Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyzes. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

Chromosome abnormalities are associated with genetic disorders, degenerative diseases, and exposure to agents known to cause degenerative diseases, particularly cancer, German, "Studying Human Chromosomes Today," American Scientist, Vol. 58, pgs. 182-201 (1970); Yunis, "The Chromosomal Basis of Human Neoplasia," Science, Vol. 221, pgs. 227-236 (1983); and German, "Clinical Implication of Chromosome Breakage," in Genetic Damage in Man Caused by Environmental Agents, Berg, Ed., pgs. 65-86 (Academic Press, New York, 1979). Chromosomal abnormalities can be of several types, including: extra or missing individual chromosomes, extra or missing portions of a chromosome (segmental duplications or deletions), breaks, rings and chromosomal rearrangements, among others. Chromosomal or genetic rearrangements include translocations (transfer of a piece from one chromosome onto another chromosome), dicentrics (chromosomes with two centromeres), inversions (reversal in polarity of a chromosomal segment), insertions, amplifications, and deletions.
Detectable chromosomal abnormalities occur with a frequency of one in every 250 human births. Abnormalities that involve deletions or aciditions of chromosomal material alter the gene balance of an organism and generally lead to fetal death or to serious mental and physical defects. Down syndrome can be caused by having three copies of chromosome 21 instead of the normal 2. This syndrome is an example of a condition caused by abnormal chromosome number, or aneuploidy. Down syndrome can also be caused by a segmental duplication of a subregion on chromosome 21 (such as, 21q22), which can be present on chromosome 21 or on another chromosome. Edward syndrome (18+), Patau syndrome (13+), Turner syndrome (XO) and Kleinfelter syndrome (XXY) are among the most common numerical aberrations. [Epstein, The Consequences of Chromosome Imbalance: Principles, Mechanisms and Models (Cambridge Univ. Press 1986); Jacobs, Am. J. Epidemiol, 105:180 (1977); and Lubs et al., Science, 169:495 (1970).]
Retinoblastoma (del 13q14), Prader-Willi syndrome (del 15q11-q13), Wilm's tumor (del 11p13) and Cri-du-chat syndrome (del 5p) are examples of important disease linked structural aberrations. [Nora and Fraser, Medical Genetics: Principles and Practice, (Lea and Febiger 1989).]
Measures of the frequency of structurally aberrant chromosomes, for example, dicentric chromosomes, caused by dastogenic agents, such as, ionizing radiation or chemical mutagens, are widely used as quantitative indicators of genetic damage caused by such agents, Biochemical Indicators of Radiation Injury in Man (International Atomic Energy Agency, Vienna, 1971); and Berg, Ed. Genetic Damage in Man Caused by Environmental Agents (Academic Press, New York, 1979). A host of potentially carcinogenic and teratogenic chemicals are widely distributed in the environment because of industrial and agricultural activity. These chemicals include pesticides, and a range of industrial wastes and by-products, such as halogenated hydrocarbons, vinyl chloride, benzene, arsenic, and the like, Kraybill et al., Eds., Environmental Cancer (Hemisphere Publishing Corporation, New York, 1977). Sensitive measures of chromosomal breaks and other abnormalities could form the basis of improved dosimetric and risk assessment methodologies for evaluating the consequences of exposure to such occupational and environmental agents.
Current procedures for genetic screening and bio-logical dosimetry involve the analysis of karyotypes. A karyotype is the particular chromosome complement of an individual or of a related group of individuals, as defined both by the number and morphology of the chromosomes usually in mitotic metaphase. It includes such things as total chromosome number, copy number of individual chromosome types (e.g., the number of copies of chromosome X), and chromosomal morphology, e.g., as measured by length, centromeric index, connectedness, or the like. Chromosomal abnormalities can be detected by examination of karyotypes. Karyotypes are conventionally determined by staining an organism's metaphase, or otherwise condensed (for example, by premature chromosome condensation) chromosomes. Condensed chromosomes are used because, until recently, it has not been possible to visualize interphase chromosomes due to their dispersed condition and the lack of visible boundaries between them in the cell nucleus.
A number of cytological techniques based upon chemical stains have been developed which produce longitudinal patterns on condensed chromosomes, generally referred to as bands. The banding pattern of each chromosome within an organism usually permits unambiguous identification of each chromosome type, Latt, "Optical Studies of Metaphase Chromosome Organization," Annual Review of Biophysics and Bioengineering, Vol. 5, pgs. 1-37 (1976). Accurate detection of some important chromosomal abnormalities, such as translocations and inversions, has required such banding analysis.
Unfortunately, such conventional banding analysis requires cell culturing and preparation of high quality metaphase spreads, which is time consuming and labor intensive, and frequently difficult or impossible. For example, cells from many tumor types are difficult to culture, and it is not clear that the cultured cells are representative of the original tumor cell population. Fetal cells capable of being cultured need to be obtained by invasive means and need to be cultured for several weeks to obtain enough metaphase cells for analysis. In many cases, the banding patterns on the abnormal chromosomes do not permit unambiguous identification of the portions of the normal chromosomes that make them up. Such identification may be important to indicate the location of important genes involved in the abnormality. Further, the sensitivity and resolving power of current methods of karyotyping are limited by the fact that multiple chromosomes or chromosomal regions have highly similar staining characteristics, and that abnormalities (such as deletions) which involve only a fraction of a band are not detectable. Therefore, such methods are substantially limited for the diagnosis and detailed analysis of contiguous gene syndromes, such as partial trisomy, Prader-Willi syndrome [Emanuel, Am. J. Hum. Genet., 43:575 (1988); Schmickel, J. Pediatr., 109:231 (1986)] and retinoblastoma [Sparkes, Biochem. Biophys. Acta., 780:95 (1985)].
Thus, conventional banding analysis has several important limitations, which include the following. 1) It is labor intensive, time consuming, and requires a highly trained analyst. 2) It can be applied only to condensed chromosomes. 3) It does not allow for the detection of structural aberrations involving less than 3-15 megabases (Mb), depending upon the nature of the aberration and the resolution of the banding technique [Landegren et al., Science, 242:229 (1988)]. This invention provides for probe compositions and methods to overcome such limitations of conventional banding analysis.
The chemical staining procedures of the prior art provide patterns over a genome for reasons not well understood and which cannot be modified as required for use in different applications. Such chemical staining patterns were used to map the binding site of probes. However, only occasionally, and with great effort, was in situ hybridization used to obtain some information about the position of a lesion, for example, a breakpoint relative to a particular DNA sequence. The present invention overcomes the inflexibility of chemical staining in that it stains a genome in a pattern based upon nucleic acid sequence; therefore the pattern can be altered as required by changing the nucleic acid sequence of the probe. The probe-produced staining patterns of this invention provide reliable fundamental landmarks which are useful in cytogenetic analysis.
Automated detection of structural abnormalities of chromosomes with image analysis of chemically stained bands would require the development of a system that can detect and interpret the banding patterns produced on metaphase chromosomes by conventional techniques. It has proven to be very difficult to identify reliably by automated means normal chromosomes that have been chemically stained; it is much more difficult to differentiate abnormal chromosomes having structural abnormalities, such as, translocations. Effective automated detection of translocations in conventionally banded chromosomes has not been accomplished after over a decade of intensive work. The probe-produced banding patterns of this invention are suitable for such automated detection and analysis.
In recent years rapid advances have taken place in the study of chromosome structure and its relation to genetic content and DNA composition. In part, the progress has come in the form of improved methods of gene mapping based on the availability of large quantities of pure DNA and RNA fragments for probes produced by genetic engineering techniques, e.g., Kao, "Somatic Cell Genetics and Gene Mapping," International Review of Cytology, Vol. 85, pgs. 109-146 (1983), and D'Eustachio et al., "Somatic Cell Genetics in Gene Families," Science, Vol. 220, pgs. 9, 19-924 (1983). The probes for gene mapping comprise labeled fragments of single-stranded or double-stranded DNA or RNA which are hybridized to complementary sites on chromosomal DNA. With such probes it has been crucially important to produce pure, or homogeneous, probes to minimize hybridizations at locations other than at the site of interest, Henderson, "Cytological Hybridization to Mammalian Chromosomes," International Review of Cytology, Vol. 76, pgs. 1-46 (1982).
The hybridization process involves unravelling, or melting, the double-stranded nucleic acids of the probe and target by heating, or other means (unless the probe and target are single-stranded nucleic acids). This step is sometimes referred to as denaturing the nucleic acid. When the mixture of probe and target nucleic acids cool, strands having complementary bases recombine, or anneal. When a probe anneals with a target nucleic acid, the probe's location on the target can be detected by a label carried by the probe or by some intrinsic characteristics of the probe or probe-target duplex. When the target nucleic acid remains in its natural biological setting, e.g., DNA in chromosomes, mRNA in cytoplasm, portions of chromosomes or cell nuclei (albeit fixed or altered by preparative techniques), the hybridization process is referred to as in situ hybridization.
In situ hybridization probes were initially limited to identifying the location of genes or other well defined nucleic acid sequences on chromosomes or in cells. Comparisons of the mapping of single-copy probes to normal and abnormal chromosomes were used to examine chromosomal abnormalities. Cannizzaro et al., Cytogenetics and Cell Genetics, 39:173-178 (1985). Distribution of the multiple binding sites of repetitive probes could also be determined.
Hybridization with probes which have one target site in a haploid genome, single-copy or unique-sequence probes, has been used to map the locations of particular genes in the genome [Harper and Saunders, "Localization of the Human Insulin Gene to the Distal End of the Short Arm of Chromosome 11," Proc. Natl. Acad. Sci., Vol. 78, pgs. 4458-4460 (1981); Kao et al., "Assignment of the Structural Gene Coding for Albumin to Chromosome 4," Human Genetics, Vol. 62, pgs. 337-341 (1982)]; but such hybridizations are not reliable when the size of the target site is small. As the amount of target sequence for low complexity single-copy probes is small, only a portion of the potential target sites in a population of cells form hybrids with the probe. Therefore, mapping the location of the specific binding site of the probe has been complicated by background signals produced by non-specific binding of the probe and also by noise in the detection system (for example, autoradiography or immunochemistry). The unreliability of signals for such prior art single-copy probes has required statistical analysis of the positions of apparent hybridization signals in multiple cells to map the specific binding site of the probe.
Wallace et al., in "The Use of Synthetic Oligonucleotides as Hybridization Probes. II. Hybridization of Oligonucleotides of Mixed Sequence to Rabbit Beta-Globin DNA," Nucleic Acids Research, Vol. 9, pgs. 879-894 (1981), disclose the construction of synthetic oligonucleotide probes having mixed base sequences for detecting a single locus corresponding to a structural gene. The mixture of base sequences was determined by considering all possible nucleotide sequences which could code for a selected sequence of amino acids in the protein to which the structural gene corresponded.
Olsen et al., in "Isolation of Unique Sequence Human X Chromosomal Deoxyribonucleic Acid," Biochemistry, Vol. 19, pgs. 2419-2428 (1980), disclose a method for isolating labeled unique sequence human X chromosomal DNA by successive hybridizations: first, total genomic human DNA against itself so that a unique sequence DNA fraction can be isolated; second, the isolated unique sequence human DNA fraction against mouse DNA so that homologous mouse/human sequences are removed; and finally, the unique sequence human DNA not homologous to mouse against the total genomic DNA of a human/mouse hybrid whose only human chromosome is chromosome X, so that a fraction of unique sequence X chromosomal DNA is isolated. Individual clones are then isolated from this fraction and are candidates for human X chromosome specific DNA sequences.
Manuelidis et al., in "Chromosomal and Nuclear Distribution of the Hind III 1.9-KB Human DNA Repeat Segment," Chromosoma Vol. 91, pp. 28-38 (1984), disclose the construction of a single kind of DNA probe for detecting multiple loci on chromosomes corresponding to the location of members of a family of repeated DNA sequences. Such probes are herein termed repetitive probes.
Different repetitive sequences may have different distributions on chromosomes. They may be spread over all chromosomes as in the just cited reference, or they may be concentrated in compact regions of the genome, such as, on the centromeres of the chromosomes, or they may have other distributions. In some cases, such a repetitive sequence is predominantly located on a single chromosome, and therefore is a chromosome-specific repetitive sequence. [Willard et al., "Isolation and Characterization of a Major Tandem Repeat Family from the Human X Chromosome," Nucleic Acids Research, Vol. 11, pgs. 2017-2033 (1983).]
A probe for repetitive sequences shared by all chromosomes can be used to discriminate between chromosomes of different species if the sequence is specific to one of the species. Total genomic DNA from one species which is rich in such repetitive sequences can be used in this manner. [Pinkel et al. (III), PNAS USA, 83:2934, (1986); Manuelidis, Hum. Genet., 71:288 (1985) and Durnam et al., Somatic Cell Molec. Genet., 11:571 (1985.]
Recently, there has been an increased availability of probes for repeated sequences (repetitive probes) that hybridize intensely and specifically to selected chromosomes. [Trask et al., Hum. Genet., 78:251 (1988) and references cited therein.] Such probes are now available for over half of the human chromosomes. In general, they bind to repeated sequences on compact regions of the target chromosome near the centromere. However, one probe has been reported that hybridizes to human chromosome, 1p36, and there are several probes that hybridize to human chromosome Yq. Hybridization with such probes permits rapid identification of chromosomes in metaphase spreads, determination of the number of copies of selected chromosomes in interphase nuclei [Pinkel et al. (I), PNAS USA, 83:2934 (1986); Pinkel et al. (II), Cold Spring Harbor Symp. Quant. Biol., 51:151 (1986) and Cremer et al., Hum. Genet, 74:346 (1986)] and determination of the relative positions of chromosomes in interphase nuclei [Trask et al., supra; Pinkel et al. (I), supra; Pinkel et al. (II), supra; Manuelidis, PNAS USA, 81:3123 (1984); Rappold et al., Hum. Genet., 67:317 (1984); Schardin et al., Hum. Genet., 71:282 (1985); and Manuelidis, Hum. Genet., 71:288 (1985)].
However, many applications are still limited by the lack of appropriate probes. For example, until the methods described herein were invented, probes with sufficient specificity for prenatal diagnosis were not available for chromosome 13 or 21. Further, repetitive probes are not very useful for detection of structural aberrations since the probability is low that the aberrations will involve the region to which the probe hybridizes.
This invention overcomes the prior art limitations on the use of probes and dramatically enhances the application of in situ hybridization for cytogenetic analysis. As indicated above, prior art probes have not been useful for in-depth cytogenetic analysis. Low complexity single-copy probes do not at this stage of hybridization technology generate reliable signals. Although repetitive probes do provide reliable signals, such signals cannot be tailored for different applications because of the fixed distribution of repetitive sequences in a genome. The probes of this invention combine the hybridization reliability of repetitive probes with the flexibility of being able to tailor the binding pattern of the probe to any desired application.
The enhanced capabilities of the probes of this invention come from their increased complexity. Increasing the complexity of a probe increases the probability, and therefore the intensity, of hybridization to the target region, but also increases the probability of non-specific hybridizations resulting in background signals. However, within the concept of this invention, it was considered that such background signals would be distributed approximately randomly over the genome. Therefore, the net result is that the target region could be visualized with increased contrast against such background signals.
Exemplified herein are probes in an approximate complexity range of from about 50,000 bases (50 kb) to hundreds of millions of bases. Such representative probes are for compact loci and whole human chromosomes. Prior to this invention, probes employed for in situ hybridization techniques had complexities below 40 kb, and more typically on the order of a few kb.
Staining chromosomal material with the probes of this invention is significantly different from the chemical staining of the prior art. The specificity of the probe produced staining of this invention arises from an entirely new source—the nucleic acid sequences in a genome. Thus, staining patterns of this invention can be designed to highlight fundamental genetic information important to particular applications.
The procedures of this invention to construct probes of any desired specificity provide significant advances in a broad spectrum of cytogenetic studies. The analysis can be carried out on metaphase chromosomes and interphase nuclei. The techniques of this invention can be especially advantageous for applications where high-quality banding by conventional methods is difficult or suspected of yielding biased information, e.g., in tumor cytogenetics. Reagents targeted to sites of lesions known to be diagnostically or prognostically important, such as tumor type-specific translocations and deletions, among other tumor specific genetic arrangements, permit rapid recognition of such abnormalities. Where speed of analysis is the predominant concern, e.g., detection of low-frequency chromosomal aberrations induced by toxic environmental agents, the compositions of this invention permit a dramatic increase in detection efficiency in comparison to previous techniques based on conventional chromosome banding.
Further, prenatal screening for disease-linked chromosome aberrations (e.g., trisomy 21) is enhanced by the rapid detection of such aberrations by the methods and compositions of this invention. Interphase aneuploidy analysis according to this invention is particularly significant for prenatal diagnosis in that it yields more rapid results than are available by cell culture methods. Further, fetal cells separated from maternal blood, which cannot be cultured by routine procedures and therefore cannot be analysed by conventional karyotyping techniques, can be examined by the methods and compositions of this invention. In acidition, the intensity, contrast and color combinations of the staining patterns, coupled with the ability to tailor the patterns for particular applications, enhance the opportunities for automated cytogenetic analysis, for example, by flow cytometry or computerized microscopy and image analysis.
This application specifically claims chromosome specific reagents for the detection of genetic rearrangements and methods of using such reagents to detect such rearrangements. Representative genetic rearrangements so detected are those that produce a fusion gene—BCR-ABL—that is diagnostic for chronic myelogenous leukemia (CML).
Chronic myelogenous leukemia (CML) is a neoplastic proliferation of bone marrow cells genetically characterized by the fusion of the BCR and ABL genes on chromosomes 9 and 22. That fusion usually involves a reciprocal translocation t(9;22)(q34;q11), which produces the cytogenetically distinctive Philadelphia chromosome (Ph1). However, more complex rearrangements may cause BCR-ABL fusion. At the molecular level, fusion can be detected by Southern analysis or by in vitro amplification of the mRNA from the fusion gene using the polymerase chain reaction (PCR). Those techniques are sensitive but cannot be applied to single cells.
Clearly, a sensitive method for detecting chromosomal abnormalities and, more specifically, genetic rearrangements, such as, for example, the tumor specific arrangements associated with CML, would be a highly useful tool for genetic screening. This invention provides such tools.
The following references are indicated in the ensuing text by numbers as indicated:    1. A. de Klein et al., Nature 300, 765 (1982).    2. J. Groffen et al., Cell 36,93 (1984).    3. N. Heisterkamp et al., Nature 306,239 (1983).    4. E. Shtivelman et al., Blood 69,971 (1987).    5. J. B. Konopka, S. M. Watanabe, O. N. Witte, Cell 37,1035 (1984).    6. Y. Ben-Neriah et al., Science 233,212 (1986).    7. P. C. Nowell and D. A. Hungerford, Science 132,1497 (1960).    8. J. D. Rowley, Nature 243,290 (June 1973).    9. G. Grosveld et al., Mol Cell Biol 6,607 (1986).    10. E. Canaani et al., Lancet 1, 593 (1984).    11. R. P. Gale and E. Canaani, Proc Natl Acad Sci USA 81,5648 (1984).    12. Konopka J. B. et al., Proc Natl Acad Sci USA 82:1810 (1985).    13. P. Benn et al., Cancer Genet Cytogenet 29,1(1987).    14. S. Abe et al., Cancer Genet Cytogenet 38,61 (1989)    15. M. Shtalrid et al., Blood 72, 485 (1988).    16. I. Dube et al., Genes Chromosomes and Cancer 1,106 (1989).    17. A. J. Fishleder, B. Shadrach and C. Tuttle, Leukemia 3:10,746 (1989)    18. C. R. Bartram et al., J Exp Med 164 (5):1389 (1986).    19. S. Hiroswa et al., Am L Hematol 28,133 (1988).    20. M. S. Lee et al., Blood 73 (8):2165 (1989).    21. E. S. Kawasaki et al., Proc Natl Acad Sci USA 85,5698 (1988).    22. M. S. Roth et al., Blood 74, 882 (1989).    23. A. L. Hooberman et al., Blood 74, 1101 (1989).    24. C. A. Westbrook et al., Blood 71 (3):697-702 (1988).    25. B. Trask, D. Pinkel, and G. van den Engh, Genomics 5,710 (1989).    26. S. J. Collins and M. T. Groudine, Proc Natl Acad Sci USA 80, 4813 (1983).    27. D. Pinkel et al., Proc Natl Acad Sci USA 83,2934 (1986).    28. D. Pinkel, T. Straume and J. W. Gray., Proc Natl Acad Sci USA 85, 9138 (1988).    29. B. Trask and J. Hamlin, Genes and Development, 3:1913 (1989).    30. J. B. Lawrence, C. A. Villnave and R. H. Singer, Cell 42,51 (1988).    31. G. D. Johnson and J. G. Nogueria J. Immunol. Methods 43, 349 (1981).    32. Hegewisch-Becker et al., J. Cell. Biochem. (Suppl.) 13E, 289 (1989).    33. Kohler et al., "Expression of BCR-ABL from Transcripts Following Bone Marrow Transplant for Philadelphia Chromosome Positive Leukemias", (manuscript submitted).    34. Heisterkamp et al., Nature, 315:758 (1985).    35. Heisterkamp et al, J. Molec. Appl. Genet., 2:57 (1983).
Fusion of the proto-oncogene. c-ABL from the long arm of chromosome 9 with the BCR gene of chromosome 22 is a consistent finding in CML (1-3). That genetic change leads to formation of a BCR-ABL transcript that is translated to form a 210 kd protein present in virtually all cases of CML (4-6). In 90% of the cases, the fusion gene results from a reciprocal translocation involving chromosomes 9 and 22 producing a cytogenetically distinct small acrocentric chromosome called the Philadelphia (Ph1) chromosome (7-12), FIG. 8. However, standard cytogenetics does not have the resolution to distinguish closely spaced breakpoints, such as those characteristic of CML and acute lymphocytic leukemia (ALL), and misses fusions produced by more complex rearrangements. Mapping and cloning of the breakpoint regions in both genes has lead to molecular techniques capable of demonstrating BCR-ABL fusion in CML cases where the Ph1 chromosome could not be detected cytogenetically (13-16). Southern analysis for BCR rearrangements has become the standard for diagnosis of CML. More recently, fusion has been detected by in vitro amplification of a cDNA transcript copied from CML mRNA using reverse transcriptase (17-23). That technique permits detection of BCR-ABL transcript from CML cells present at low frequencies. Both of those techniques utilize nucleic acid obtained from cell populations so that correlation between genotype and phenotype for individual cells is not possible.
Described herein are chromosome-specific reagents and methods to detect genetic rearrangements, such as those exemplified herein for the BCR-ABL fusion, that supply information unavailable by existing techniques.

Method of detecting genetic deletions identified with chromosomal abnormalities

The Regents of the University of California


A cargo restraint system having a load bearing perimeter rail and a tie-down ring assembly. The load bearing perimeter rail further comprised of a plurality of protruding bosses with a hole within each boss. Further, a tie-down ring assembly comprised of a tie-down ring and a pin wherein the tie-down ring is inserted through the hole in the plurality of protruding bosses of the load bearing perimeter rail.

Conventional air cargo pallets consist of an outer rail which runs along the perimeter of a sandwich panel core. This outer rail has holes in which a tie-down ring and bracket assembly are then attached to said outer rail by one time use fasteners. Said fasteners are difficult to remove when replacing a tie-down ring and bracket assembly. Additionally, because tie-down rings and brackets are a fixed assembly, when one or the other is damaged, both must be replaced, increasing the cost of repair. Also, due to the nature of the current fasteners, point loads incur upon force being applied to said tie-down ring and high levels of stress are experienced at the attachment points between the outer rail and tie-down ring. The described tie down ring and load bearing rail assembly obviates these problems by providing a much stronger ring assembly that can carry higher loads, but is designed in a way that provides load paths that distribute and avoid the concentrated high stress loading points, and is furthermore assembled from components that are re-usable and provide a simple mechanism to assemble, disassemble, and reassemble the tie down ring and load bearing rail assembly.

Load bearing rail and tie-down ring assembly


A perovskite thin film and method of forming a perovskite thin film are provided. The perovskite thin film includes a substrate, a hole blocking/electron transport layer, and a sintered perovskite layer. The method of forming the perovskite solar cell includes depositing a perovskite layer onto a substrate and processing (for example, by sintering) the perovskite layer with intense pulsed light to initiate a radiative thermal response that is enabled by an alkyl halide additive.

There have been several innovations established in the last few years across all of the solar cell technologies that are geared towards reducing the cost of implementation of solar energy. These include newer architectures with higher efficiencies, refined material usage, lower cost materials, improved durability and higher throughputs. Much more rapid declines in the costs of solar power will in all likelihood require flexible modules that are not addressable using the market dominant crystalline silicon materials.
The perovskite solar cell is a relatively newer entrant into the solar photovoltaic technologies and has seen vast improvement in the power conversion efficiencies in a very short period of time. In particular, since the first report of perovskite solar cells in 2012, the technology has evolved to over 20% certified power-conversion efficiency. The cells are based on organometal halide perovskite materials characterized by high extinction coefficients and carrier mobilities. The perovskite structure is generally represented by the formula ABX3 and in the case of the organometal halide the A site refers to an organic group, B represents a metal such as lead (Pb), and X is a halide group such as iodine (I), chlorine (Cl), or bromine (Br).
Perovskite solar cells provide ease of manufacturing, use of common materials, and respectable efficiencies. More specifically, these solar cells combine the crystallinity and high charge-transfer found in inorganic semiconductors with the cost-effective low-temperature solvent-based manufacturing of organic solar cells. Additionally, unlike traditional semiconductor solar cells, the perovskite solar cell is amenable to changes in the atoms of its crystal structure. This opens up many possibilities in tuning band gaps, using different cell configurations, and experimenting in processing techniques.
Although there are many different variations in perovskite solar cell technology, the fundamental concepts of semiconductors devices apply to them all. Larger crystal sizes lead to fewer grain boundaries and enhanced charge-transfer with longer charge-carrier diffusion lengths. Grain boundaries have been known to introduce allowed energy levels in the band gap of a semiconductor and act as recombination centers. In other semiconductor technologies, the grain size can be increased by sintering the semiconductor at high temperatures.
However, because of the instability of the methylammonium lead iodide (CH3NH3PbI3) perovskite structure, annealing of perovskite materials is limited to temperatures <150° C. Above this temperature, the methylammonium iodide (MAI) begins to evaporate from the cell and the CH3NH3PbI3 decomposes into lead iodide (PbI2) and MAI. Additionally, when annealing at high temperatures, surface coverage is often reduced, resulting in the formation of perovskite islands due to agglomeration. More specifically, it has been demonstrated that as the annealing temperature increases, the number of pores in the final film decreases, but the size of the pores increases and the morphology transitions from a continuous layer into discrete islands of perovskite. An active layer morphology composed of discrete islands can create multiple shunting pathways by exposing the underlying contact and thus limiting performance. For at least these reasons, to date, the sintering techniques of other semiconductor technologies have not been explored as a viable alternative for the recrystallization of the unstable CH3NH3PbI3 material in connection with perovskite formation.
Other methods for creating larger perovskite crystals and improving the surface coverage of perovskite films is therefore important for optimizing device performance and has been a topic of discussion in perovskite solar cell research. Initially researchers improved the crystal formation utilizing a two-step sequential deposition of PbI2 followed by MAI. Others improved on that method by showing that heating the substrates prior to spin coating the PbI2 solution resulted in better surface coverage and pore filling of the perovskite formed after dipping the films in MAI solution. However, this two-step method (PbI2 spin coating followed by a MAI dip coat) is not ideal for roll-to-roll manufacturing. A more expedient one-step deposition of CH3NH3PbI3 has also recently been advanced by using solvent-solvent extraction techniques. These techniques utilize low boiling point solvents such as diethyl ether to remove high boiling point solvents such as Dimethyl sulfoxide (DMSO) or Dimethylformamide (DMF) from the perovskite films after spin coating. While these advances are significant in improving the morphology of perovskite thin films and device performance, they are difficult to scale.
In addition to the morphology issues, the CH3NH3PbI3 material of the perovskite solar cells can be susceptible to degradation from humidity, UV, and temperature. While a simple solution would be to hermetically seal the device, the same degradation mechanisms also limit the production of the perovskite layer to well controlled environs. As such, hermetically sealing the device does not solve the problem of manufacturing in ambient environments. Furthermore, the added sealing technologies and processing limitations add costs to the CH3NH3PbI3 perovskite solar cell that can offset the opportunities of these low priced materials.
Notwithstanding the issues discussed above, recently, there has been increasing interest among the research community in depositing perovskite films under ambient conditions. For example, some researchers have demonstrated that the film deposition under low humidity conditions and post-treatment of the films under high humidity conditions yields better crystallinity and performance. Others have investigated the role of moisture exposure during the perovskite film fabrication. Their results conclude that the moisture exposure enhanced the open-circuit voltage. Further researchers have studied the humidity induced grain boundaries in perovskite films where prolonged exposure of the film to high humidity conditions created additional grain boundaries. More recently, air stable and high efficiency perovskite cells with dissolving HCl gas in MAI, PbI2 and DMF solution were reported. Even though the perovskite film was formed with overnight drying at room temperature, the fabrication process was carried out in a nitrogen filled glove box over a prolonged time for drying, which likely is not a viable option for cost-effective large scale manufacturing.
To date, the role of alkyl halides in the crystal formation, solvent and solute interaction, and influence on film surface morphology has not been explored with photonic annealing techniques (such as intense pulsed light (IPL)). IPL heats a thin film using light energy, but the wavelengths span from the UV to the visible (vis) into the near infrared (NIR) and the duration of the pulse is on the order of a millisecond.
Accordingly, a heat treatment technique that can create a dense layer of perovskite particles with enlarged crystal sizes, and particularly a heat treatment technique for the production of perovskite films under ambient conditions, would be both highly desirable and beneficial. Likewise, a single-step perovskite deposition process under low humidity conditions would also be desirable.

Methods for forming a perovskite solar cell

UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION, INC.


Technology is discussed for self-optimization approaches within wireless networks to optimize networks for energy efficiency, load capacity, and/or mobility, together with new, supporting channel state measurements and handover techniques. New, Channel State Information-Reference Signals (CSI-RSs) for yet-to-be-configured Cell-IDentifications (Cell-IDs) can be used to determine whether adjacent transmission cells can provide coverage for transmission cells that can be switched off for energy efficiency during formation of a Single Frequency Network (SFN). New approaches are also discussed to facilitate mobility within such a network. The new CSI-RSs and mobility approaches can also be used to split up such a SFN when changing load demands so require. Additionally, such new approaches can be used to create a SFN with a common Cell-ID where high mobility is required, such as near a roadway, and to break it up where high capacity is required, such as during a period of traffic congestion.

To improve performance with respect to different parameters, wireless networks can self-optimize. A wireless network can be optimized by making changes at transmission cells within a wireless network. In a self-optimizing network, these changes can be determined and implemented by the network itself.
Self-optimization approaches are currently applied within wireless networks in a limited number of ways with respect to a limited number of parameters. Due to the limited ways in which self-optimizing networks have been applied, a potential exists to improve wireless networks in different ways through self-optimization. The ways in which such improvements can be achieved remain to be discovered. However, several difficulties can arise with respect to the implementation of a self-optimization approach even once an application is discovered.
Self-optimization within a wireless network involves changes within the wireless network. These changes rely on supporting infrastructure to allow the changing network to continue to perform its function. In particular, a wireless network still needs infrastructure to provide services to mobile communication devices within the network despite the changes taking place at transmission cells therein. Limitations in supporting infrastructure can prevent the flexibility with which wireless networks can self-optimize.
Reference will now be made to the exemplary examples illustrated, and specific language will be used herein to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended.

Supported, self-optimizing wireless networks, optimized with respect to energy, mobility, and capacity


A support structure for a shoe includes a bladder arrangement having at least one (and preferably two) fluid-filled chamber arranged in a heel region of the sole of the shoe. The fluid-filled chamber has outer walls with a pressurized fluid disposed therein. The fluid-filled chamber is configured to be compressively deformed when an external pressure is applied thereto, such as the pressure exerted by a wearer""s foot. The support structure also includes at least one pillar disposed in the fluid-filled chamber. The pillars are configured to decrease the amount by which the fluid-filled chamber is compressively deformed when the external pressure is applied thereto, while still permitting the fluid-filled chambers to be deformed sufficiently to provide-adequate protection against the force of impact during use.

The present invention relates to support structure for a shoe and, more particularly, to a bladder arrangement comprising fluid filled chambers having support pillars that provides additional stability to the shoe.
The human foot and leg endures a great deal of stress, even during the performance of simple activities like walking. More rigorous activities, such as running and jumping, subject a person""s feet and legs to even greater stress. This is particularly true of athletes, many of whom perform such rigorous activities on a daily basis.
In order to alleviate the unusually high levels of stress imparted on an athlete""s feet and legs, athletic shoes are typically designed to absorb the force of impact associated with running and jumping. Specifically, athletic shoes often include supporting and cushioning structures to absorb these forces of impact. These supporting and cushioning structures are typically positioned in the rear foot or heel section of the shoe where the forces of impact are most likely to be experienced. Many athletic shoes also provide supporting and cushioning structures on the sides of the shoe, not merely in the region of the heel. These supporting and cushioning side structures absorb the force of impact along the sides of the athlete""s foot.
Currently, there are many configurations for these supporting and cushioning structures. Some of these configurations include the use of fluid-filled chambers. A fluid-filled chamber typically comprises a fluid-filled chamber or pocket located in the sole of an athletic shoe. The fluid may be air or else any other type of gas or liquid that is deemed to provide the desired level of stability. Depending on the amount of support desired, the fluid-filled chambers may be maintained at the ambient pressure, may be pressurized beyond the ambient pressure level, or else may be de-pressurized below the ambient pressure level.
U.S. Pat. No. 5,575,088 discloses a fluid-filled bladder arrangement imparting cushioning to a heel section of a shoe. The bladder arrangement includes individual, concentric chambers that are connected so as to allow fluid to be communicated between the chambers. The concentric chambers are ring-shaped with the inner ring having a lower height than the outer ring. The arrangement forms a cradle for the heel, providing support and stabilization therefor. The pressure within the chambers of the bladder is uniform because fluid pressure is equalized between the ring sections, which are in fluid communication with one another.
U.S. Pat. No. 5,353,459 to Potter et al. discloses a bladder arrangement in which separate chambers are maintained at different pressures through the use of distinct interconnecting tubes. Specifically, Potter discloses a bladder arrangement having tube-shaped chambers that are disposed at and form the lateral and medial sides of the bladder, a rear central chamber disposed between these tube-shaped chambers at one end thereof, and a front central chamber disposed between these tube-shaped chambers at another end thereof. When disposed within a shoe, the rear central chamber of the bladder arrangement provides support to the heel of the wearer, the front central chamber provides support to the middle of the wearer""s foot, and the two tube-shaped chambers provide support to the medial and lateral sides of the wearer""s foot.
One problem that is experienced by the use of fluid-filled chambers as supporting and cushioning structures in shoes is that, due to their compressibility, the fluid-filled chambers may not provide the desired amount of support and stability. For example, in addition to the impact forces that are experienced by the feet and legs of an athlete, many sports require an athlete to rapidly change his or her direction of motion. Still other sports require an athlete to place his or her foot on a field or playing surface which is not perfectly flat. Both of these situations may result in the athlete""s foot undesirably rotating relative to the athlete""s leg. This may result in the athlete performing inadequately, e.g., failing to execute a desired movement. In addition, if the athlete""s foot rotates too far relative to the athlete""s leg, the athlete may suffer an injury. For instance, if the inner (e.g., medial) side of the foot is rotated downwardly too far relative to the outer (e.g., lateral) side of the foot, the foot may be over-pronated and an injury may occur. Likewise, if the medial side of the foot is rotated upwardly too far relative to the lateral side of the foot, the foot may be over-supinated and an injury may also occur. Of course, these are merely two types of excessive rotations that can cause foot injuries.
Thus, while fluid-filled chambers may provide adequate protection against impact forces, they may not provide adequate stability if they deform too much when they are compressed. For instance, even though a fluid-filled chamber may be pressurized, the fluid-filled chamber may not be able to provide an adequate amount of support to stabilize the foot of a large athlete. In addition, the fluid-filled chamber may not be able to provide an adequate amount of support to stabilize the foot of an athlete that participates in a sport that requires rapid changes in direction, e.g., basketball, even if it is able to provide an adequate amount of support to stabilize the foot of an athlete that participates in a sport that does not require these movements, e.g., marathon running. If the amount of support provided by the fluid-filled chamber is inadequate, the athlete may not receive the support need to perform optimally, or else may risk injury when the athlete""s foot undesirably rotates relative to the athlete""s leg.
The present invention, in accordance with one embodiment thereof, relates to a support structure for a shoe. The support structure comprises a bladder arrangement including at least one (and preferably two) fluid-filled chamber arranged in a sole of the shoe. The fluid-filled chamber has outer walls with a fluid disposed therein. Preferably, the fluid is pressurized. The fluid-filled chamber is configured to be compressively deformed when an external pressure is applied thereto, such as the pressure exerted by a wearer""s foot.
The support structure also includes at least one pillar disposed in the fluid-filled chamber. The pillars are configured to decrease the amount by which the fluid-filled chamber is compressively deformed when the external pressure is applied thereto. Preferably, the pillars are configured such that, although they decrease the amount by which the fluid-filled chamber is compressively deformed when the external pressure is applied thereto, they do permit the fluid-filled chambers to be deformed sufficiently to provide adequate protection against the force of impact during use. Advantageously, the pillar has a tapered shape, such that it tapers from a first, e.g., larger, dimension at its connection to the outer walls of the fluid-filled chamber to a second, e.g., smaller, dimension at a point between the outer walls of the fluid-filled chamber, so as to provide a desirable amount of structural rigidity.
In a preferred embodiment, the bladder arrangement of the support structure includes two fluid-filled chambers, each of which are positioned along a medial side and a lateral side of the heel region of the shoe. The fluid-filled chambers are preferably encapsulated by a cushioning material such as polyurethane foam.


The present invention is directed to compounds, methods and compositions for treating or preventing viral infections using nucleosides analogs. Specifically, the present invention provides for the design and synthesis of acyclic fleximer nucleoside analogues having increased flexibility and ability to alter their conformation structures to provide increased antiviral activity potential with the result of inhibiting flaviviruses, filoviruses and/or coronaviruses.

Viruses are small infectious agents that can only multiply within the cells of animals, plants, and bacteria. The structures of viruses are simple compared to living cells and contain a small haploid DNA or RNA genome and a protein or glycoprotein coat called a capsid. In addition, some viruses called enveloped viruses are surrounded by a lipid membrane.
A number of viruses appear on the United States National Institutes of Allergy and Infectious Disease (NIAID) list of Emerging Diseases/Pathogens list, which include Flaviviruses (Dengue, Zika and West Nile) and Filoviruses (Ebola, Sudan and Marburg) to name a few.
Filoviruses are enveloped viruses with a genome consisting of one linear single-stranded RNA segment of negative polarity. The viral genome encodes 7 proteins. Nucleoprotein (NP), virion protein 35 kDa (VP35) and virion protein 30 kDa (VP30) are associated with the viral ribonucleoprotein complex. Members of the filovirus genus include Zaire Ebola virus, Sudan Ebola virus, Reston Ebola virus, Cote d'Ivoire Ebola virus and Marburg virus. Ebola and Marburg viruses can cause severe hemorrhagic fever and have a high mortality rate. Ebola virus (Zaire and Sudan species) was first described in 1976 after outbreaks of a febrile, rapidly fatal hemorrhagic illness were reported along the Ebola River in Zaire (now the Democratic Republic of the Congo) and Sudan. The natural host for Ebola viruses is still unknown. Marburg virus, named after the German town where it was first reported in 1967, is primarily found in equatorial Africa. The host range of Marburg virus includes non-human and human primates. Marburg made its first appearance in Zimbabwe in 1975 and was later identified in other African countries, including Kenya (1980 & 1987) and Democratic Republic of the Congo (1999).
Viruses in the genus flavivirus are known to cause viral hemorrhagic fevers (VHFs). Flaviviruses are enveloped viruses with a genome consisting of one linear single-stranded RNA segment of positive pola The polyprotein is co- and post-transcriptionally cleaved by cell signal peptidase and the viral protease to generate individual viral proteins. Viral structural proteins include capsid (C), precursor to M (prM), minor envelope (M) and major envelope (E).
Members of the flavivirus genus include yellow fever virus, Apoi virus, Aroa virus, Bagaza virus, Banzi virus, Bouboui virus, Bukalasa bat virus, Cacipacore virus, Carey Island virus, Cowbone Ridge virus, Dakar bat virus, dengue virus, Edge Hill virus, Entebbe bat virus, Gadgets Gully virus, Ilheus virus, Israel turkey meningoencephalomyelitis virus, Japanese encephalitis virus, Jugra virus, Jutiapa virus, Kadam virus, Kedougou virus, Kokobera virus, Koutango virus, Kyasanur Forest disease virus, Langat virus, Louping ill virus, Meaban virus, Modoc virus, Montana myotis leukoencephalitis virus, Murray Valley encephalitis virus, Ntaya virus, Omsk hemorrhagic fever virus, Phnom Phenh bat virus, Powassan virus, Rio Bravo virus, Royal Farm virus, Saboya virus, Sal Vieja virus, San Perlita virus, Saumarez Reef virus, Sepik virus, St. Louis encephalitis virus, Tembusu virus, tick-borne encephalitis virus, Tyuleniy virus, Uganda S virus, Usutu virus, Wesselsbron virus, West Nile virus, Yaounde virus, Yokose virus, Zika virus, cell fusing agent virus and Tamana bat virus.
There are relatively few prophylactic or therapeutic agents for treatment of viral diseases caused by Flaviviruses and Filoviruses. The need for new and more effective antiviral therapeutics, particularly those targeting emerging and reemerging infectious diseases and pathogens continues to increase. Thus, in light of the above discussion, there is a need for discovering and providing new and more efficient antiviral drugs.

Flex-nucleoside analogues, novel therapeutics against filoviruses and flaviviruses

UNIVERSITY OF MARYLAND, BALTIMORE COUNTY


A moisture absorbent composition is provided with a thermoplastic resin; and a moisture absorbent kneaded into the thermoplastic resin, having a secondary particle size of substantially 1 to 40 μm, wherein equilibrium humidity is controlled by selecting the specific gravity of the thermoplastic resin. A method for controlling equilibrium humidity in a moisture absorbent composition obtained by kneading a moisture absorbent into a thermoplastic resin is provided, which includes kneading the moisture absorbent such that a secondary particle size of the moisture absorbent is substantially 1 to 40 μm; and controlling equilibrium humidity by selecting specific gravity of the thermoplastic resin.

1. Field of the Invention
The present invention relates to a moisture absorbent composition and a moisture absorbent molding, and in particular to a moisture absorbent composition and a moisture absorbent molding having a humidity conditioning function capable of holding humidity constant. The present invention further relates to a method for controlling the equilibrium humidity, and a method for controlling the equilibrium humidity maintaining time.
2. Description of Related Art
Moisture absorbents, such as silica gel, calcium chloride, quicklime, and zeolite, are used conventionally for preventing the quality deterioration of products due to oxidation or the like caused by moisture absorption in all fields of foodstuffs, pharmaceuticals, electronic components, precision machines, or the like. These moisture absorbents are wrapped with paper, nonwoven fabric, or the like or placed in a container in a granular or powdered state, and enclosed in packaging or the like with products.
On the other hand, for example, Patent document 1 (JP 07-53222B) and Patent document 2 (JP 07-96092B) propose to provide moisture absorbent compositions and moisture absorbent moldings in which specific moisture absorbents (for example, magnesium sulfate) are kneaded into thermoplastic resins to exhibit high moisture absorbency and water-holding capacity without bringing such drawbacks as scattering, moisture absorbency, and liquid leakage due to deliquescence.
Meanwhile, the development of various products is progressing according to diversification of needs for products, the advancement of manufacturing technologies, or the like, in recent years, and accordingly, there is a tendency to diversify the environment of product storage or the like. For example, cereals produce cracks or the like when moisture content is too low, and when moisture content is excessive, on the contrary, an enzymatic reaction progresses to cause deterioration in quality. Therefore, an environment capable of storing the cereals in an equilibrium humidity zone (approximately RH 50%) can be said to be a desirable storage environment. Further, products such as tea leaves, in which water is evaporated to some extent, deteriorate in quality through the enzymatic reaction or oxidation when moisture content increases due to moisture absorption. Therefore, an environment capable of storing the products in an equilibrium humidity zone (approximately RH 20%) is a desirable storage environment.
However, the moisture absorbents, such as silica gel, calcium chloride, quicklime and zeolite, which have been conventionally used as moisture absorbents, have strong desiccative capability and moisture absorbency according to the physical and chemical properties. When these moisture absorbents are put in sealed vessels, bags, and the like, the moisture absorbents absorbs internal moisture in a short period of time, and continue taking up the moisture infinitely until humidity reaches 0%. Thus, the conventional moisture absorbents did not have a humidity control function, and had a problem of incapability of responding to the storage of increasingly diversified products.
On the other hand, for example, Patent document 3 (JP 05-39379A) proposes a humidity conditioning composition and a humidity conditioning molding to which a humidity conditioning function is imparted by kneading a specific moisture absorbent (magnesium sulfate) into a thermoplastic resin.
In the case where magnesium sulfate is kneaded into a thermoplastic resin as a specific moisture absorbent, the composite of the resin and the magnesium sulfate brings about constant vapor pressure. However, the above Patent document 3 focuses on a fact that the vapor pressure in this case is affected by a kneaded resin and shows a value different from a case of the magnesium sulfate single body. Thus, constant humidity to be held was controlled suitably by changing a kind of resin.
That is, the description of the above Patent document 3 is based on an idea of obtaining the composition and the molding having different equilibrium humidity by changing the kind of resin by utilizing the fact that moisture permeability changes depending on the kind of resin. Therefore, the above Patent document 3 did not take the specific gravity of the resin itself into consideration in any way. This is probably based on the following reasons.
Generally, the amount of gas permeation is determined by the following formula: (amount of gas permeation)=(gas permeation coefficient)×(gas pressure difference)×(area)×(time)÷(film thickness). A gas permeation rate (moisture permeability) is obtained by measurement made by fixing the pressure difference, the area, the time, and the film thickness in this formula. The gas permeation rate is a value which changes depending on a gas permeation coefficient, and generally the gas permeation coefficient is determined by the following formula: (gas permeation coefficient)=(diffusion coefficient)×(solubility coefficient). Therefore, when comparison is made by using identical film thickness, the same area, the same time, and the partial pressure difference of the same gas, the amount of gas which moves through a resin film (amount of gas permeation) is decided by the product of the easiness of incorporation of the gas into the film (solubility coefficient), and the easiness of movement of the gas within the film (diffusion coefficient).
If the kind of gas is decided, the solubility coefficient will not change greatly even when a kind of resin (polymer) changes, but changes drastically according to gases for a predetermined polymeric membrane.
The diffusion coefficient changes drastically according to the kind of resin (polymer) forming the polymeric membrane for the same gas, and has no quantitative relationship with the kind of gas, that is, a molecular size and a molecular weight, in a polymeric membrane of the same kind.
Further, resins having a hydroxyl (—OH) or an amide (—CONH—) in the resins are sensitive to water vapor, although polymers are combined firmly together by hydrogen bonds.
When water enters such resins, the hydrogen bonds are destroyed and lost, and as a result, the intermolecular force of the resins is extremely weakened. That is, resin chains are plasticized by the water, gas permeability is increased, and the movement of the resin chains is also activated. Therefore, the gas easily diffuses. Table 1 shows how the gas permeability is increased, when polymers sensitive to the water absorb the water (an extract from "Food Packaging Handbook" published by the Japan Packaging Institute). On the other hand, polymers having a hydrophobic structure (polyethylene and polypropylene) and polymers having low polarity (PVC, PVCD and PET), polymers having a low gas permeation properties due to dipole interactions (PAN), or the like have a smaller amount of water absorption, and gas permeability does not change even when the polymers contain water.
TABLE 1O2 permeation rateResinsConditionsat 25° C.(Note 1)Polyvinyl alcoholDry0.06Polyvinyl alcoholRH 95%310Cellophane (uncoated product)Dry2RH 100%3,110Nylon 6Dry18Nylon 6RH 100%78Eval F(Note 2)Dry0.26Eval FRH 100%31PEDry7,510PERH 100%7,510PolyacrylonitrileDry1.6PolyacrylonitrileRH 100%1.7(Note 1)O2 permeation rate: cc · 25.4 μ/m2 · 24 hr/atm(Note 2)Eval F is a copolymer of ethylene and vinyl alcohol, wherein vinyl alcohol content is approximately 70%.
Table 2 shows O2 and H2O permeation rate of resins generally used currently (an extract from "Food Packaging Handbook" published by the Japan Packaging Institute).
As clearly shown in the table, there is no relationship between the O2 permeation rate and the H2O permeation rate which is generalized in any way.
In the case of gas permeation rate, diffusion is a control factor, and in the case of water vapor permeation rate, the affinity between the water and the resin is a control factor. That is, hydrophobic resins always have small water vapor permeation rates, and hydrophilic resins always have large water vapor permeation rates.
TABLE 2Permeation rate at 25° C.(Note 1)PolymersO2H2OPolyvinyl alcohol (dry)0.065Polyvinyl alcohol (wet)3101,097 (RH 95%)Eval (dry)0.3Eval (wet)3138Polyacrylonitrile (crystallized)0.655.5PVDC (homopolymer)1.60.07PVDC (copolymer)40.5Cellophane (dry)2Polyacrylonitrile copolymer (70%1619AN)Nylon 6 (dry)18Nylon 6 (wet)7847PET (biaxially-stretched film)475PET (biaxially-oriented bottle)788Polychloro trifluoroethylene471.6Nylon 6-10 (dry)93Nylon 6-10 (wet)15522PVC (hard)1245.5PVC (for bottles)1687Polyacetal15547Polymethylmethacrylate26041PET copolymer (PRTG)41426Polyvinyl acetate (dry)910SAN (AN: 25%; ST: 75%)1,01044ABS1,55033High-density PE(d = 0.955)1,7100.5PP2,3301.6Polystyrene6,73030Low-density polyethylene (d = 0.92)7,5102.7Teflon7,7701.2Polybutadiene38,84058Poly-4-methylpentene-162,14047Silicone elastomer1,398,060823(Note 1)O2: cc · 25.4 μ/m2 · 24 hr · atm, RH 65% H2O: g/m2 · 24 hr · atm
As described above, the gas permeation rate, especially the water vapor permeation rate, is a value which changes according to the kinds of gases and resins. Thus it is understood that the value is totally unrelated to the difference in specific gravity of the resins. For this reason, when conventionally obtaining compositions and moldings having different equilibrium humidity, the specific gravity of the resins was probably not taken into consideration.
Further, technical information of a resin manufacturer (Sumitomo Chemical Co., Ltd., "Moisture vapor permeation rate of polyethylene film", PE technical information III-4{circumflex over (1)}) teaches, as shown in FIG. 18, for example, (sample: LDPE 60 μ-single layer film; measurement conditions: 40° C., RH 90%), that it may be roughly guessed that, when a difference in specific gravity within the same resin is considered, a resin having larger specific gravity has smaller moisture permeation rate. However, in the conventionally common technical knowledge, it was considered that "it is not necessary to take the specific gravity into consideration since the difference in moisture permeation rate due to the difference in the specific gravity is very small", and there is no definite relational expression for the specific gravity difference in the same resin, and no major difference arises from the specific gravity difference, and accordingly, the specific gravity of the resins was hardly considered.
Under such circumstances, only one equilibrium humidity could be set for one kind of resin in the conventional art, and it was necessary to change the kind of resin for changing constant humidity (equilibrium humidity) to be maintained.
However, manufactured articles acquired different gas barrier properties, physical properties, or the like as a result of changing the kind of resin, and, in many cases, it was difficult to secure an aesthetic property required for products to be stored, or too complicated processing methods adversely affect cost and techniques, which causes a problem of difficulty to form a suitable storage environment for increasingly diversified products.

Moisture absorbent composition, moisture absorbent molding, and method for controlling equilibrium humidity, method for controlling time of maintaining equilibrium humidity


A capacitor component includes a lamination portion in which first and second internal electrodes are disposed to face each other in a first direction and separated from each other by a dielectric layer, and a body comprising the lamination portion and first and second connection portions disposed on both sides of the lamination portion in a second direction, perpendicular to the first direction, and connected to the first and second internal electrodes. The first and second connection portions each include a metal layer including nickel and disposed on the lamination portion and a ceramic layer disposed on the metal layer, and an average thickness of each of the first and second internal electrodes is 0.4 μm or less.

A multilayer ceramic capacitor (MLCC), among capacitor components, has advantages of a small size, high capacity and ease of mounting thereof.
A method of dipping a surface, on which an internal electrode of a body is exposed, in a paste, where the paste includes a conductive metal, has conventionally been used when forming an external electrode of the MLCC.
However, the external electrode formed by the dipping method results in uneven thickness thereof, and the external electrode formed at an edge portion of the body may be excessively thin. Further, when forming a deposition layer on the external electrode, deposition liquid penetrates into the body, thereby reducing reliability of the MLCC.


The present invention relates to the use of deuterium oxide (D2O) for prevention and/or treatment of virus-based diseases of the skin, in particular herpes virus-based and verrucal virus-based diseases of the skin.

Diseases caused by viruses (viral infections) are widespread throughout the world and constitute a serious problem in medicine, in particular because of the high variability, adaptability and mutation rate of viruses. Viruses are small particles of approximately 15 to 400 nm, which are unable to replicate themselves but instead require a host cell to do so. Depending on their host specificity, viruses are differentiated according to those which attack animals (invertebrates and vertebrates), plants, bacteria or algae, fungi and protozoa. Viral infections are characterized in general by a high replication rate of the viral particles in the infected host cells, which can be described with an exponential law. The general reproduction cycle of viruses takes place via injection of their nucleic acid (RNA or DNA) into the host cell, in which the replication of the nucleic acid takes place by utilizing the replication apparatus of the host cell. Replication of viruses may take place either in the lytic or lysogenic cycle. In the lytic cycle (active infection), the viral nucleic acid is replicated in the cell nucleus of the host cell after injection of the nucleic acid, the new viral particles are assembled in the cytoplasm, whereupon the host cell is ultimately lysed (destroyed) and the viruses are released. Viruses released in this way then infect other host cells. In the lysogenic cycle, the nucleic acid (DNA) of the virus is integrated into the genome of the host cell, where it remains without destroying the host cell. This lysogenic cycle may be converted to a lytic cycle as described above due to external influences (e.g., UV radiation, addition of mutagenic substances).
Virus-based diseases of the skin are understood in general to be diseases of the skin caused by a virus. Virus-based diseases of the skin include in particular diseases and/or infections which are caused by herpesviruses and are also referred to colloquially simply as herpes. Herpesviruses occur widely in vertebrates, in particular in mammals and especially in humans, horses, swine, cattle, goats, sheep, cats and dogs.
Human pathogenic herpesviruses (HHV) are differentiated according to alpha, beta, and gamma-herpesviruses (HHV-1 through HHV-8), where the alpha and gamma viruses are also among viruses that can infect animals, e.g., the horse (equine herpesvirus), cattle (bovine herpesvirus), swine (porcine herpesvirus), cat (feline herpesvirus), dog (canine herpesvirus) and chicken (chicken herpesvirus 1).
Of the human pathogenic herpesviruses, those which infect humans, in particular the alpha-herpesviruses, are of great importance. The alpha-herpesviruses include herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2) and varicella zoster virus (VZV).
The diseases of the skin caused by herpes simplex viruses HSV-1 and HSV-2 include, for example, herpes labiales, also known as fever blisters or herpes of the lips, and herpes nasalis, both caused primarily by HSV-1, keratoconjunctivitis herpetica, stomatitis herpetica, herpes facialis, herpes buccalis, herpes genitales, herpes perianalis, herpes glutealis. Varicella zoster viruses (VZV) cause chickenpox and shingles, for example.
Virologists have estimated that 80% of the population worldwide has latent HSV-1 infections and 30% HSV-2. HSV-1 and HSV-2 are closely related to one another and have a high percentage of identical nucleotide sequences. Although HSV-1 infects primarily the oral and facial area, HSV-2 occurs mainly in the genital area.
Alpha-herpesviruses usually first infect epithelial cells such as skin cells, mucous cells and mucosal cells, followed by a marked replication of the virus in the host cell and death of the infected host cell.
For example, HSV-1 will spread in skin cells and/or mucosal cells of the face and mouth, usually causing local damage, namely in the form of a vesicle. Antibodies neutralize the viruses in the vesicles after a short period of time, but viruses are also released by lysis of the infected host cells before a humoral immune response can take place. The viruses thereby released also infect certain nerve cells (neurons) by adhering to receptors on the nerve endings in the mouth, which can lead to the neural node of the facial nerve (trigeminus). The viral DNA penetrates into an axon, enters the cytoplasm of the nerve cells and finally enters the cell nucleus where the viral DNA is incorporated into the genome of the nerve cell, leading to a latency in which only a few viral genes are expressed (lysogenic cycle). Various external stimuli can be lead to renewed activation of the virus, i.e., the transition from latency and/or the lysogenic cycle to the lytic cycle which ultimately results in destruction (lysis) of the nerve cell. Such stimuli include, for example, immunosuppression, stress, hormone fluctuations, physical or emotional stresses, fever (which is also why they are called fever blisters), UV radiation, tissue damage and in many cases an immunological weakness. The incidence of such activation of HSV-1 probably depends on both genetic and environmental factors, and both age and hormone changes can play a role. The viral progeny occurring as part of an activation are first transported by the axon to the site and/or the region of the original skin infection where they again create vesicles or blisters (fever blisters) by infection of and replication in the skin cells and/or mucosal cells. Even if these viruses are again neutralized by the immune system, it is impossible to free the body completely of HSV-1 through the immune system because additional nerve cells in which the viral DNA remains integrated into the genome (latency) are constantly being infected.
Additional virus-based diseases of the skin, which are widespread, include diseases and/or infections which are caused by verrucal viruses and are referred to colloquially as warts.
Warts (verrucae) are small, flat or slightly raised, sharply delineated and highly contagious (under some circumstances) but usually benign epithelial tumors and/or proliferations of skin, in particular epidermis. They occur on the hands and feet in particular. Warts usually have a thick, horny, partially fissured coating of squamous epithelial cells beneath which there are soft tissue of keratinocytes.
These diseases of the skin (warts) are caused by a virus infection, mainly by papillomaviruses, in particular human papillomaviruses (HPV) such as verrucae vulgares, verrucae planae juvenilis, verrucae plantares, condylomata acuminata, verrucae planae, verrucae filiformes and molluscipox viruses, e.g., molluscum contagiosum. The infection occurs through small injuries in the skin and/or mucosa. Verruca viruses infect skin cells of vertebrates, in particular mammals and especially humans.
Warts are fundamentally benign proliferations which may cause severe pain in certain areas, e.g., in the genital area and may in extremely rare cases develop into a malignancy. They may also become a cosmetic problem due to their appearance and frequent further propagation on the skin. Treatment of warts is very tedious. So far various therapeutic approaches have been developed:
Surgical removal                Electrocoagulation        Laser removal        Cryosurgery (freezing)        Cauterization (use of electric current or caustic agents)        Cytostatics such as 5-fluorouracil, podophyllotoxin and podophylline which are painted on the warts.
All the therapeutic approaches listed above are, however, based on treatment of the sequelae of a verrucal virus infection, not on inhibition or prevention of viral replication.
In contrast with that, the herpesvirus-based diseases of the skin mentioned above are generally treated by using antiviral active ingredients which intervene in viral replication in particular. This will be discussed in greater detail below.
An important general approach in the development of antiviral active ingredients and thus also in the prevention and/or treatment of virus-based diseases of the skin is thus to intervene in the viral replication cycle and to inhibit viral infection of the host cell or replication of the viral nucleic acid in the host cell, e.g., by inhibiting expression of the viral proteins coded by the viral nucleic acid.
In recent decades, such antiviral active ingredients, so-called virustatics have been developed. Many virustatics inhibit the enzyme DNA polymerase, reverse transcriptase or proteases, for example, and thus inhibit replication of the virus and/or processing of a synthesized long virus protein into smaller protein segments. Examples of these therapeutic approaches are to be found here in particular in the treatment of HIV infections. However, virustatics that are administered systemically or topically are also known in the field of treatment of virus-based diseases of the skin caused by herpesviruses HSV-1 or HSV-2. Examples include the active ingredients aciclovir, valaciclovir, foscarnet and peniclovir.
In general two approaches are known for prevent and/or treatment of virus-based diseases of the skin with virustatics:                (1) systemic administration: by systemic administration of virustatics, a significant reduction in the activation of viruses present in host cells can be achieved because the active ingredients inhibit the replication of the viral nucleic acid in the cell nucleus or the assembly of the viral particles to form complete viruses in the cytoplasm of the host cells;        (2) topical administration: by topical administration of virustatics in the area of an initial infection by the virus, the additional route of replication of the viruses, e.g., in the resulting fever blisters in the case of an HSV-1 infection, can be prevented in an early stage of activation, which can result in more rapid detumescence of the fever blisters.
Both approaches have some important disadvantages for administration of virustatics:                In systemic administration, the dose required for effective treatment is relatively high and is associated with serious adverse effects for the organism thereby treated such as, for example, nonspecific immune responses and autoimmune responses. In the case of aciclovir, numerous such adverse effects are known from the literature. Therefore, neither long-term treatment nor repeat treatment is advisable nor can it be expected of a patient.        In topical administration, the amount of active ingredient (virustatic) that can be released and be bioavailable per unit of time in the area of the virus infection, e.g., the fever blister is very low. This low bioavailability of the virustatic is an important obstacle for effective topical treatment. In the case of aciclovir which has a very low water solubility, the low bioavailability is due to the poor percutaneous transport of the active ingredient, for example. Various chemical modifications of virustatics as prodrug concepts for an improved supply of virustatic active ingredient have not led to any improvement in this phenomenon.
Of the virustatics described in the literature for treatment of virus-based diseases of the skin, aciclovir which has already been mentioned is described as one of the most effective virustatics for which there are almost no alternatives.
There are alternatives to the known antiviral active ingredients, in particular the virustatics, for prevention and/or treatment for virus-based diseases of the skin, which overcome the disadvantages known in the state of the art. There is therefore a need for developing improved and better tolerated antiviral active ingredients, which will intervene in the replication cycle of the virus and preferably inhibit (i.e., prevent) viral infection of the host cell and replication of the viral nucleic acid in the host cell.

Use of deuterium oxide for treatment of herpes virus-based diseases of the skin


An improved solution for limiting the transmission rate of data over a network is provided according to an aspect of the invention. In particular, the transmission rate for a port is limited by rate limiting one of a plurality of queues (e.g., class/quality of service queues) for the port, and directing all data (e.g., packets) for transmission through the port to the single rate limited queue. In this manner, the transmission rate for the port can be effectively limited to accommodate, for example, a lower transmission rate for a port on a destination node.

In modern networks, data, such as packetized data, is frequently routed between several network nodes during transmission. Typically, each network node includes one or more ports over which data is transmitted and received. Each port has a maximum transmission rate at which it can process data (e.g., packets).
A problem occurs when two network nodes have different transmission rates. For example, a first network node may be capable of transmitting data at a rate of 1 Gigabits/second (Gbs), however a destination network node may only be capable of processing data at a rate of 100 Megabits/second (Mbs). In this case, the destination network node can be overrun with data, particularly broadcast and/or multicast data. This results in packets being lost, and therefore not processed, at the destination network node. Additionally, the lost packets may result in a lower throughput for the network due to additional traffic from retry request(s) for and/or retransmission(s) of required data packets before they are successfully processed by the destination network node.
An approach to addressing this problem is the use of a flow control mechanism. In this case, the receiving node can notify the transmitting node to slow down the data transmission in a response. However, this approach results in a relatively long recovery time since the lost packets occur further along a network path. Additionally, some data, such as broadcast and mulitcast data, do not generate a response. As a result, there is no way for the receiving node to control the rate or retries of this type of data. Other approaches suggest inserting and removing symbols in the data stream at both ends of the transmission. However, this requires all nodes on a network to support such an approach.
In view of the foregoing, a need exists to overcome one or more of the deficiencies in the related art.

This patent is subject to a terminal disclaimer.

International Business Machines Corporation


An integrated circuit having a mis-alignment tolerant electrical contact is formed by providing a semiconductor containing substrate over which is a first FET gate laterally bounded by a first dielectric region, replacing an upper portion of the first FET gate with a second dielectric region, applying a mask having an opening extending partly over an adjacent source or drain contact region of the substrate and over a part of the second dielectric region above the first FET gate, forming an opening through the first dielectric region extending to the contact region and the part of the second dielectric region, and filling the opening with a conductor making electrical connection with the contact region but electrically insulated from the first FET gate by the second dielectric region. A further FET gate may also be provided having an electrical contact thereto formed separately from the source-drain contact.

It is very common in the semiconductor (SC) device and integrated circuit (IC) arts to place contacts to a semiconductor (SC) body or layer in close proximity to other device regions that often must remain substantially insulated from such contacts. A well known example is source and/or drain (S-D) contacts of field effect transistors (FETs). The S-D contacts are electrical conductors that provide Ohmic electrical connections to underlying source and/or drain regions of the FET. Such source and/or drain (S-D) contacts are generally desired to be laterally very close to but insulated from a gate conductor that overlies and is insulated from the portion of the semiconductor body or layer between the source and drain regions. When the gate conductor is appropriately biased with respect to the S-D contacts and the S-D regions, it creates a conductive channel extending between the S-D regions. It is this controllable conductive channel that gives rise to the desirable properties of such FETs and of the ICs made up of multiple interconnected FETs.
There is an ongoing need to provide ever denser and more complex SC devices and ICs. This is accomplished in part by reducing the dimensions and spacing of the various device regions. The spacing and alignment of the various device regions are generally determined lithographically, that is by using doping, deposition and/or etching masks. However, as dimensions of the various mask openings and the spacing of such openings become smaller and smaller, alignment tolerance, dimensional tolerance and other errors inherent in the photo-lithographic process become more and more significant and can adversely affect manufacturing yield and cost. Thus, there is an ongoing need to be able to provide contacts closely spaced to but insulated from other device regions or elements where the structure and process used to form such contacts are more tolerant of inherent errors in contact alignment, placement and/or size. This is especially important in connection with field effect transistors (FETs) but also applies to many other semiconductor devices and ICs where contacts must be placed in close proximity to but insulated from other electrical conductors or device regions. Accordingly, the present invention is not limited to FETs but applies generally to any types of semiconductor devices and ICs where such closely spaced contacts are needed.

Integrated circuit contact structure and method


A process is described for drying and packaging moisture-sensitive materials such as roughages and other feedstuffs for animals. The process involves producing particles, drying the particles, cooling the particles, and then compressing them into a container or package. The package can be sealed to keep out moisture. Preservatives, molasses, or other additives may be included with the particles before packaging. The types of feedstuff or other material which is processed and packed may vary. Blends of particles can also be packaged.

Conventionally, forage crops such as hay (e.g., alfalfa, grass, clover, mixtures thereof, and the like) have been cut or severed from the main stem slightly above ground level and then left in the field for a few days to dry in the sun to a moisture level of about 15-20%. Then the dried hay is typically baled in the field and tied with twine or wire to produce bales weighing 50-100 pounds for small bales and up to a ton or more for large bales. The length of the individual stems of hay may be as long as 15-20 inches (depending upon the height of the hay when it was cut in the field).
Drying of the hay in the field is totally dependent upon weather conditions. If there is high humidity in the air when the hay is laying on the ground it will dry only very slowly. Also, if there is rain or drizzle while the hay is on the ground the amount of time required for drying the hay will naturally be increased. If there is too much rain or too much moisture present in the hay, then the hay could become spoiled while it is laying on the ground. Even if the hay doesn't become spoiled while laying on the ground, it could lose some of its protein value before it can be baled.
If the hay is not sufficiently dried before it is baled it will likely spoil in the bale because air is not able to penetrate the bale. The density of hay in a typical bale may be about 15 pounds per cubic foot. Also, when too much moisture is present in the bale, there is a very real danger of the heat of fermentation starting the hay on fire.
On the other hand, the more the hay is dried in the field the greater is the tendency for the leaves to fall off the stem when the hay is handled. This is extremely undesirable because of the relatively high food value in the leaves as compared to the food value of the stem. Also, if the hay is left in the field too long, it can become bleached by the sun. Thus, much luck and a good deal of care are required in order to cut and bale hay such as a1falfa in the field and obtain the highest quality product which does not spoil during storage.
An alternative manner of handling forage crops is to chop them green and place them into an airtight structure while they still contain high moisture. This causes the forage crop to ferment and form silage after a few days. Such a procedure may be useful in some instances for producing a suitable feed for certain animals (e.g., cattle) but it is not suitable for other types of livestock such as horses, pigs, sheep, etc. Also, this manner of storing the product requires large permanent storage structures at fixed locations. Consequently, there are numerous limitations and disadvantages associated with this type of storage and handling.
More recently there has been proposed the use of hay cubes which are typically about 1-2 inches square in cross-section. The hay is forced through square or rectangular dies which are about 1-2 inches by 1-2 inches and the extruded product is cut to a length of about 2-4 inches or so by a large knife. The hay must contain a certain amount of moisture in order for it to stick together in a cube form after it is cut by the knife. If too much moisture is present the cubed product may spoil. On the other hand, if there is too little moisture present the cube will break or fall apart.
The cubed hay product may be packaged in large sacks or handled in bulk form. Unfortunately, the cubes attract and absorb moisture easily in high humidity environments and then can spoil. As a result, this type of product has met with limited success.
Yet another previously known concept is the making of small pellets of hay (such as alfalfa). However, in making the pellets the roughage characteristics of the product are reduced and palatability is also reduced. Thus, a different type of feed is obtained as compared to the original material. Normally it is not fed directly to animals. Rather, it must be blended with other feeds before being fed to animals.
There has not heretofore been provided a technique for handling and packaging forage and roughage products in a manner which has overcome the problems and limitations associated with the prior conventional techniques. Also, there has not heretofore been provided a simple and convenient packaging technique for other moisture-sensitive feed products.


A power shift transmission having a ratio matching feature whereby the disengagement of the transmission by moving the gearshift lever to the neutral position or by depressing the clutch pedal initiates a routine in the microprocessor controlling the operation of the transmission to calculate the ratio of the rotation of the input and output shafts of the transmission and select the gear most closely matching the calculated ratio is disclosed wherein the ratio matching routine can be manually overridden by signalling a gear change with the gearshift lever. The override feature for the ratio matching routine can be permanent for each disengagement of the transmission or temporary for the running of a timer for a predetermined length of time.

Power shift transmissions are well known in the art. Some power shift transmissions provide shuttle shift capability which permits the vehicle to change direction of operation without requiring the movement of the gearshift lever through each intermediate gear ratio. To accomplish this operation, these known types of shuttle shift transmissions will typically include torque converters. In such transmissions utilizing torque converters for shuttle shifting at high or even moderate speeds, a high energy load is placed on the clutches.
Some power shift transmissions are characterized in that they do not require a different gearshift lever position for each gear ratio which may be selected. While such transmissions have simplified operator control, such transmissions do have drawbacks and lack certain desirable features. For example, these transmissions provide automatic speed ratio matching with no means permitting an operator to intervene manually in the automatic speed ratio matching process.
The operation or response of the transmission clutches vary from one transmission to another, or in a given transmission over a period of time. The present invention alleviates some of these problems and, in addition, provides new methods by which an operator may effect the shuttle shifting process.

Method of overriding ratio matching feature in power shift transmissions


For power efficiency, it can be desirable to use a 1-bit ADC or slicer to receive a wired data transmission. A plurality of N samples per baud period are taken. N can be, for example, 4 or more. At least a portion of the samples are included in a window of samples, the size of which is based at least partly on earlier determined values of prior symbols. For example, a polynomial function or other numerical function can be embedded in a lookup table to map previously determined data bits to an address, and the address can be used to control an input of multiplexers to vary the size of the window. The value for a current symbol is determined based at least partly on one or more values within the window of samples.

1. Field of the Invention
Embodiments of the invention generally relate to electronics, and in particular, to receivers for communication links using binary non-return-to zero (NRZ) as the method of transmission and in which multiples samples per baud period are available.
2. Description of the Related Art
In any communication channel, the ability of the receiver to accurately detect the transmitted data is impacted by the presence of channel impairments. Channel impairments can include both correlated and uncorrelated sources. A common example of correlated impairment is Inter-Symbol Interference (ISI), also sometimes referred to as Data Dependent Jitter (DDJ) in some fields of communication receivers.
As the amount of ISI increases, it becomes increasingly difficult for a receiver to correctly detect the transmitted information. If the amount of ISI increases enough, techniques to mitigate at least a portion of the ISI are typically used so that the receiver can function properly.
A very common technique to mitigate ISI is to apply an equalizer to the received signal. This can be done in the analog domain or in the digital domain after suitable conversion with an analog-to-digital converter (ADC). The equalizer is typically designed to have a frequency response that is approximately equal to or the reciprocal of the channel response inducing the ISI. For example, a low pass frequency response is common in communication channels. Mitigation of the ISI induced by the low-pass response can be achieved by applying an equalizer with a corresponding reciprocal high-pass frequency response or a pre-emphasis response or by negating the impairment via subtraction with an approximately equal low-pass frequency response.
The ability to mitigate channel dependent impairments allows a receiver to tolerate an increased amount of other impairments that are not as easily mitigated.
Modern receivers in use in many different fields of communication (such as wireless, serdes, reed channels, etc.), perform an increasing amount of channel impairment mitigation in the digital domain. The received signal is sampled multiple times per baud period with an ADC having a prescribed number of sample threshold levels. Increasing the number of samples per baud taken of the signal, and/or increasing the number of threshold levels used per sample, provides increasing fidelity in the digital domain of the received analog signal. This increased fidelity allows for better and stronger ISI mitigation techniques. Those versed in the art will recognize the application of Feed-Forward Equalizers (FFE) and Decision-Feedback Equalizers (DFE), as well as more complex Maximum Likelihood Sequence Estimators (MLSE), and other techniques, for these situations.
The product of the number of samples per baud period and the number of threshold levels per sample directly affects the cost and complexity of a receiving device. Much effort by designers is devoted to reducing the number of samples per baud used and/or reducing the number of thresholds per sample. Both approaches reduce the complexity of the receiver, but make it increasingly difficult to mitigate ISI. This is particularly true when reducing the number of amplitude thresholds per sample.
To reduce complexity of a receiver, it is desirable to sample a received signal with an ADC or slicer having only a single amplitude threshold. Multiple samples per baud period are available, but each sample has one of two possible values, depending on whether the received signal is greater in amplitude or lesser in amplitude than a set threshold.
To increase the usefulness of a receiver it is desirable for the receiver to mitigate and/or tolerate an increasing amount of correlated channel impairment (e.g., ISI or DDJ). With only 1 threshold level per sample, conventional equalizer-based techniques for mitigating correlated channel impairments will not work.
Embodiments of the invention advantageously increase the amount of correlated channel impairment that can be tolerated/mitigated by a receiver having only a single amplitude threshold per sample.
Current state of the art in decision feedback equalizer processing to combat correlated channel impairments is represented by the following U.S. Pat. Nos. 5,132,988; 7,606,301; 7,184,477; 6,192,072; and 6,363,112, which are incorporated by reference in their entirety and discussed in the following:
The concept of using current and past decisions to adjust the detection and determination of subsequent symbols is well established in the current art. A decision feedback equalizer (DFE) is a well recognized form of this concept. The common theme of systems employing this technique is that the amplitude of the received signal is preserved and processed, either in analog or digital domain. Variations exist on basic concept of the DFE.
U.S. Pat. No. 5,132,988 to Fisher, et al., the linear feedback structure of the DFE is replaced with a RAM table that is addressed by the current and recent history of the determined bits.
Another DFE implementation is described in U.S. Pat. No. 7,606,301 to Aziz, in which it is recognized that the optimal sampling phase for DFE operation may be different than that provided by a non-DFE based clock and data recovery (CDR) circuit.
A DFE described in U.S. Pat. No. 7,184,477 to Haunstein, et al., adjusts the decision threshold and the sample timing for the next baud interval based on at least the previous bit decision.
In U.S. Pat. No. 6,192,072, and U.S. Pat. No. 6,363,112, both to Azadet, et al., a parallel implementation of a DFE is disclosed. Implementation in a parallel architecture allows for much higher data rates than is possible with a linear implementation.
FIG. 1 illustrates a conventional SerDes system with a transmitter (data source 102) and a receiver (data receiver 106). Those knowledgeable in the art will recognize that there are numerous variations on this basic implementation architecture. For simplicity, the description is given with the assumption of a serial implementation. The circuit of FIG. 1 illustrates a generic timing recovery mechanism that aligns the data recovery window with the sampled data stream based on recent sample data. This function is typically present in the receiver 106. The timing recovery function can be performed with a feedback loop entirely within the digital domain or by controlling the frequency of the ADC sampling clock. A feed-forward timing recovery mechanism can also be employed, although this is not shown in FIG. 1.

Reduction of correlated channel impairments