A thermally expandable fire-stop system for placement in a thermally stable conduit having an inner wall defining an inner space through which a single pipe, being a, relatively, thermally weakenable pipe having an outer wall, extends, or will extend, the system comprising at least a device which includes at least one component having a non-linear thermal expansion characteristic.

Conduits are normally incorporated in a construction element that divides, for instance, two compartments. Such a construction element may also be referred to as a partition. A pipe may extend through the conduit from one of the two compartments into the other. These conduits are often referred to as pipe penetrations or transit systems. Such a conduit is often present in constructions formed on the basis of civil engineering. Factories, buildings, drainage systems, tunnels, subways, etc. all comprise such penetrations. However, also constructions formed on the basis of nautical engineering do comprise such conduits. One finds them on board of vessels and/on other offshore applications such as oil rigs.
These penetrations are seen as unwelcome necessities in such a construction. Pipes for, for instance, water distribution and water wastage systems, air-conditioning systems, hydraulic and pneumatic control, sprinklers etc but also for transport of gas, or oil, need to be extending throughout such a construction, even though this entails introducing weak spots in a separation of the compartments.
Such weak spots do not manifest themselves to a great extent in the mechanical strength of the construction but much more in the possibility of undesired transport of physical phenomena throughout the structure.
An example is a fire which itself needs to be confined, as long as possible, to only one area. This is important not only to allow for control and extinguishing the fire, but also to provide time for people present in compartments near to the fire for reaching a safe distance from the fire before it further expands. To prevent smoke and/or fire from passing through the conduit from one compartment to another, the conduit is usually provided with a material that closes the conduit, at least for some time, when the conduit is exposed to heat due to a nearby fire.
Another form of transport that needs to be prevented is the supply of air to a fire which takes place in a compartment. Particularly for on-shore constructions, it is believed that fire is fed with oxygen as supplied through burned-out conduits and that it spreads itself throughout a multi-storey building, if transport of air can freely occur between different levels of compartments. It is also for this reason desirable that a conduit is closed off, when on one side of the conduit a fire takes place.
Although above reference is made to a construction element having a conduit and dividing two compartments, it is also possible that a construction element separates a compartment from the surrounding environment. It is thus possible that one side of the construction element is exposed to atmospheric conditions.
It will be appreciated that a pipe extending through a conduit, the conduit itself and the construction element into which the conduit is incorporated, may each be made of a material that allows for the conduction of heat. The efficiency for conducting heat depends on the type of material and the dimensions of that material. In principle, heat can in such a situation be supplied to the inner space of the conduit via at least two different routes. The first route is via the pipe extending through the conduit and the second route to the inner space of the conduit is via the material out of which the conduit itself is made. As in offshore constructions and vessels, conduits are usually made of metal, i.e. a good heat-conducting material, heat is usually rapidly supplied to the inner space of the conduit via the second route. Of course, heat may also exclusively be applied to the inner space of the conduit via the first route, in a situation where the partition is for instance a concrete wall and the conduit is formed by a through-hole in that wall.
There is a strong tendency in both the offshore and the on-shore construction industry to make pipes, in particular pipes of so-called service systems as referred to above, of a plastic material such as for instance PVC, PP-R, ABS and HOPE. Relative to aluminium or metal pipes, such plastic pipes offer an enormous reduction in weight, clearly advantageous in shipbuilding. As known, plastics are not susceptible and do not contribute to corrosion, advantageous in both the offshore and on-shore construction industry. Such plastic pipes are observed to suffer much less from sedimentation in the pipes, particularly when compared to steel pipes, giving plastic pipes advantages in waste water installations. On exposure to heat, however, such plastic pipes may weaken, i.e. become soft, and are therefore further in this specification referred to, as made of a thermally weakenable or a thermally softenable material, or in short as thermally weakenable pipes. The phrase thermally weakenable material refers thus in general to materials comprising or consisting of plastic. However, it is envisagable that also pipes made of or made with fibreglass form thermally weakenable material and these are therefore equally embraced by the term thermally weakenable pipes.
It will be clear that such weakening of the pipe will occur more rapidly in a conduit which is made of metal and incorporated in a metal construction element or partition. The conduit will then act as a kind of oven surrounding the pipe of the weakenable material, leading to local collapse of the pipe. However, a heated inner wall of a through-hole in a stone or concrete wall which is exposed to a fire, may equally act like an oven, even though the heating-rate will in that case be different than the heating-rate for "the metal oven". A stone or concrete wall will absorb much more heat and is a poor conductor of heat. The second route for the supply of heat into the conduit is in that case therefore much less effective. In such a situation it may well be that the first route, i.e. transport of heat into the conduit via the pipe itself, is by far the most dominant route if not effectively the only one.
It is common practice to seal the space between a conduit and a pipe as extending through the conduit, with a sealing system. Such a sealing system may provide sealing capacities before exposure to heat, and may for instance seal such that gas and/or water cannot penetrate through the annular space between the pipe and the conduit.
In particular for conduits through which a single pipe of a thermally weakenable material extends, advanced sealing systems have been developed. Reference is made to EP 120 075.9 31of the same inventor, describing so-called "crusher plugs". At each end of the conduit is a plug inserted in the annular space between the conduit and the pipe extending to the conduit. The crusher plug is made of a thermally expandable material. Upon exposure to heat, the crusher plug expands. However, as the conduit is of a very rigid material, expansion is only possible radially inwards. As upon the exposure to heat the thermally weakenable pipe has started weakening, the radial inward expansion of the plug crushes the pipe further and therewith closes the pipe off, as well as the complete conduit. The use of such plugs is very advantageous for conduits through which a single pipe extends, as the annular space which needs to be shut off by the plug is very well defined.
WO 2006/097290, also of the present inventor, discloses a conduit through which a plurality of pipes extend. For sealing that conduit a system is described that comprises a multitude of heat expandable rubbery sleeves. The sleeve material is made heat expandable by incorporation of heat expandable graphite into the rubbery material. Such a sleeve is also referred to as a filler sleeve. Usually, the sleeve is easily bendable, soft, and has relatively poor mechanical properties. This makes the sleeves perfect for inserting in a conduit and therewith filling the conduit. The sleeves are applied in a fashion parallel to each other and parallel to the pipe. The system further comprises a fire-resistant and/or watertight sealant. The sealant is applied against the ends of the sleeves and forms a sealing layer that seals off the conduit.
A system as described in WO 2006/097290 is usually applied in a conduit which is very large in cross-section relative to the cross-section of the pipe extending through the conduit. The main reason for this is that there has to be enough space in the conduit for filling the conduit with the heat expandable rubber sleeves, so that these heat expandable sleeves are during expansion in radial (transverse) direction capable of closing the conduit fully off. As there is space between the filler sleeves as well as in each empty sleeve, thermal expansion can freely occur in the radial (transverse) direction as soon as the temperature in the conduit reaches a point from where the thermally expandable rubber material will expand.
Although there is in axial (longitudinal) direction per unit of length between the sealant layers, no space for expansion available, and the expansion is expected to be larger in axial direction than in radial direction given the amount of heat expandable material that is axially aligned, the expansion of the filler sleeves is initially still predominantly radially oriented.
Without wishing to be bound by any theory this is thought to be a result of three factors. Firstly, as soon as thermal expansion occurs, even though at low temperatures and therefore still only to a limited extent, the axially expanding sleeves feel constrained between the sealant layers and start buckling, therewith removing pressure on the inner wall of the sealant layers. Secondly, the expansion will find its way radially given the little resistance the expansion experiences on radially expanding. (Remember, space is available radially, not only due to the space in and between the sleeves, but at higher temperatures also due to the weakening pipe within the conduit). Thirdly, air originally trapped in the conduit and reaching a high pressure due to the raised temperature and volume reduction in the conduit, will at some stage find its way out presumably through small cracks which have become available in the sealant layer without a breaking up of the sealant layer. This escaping of air offers "new volume" made available in the conduit, into which the expanding sleeve layers can expand into, whilst staying within the confinement of the conduit and the sealant layers.
At some stage, the expanding forces in the conduit as restrained by the sealant layers become so high that the sealant layer breaks.
This breaking is then in itself not a problem as the expanded sleeves have sealed off the conduit before the sealant layer breaks.
Currently there is a strong desire to have smaller and shorter conduits, in order to save both weight and space, without compromising sealing capacity both before and during exposure to a fire.
Conduits which are smaller in cross-sectional dimensions do have little capacity for letting the onset of expansion of the filler sleeve material to predominantly take place in radial direction. In such conduits, it is the radial expansion which is constrained. Hence, the expansion will at a much earlier stage attempt to find its way axially, resulting in early breaking of the sealant layer, with a possibility that the sealant layer breaks before the conduit has been fully closed off by the expanding material. In such a situation it is needed to apply instead of a sealant layer a much stronger "structure". In response thereto one applies in practice a plug designed to sustain high pressures rather than a sealant layer. It turns out that a conduit with expandable filler sleeve in the annular gap between the conduit and the pipe extending therethrough, on both ends of the conduit closed off by a deeply inserted plug, effectively allows the filler sleeves to expand radially and close the conduit and pipe fully off.
However, the drive for further reduction of the cross-sectioned area of the conduit relative to the pipe, continues in attempts to save even more space and even more weight.
When the annular gap between the conduit and the pipe becomes very small, a plug cannot be inserted and can thus not offer resistance against axial expansion of the tiller sleeve material. The situation becomes even worse when the pipe is slightly off-centre relative to the conduit.
On the market is a system available that comprises two steel collar-shaped casings filled with relatively thin, usually wrappable sheets of rubbery heat expandable material. Each of these casings is mountable in front of the conduit around the pipe and against the partition to provide resistance against axial expansion of the heat expandable material and to force the expansion to direct itself radially inward so as to close the pipe (and ideally also the conduit) fully off upon exposure to heat. Such a system has many drawbacks. First, it requires two extra mounting steps (one casing on each side of the partition) and facilities for mounting at parts of the partition "surrounding" the conduit. Secondly, the space saved in cross-sectional direction is to some extent lost due to the need to mount these to the parts of the partition surrounding the conduit. Thirdly, the casings itself require space, so that in axial direction the conduit or the penetration effectively has become longer instead of shorter.
It is an object of the invention to provide a thermally expandable fire-stop system for application in combination with a rigid and thermally stable conduit having an inner wall defining an inner space through which a pipe, being a, relatively, weakenable pipe, extends, or will extend.
It is an object of the invention to provide a rigid and thermally stable conduit having an inner wall through which a pipe, being a, relatively, thermally weakenable pipe having an outer wall, extends, or will extend, such that it includes a thermally expandable fire-stop system in an economically attractive way.
It is an object of the invention to provide a method for providing a fire-stop system in a rigid and thermally stable conduit having an inner wall defining an inner space through which a pipe, being a, relatively, thermally weakenable pipe, extends or will extend.

Fire-stop system for placement in a conduit through which a thermally weakenable pipe extends, method for placing the system and conduit provided with such a system


In vitro SELEX has been used to discover high affinity RNA aptamers interacting with the tetracycline repressor protein in a tetracycline-dependent manner. Using in silico RNA folding predictions to guide the design of both aptamer truncations and mutants, minimized tetracycline repressor protein high affinity binding aptamers have been defined. Using one such aptamer, inducible post-transcriptional regulation in vivo has been demonstrated that is predicated on a direct interaction between a tetracycline repressor protein and a RNA aptamer element. These aptamer components can be integrated in any organism to inducibly regulate RNA translation of a gene of interest.

As genome sequencing becomes increasingly routine, the ability to genetically manipulate organisms of interest has become indispensable in order to rigorously parse gene function. Whereas commonly used model organisms often have robust (although sometimes limited) options for controlling gene expression, these techniques are not always applicable in less commonly studied organisms. Meissner et al., "Molecular tools for analysis of gene function in parasitic microorganisms" Appl Microbiol Biotechnol 75:963-975 (2007). For example, RNA interference is only useful in cells possessing the requisite machinery. Hammond S. M., "Dicing and slicing: the core machinery of the RNA interference pathway" FEBS Lett 579:5822-5829 (2005); and Hannon G. J., "RNA interference" Nature 418:244-251 (2002). Further, transcriptional control requires detailed knowledge of protein components, regulatory sequences, and promoter architecture, which are often evolutionarily divergent. Borneman et al., "Divergence of transcription factor binding sites across related yeast species" Science 317:815-819 (2007); and Odom et al., "Tissue-specific transcriptional regulation has diverged significantly between human and mouse" Nat Genet 39:730-732 (2007). Techniques to make knockouts are sometimes available but are not always adaptable to studying essential genes. Furthermore, the study of newly discovered organisms would benefit significantly from experimenter-controlled regulatory systems that obviate extensive upfront characterization of their particular genetics. Beyond elucidating basic biology, a larger set of genetic control techniques will be required for building complex intracellular circuits, as is vital to the field of synthetic biology.
Since many mechanistic details of protein translation are highly conserved across different genera, protein translation is an attractive platform for designing modular, inducible gene expression systems. Bruell et al., "Conservation of bacterial protein synthesis machinery: initiation and elongation in Mycobacterium smegmatis" Biochemistry 47:8828-8839 (2008); and Kapp et al., "The molecular mechanics of eukaryotic translation" Annu Rev Biochem 73:657-704 (2004). In principle, these systems can be readily implemented in a wide variety of contexts. Nature provides numerous examples of post-transcriptional regulation, including: i) antisense (Good L., "Translation repression by antisense sequences" Cell Mol Life Sci 60:854-861 (2003)); ii) attenuation (Kolter et al., "Attenuation in amino acid biosynthetic operons" Annu Rev Genet 16:113-134 (1982); and iii) RNA interference (Mello et al., "Revealing the world of RNA interference" Nature 431:338-342 (2004)).
What is needed in the art are broadly-applicable methods to specifically control protein translation in a desired organism or cell-free biological system by the presence or absence of endogenous and/or exogenous ligands.

Post-transcriptional regulation of RNA-related processes using encoded protein-binding RNA aptamers


A wireless communications system providing interactive voice response is disclosed. The system is menu driven, and can accept information as well as deliver information to the customer in the form of prompts or prompt information. The system includes provisions that permit customers to vary the prompt information. In prompt information can be varied in a number ways, including the method of delivery, the content, pre or post-call prompts, and the frequency in which the prompt information is delivered.

1. Field of the Invention
The present invention is directed to a wireless interactive voice response system, and more particularly, to an interactive voice response system for pre-paid wireless customers.
2. Background of the Invention
Current pre-paid wireless communications systems require more voice channels to provide voice, data, and IVR (xe2x80x9cInteractive Voice Responsexe2x80x9d) services than post-paid wireless services. The requirement of additional voice channels is needed to ensure that all prepaid calls are properly managed by a prepaid system for real-time debiting. These additional resources are inefficient and costly for wireless carriers. Wireless standard organizations throughout the world, such as TIA/EIA-41 and European Telecommunications Standards Institute (ETSI), have recognized this problem and have recently proposed the use of Common Channel Signaling System 7 (CCS7) Intelligent Network (IN) services. The following example shows a typical prior art pre-paid wireless system without Intelligent Network functionality.
FIG. 1 is a schematic drawing of a prior art system 100 for providing IVR services for pre-paid customers. When a call is placed from a wireless device 106 (for example, a wireless telephone), the call is routed to mobile switching system 102 (which contains a Home Location Register (HLR), Visiting Location Register (VLR) and switch) through a first voice path or voice channel 107. The call is then routed through a second voice path 108 to a peripheral device 104. The peripheral device 104 communicates with a database 110 and retrieves information regarding the calling party""s account. One of the items peripheral device 104 retrieves is information regarding the amount of funds the calling party has available in the account. It is important to monitor pre-paid customer accounts on a per-call basis to prevent pre-paid customers from exceeding their account balances.
Once peripheral device 104 has retrieved the calling party""s account information, peripheral device 104 determines if the calling party has sufficient funds in the account to complete the call. If the peripheral device 104 determines that the calling party has sufficient funds, then peripheral device 104 returns the call back to mobile switch 102 via a third voice path 112. Mobile switching system 102, upon receiving the call from peripheral device 104, then completes the call via a fourth voice path 114.
Alternatively, if peripheral device 104 includes a switch fabric, then peripheral device 104 can complete the call via a fifth voice path 116. In this case, peripheral device 104 would not need to route the call back to mobile switching system 102 via the third voice path 112, nor would the fourth voice path 114 be needed.
Peripheral device 104 must remain active for the duration of the call. Peripheral device 104 decrements the customer""s account in real time during the call, and if the customer exhausts all of the funds available in the account, peripheral device 104 terminates the call. Peripheral device 104 is capable of terminating the call because the voice path is routed through it.
The process for handling incoming calls is similar. Mobile switching system 102 routes the incoming call to peripheral device 104 via a second voice path 108. Peripheral device 104 communicates with database 110 to determine account information and to manage the call. Peripheral device 104 then returns the call to mobile switching system 102 via a third voice path 112. Mobile switching system 102 then completes the call to the mobile device 106 via a first voice path 107.
In addition to participating in every outgoing and incoming call, the peripheral device 104 also provides IVR (xe2x80x9cInteractive Voice Responsexe2x80x9d) services. The user of mobile device 106 dials a predetermined number, the xe2x80x9ccustomer service numberxe2x80x9d or a unique number dedicated to accessing the prepaid IVR, to obtain customer service or prepaid IVR menu access. When the customer service number or unique number is dialed, mobile switching system 102 routes the call to peripheral device 104. This peripheral device can be the same device that manages and accounts for calls, or it can be a different peripheral device
Because peripheral device 104 must both receive instructions from a user and also communicate with the user, two voice paths 108 and 112, one to and one from the peripheral device 104, are required for prepaid IVR services. After peripheral device 104 has been contacted by mobile switching system 102, peripheral device 104 determines that the call is a customer service or prepaid IVR call based on the dialed telephone number. After peripheral device 104 has determined that the customer service number or unique number has been dialed, peripheral device 104 provides customer service by the use of prepaid IVR.
Traditional IVR systems are generally menu-driven, and users indicate their selections by pressing numbers on their numeric keypads. With traditional prepaid IVR systems, users could perform basic functions, such as checking their current account balances.
One of the major drawbacks of conventional pre-paid wireless systems is the number of voice paths, or channels, required to complete a call. In the examples above, either three or four voice paths were required to complete one telephone call. In addition, at least one or two voice paths were required between a mobile switching system and a peripheral device. This conventional arrangement consumes excessive system resources. Additionally, the prior art peripheral devices, such as peripheral device 104 mentioned in the examples above, are expensive and proprietary. They are often custom-built devices that are made for a single application. Thus, they are expensive to purchase or lease, and maintenance is also expensive. Accordingly, the use of a custom-built proprietary device and the use of multiple-voice paths is not cost-effective and consumes excessive system resources.
Another drawback of conventional pre-paid IVR systems is the lack of useful features and the lack of flexibility of the IVR. Conventional pre-paid wireless IVR systems include only basic and rudimentary functions. Because of this, they often fail to fulfill the service needs of customers. When this occurs, customers request the help of a live CSR (xe2x80x9cCustomer Service Representativexe2x80x9d). Live CSR""s are very costly, and any system that can reduce the number of customers who request the assistance of a live CSR (because they are unsatisfied with the assistance they receive from the IVR), greatly increases cost savings to the wireless communications service provider.
Pre-paid wireless customers are a particular group of customers that frequently request customer assistance. This is due to their accounting arrangement. In contrast to post-paid customers, who receive periodic bills after they have used wireless communications services, pre-paid wireless customers first provide funds to a pre-paid wireless account. As they use wireless communications services, funds are deducted from their pre-paid account. It is often difficult for pre-paid wireless customers to remember the frequency and duration of each call they place, and even more difficult for them to calculate or estimate the amount of funds deducted for each call. In addition to these difficult tasks, pre-paid wireless customers do not always keep a running total of funds deducted from their pre-paid accounts.
Most pre-paid wireless customers do not record or remember such detailed information about their pre-paid accounts, so they frequently resort to calling customer service simply to check the remaining balance on their pre-paid accounts. Another need, the need to add funds to the accounts, also generates frequent calls to customer service. This results in very frequent calls in to customer service by pre-paid wireless customers. Because pre-paid wireless customers tend to be the least profitable customers, traditional pre-paid wireless communications service providers are left in a situation where their least profitable customers are the customers who are the most costly to support. This higher need for customer service to support prepaid wireless customers forces wireless carriers to purchase or design IVR""s that support these needs.

Pre-paid wireless interactive voice response system with variable announcements

BellSouth Intellectual Property Corporation


The present invention encompasses engineered nucleases which recognize and cleave a recognition sequence within the int22h-1 sequence of a Factor VIII gene. The present invention also encompasses methods of using such engineered nucleases to make genetically-modified cells, and the use of such cells in a pharmaceutical composition and in methods for treating hemophilia A. Further, the invention encompasses pharmaceutical compositions comprising engineered nuclease proteins, nucleic acids encoding engineered nucleases, or genetically-modified cells of the invention, and the use of such compositions for treating of hemophilia A.

Hemophilia A is a common genetic bleeding disorder with an incidence of 1 in 5000 males worldwide. This genetic disease can result from various mutations within the coagulation Factor VIII (F8) gene located on the X chromosome, which include large deletions, insertions, inversions, and point mutations. Clinically, hemophilia A can be classified based on relative Factor VIII activity in the patient's plasma as mild (5-30% activity; 50% of patients), moderate (2-5% activity; 10% of patients), or severe (<1% activity; 50% of patients). Currently, there is no cure for hemophilia A. Standard therapy includes the administration of recombinant Factor VIII, but this approach is limited by cost, the requirement for frequent injections, and the formation of Factor VIII-inactivating antibodies in the subject which reduce the effectiveness of therapy. Therefore, a clear need still exists for alternative treatments for hemophilia A. Gene therapy, targeting mutations in the Factor VIII gene, remains an attractive yet elusive approach to treatment.
Factor VIII is an essential component of the clotting cascade. The protein circulates in the body in an inactive form that is attached to von Willebrand factor. In response to injury, Factor VIII is activated (Factor VIIIa) and separates from von Willebrand factor, then interacts with Factor IXa as part of the clotting cascade which leads to the formation of firbin and stable clotting. A number of studies have suggested that Factor VIII is produced by liver sinusoidal endothelial cells, as well as extra-hepatic, hematopoietic cells throughout the body.
The Factor VIII gene on the X chromosome is large and structurally complex, comprising ˜180 kb and 26 exons. The wild-type Factor VIII gene encodes two proteins. The first protein is the full-length Factor VIII protein, which is encoded by the 9030 bases found in exons 1 to 26, and has a circulating form containing 2332 amino acid residues. The second protein, referred to as Factor VIIIb, is encoded by 2598 bases in 5 exons present in the Factor VIII gene. The resulting protein comprises 216 amino acids and has a presently unknown function.
Approximately 45% of severe hemophilia A cases are caused by an intra-chromosomal inversion that involves intron 22 of the Factor VIII gene. This inversion arises when an ˜9.5 kb segment of intron 22, referred to as int22h-1, recombines with one of two repeat copies (referred to as int22h-2 and int22h-3, respectively) which are positioned approximately 400 kb and 500 kb telomeric to the Factor VIII gene on the X chromosome. Following recombination, exons 1-22 of the Factor VIII gene become inverted in the genome relative to exons 23-26, resulting in the expression of a truncated, inactive Factor VIII protein that lacks the amino acids encoded by exons 23-26 (Sauna et al. (2015) Blood 125(2): 223-228).
The upstream repeat copy involved in exon 1-22 inversion is oriented in the opposite direction as int22h-1. Early studies suggested that int22h-2 and int22h-3 were both in reverse orientation relative to int22h-1, allowing for recombination to occur with either repeat sequence. This was referred to as Type I inversion and Type II inversion. However, more recent evidence indicates that int22h-2 and int22h-3 are found in an inverse orientation to one another on the X chromosome, and are part of an imperfect palindrome (FIG. 1). Recombination of sequences within this palindrome allows int22h-2 and in22h-3 to swap places in the genome and, consequently, change their orientation relative to int22h-1. As a result, the int22h-1 sequence can, in different circumstances, recombine with the int22h-2 repeat or the int22h-3 repeat, depending on which is in the opposite orientation to int22h-1 (Bagnall et al. (2006) Journal of Thrombosis and Haemostasis 4: 591-598).
Of note, intron 22 of the Factor VIII gene contains a CpG island that acts as a bi-directional promoter for two further genes, referred to as F8A1 (Factor VIII-associated 1) and F8B. The CpG island and the intron-less F8A1 gene (SEQ ID NO: 5) are both contained within the int22h-1 sequence (and consequently, within int22h-2 and in22h-3) and are transcribed in the opposite direction as the Factor VIII gene (Bowen (2002) J. Clin. Pathol: Mol. Pathol. 55: 127-144). Interestingly, the inventors have determined that the sequence of the F8A1 gene is the only region of the human Factor VIII gene that exhibits significant homology to the Factor VIII gene in the canine genome, and particularly in a clinically-relevant population of canines that are Factor VIII-deficient and exhibit an inversion of exons 1-22 in their Factor VIII gene (Lozier et al. (2002) PNAS 99(20): 12991-12996).
The present invention requires the use of site-specific, rare-cutting endonucleases that are engineered to recognize DNA sequences within the int22h-1 sequence in order to generate a double-strand break and promote recombination between int22h-1 and an inversely-oriented repeat sequence (int22h-2 or int22h-3) positioned telomeric to the Factor VIII gene. The inventors have found that nuclease-induced recombination between these regions results in an inversion or reversion of exons 1-22 of the Factor VIII gene.
Methods for producing engineered, site-specific endonucleases are known in the art. For example, zinc-finger nucleases (ZFNs) can be engineered to recognize and cut pre-determined sites in a genome. ZFNs are chimeric proteins comprising a zinc finger DNA-binding domain fused to the nuclease domain of the FokI restriction enzyme. The zinc finger domain can be redesigned through rational or experimental means to produce a protein which binds to a pre-determined DNA sequence ˜18 basepairs in length. By fusing this engineered protein domain to the FokI nuclease, it is possible to target DNA breaks with genome-level specificity. ZFNs have been used extensively to target gene addition, removal, and substitution in a wide range of eukaryotic organisms (reviewed in S. Durai et al., Nucleic Acids Res 33, 5978 (2005)).
Likewise, TAL-effector nucleases (TALENs) can be generated to cleave specific sites in genomic DNA. Like a ZFN, a TALEN comprises an engineered, site-specific DNA-binding domain fused to the FokI nuclease domain (reviewed in Mak, et al. (2013) Curr Opin Struct Biol. 23:93-9). In this case, however, the DNA binding domain comprises a tandem array of TAL-effector domains, each of which specifically recognizes a single DNA basepair.
Compact TALENs are an alternative endonuclease architecture that avoids the need for dimerization (Beurdeley, et al. (2013) Nat Commun. 4:1762). A Compact TALEN comprises an engineered, site-specific TAL-effector DNA-binding domain fused to the nuclease domain from the I-TevI homing endonuclease. Unlike FokI, I-TevI does not need to dimerize to produce a double-strand DNA break so a Compact TALEN is functional as a monomer.
Engineered endonucleases based on the CRISPR/Cas9 system are also known in the art (Ran, et al. (2013) Nat Protoc. 8:2281-2308; Mali et al. (2013) Nat Methods. 10:957-63). A CRISPR endonuclease comprises two components: (1) a caspase effector nuclease, typically microbial Cas9; and (2) a short "guide RNA" comprising a ˜20 nucleotide targeting sequence that directs the nuclease to a location of interest in the genome. By expressing multiple guide RNAs in the same cell, each having a different targeting sequence, it is possible to target DNA breaks simultaneously to multiple sites in the genome.
In the preferred embodiment of the invention, the DNA break-inducing agent is an engineered homing endonuclease (also called a "meganuclease"). Homing endonucleases are a group of naturally-occurring nucleases which recognize 15-40 base-pair cleavage sites commonly found in the genomes of plants and fungi. They are frequently associated with parasitic DNA elements, such as group 1 self-splicing introns and inteins. They naturally promote homologous recombination or gene insertion at specific locations in the host genome by producing a double-stranded break in the chromosome, which recruits the cellular DNA-repair machinery (Stoddard (2006), Q. Rev. Biophys. 38: 49-95). Homing endonucleases are commonly grouped into four families: the LAGLIDADG family, the GIY-YIG family, the His-Cys box family and the HNH family. These families are characterized by structural motifs, which affect catalytic activity and recognition sequence. For instance, members of the LAGLIDADG family are characterized by having either one or two copies of the conserved LAGLIDADG motif (see Chevalier et al. (2001), Nucleic Acids Res. 29(18): 3757-3774). The LAGLIDADG homing endonucleases with a single copy of the LAGLIDADG motif form homodimers, whereas members with two copies of the LAGLIDADG motif are found as monomers.
I-CreI (SEQ ID NO: 1) is a member of the LAGLIDADG family of homing endonucleases which recognizes and cuts a 22 basepair recognition sequence in the chloroplast chromosome of the algae Chlamydomonas reinhardtii. Genetic selection techniques have been used to modify the wild-type I-CreI cleavage site preference (Sussman et al. (2004), J. Mol. Biol. 342: 31-41; Chames et al. (2005), Nucleic Acids Res. 33: e178; Seligman et al. (2002), Nucleic Acids Res. 30: 3870-9, Arnould et al. (2006), J. Mol. Biol. 355: 443-58). Methods for rationally-designing mono-LAGLIDADG homing endonucleases were described which are capable of comprehensively redesigning I-CreI and other homing endonucleases to target widely-divergent DNA sites, including sites in mammalian, yeast, plant, bacterial, and viral genomes (WO 2007/047859).
As first described in WO 2009/059195, I-CreI and its engineered derivatives are normally dimeric but can be fused into a single polypeptide using a short peptide linker that joins the C-terminus of a first subunit to the N-terminus of a second subunit (Li, et al. (2009) Nucleic Acids Res. 37:1650-62; Grizot, et al. (2009) Nucleic Acids Res. 37:5405-19.) Thus, a functional "single-chain" meganuclease can be expressed from a single transcript. This, coupled with the extremely low frequency of off-target cutting observed with engineered meganucleases makes them the preferred endonuclease for the present invention.
The use of engineered nucleases for gene therapy in severe hemophilia A has been limited. Park et al. described the use of a TALEN to induce an inversion of exon 1 in the Factor VIII gene in HEK 293T cells and induced pluripotent stem cells (iPSCs) (Park et al. (2014), PNAS 111(25): 9253-9258). Inversions of exon 1 are also associated with the occurrence of hemophilia A occur due to homologous recombination between an int1h-1 sequence in intron 1 of the Factor VIII gene and a single homologous region (int1h-2) positioned telomeric to the Factor VIII gene. The TALEN selected for this study cut within the intron 1 homology region in order to induce an inversion of this shorter sequence with an efficiency of 1.9% and 1.4% in the HEK 293T cells and iPSCs, respectively. The authors further demonstrated reversion of exon 1 in the iPSCs at a similar efficiency of 1.3%.
In a subsequent study, Park et al. reported the use of a CRISPR/Cas system to induce a reversion of exons 1-22 of the Factor VIII gene in iPSCs obtained from patients suffering from severe hemophilia A (Park et al. (2015) Cell Stem Cell 17: 213-220). The authors noted that inversions of exons 1-22 are eight times more prevalent than inversions of exon 1, but emphasized that the exon 1-22 inversion is technically more challenging to revert due in part to the substantially larger size of the inversion (600 kbp compared to 140 kbp) and the presence of three homologs of the int22h-1 sequence on the X chromosome, compared to only two homologs of the int1h-1 sequence. Indeed, Park et al. specifically targets recognition sequences outside of the int22h-1, int22h-2, and int22h-3 homology regions in order to rule out the possibility that unwanted deletions or inversions involving any two of the three int22 homologs, rather than the desired reversion of the inverted 600-kbp segment, would be induced by cutting within an int22h homology region. Using this approach, the authors observed a reversion frequency of approximately 3.7% in iPS cells.
The present invention improves on the art in several aspects. Despite suggestions in the art to avoid targeting recognition sequences within the int22h homology regions, the inventors surprisingly found that targeting recognition sequences within int22h-1 can, in fact, produce an inversion or reversion of exons 1-22 in the Factor VIII with high efficiency. Further, several recognition sequences targeted within the int22h-1 sequence are found within the F8A1 sequence, which the inventors found to be the only region of the Factor VIII gene which shares a high degree of homology with the canine Factor VIII gene. Thus, the methods of the invention are useful not only in human subjects suffering from hemophilia A, but also in the clinically-relevant canine hemophilia A population which also expresses an inversion of exons 1-22. Accordingly, the present invention fulfills a need in the art for further gene therapy approaches to severe hemophilia A.

Engineered nucleases useful for treatment of hemophilia A


A method of and system for flushing one or more cells or components thereof in a particle-based electrochemical power source is provided. Reaction solution is delivered to and withdrawn from the one or more cells when the electrochemical power source is in a standby mode of operation.

This invention relates generally to the field of particle-based electrochemical power sources, and, more specifically, to techniques for flushing the cells thereof
Particle-based electrochemical power sources, including without limitation metal-based fuel cells, are emerging as an attractive alternative to traditional energy sources. In metal-based fuel cells, when metal anodes within the cell cavities are exposed to an electrolysis agent such as hydroxide, an electrochemical reaction takes place whereby the metal releases electrons, and a reaction product is formed, typically one or more ions or oxides of the metal. Through this process, the metal anodes are gradually consumed. The released electrons flow through a load to a cathode, where they react with a second reactant such as oxygen.
Particle-based electrochemical power sources, including without limitation metal-based fuel cells, which employ particulate anodes and which deliver reaction agents such as hydroxides to the anodes through a reaction solution pose particular challenges since, for such power sources (e.g., fuel cells) to function efficiently, it is appropriate to re-circulate the reaction solution throughout and within the particulate anodes so that the appropriate electrochemical reaction can take place. However, this recirculation and electrochemical reaction can have undesired consequences.
These unintended consequences include certain problems of particle buildup, reduction in reaction solution flow through anode bed (e.g., clogging), and precipitation of solid zinc oxide that can occur during either the discharge cycle mode of operation due to the electrochemical reaction or the standby mode of operation due to the corrosion reaction described above.
For example, as the electroactive (e.g., metal) particles in the anode beds are consumed during the electrochemical reaction, they become smaller and smaller, and can become more densely packed together. The dense packing of the small particles can lead to particle buildup, clogging and interference with, and resulting reduction of, the flow of reaction solution throughout and within the particulate anodes. This in turn can lead to the generation of insoluble reaction products, which can further reduce the flow of reaction solution throughout the cell and/or the reaction bed. The result is typically a substantially less efficient fuel cell.
In a zinc-based fuel cell, for example, clogging caused by the generation of small particles can lead to the following electrochemical reaction occurring at the anode beds:
Zn+2OHxe2x88x92xe2x86x92Zn(OH)2(s)+2exe2x88x92xe2x80x83xe2x80x83(1)
The reaction product Zn(OH)2(s), unlike Zn(OH)42xe2x88x92, is insoluble.
A related problem is that, as electrochemical dissolution occurs, the concentration of reaction products can increase. For example, during electrochemical dissolution in a zinc-air fuel cell, zincate, Zn(OH)42xe2x88x92, in the KOH reaction solution increases. When the zincate saturation point is reached, any further electrochemical dissolution that occurs will cause zinc oxide, ZnO, to precipitate out of the KOH solution. Again, the generation of insoluble reaction products such as ZnO can further reduce the flow of reaction solution throughout the cell.
Even when the fuel cell is in a standby mode, and is not undergoing electrochemical dissolution, these problems can occur through a corrosion reaction that occurs. In the zinc fuel cell, for example, the corrosion reaction, in which zinc reacts with water, can be expressed as follows:
Zn+2H2O+2OHxe2x88x92xe2x86x92Zn(OH)42xe2x88x92+H2 xe2x80x83xe2x80x83(2)
As can be seen, zincate is the by-product of this reaction. Consequently, as this reaction occurs, zincate will build up, and when the zincate saturation level is reached, solid zinc oxide can precipitate out and clog the anode beds as described above. Moreover, because zinc is consumed in this reaction, this reaction will also result in smaller zinc particles, which can also lead to clogging of the anode beds as described above.
To solve these and other problems, the invention provides a method of and system for flushing one or more cells or components thereof in a particle-based electrochemical power source. According to this method and system, reaction solution is delivered to and withdrawn from the one or more cells when the electrochemical power source is in a standby mode of operation.
Other systems, methods, features and advantages of the invention will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the invention, and be protected by the accompanying claims.

Method of and system for flushing one or more cells in a particle-based electrochemical power source in standby mode


Embodiments of an ESD protection device are described. In an embodiment, an ESD protection device includes a first voltage rail electrically connected to a first node, a second voltage rail electrically connected to a second node, and ESD cells connected between the first and second voltage rails and configured to shunt current in response to an ESD pulse received between the first and second nodes. Each of the ESD cells includes clamp circuits electrically connected to the second voltage rail, ballast resistors connected between the first voltage rail and the clamp circuits, where at least some of the ballast resistors are electrically connected to a third voltage rail, a driver circuit connected between the second and third voltage rails and configured to generate a driver signal, and an output stage configured to generate an output signal in response to the driver signal.

Embodiments of the invention relate generally to electronic hardware, and, more particularly, to electrostatic discharge (ESD) protection devices.
Electrostatic discharge is a sudden flow of electricity that can be caused by a buildup of static electricity. An ESD protection device can be used to shunt ESD current to prevent damage in a device. For example, an ESD protection device can be integrated onto an electrical device, such as an integrated circuit (IC) chip, to provide a low impedance channel to prevent thermal damage to components of the electrical device. The operating characteristics (e.g., current distribution and/or internal voltage when shunting ESD current) of an ESD protection device can affect the performance of the ESD protection device.

Electrostatic discharge (ESD) protection device


A container is used to hold and transport punched diskette media to prevent contamination of and damage to the media. The container includes an outer shell comprising a cover and a base formed of a durable, pre-formed material. The base has an inner surface having at least one protruding male structure suitable for receiving and mounting a first hollow portion of a spindle. The cover has a second inner surface having a recessed female structure suitable for receiving another portion of a spindle. In addition, a spindle mounting member designed to carry a plurality of punched diskette media is included in the container. The spindle mounting member is an elongate spindle with a hollowed end for placement on the protruding male structure in the base and an end suitable for placement within the recessed female structure in the cover. The spindle mounting member includes a circumferential or annular media holder suitable for supporting media placed on the spindle. A closure member securely closes the container. A handle is provided for carrying the container in a position which places the spindle in a horizontal plane so that the weight of the media is on the spindle during shipment.

Large rolls of a magnetic media material, or webs, are mass punched to form diskette punched magnetic media which are commonly used in the computer industry. The magnetic media is punched in a circular shape, with a circular center piece also punched out. These disk media, commonly known as cookies in the industry, are then stacked for transport one on top of the other.
As the media corner of the punch press, they are stacked into round plastic containers or canisters. After the canisters are filled with approximately five hundred diskettes in a horizontal orientation, the canister is closed with a cover. A number of plastic canisters are stacked into larger, typically cardboard, shipping containers, and are then shipped to other assembly sites. The larger cardboard shipping containers containing a large number of media canisters are often quite heavy, and may be difficult for some people to pick up. The containers also generally do not have a handle. A significant amount of time is expended loading and unloading the numerous canisters from the shipping container, since each canister contains only about five hundred media. The canisters also do not generally have handles. Use of certain cardboard and plastic shipping containers produces much disposable waste, which adds to environmental problems.
At the assembly site, the cover is pried off of each of the canisters. A worker typically inverts the canister to remove the contents and places the media on a spindle. The worker then takes the media stacked on the spindle to the next processing step, such as burnishing.
There are several disadvantages to having the punched media stacked and shipped horizontally in the shipping containers as described above. The magnetic media material is very sensitive. A pressure applied to the top of the horizontal stack of punched media will cause a defect or debris to be transmitted through numerous layers of the media. This damages the media and may result in significant rejection rates of shipped media. For example, the pressure exerted against the media during shipping and removal of the media from the container may cause a defect to be transmitted to perhaps twenty or thirty of the diskettes in the stack. In addition, when the cover is removed from the plastic shipping container, the downward pressure during removal of the lid may also damage some of the media.
Debris, such as dust, on one of the diskettes may also cause damage when the vertical stacking weight of the media causes the debris to affect the closely packed surrounding media. Media also tends to move during shipping due to vibration, which causes damage to the media from abrasion. Media movement may also generate debris trails in the media surface that result in further defects.
Media are sometimes shipped in a compressed state in a packing arrangement known as a brick. The media are placed on a spindle, plates are positioned on either end of the spindle, and bolts are tightened against the plates to exert pressure on the media to form the brick. The pressure can damage the media, especially if debris is positioned against the media since the debris cannot be dislodged from the compressed media. U.S. Pat. Nos. 4,955,471 and 4,883,178 illustrate this type of packing structure used for magnetic tapes. The brick packing arrangement is heavy because construction plates are bolted together by metal bolts. In addition, these bricks are more difficult, costly, and time consuming to use since the packing arrangement must be bolted together and then loosened when the media are to be used, which requires more labor.

Minnesota Mining and Manufacturing Company


A clip for a pin that extends from an outer surface of a member, the clip comprising a pin retaining portion and a clamp portion that surrounds the member outer surface, the clamp portion having a pin receiving opening therein adapted to receive the exposed end of the pin, and a pin retaining portion adjacent the pin receiving opening to retain the pin in the member.

The present disclosure relates to clip retainers used to secure a pin in a member. More particularly, the disclosure relates to clip retainers used to secure a staple in a hydraulic hose connection.
In many hydraulic pieces of machinery, a large number of hose connections are required. One such piece of machinery is a longwall mining installation having a large number of hydraulic roof supports. The roof supports are powered by a number of hydraulic cylinders, controlled by a series of valves. High-pressure hydraulic fluid, at around 5,000 psi, is transported around the roof supports, between the valves and cylinders using numerous hoses.
The hoses typically have staple type connections, and these connections range in both length and bore size. A staple type hose connection 10, as shown in FIG. 1, includes a female sleeve piece 12, a male piece 14 of a size and configuration to permit insertion into the female sleeve piece 12, and a generally U-shaped staple 16.
The male piece has a groove 18, and, when the male piece is received within the female sleeve piece, the groove is aligned with two spaced apart openings 20 and 22 in the female sleeve piece 12. The openings receive the ends of the U-shaped staple 16. As illustrated in FIG. 1, the legs of the U-shaped staple 16 are received within the groove 18 of the male piece 14 and secured by the female sleeve piece 12, thus locking the male piece 14 within the female piece 12. If one attempts to remove the male piece from the female piece, the portion of the male piece forming the groove contacts the staple legs, thus preventing the male piece from being removed from the female piece, until the staple is removed from the connection.
More particularly, staples are shaped so that, when fitted, they are self retaining. The open ends 24 and 26 are wider than the portion of the staple that retains the fitting. The open ends are initially squeezed together so that the staple can be pushed into a connection. The open ends of the staple can then spring out, once the staple is fully inserted. This retains the staple within the hose connection.
But staples can fall out. This concern has lead to additional methods of retention being requested. One method, as illustrated in FIG. 2, is to drill a hole in each of the staple legs, and then to place a wire 30 in each of the holes after assembly of the connection. This stops the staple 16 from falling out under its own weight. But it makes it difficult to later remove the staple from the hose connection. This wire staple retention method significantly increases costs and is time-consuming. It also increases the expenses associated with the operation of the hydraulic equipment.


A mobile device includes an electronic card slot to be connected to an electronic card, and a baseband module. The baseband module includes a baseband unit, a switching unit, and a control unit. When it is determined by the control unit that the electronic card conforms with a subscriber identification communication protocol, the baseband unit and the electronic card slot are electrically interconnected via the switching unit such that the baseband unit is able to communicate with the electronic card that is connected to the electronic card slot. When the determination is otherwise, the baseband unit and the electronic card slot are electrically interconnected via the control unit.

1. Field of the Invention
The invention relates to a mobile device that is able to communicate with various externally connected electronic cards via software-controlled electronic components.
2. Description of the Related Art
FIG. 1 is a schematic block diagram of a conventional mobile device 900. The mobile device 900 includes a baseband module 910, two electronic card slots 920 coupled to the baseband module 910, and a secure digital (SD) card slot 930 coupled to the baseband module 910 and to be connected to a SD card. A subscriber identity module (SIM) card is typically provided by a telephony service provider for authenticating a subscriber, and may be removably connected to one of the electronic card slots 920 for communication with the baseband module 910.
Generally, the SIM card employs a communication protocol that is different from that employed by the SD card, and therefore cannot communicate directly with the SD card. Moreover, since that the electronic card slots 920 are only coupled with the baseband module 910, electronic cards other than the SIM card may not be able to communicate with the mobile device via the electronic card slots 920.
However, in view of rapid expansion in functionality of the mobile device 900, it may be increasingly desirable to connect various electronic cards to the mobile device 900, and/or to allow communication between the electronic card slots 920 and the SD card slot 930.

Baseband module, mobile device including the baseband module, and method of signal transmission in a mobile device


Method for adjusting a layout used in making an integrated circuit includes one or more interconnects in the layout that are susceptible to dielectric breakdown are selected. One or more selected interconnects are adjusted to increase via to wire spacing with respect to at least one via and one wire of the one or more selected interconnects. Preferably, the selecting analyzes signal patterns of interconnects, and estimates the stress ratio based on state probability of routed signal nets in the layout. An annotated layout is provided that describes distances by which one or more via or wire segment edges are to be shifted. Adjustments can include thinning and shifting of wire segments, and rotation of vias.

Lithography is an optical patterning process that patterns a material, e.g., photoresist, which is then developed to define a mask for integrated circuit fabrication processes. Reducing feature sizes to be smaller than the wavelength of light used to form the pattern in photoresist is referred to as sub-wavelength lithography. Sub-wavelength lithography presents many challenges to manufacturers trying to maintain the economic scaling of semiconductors postulated by Moore's Law. Double patterning lithography techniques are sub-wavelength techniques that are used to achieve sub 45 nm nodes with presently available manufacturing equipment. A standard single photoresist pattern begins to blur at about 45 nm feature size. With double patterning lithography methods, coarse patterns can be used to define patterns that exceed the resolution limit of the optical lithography tool used to pattern the material being patterned and developed as a mask.
Very narrow process windows are provided for the interconnect formation in back-end-of-line processing as feature sizes get smaller. The spacing between a signal line in a particular metallization layer and the adjacent line can be smaller than the width of the lines themselves. A via from another metallization layer must land on the intended wire in the layer below. The limits of modern lithography techniques and inherent variation in processing capabilities often create misalignments between vias and wires. The misalignments vary from the intended layout. The double patterning technique, for example, processes odd numbered and even numbered signal lines in separate steps. While this permits reducing node size, it increases the risk of via misalignment during manufacture.
The reliability of modern integrated circuits is dependent upon the reliability of the signals transmitted using such layer interconnections, i.e., vias and wires. The interconnections are isolated by insulating dielectric material, which degrades over IC lifetime when there is an electric field across the dielectric. An undesirable conducting path forms between interconnects adjacent interconnects when dielectric breakdown occurs. Such time-dependent dielectric breakdown (time-dependent dielectric breakdown) creates short circuits between interconnects. Dielectric mean time to failure is the expected time for the dielectric to form a conductive path between interconnects. The mean time to failure is inversely proportional to the strength of electrical field across the dielectric, and therefore reduces when voltage difference between interconnects increases or when the spacing between interconnects reduces.
Photomask misalignment between via and wire has been recognized as a cause of smaller via-to-wire spacing, and degraded time-dependent dielectric breakdown reliability. S.-C. Lee, et al., "Limitation of Low-k Reliability due to Dielectric Breakdown at Vias" IEEE International Interconnect Technology Conference, pp. 177-79 (2008); M. Stucchi and Z. Tkei, "Impact of LER and Misaligned Vias on the Electric Field in Nanometer-Scale Wires," IEEE International Interconnect Technology Conference, 174-176 (2008). The smaller via-to-wire spacings increase the electric field across dielectric, which accelerates dielectric breakdown.
Others have shown that time-dependent dielectric breakdown is dominated by via-to-wire spacing rather than wire-to-wire spacing. Xia et al., "Characterization and Challenge of time-dependent dielectric breakdown Reliability in Cu/Low K Dielectric Interconnect," IEEE International Reliability Physics Symposium, pp. 2C.1.1-2C.1.4 (2011). This report also showed that dielectric mean time to failure increases when the minimum spacing between interconnects (via-to-wire spacing) increases. Past efforts to improve interconnect dielectric reliability have focused on improving fabrication techniques.
Cabral et al. US Published Application No. US 20120038056 discloses an interconnect structure for improving time dependent dielectric breakdown. Techniques are disclosed to form trapezoid shaped interconnect vias. The base width of the vias are greater than the upper surfaces. By increasing the distance between the upper surfaces of adjacent interconnect structures, an increased amount of dielectric material is present between the interconnects, and this is intended to increase the reliability of time-dependent dielectric breakdown.
Colburn et al. US Published Application 20090200683 discloses method for forming interconnect structures described to produce partially self-aligned vias. The process elongates via patterns in a direction orthogonal to the metal line level above the via. The line pattern is extended past the elongated via patterns. Transfer of the two patterns into the interlayer dielectric defines vias by the coincidence of the line and via pattern, which accommodates mask alignment and overlay issues. The via pattern is elongated so that the line and via pattern have a maximum overlay error in the direction orthogonal to the line. Thus, the width of the via in the direction orthogonal to the line will still correspond to the line width.
Zhang et al., U.S. Pat. No. 7,380,231 describes a method to spread wires in an IC layout. Given a routed layout as an input, the method adjusts the input layout by spreading wires based on design rules or available spacing. This method is inapplicable for layouts constrained to having wires are at the minimum allowed spacing, as the method seeks to increase wire-to-wire spacing to more than the minimum spacing requirement without causing any design rule violations.
Bergman Reuter et al. U.S. Pat. No. 7,930,667 describes a method that adjusts the layout of wires and vias to reduce opens and shorts. Spacing between vias and wires are increased by several layout adjustments. Plural small vias in a routed layout are replaced by larger vias and vias of different shapes, vias are shifted away from adjacent vias and wire edges, and wire widths are reduced. The impact of layout adjustment on time-dependent dielectric breakdown is unaccounted for in the adjustment, however, and may produce poor time-dependent dielectric breakdown reliability. For example, the layout adjustment method might apply a wire width reduction larger than what is required to meet a time-dependent dielectric breakdown reliability target.
Various models for time-dependent dielectric breakdown reliability have been proposed. Models show that slightly enlarging interconnect spacing can change dielectric mean time to failure in technology with small interconnect spacing. One model is provided by Y. K. Siew, et al., "Line Edge Roughness (LER) Correlation and Dielectric Reliability with Spacer Defined Double Patterning (SDDP) at 20 nm Half Pitch" (IEEE International Interconnect Technology Conference and 2011 Materials for Advanced Metallization, pp. 1-3). This model defines the relationship between dielectric mean time to failure as follows:mean time to failure∝exp(A(V/S)m)  (1)
where parameters V and S are the voltage and spacing of interconnects under investigation, and parameters A and m are fitting parameters that can be calibrated with measurement data obtained from time-dependent dielectric breakdown test-structures.
Another model is provided by M. Bashir and L. Milor, "Towards a Chip Level Reliability Simulator for Copper/Low-k Backend Processes," IEEE Design Automation and Test in Europe, pp. 279-282 (2010). This is a chip-level time-dependent dielectric breakdown reliability model of a chip, which can be written as
                                          t            f                    =                      (                                          -                                                      ln                                                              (                                              1                        -                                                  F                          chip                                                                    )                                                                            1                    /                    β                                                              ·              H              ·                                                ∑                  ij                                                                                ζ                  ij                                                      )                                                                                ζ            ij                    =                                                    (                                  1                  /                                      L                    ij                                                  )                                            1                /                β                                      ·                          exp                                            (                                                      -                    γ                                                                                V                      m                                        ·                                          S                      ij                                              -                        m                                                                                )                                                                        (        2        )
where β, γ and H are model fitting parameters, which can be calibrated with time-dependent dielectric breakdown measurement data. Fchip, is a user-defined chip failure rate, which has a value ranging from zero to one. Sij is the spacing between interconnects i and j, Lij is the length of the dielectric between interconnects i and j. The model described in Equation (2) assumes that the dielectric is always under electrical stress.
While time-dependent dielectric breakdown reliability has been studied and characterized, time-dependent dielectric breakdown remains a major reliability issue for advanced integrated circuit technology, especially with the push to achieve reliability with sub 45 nm nodes. spacing and voltage trends projected by the International Technology Roadmap for Semiconductors (ITRS) lead to an increasing electric field as technology scales. Since time-to-failure reduces with an increasing electric field, time-dependent dielectric breakdown will be a major reliability concern for back-end-of-line dielectric. At the 20 nm node size (sub-70 nm local metal pitch) with litho-etch-litho-etch double-patterning, time-dependent dielectric breakdown reliability is a primary limiter to further wiring density improvement. When the via-to-wire spacing is reduced from 70 nm to 60 nm due to via misalignment, the electric field around the via is 25% higher than the average electric field between the wires. Moreover, the via-to-wire misalignment is expected to worsen in advanced technology when the vias must land on wires that are misaligned due to litho-etch-litho-etch double-patterning Such a worsening time-dependent dielectric breakdown reliability trend will limit wiring pitch and/or the maximum allowed supply voltage.
The present invention provides a layout adjustment method which accounts for dielectric reliability. Since the invention improves time-dependent dielectric breakdown reliability with layout adjustment, it can be applied in complement to the above discussed and other state-of-the art manufacturing techniques.

IC layout adjustment method and tool for improving dielectric reliability at interconnects

The Regents of the University of California


A system for abrading and scoring glass. An abrading/scoring station includes a table for supporting a large sheet of glass on a generally flat support. A first tool support moves an abrading tool for abrading a coating material from the glass. A second tool support moves a scoring or cutting tool that scores a region of the glass. By coordinating a movement of the first and second tool supports with respect to a piece of glass, a controller causes the respective tools to first abrade and then score controlled paths on the piece of glass while avoiding contact between the first and second tool supports and their respective tools.

It is known in the window and door fabrication industry to treat large glass sheets for use in the fabrication of windows and doors with a material that provides specified light transmission or reflection properties. One common treatment applies a layer of material uniformly across a glass sheet to provide lower radiation transmissivity. When such glass is used in fabricating a insulating glass unit (IGU) having multiple spaced apart lites, the low transmissivity layer can be located on an outside of the glass unit to lower the tendency of the sun's radiation to heat a building interior. On other insulating glass units, the low transmissive layer can be placed on the inside of the IGU to reduce the amount of heat radiation exiting the building. In known applications, a silver containing compound is uniformly applied to a surface of glass sheets from which IGU lites (or panes) are cut to achieve such properties.
Experience with fabricating window or door lites from large sheets of glass indicate it is preferable to remove radiation reflecting or transmitting material before scoring the glass for breakout into smaller pane sized lites. If these coatings are not first removed, the glass tends to break, chip or otherwise become damaged in the region of the glass scoring. If the coating is removed at a processing station downstream from the cutting station, the probability of damage is increased due to handling of the glass sheets. The coating is removed in a region of the glass to which sealant is applied to promote adhesion properties of the sealant.
One prior art patent that addresses the problems of removing such coating material is U.S. Pat. No. 5,449,312 to Lisec. This patent discloses a process for simplifying the cutting of a glass sheet with the help of a cutting tool and the removal of a coating applied on a glass sheet with the help of a grinding tool.


A polyamide resin composition including a polyamide resin (A), a copper compound (B), a bromide of an alkali metal and/or a bromide of an alkaline earth metal (C), and at least one fatty acid compound (D) selected from the group consisting of fatty acid esters, fatty acid amides, and fatty acid metal salts, wherein the fatty acid compound (D) has an acid value of 5 mgKOH/g or less.

Field of the Invention
The present invention relates to polyamide resin compositions and molded articles.
Description of the Related Art
Polyamide resins have high mechanical properties (such as mechanical strength, rigidity, and impact resistance), toughness, heat resistance, and chemical resistance, and have been used in various industrial fields such as clothing materials, industrial materials, vehicles, and electrical and electronic apparatuses and devices, and other industrial fields.
In particular, polyamide resins have higher heat aging resistance than that of other resins, and are suitably used as materials for parts which receive a significantly large amount of heat, such as parts for engine compartments of vehicles.
The environmental temperatures inside the engine compartments of vehicles have been increased recently in connection with higher density of parts for engine compartments of vehicles and higher outputs of engines. For this reason, a polyamide resin which can maintain significantly higher heat aging resistance for a longer period of time than those of the traditional polyamide resins has been required.
One of the traditional techniques of enhancing the heat aging resistance of the polyamide resins is addition of a copper compound (oxide or salt of copper) and a halogen compound.
Among the halogen compounds, an iodine compound is typically added. A technique of compounding a polyamide resin, a copper compound, an iodine compound, and an aliphatic carboxylic derivative is known (for example, see Japanese Patent Laid-Open No. 7-18176).
Unfortunately, iodine as a resource is mined from the ground, and its efficient mining areas are limited. These have been increasing the cost of iodine compounds recently, and thus use of iodine compounds in polyamide resins has a problem of increased production cost.
In contrast, bromine as a resource can be extracted from sea water or the like, and is more inexpensive and industrially useful than iodine. For this reason, other techniques of adding a bromine compound rather than an iodine compound have been developed to enhance the heat aging resistance of the polyamide resin (for example, see International Publication No. WO 2013-143858 and National Publication of International Patent Application No. 2011-511097).
Unfortunately, bromine compounds are more readily corrode metals than iodine compounds. If polyamide resin compositions containing a bromine compound are used as materials for parts for engine compartments of vehicles and the like, there is a concern that the bromine compound may corrode metallic parts of processing machines such as extruders and molding machines, therefore the conditions on usage and the like should be considered. Accordingly, a polyamide resin composition which causes less corrosion of metal than before has been required.
An object of the present invention is to provide a polyamide resin composition which has high heat aging resistance, and is less likely to cause corrosion of metal and deposition of copper.

This patent is subject to a terminal disclaimer.

Polyamide resin composition and molded article


A process of producing 8a- and 9a- azalide compounds is disclosed, comprised of reacting an 8a- aza or 9a- aza azalide eastern fragment or a derivative thereof with a compound of the formula: EQU X--A'--Y. wherein X and Y are appropriate reactive groups and A' is a fragment or compound which forms the western portion of the azalide, and. cyclizing this intermediate to form the target 8a- or 9a-azalide compound. Compounds of formula I, II and III as well as other azalides can be synthesized according to this process.

The present invention is drawn to a process of producing azalide antibiotics which are useful in the therapy of bacterial infections in mammals.
Modifications of the western fragment of erythromycin A have been difficult to obtain. There is a long felt need for new azalide antibiotics, and in particular, for a process of varying the western fragment of such azalides. The invention thus provides a process of making azalide compounds with modified western fragments.
Erythromycin A has been the subject of investigation for many years. Erythromycin A has the following structural formula: ##STR1##
Reactions can be conducted which lead to rupture of the ring and formation of the C.sub.1 carboxylate. This reaction can generally be conducted as follows: ##STR2##
The present invention utilizes the fragments above, as well as other eastern fragments to produce novel 8a- and 9a- azalides. By modifying these fragments to produce 8a- and 9a- aza fragments, and combining the modified eastern fragments or derivatives thereof with an appropriate compound which forms the western portion of the molecule, the azalide ring structure can be formed. Thus, a large number of azalides can now be produced with modifications in the western portion of the molecule.

Process of producing 8A- and 9A-azalide antibiotics