in a direction reverse to the conveyance direction so that an appropriate tension can be generated in the sheet between the rolled portion and the conveyance roller.
For example, Japanese Patent Laid-Open No. 9-164737 discloses an image printing apparatus including a conveyance apparatus provided with a remaining sheet detection unit that detects the remaining amount of a sheet wound into roll paper, and a back tension application unit capable of changing the torque of a load engaging with the axis of the roll paper.
In Japanese Patent Laid-Open No. 2009-263044, however, since the sheet portion is always given a tension, the sheet may slip on the conveyance roller due to the tension, and the actual conveyance amount may be smaller than that instructed by the control unit. This may affect the conveyance accuracy not a little.
To the contrary, according to an arrangement disclosed in Japanese Patent Laid-Open No. 2007-203564, the conveyance amount never becomes smaller because no tension is applied to the roll paper at all. On the other hand, skewed conveyance of the sheet portion may occur due to inappropriate setting by the user, a slightly nonuniform roller conveyance force in the direction of the roll paper width, or a slightly shifted parallelism between the roll center axis and the roller shaft.
To prevent the skewed conveyance, a method of applying a load by controlling the roll paper motor or using, for example, a torque limiter engaging with the axis of the roll paper is employed. When the load is applied to the roll paper as a back tension in a direction reverse to the conveyance direction, skewed conveyance of the roll paper is corrected by the back tension and the conveyance force so that wrinkles can be prevented.
However, in the arrangement of Japanese Patent Laid-Open No. 2007-203564, the back tension cannot be applied because of the absence of the load on the roll paper. Hence, it is difficult to correct skewed conveyance of the sheet portion.
In a printing apparatus for printing an image by serially scanning a carriage including a printhead, sheet conveyance and printing by carriage scan are alternately repeated, thereby printing an image on the entire sheet. In this case, the sheet conveyance amount at a time is equal to or smaller than the print length of the printhead. Let us examine one operation from the start to end of conveyance. There are the acceleration section, the steady section, and the deceleration section of the sheet, or only the acceleration section and the deceleration section. That is, the ratio of the acceleration and deceleration sections during the conveyance is high. In addition, to implement fast printing demanded of recent printing apparatuses, a higher conveyance velocity and a more abrupt acceleration/deceleration operation are required in some cases. Hence, the difference between the steady load set value and the load set value necessary at the time of acceleration/deceleration is supposed to be larger.
Under these circumstances, in the arrangement disclosed in Japanese Patent Laid-Open No. 9-164737 where the back tension variation caused by acceleration/deceleration of sheet conveyance is not taken into consideration, the sheet may slack because only the steady load torque corresponding to the remaining amount of the sheet is set. As a result, tension and slack repetitively occur in every conveyance operation. This may deteriorate the conveyance accuracy, resulting in poorer image quality.

Printing apparatus, conveyance apparatus, and conveyance control method


Disclosed are salts, such as nitrates, of acetyl-L-carnitine and propionyl-L-carnitine and methods of making the compounds.

Carnitine is a quaternary ammonium compounds synthesized from the amino acids lysine and methionine. In eukaryotes, carnitine is required for the transport of fatty acids from the intermembraneous space of the mitochondria into the mitochondrial matrix during the breakdown of lipids for the generation of metabolic energy. In animals, biosynthesis of carnitine primarily occurs in the liver and kidneys. However, carnitine may also be absorbed in the diet, primarily from red meats, but also in significantly lower levels in many other foods, such as, nuts and seed, legumes, vegetables, fruits, and cereals. Although carnitine naturally occurs in two stereoisomers, only the L-enantiomer is biologically active. The efficacy of L-carnitine has been reported for numerous applications. It is an important dietary/nutritional supplement. L-carnitine has been widely used in the food industry and may also be therapeutically effective.
Acetyl-L-carnitine and propionyl-L-carnitine are derivatives of L-carnitine that are naturally produced in the body. For example, during strenuous exercise, L-carnitine and used acetyl-CoA are converted into acetyl-L-carnitine and CoA by carnitine acetyltransferase inside the mitochondria. Acetyl-L-carnitine is then transported outside of mitochondria and converted back to L-carnitine, for example, by plasma esterases in the blood, before it is cycled back into the mitochondria for transporting of fatty acid. The mechanism of propionyl-L-carnitine biosynthesis is similar to that of acetyl-L-carnitine. Instead of converting L-carnitine and acetyl-CoA, carnitine acetyltransferase converts L-carnitine and propionyl-CoA in the mitochondria into propionyl-L-carnitine and CoA.
Both acetyl-L-carnitine and propionyl-L-carnitine are believed to have many advantageous properties over L-carnitine, such as increased bioavailability. For example, researchers prefer to use acetyl-L-carnitine to study the effects of carnitine in the body, because it has better absorption than L-carnitine in the small intestine and is more able to cross the blood/brain barrier.
Notwithstanding, the typical method of production for propionyl-l-carnitine and acetyl-l-carnitine involves the reaction of propionyl chloride and acetyl chloride respectively. During the reaction the end product would be propionyl-l-carnitine/acetyl-l-carnitine which would readily react with the hydrochloric acid formed by the reaction to wield the respective hydrochloride salts (acetyl-l-carnitine hydrochloride and propionyl-l-carnitine hydrochloride). Being a strong inorganic acid, HCl is practically impossible to replace with nitric acid and other acids to achieve nitrate and other salts of acetyl and propionyl l-carnitine. Thus, to this day, acetyl and propionyl carnitine are offered only as hydrochloride salts for sale and use in the supplement industry.

Salts of carnitine derivatives and methods of production