The present invention provides compositions and methods useful in the diagnosis and prognosis of Carney complex (CNC), as well as methods and compositions for the identification of compounds useful in the treatment and/or prevention of CNC. In addition, the present invention provides compositions and methods useful in the diagnosis and treatment of conditions associated with skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. In addition, the present invention provides methods and compositions for the diagnosis and treatment of various types of cancers associated with abnormal activity of protein kinase A. In particular, the present invention provides genetic and other sequence information, as well as assay systems that will find use in these and related areas.

The present invention provides compositions and methods useful in the diagnosis and prognosis of Carney complex (CNC), as well as methods and compositions for the identification of compounds useful in the treatment and/or prevention of CNC. In addition, the present invention provides compositions and methods useful in the diagnosis and treatment of conditions associated with skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. In addition, the present invention provides methods and compositions for the diagnosis and treatment of various types of cancers associated with abnormal activity of protein kinase A. In particular, the present invention provides genetic and other sequence information, as well as assay systems that will find use in these and related areas.
Carney complex (CNC) is a multiple endocrine neoplasia (MEN) syndrome that affects the adrenal cortex, pituitary gland, thyroid gland, and the gonads. It is also associated with skin and mucosa pigmentation abnormalities, as well as myxoid and other neoplasms of mesenchymal and neural crest origin. The syndrome is characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas (Carney and Young, Endocrinologist 2:6-21 [1992]; Carney, Semin. Dermatol., 14:90-98 [1995]; Stratakis et al., Am. J. Med. Genet., 80:183-185 [1998]; Carney et al., Mayo Clin. Proc., 61:165-172 [1985]; and Stratakis, Front. Biosci., 5:D353-366 [2000]). The syndrome also belongs to another group of genetic disorders, referred to as the xe2x80x9clentiginosesxe2x80x9d (lentigenoses), which also includes Peutz-Jeghers, LEOPARD, arterial dissections and lentiginosis, Laugier-Hunziker syndrome, Cowden disease, and Ruvalcaba-Myhre-Smith (Bannayan-Zonana) syndrome, and the centrofacial, benign patterned and segmental lentiginoses, all of which have been associated with a variety of developmental defects. The components of the complex have previously been described by the acronyms NAME (nevi, atrial myxomas and ephelides) or LAMB (lentigines, atrial myxomas, and blue nevi) (See e.g., Atherton et al., Br. J. Dermatol., 103:421-429 [1980]; and Rhodes et al., J. Am. Acad. Dermatol., 10,72-82 [1984]). However, it is presently accepted that most, if not all, of these patients had Carney complex (Stratakis, Pediatr. Pathol. Mol. Med., 19:41-68 [2000]).
Although it is relatively rare, the impact of the syndrome on affected patients is significant. As with other multiple neoplasias and lentigenosis syndromes, Carney complex affects many organs and systems. Typically, patients simultaneously have at least two endocrine tumors (e.g., primary pigmented nodular adrenocortical disease [PPNAD], growth hormone and/or prolactin-producing pituitary adenomas, thyroid nodules or carcinomas, testicular neoplasms [primarily large cell calcifying Sertoli cell tumor (LCCSCT)], and ovarian cysts), as well as psammomatous melanotic schwannoma (PMS), epithelioid blue nevus, breast ductal adenoma, and osteochondromyxoma (i.e., a rare bone tumor). The lesions are multicentric, often bilateral in paired organs, and originate in cells of mesenchymal (myxomas) or neural crest origin (spotty skin pigmentation and endocrine tumors). Thus, it is contemplated that the genetic defects associated with Carney complex are involved in the early development, growth, and proliferation of affected cells.
Early reports suggested that Carney complex was an inherited disease of immunological origin (Young et al., N. Eng. J. Med., 321:1659-1664 [1989]; and Berkhout et al., Clin. Endocrinol., 31:185-191 [1989]). Later reports indicated no association with autoimmune disease or immune dysfunction in affected patients (See e.g., Stratakis et al., J. Clin. Invest. 97:699-705). More recently, CNC has been reported to be inherited as an autosomal dominant trait and the responsible genes have been mapped to 2p16 and 17q22-24 (Stratakis et al., J. Clin. Invest., 97:699-705 [1996]; and Casey et al., Circul., 98:2560-2566 [1998]). Nonetheless, the genetic defects responsible for the complex remained unknown, making diagnosis and treatment of Carney complex problematic.
Currently, to make a diagnosis of Carney complex, a patient must either exhibit two of the manifestations listed in Table 1 below, or exhibit one of these manifestations and meet one of the supplemental criteria (i.e., an affected first-degree relative or an inactivating mutation of the PRKAR1A gene).
Additional findings that are suggestive or possibly associated with Carney complex, but are not diagnostic for the disease include: (1) intense freckling (without darkly pigmented spots or typical distribution); (2) blue nevus, usual type (if multiple); (3) cafxc3xa9-au-lait spots or other xe2x80x9cbirthmarksxe2x80x9d; (4) elevated IGF-1 levels, abnormal oGTT, or paradoxical growth hormone responses to TRH testing, in the absence of clinical acromegaly; (5) cardiomyopathy; (6) pilonidal sinus; (7) history of Cushing syndrome, acromegaly, or sudden death in extended family; (8) multiple skin tags and other skin lesions; lipomas; (9) colonic polyps (usually in association with acromegaly); (10) hyperprolactinemia (usually mild and almost always in association with clinical or subclinical acromegaly); (11) single, benign thyroid nodule in a young patient or multiple thyroid nodules in an older patient (detected by ultrasonography); and (12) family history of carcinoma, in particular of the thyroid, colon, pancreas, and the ovary, or other multiple benign or malignant tumors.
Once the above diagnostic criteria have been applied, and a diagnosis has been confirmed, for post-pubertal pediatric and adult patients, the recommended clinical surveillance of patients with Carney complex involves: echocardiograms (annually or biannually for adolescent patients with a history of excised myxoma), testicular ultrasound (annually), thyroid ultrasound (baseline examination; it may be repeated, as needed), transabdominal ultrasound of the ovaries (baseline examination; it may be repeated, as needed); urinary free cortisol levels (annually); and serum IGF-1 levels (annually). For pre-pubertal pediatric Carney complex patients, the recommended clinical surveillance typically involves echocardiograms (annually; biannually for patients with a history of excised myxoma), testicular ultrasound for boys, and close monitoring of growth rate and pubertal staging (annually). In addition to monitoring of urinary free cortisol levels, further evaluation of patients with primary pigmented nodular adrenocortical disease (all age groups) includes monitoring of diurnal cortisol levels (11:30 PM, 12:00 MN, 7:30 AM, and 8:00 AM sampling), dexamethasone-stimulation test (modified Liddle""s test; See, Stratakis et al., Ann. Intern. Med., 131:585-591 [1999]), and adrenal computed tomography. In addition to monitoring of serum IGF-1 levels, further evaluation of Carney complex patients with gigantism/acromegaly (all age groups) includes pituitary magnetic resonance imaging, 3 hour glucose tolerance test (oGTT), and 90 minute TRH testing. For Carney complex patients of all ages with psammomatous melanotic schwannoma, further evaluation includes magnetic resonance imaging (brain, spine, chest, abdomen, retroperitoneum, pelvis).
In view of the vagaries associated with the currently used methods of diagnosis and prognosis of Carney complex, there remains a need in the art for methods and compositions for the diagnosis, prognosis, and treatment of Carney complex, as well as for methods and compositions useful in the identification of compounds suitable for the treatment of Carney complex and the symptoms associated with the disease.
The present invention provides compositions and methods useful in the diagnosis and prognosis of Carney complex (CNC), as well as methods and compositions for the identification of compounds useful in the treatment and/or prevention of CNC. In addition, the present invention provides compositions and methods useful in the diagnosis and treatment of conditions associated with skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. In addition, the present invention provides methods and compositions for the diagnosis and treatment of various types of cancers associated with abnormal activity of protein kinase A. In particular, the present invention provides genetic and other sequence information, as well as assay systems that will find use in these and related areas.
The present invention provides compositions comprising various mutations in the PRKAR1A gene. In particular, the present invention provides the sequence of wild-type exon 2 (SEQ ID NO:27), as well as the amino acid sequence of wild-type exon 2 (SEQ ID NO:28). The present invention also provides exon 2 mutants with the sequence of SEQ ID NO:29, as well as mutants with the sequences of SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33.
The present invention further provides the sequence of exon 3 (SEQ ID NO:34), as well as the amino acid sequence of wild-type exon 3 (SEQ ID NO:35). The present invention also provides an exon 3 mutant with the sequence of SEQ ID NO:36.
The present invention further provides the sequence of exon 4A (SEQ ID NO:37), as well as the amino acid sequence of wild-type exon 4A (SEQ ID NO:38). The present invention further provides the sequence of exon 4B (SEQ ID NO:39), as well as the amino acid sequence of wild-type exon 4B (SEQ ID NO:40), and an exon 4B mutant (SEQ ID NO:41).
The present invention further provides the sequence of exon 5 (SEQ ID NO:42), as well as the amino acid sequence of wild-type exon 5 (SEQ ID NO:43), and an exon 5 mutant (SEQ ID NO:44).
The present invention also provides the sequence of exon 6 (SEQ ID NO:45), as well as the amino acid sequence of wild-type exon 6 (SEQ ID NO:46). The present invention further provides exon 6 mutants, with the sequences SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50.
The present invention further provides the sequence of exon 7 (SEQ ID NO:51), as well as the amino acid sequence of exon 7 (SEQ ID NO:52), and an exon 7 mutant (SEQ ID NO:53).
The present invention also provides the sequence of wild-type exon 8 (SEQ ID NO:54), as well as the amino acid sequence of wild-type exon 8 (SEQ ID NO:55). The present invention also provides exon 8 mutants with the sequences of SEQ ID NO:56, and SEQ ID NO:57.
The present invention further provides the sequence of wild-type exon 9 (SEQ ID NO:58), as well as the amino acid sequence of exon 9 (SEQ ID NO:59), and an exon 9 mutant (SEQ ID NO:60).
The present invention also provides the sequence of wild-type exon 10 (SEQ ID NO:61), as well as the amino acid sequence of wild-type exon 10 (SEQ ID NO:62).
In some embodiments, the present invention provides an isolated nucleotide sequence of the wild-type protein kinase regulatory subunit 1A gene, wherein the sequence is selected from the group consisting of SEQ ID NO:27, SEQ ID NO:34, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:45, SEQ ID NO:51, SEQ ID NO:54, SEQ ID NO:58, and SEQ ID NO:61.
In other embodiments, the present invention provides an isolated amino acid sequence of the wild-type protein kinase regulatory subunit 1A, wherein the sequence is selected from the group consisting of SEQ ID NO:28, SEQ ID NO:35, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:55, SEQ ID NO:59, and SEQ ID NO:62.
In further embodiments, the present invention provides a nucleotide sequence of mutant protein kinase regulatory subunit 1A gene, wherein the mutation is selected from the group consisting of SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:56, SEQ ID NO:57, and SEQ ID NO:60.
In addition, the present invention provides screening methods for detection of mutations in PKA. In some preferred embodiments, the screening methods include, but are not limited to D-HPLC, sequencing, and cDNA PCR amplification. It is contemplated that these methods will find use either alone or in combination, as well as in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutations in the genes encoding R1A are detected using the methods of the present invention. However, it is contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA.
In alternative embodiments, the present invention provides methods and compositions for the detection and screening of subjects suffering from or suspected of suffering from Carney complex and/or skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. In particularly preferred embodiments, these methods include, but are not limited to D-HPLC, sequencing, and cDNA PCR amplification. It is contemplated that these methods will find use either alone or in combination, as well as in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutations in the genes encoding R1A are detected using the methods of the present invention. However, it is contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA.
In other embodiments, present invention provides methods for the detection of mutations in PKA (e.g., for screening and diagnosis) involving restriction digestion of genomic DNA or cDNA obtained from a subject and detection of alterations in the restriction patterns. These alterations in restriction patterns are then correlated with changes in the sequence of the PKA genes. In further embodiments, the samples used in these methods are obtained from subjects who are suffering from or are suspected of suffering from skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. It is contemplated that these methods will find use either alone or in combination, as well as in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutations in the genes encoding R1A are detected using the methods of the present invention. However, it is contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA.
In still further embodiments, the present invention provides methods involving cold or hot SSCP. In preferred embodiments, these methods utilize the primers described herein (e.g., SEQ ID NOS:1-26, and 63-66). In further embodiments, samples used in these methods involve samples obtained from subjects that are suffering from or are suspected of suffering from skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. It is contemplated that these methods will find use either alone or in combination, as well as in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutations in the genes encoding R1A are detected using the methods of the present invention. However, it is contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA.
The present invention also provides methods and compositions for PCR, in particular quantitative PCR (e.g., Taqman) for determination of the relative expression of PRKAR1A mRNA in tumors and/or cell lines. In further embodiments, the mutant tumors and/or cell lines are obtained from subjects who are suffering from or are suspected of suffering from skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. It is contemplated that these methods will find use either alone or in combination, as well as in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutations in the genes encoding R1A are detected and analyzed using the methods of the present invention. However, it is contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA.
In yet other embodiments, the present invention provides protein truncation detection methods which are utilized following expression (e.g., in vitro expression) of cloned mutant PKA DNA. Such protein detection methods are known to those in the art and are suitable for use to detect the truncation mutants of the present invention. In further embodiments, the mutant PKA DNA is obtained from subjects who are suffering from or are suspected of suffering from skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. It is contemplated that these methods will find use either alone or in combination, as well as in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutations in the genes encoding R1A are detected using the methods of the present invention. However, it is contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA.
The present invention also provides methods for detecting a nucleic acid encoding a mutant protein kinase regulatory subunit 1A gene, comprising providing a biological sample from a patient suspected of containing a nucleic acid sequence encoding mutant protein kinase regulatory subunit 1A gene, and a polynucleotide sequence comprising at least ten nucleotides capable of hybridizing to the nucleic acid sequence; hybridizing the polynucleotide sequence to the nucleic acid sequence encoding a mutant protein kinase regulatory subunit 1A gene to produce a hybridization complex; and detecting the hybridization complex. In other embodiments the polynucleotide sequence comprises fewer than ten nucleotides, with the number of nucleotides as desired by the user of the method and/or as appropriate for the particular embodiment of the method used.
In some embodiments of these methods, the mutant protein kinase regulatory subunit 1A gene comprises a mutant exon having a nucleotide sequence selected from the group consisting of SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:56, SEQ ID NO:57, and SEQ ID NO:60.
In still further embodiments, the methods, further comprise the step of amplifying nucleic acid encoding a mutant protein kinase regulatory subunit 1A gene before the hybridizing step. In some embodiments, amplifying is accomplished using primers selected from the group consisting of SEQ ID NOS:1-26 and SEQ ID NOS:63-66. In additional embodiments, the detecting step comprises the step of detecting the presence of nucleic acid sequence encoding mutant protein kinase regulatory subunit 1A gene. In some embodiments, the detecting is by Northern blotting. In some preferred embodiments, the patient has Carney complex. In some particularly preferred embodiments, the patient is related to at least one individual having Carney complex. In some additional embodiments, the patient exhibits at least one skin pigmentation defect. In still further embodiments, the patient has a least one lesion selected from the group consisting of adrenal tumors, thyroid tumors, pituitary tumors, myxomas, psammomatous melanotic schwannomas and testicular tumors. In other embodiments, the mutant protein kinase regulatory subunit 1A gene is a truncation mutant. In some preferred embodiments, the method further comprises restriction digestion of nucleic acid in the biological sample. In alternative embodiments, the methods further comprise the step of assaying the biological sample from the patient for protein kinase A activity. In still other alternative embodiments, the methods further comprise the step of assaying the biological sample for PK1 inhibition of protein kinase A activity.
The present invention also provides methods for detecting a nucleic acid encoding a mutant protein kinase R1A, comprising the steps of providing: a biological sample from a cell line suspected of containing a nucleic acid sequence encoding mutant protein kinase regulatory subunit 1A gene, and a polynucleotide sequence comprising at least ten nucleotides capable of hybridizing to nucleic acid sequence; hybridizing the polynucleotide sequence to the nucleic acid sequence encoding a mutant protein kinase regulatory subunit 1A gene to produce a hybridization complex; and detecting the hybridization complex. In other embodiments the polynucleotide sequence comprises fewer than ten nucleotides, with the number of nucleotides as desired by the user of the method and/or as appropriate for the particular embodiment of the method used.
In some preferred embodiments, the mutant protein kinase regulatory subunit 1 A gene comprises a mutant exon having a nucleotide sequence selected from the group consisting of SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:56, SEQ ID NO:57, and SEQ ID NO:60.
In still other embodiments, the methods further comprise the step of amplifying the nucleic acid encoding a mutant protein kinase regulatory subunit 1A gene before the hybridizing step. In some particularly preferred embodiments, amplifying is accomplished using primers selected from the group consisting of SEQ ID NOS:1-26 and SEQ ID NOS:63-66. In additional embodiments, the detecting step comprises the step of detecting the presence of the nucleic acid sequence encoding the mutant protein kinase regulatory subunit 1A gene. In some preferred embodiments, the detecting is by Northern blotting.
In some embodiments of the methods, the cell line is obtained from a patient with Carney complex. In still other embodiments, the cell line is obtained from a patient who is related to at least one individual having Carney complex. In additional embodiments, the cell line is from a patient who exhibits at least one skin pigmentation defect. In further embodiments, the cell line is from a patient with at least one lesion selected from the group consisting of adrenal tumors, thyroid tumors, pituitary tumors, myxomas, psammomatous melanotic schwannomas and testicular tumors. In some embodiments, the cell line is obtained from at least one or more lesion. In additional embodiments, the mutant protein kinase R1A is a truncation mutant. In still further embodiments, the methods further comprise restriction digestion of the nucleic acid in the biological sample. In some preferred embodiments, the methods further comprise the step of assaying the cell line for protein kinase A activity. In some alternative embodiments, the methods further comprise the step of assaying the cell line for PK1 inhibition of protein kinase A activity.
The present invention also provides antibodies directed against protein kinase regulatory subunit 1A protein. In some preferred embodiments, the antibody is directed against wild-type protein kinase regulatory subunit 1A protein, while in other preferred embodiments, the antibody is directed against mutant protein kinase R1A regulatory subunit 1A gene protein.
The present invention also provides immunohistochemistry methods. In some embodiments, these methods involve the use of antibodies directed against PRKAR1A antibody (e.g., the antibodies used in the Examples below), while other embodiments involve the use of indirect methods (e.g., sandwich type assays). It is contemplated that these methods will find use in the detection of samples in which decreased expression of PRKAR1A is suspected. In further embodiments, samples used in these immunohistochemistry methods are from subjects that are suffering from or are suspected of suffering from skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. It is contemplated that these methods will find use either alone or in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutant R1As are detected using the methods of the present invention. However, it is contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA.
The present invention further provides methods for detecting a protein kinase regulatory subunit 1A, comprising: providing a biological sample suspected of containing protein kinase regulatory subunit 1A, and an antibody directed against protein kinase regulatory subunit 1A; exposing the biological sample to the antibody to form a complex comprising protein kinase regulatory subunit 1A bound to the antibody; and detecting the complex.
In some embodiments, the biological sample is from a patient suspected of having Carney complex. In other embodiments, the biological sample is from a patient who is related to at least one individual who has Carney complex.
In some preferred embodiments, the protein kinase regulatory subunit 1A is a mutant protein kinase regulatory subunit 1A. In still further embodiments, the antibody is selected from the group consisting of antibodies directed against wild-type protein kinase regulatory subunit 1A and antibodies directed against mutant protein kinase regulatory subunit 1A. In some preferred embodiments, the method is selected from the group consisting of Western blotting, immunoassays, and immunohistochemistry.
In still further embodiments, the present invention provides screening methods for PKA activity in tumors or cell lines suspected of having at least one PRKAR1A mutation. In some embodiments, the methods comprise cAMP stimulation followed by PKA assay analysis, as well as PK1 inhibition assays of PKA activity. The present invention also provides methods involving the use of Northern blots for detection of mutant PRKAR1A mRNA. However, it is not intended that the present invention be limited to these particular assays, used alone or in combination. In further embodiments, the tumors or cell lines are obtained from subjects who are suffering from or are suspected of suffering from skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. It is contemplated that these methods will find use either alone or in combination, as well as in combination with other diagnostic and prognostic methods. In particularly preferred embodiments, mutations in the genes encoding R1A are detected using the methods of the present invention. It is also contemplated that the methods of the present invention will find use in the detection and screening of mutations in the other subunits of PKA. In addition, it is contemplated that the methods of the present invention will find use in the identification and/or characterization of compounds that are effective in treating Carney complex, pigmentation defects, and/or tumors.
The present invention also provides methods and compositions for the identification and/or characterization of compounds useful for the treatment of Carney complex, pigmentation defects, and/or tumors.

The United States of America as represented by the Department of Health and Human Services


A signal strength detecting device includes a logarithmic amplifier and an amplitude detector. A constant current source whose current is proportional to the absolute temperature is used as a current source for biasing the logarithmic amplifier. In contrast, a constant current source whose current is not proportional to the absolute temperature is used as a current source for biasing the amplitude detector. This makes it possible to solve a problem of a conventional signal strength detecting device of being unable to detect the signal strength of a received signal correctly because it employs a constant current source whose current is proportional to the absolute temperature as the current source for biasing the amplitude detector, and hence the collector current output from differential amplifiers constituting the amplitude detector can vary in response to the absolute temperature even if the signal strength of the received signal is kept constant.

1. Field of the Invention
The present invention relates to a signal strength detecting device mounted on a radio communications apparatus for detecting the signal strength of a signal received by an antenna.
2. Description of Related Art
A large number of radio communications apparatuses incorporate a signal strength detecting device for detecting the signal strength of a signal received by an antenna.
In particular, in a mobile communications system employing a CDMA (Code Division Multiple Access) scheme, a base station and a mobile station each detect the signal strength of a signal transmitted from their party, so as to precisely control the strength of a signal to be transmitted to the party in accordance with the signal strength.
For example, when the base station and mobile station are far away from each other, since the signal strength of the received signal is weak, the strength of the transmitted signal is increased so that the party can receive the transmitted signal with sufficient intensity.
In contrast with this, when the base station and mobile station are close to each other, since the signal strength of the received signal is strong, the strength of the transmitted signal is reduced so that it does not interfere radio signals from other base stations or mobile stations.
FIG. 6 is a circuit diagram showing a conventional signal strength detecting device. In FIG. 6, the reference numeral 1 designates a logarithmic amplifier for amplifying a signal received by an antenna; 2 designates an input terminal for supplying the signal received by the antenna; 3-5 each designate a differential amplifier for amplifying the received signal supplied from the input terminal 2; 6-8 each designate a transistor constituting the differential amplifiers 3-5; 9-11 each designates an emitter follower for regulating the DC level of the received signal amplified by the differential amplifiers 3-5; and 12 designates a current source for biasing the logarithmic amplifier 1. The current source 12 is a constant current source whose current is proportional to the absolute temperature.
The reference numeral 21 designates an amplitude detector for detecting the signal strength of the received signal by comparing the received signal whose DC level is regulated by the emitter followers 9-11 of the logarithmic amplifier 1 with a reference voltage; 22 designates a reference voltage generator for generating the fixed reference voltage; 23-25 each designate a differential amplifier for comparing the received signal whose DC level is regulated by one of the emitter followers 9-11 of the logarithmic amplifier 1 with the reference voltage generated by the reference voltage generator 22, and for producing a collector current proportional to the difference between the two; 26-28 each designate a transistor constituting the differential amplifiers 23-25; 29 designates a capacitor for smoothing the collector current output from the differential amplifiers 23-25; 30 designate a PNP current mirror circuit for inverting the polarity of the collector current smoothed by the capacitor 29; 31 designates a resistor for converting the collector current to a voltage signal; 32 designates an output terminal for producing the voltage signal indicating the signal strength of the received signal; and 33 designates a current source for biasing the amplitude detector 21. The current source 33 is a fixed current source whose current is proportional to the absolute temperature.
Next, the operation of the conventional signal strength detecting device will be described.
First, when the signal received by the antenna is supplied to the input terminal 2, the differential amplifier 3 of the logarithmic amplifier 1 amplifies the received signal.
The received signal amplified by the differential amplifier 3 is output from the collectors of the transistors 6 and 7. The received signal output from the collector of the transistor 6 is subjected to the DC component regulation by the emitter follower 9, and then supplied to the differential amplifier 23 of the amplitude detector 21 as well as to the transistor 6 of the post-stage differential amplifier 4. On the other hand, the received signal output from the collector of the transistor 7 is supplied to the transistor 7 of the post-stage differential amplifier 4.
Receiving the received signal output from the differential amplifier 3, the differential amplifier 4 of the logarithmic amplifier 1 further amplifies the received signal.
The received signal amplified by the differential amplifier 4 is output from the collectors of the transistors 6 and 7. The received signal output from the collector of the transistor 6 is subjected to the DC component regulation by the emitter follower 10, and then supplied to the differential amplifier 24 in the amplitude detector 21 as well as to the transistor 6 in the post-stage differential amplifier 5. On the other hand, the received signal output from the collector of the transistor 7 is supplied to the transistor 7 in the post-stage differential amplifier 5.
Receiving the received signal output from the differential amplifier 4, the differential amplifier 5 in the logarithmic amplifier 1 further amplifies the received signal.
The received signal amplified by the differential amplifier 5 is output from the collector of the transistor 6. The received signal output from the collector of the transistor 6 is subjected to the DC current regulation by the emitter follower 11, and then supplied to the differential amplifier 25 in the amplitude detector 21.
Receiving the received signal amplified by the differential amplifiers 3-5 in the logarithmic amplifier 1, the differential amplifiers 23-25 in the amplitude detector 21 compare the received signal with the reference voltage generated by the reference voltage generator 22, and output the collector currents Ic proportional to the difference between the two.
The collector currents Ic output from the differential amplifiers 23-25 are smoothed by the capacitor 29, undergo the polarity inversion by the PNP current mirror circuit 30, and are converted by the resistor 31 to a voltage signal (that indicates the signal strength of the received signal) to be output from the output terminal 32.
Here, the reason will be described for using the fixed current source proportional to the absolute temperature as the current source 12 for biasing the logarithmic amplifier 1.
First, the gain characteristic of the differential amplifiers 3-5 in the logarithmic amplifier 1 is given by the following expression.
G=(qI/kT)RL
where G is the gain, q is the elementary charge, I is the magnitude of the collector current, k is the Boltzmann constant, T is the absolute temperature, and RL is a load resistance.
If the logarithmic amplifier 1 is biased by a current source without temperature dependence, the collector current I will be fixed, and the gain G of the differential amplifiers 3-5 will be reduced in inverse proportion to the absolute temperature T.
However, this will reduce the gain G of the differential amplifiers 3-5, making it impossible to amplify the received signal to a desired level. Accordingly, the collector current I must be made proportional to the absolute temperature T.
In view of this, the fixed current source with temperature dependence is used to provide the logarithmic amplifier 1 with the bias current proportional to the absolute temperature T.
Thus, the conventional signal strength detecting device with the foregoing configuration can amplify the received signal by means of the logarithmic amplifier 1 without being affected by temperature change. However, since the current source 33 for biasing the amplitude detector 21 also consists of the constant current source whose current is proportional to the absolute temperature T, even if the signal strength of the received signal is kept constant, the change in the absolute temperature T will vary the collector current Ic output from the differential amplifiers 23-25. This presents a problem of hindering accurate detection of the signal strength of the received signal.
The present invention is implemented to solve the foregoing problem. It is therefore an object of the present invention to provide a signal strength detecting device capable of detecting the signal strength of a received signal accurately without being affected by the temperature change.
According to one aspect of the present invention, there is provided signal strength detecting device comprising: an amplifier for amplifying a received signal received by an antenna; a strength detector for detecting signal strength of the received signal by comparing the received signal amplified by the amplifier with a reference voltage; a first current source for biasing the amplifier; and a second current source for biasing the strength detector, wherein temperature characteristic of the second current source differs from that of the first current source.
Here, the first current source may consist of a fixed current source whose current is proportional to absolute temperature, and the second current source may consist of a constant current source whose current is not proportional to the absolute temperature.
The amplifier may comprise differential amplifiers, at least one of two outputs of each of the differential amplifiers being connected to an emitter follower.
The amplifier may comprise differential amplifiers, at least one of two outputs of an initial stage of the differential amplifiers being connected to an emitter follower.

Signal strength detecting device with little temperature dependence


A tool and method of using the tool are provided for use in making brake backlash adjustments in heavy duty vehicles. The tool is specially designed to overcome a problem of locking collars for brake adjusting screws becoming stuck in retracted positions. The tool features an adjustable clamp, a pivot support, and a lever arm which cooperate to restore locking collars to their original positions.

Brake mechanisms used in heavy duty automotive applications are generally of the pneumatic type in which air pressure is used to apply the vehicle's brakes. Typically, such brake mechanisms include a drum which rotates concentrically with a wheel to be braked and a brake shoe carried by the frame of the vehicle that may be frictionally engaged with an interior wall of the drum by air pressure.
The brake shoe is moved into and out of engagement with the drum about a crankshaft that is mounted on the vehicle frame for rotation about its axis. The crankshaft is turned about its axis by a slack adjuster that is connected to a pneumatic actuator. The slack adjuster includes an interiorly splined adjustment ring at one end for receiving the crankshaft and is attached at its other end to the pneumatic actuator. Together, the crankshaft and slack adjuster form a lever arm acting about the rotational axis of the crankshaft for pivoting the brake shoe into and out of engagement with the drum in response to movement of the pneumatic actuator.
Typically, the pneumatic actuator includes a cylinder mounted on the vehicle frame and a piston having a limited range of travel within the cylinder. The piston includes an arm that is connected to the slack adjuster. In accordance with the known operation of such actuators, pressurized air introduced into the cylinder moves the piston within the cylinder and, through the piston's connection to the slack adjuster, also moves the brake shoe into engagement with the drum. However, when the pressurized air is released from the cylinder, a spring biases the brake shoe away from the drum and returns the piston to its initial or "resting" position within the cylinder.
When the brake shoe is so biased away from the drum, a small clearance space is defined between the shoe and drum which permits the associated wheel to rotate freely. The amount of clearance space, also referred to as backlash, must be maintained within a specific tolerance to insure proper operation of the brakes. For example, if not enough backlash is present, the brake shoe may continuously drag against the drum leading to a buildup of heat and premature wear of the contacting parts. Alternatively, if too much backlash is present, the distance through which the piston must travel prior to the brake shoe making contact with the drum increases; and this may undesirably delay braking response of the vehicle. Variations in the amount of backlash between different wheels may also result in uneven braking responses of the wheels and thereby destabilize the vehicle during braking.
Accordingly, it is of well-recognized importance to maintain backlash between the brake shoe and drum within a specified tolerance. However, during the course of ordinary vehicle use, the brake shoe and drum tend to wear, thereby increasing the amount of backlash between them. In contrast, if a worn brake shoe is replaced with a new one, backlash may be decreased. Thus, periodic adjustments to the amount of backlash between the brake shoe and drum are required to maintain the brakes in good working order.
The slack adjuster includes an adjusting screw for this purpose. The adjusting screw includes a shaped head portion at one end which extends out of the slack adjuster and a threaded portion at its other end that engages the outer surface of the adjustment ring which receives the crank shaft. When the screw is turned, the crank shaft is rotated, thereby moving the brake shoe toward or away from the drum. Backlash may be set by turning the adjusting screw in an appropriate direction until the amount of clearance space between the brake shoe and drum is within a specified tolerance.
The shaped head portion of the adjusting screw is protected by a retractable collar which is slidably mounted in a chamber formed in the outer surface of the slack adjuster. The locking collar is spring loaded within the chamber to urge the locking collar into engagement with the shaped head portion of the adjusting screw, thereby capturing the head portion of the screw within the collar. A keyway is provided within the slack adjuster chamber to receive a key portion of the collar to prevent the collar and the captured head portion of the adjusting screw from turning. However, when an adjustment is to be made to backlash, the locking collar may be retracted against the spring within its chamber to fully expose the head portion of the adjusting screw. A wrench may be used on the exposed head portion of the adjusting screw to turn the screw to a desired backlash setting. Following removal of the wrench, the locking collar is allowed to return to its original position to prevent any further turning of the screw.
However, even after relatively short periods of vehicle use, rust begins to form on the locking collar and in the chamber within which it is mounted. This condition is often aggravated by road salts and acids used for cleaning trucks. As a result, the locking collar is no longer easily slidable within its chamber. When this happens, it is a common practice to retract the locking collar by pounding it with a hammer to expose the adjusting screw. Although this practice is generally effective for retracting the locking collar, a more serious problem may follow with the locking collar becoming stuck in its retracted position. However, common practices for freeing locking collars stuck in retracted positions, such as pounding on the collar with chisels or attempting to grab the locking collar with vise grips, are often not very effective for freeing the collar and may permanently damage the collar.
Unless the locking collar can be returned to its original position protecting the adjusting screw, the entire slack adjuster must be replaced at a cost of considerable time and expense. Further, if it is necessary to make an emergency brake adjustment where replacement parts are not available and the locking collar becomes permanently stuck in a retracted position, it is possible that the vehicle will be driven without the protective benefits of the locking collar guarding against loosening of the adjusting screw. If the adjusting screw is left unguarded for even a relatively short period of time, vibrations associated with normal brake use may result in a loss of proper braking at the affected wheel.


Method for estimating the movement of an observation instrument on-board a vehicle flying over a celestial body, the instrument including at least two strips with different lines of sight, each strip realizing the acquisition of successive image lines making up a composite image, parts of the composite images representing substantially a same scene of the celestial body. The estimated movement is determined by optimization of an image similarity function that associates, to a given movement hypothesis, a similarity between values of matched pixels of at least a pair of composite images. The method includes, for each movement hypothesis considered during the optimization: determining, for the at least one pair of composite images, at least one spatio-temporal transformation using the considered movement hypothesis and a geometric model of the observation instrument, and matching the pixels of the at least one pair of composite images using the at least one spatio-temporal transformation.

1. Field of the Invention
This invention belongs to the field of using images obtained by at least two strips of a scanning observation instrument mounted on board a vehicle (airplane, drone, helicopter, satellite, etc.) flying over a celestial body, such as the Earth.
2. Description of the Related Art
A strip of a scanning instrument comprises a plurality of sensitive cells (typically from 100 to 100,000) generally arranged in line and possibly on several lines. The line of sight of the strip is pointed toward the Earth's surface, and forms a plane with the line of sensitive cells, called "plane of sight".
The instrument's main line of sight can be defined either as the line of sight of the central pixel of one of the two strips or as the line of sight of the central pixel of a fictitious strip that would be located, for example, at an equal distance from the two strips.
During image capture, each strip acquires successively images rows representing different linear portions of said scene, as its plane of sight scans the observed scene. Each sensitive cell of the strip records in a pixel the luminous intensity, within the wavelength considered, of an area of the linear portion aimed at.
The scanning of the plane of sight of each strip is achieved, for example, by moving the vehicle. This is generally the case for instruments on board a low-orbit satellite.
In general, the acquisition of images rows of a single strip is performed during a fixed time period (duration of acquisition), and with a substantially constant frequency of acquisition.
For a typical spatial application, an observation instrument is on board a satellite in orbit at 500 to 800 kilometers altitude; its line of sight is nominally pointed toward the center of the Earth; the instrument's focal length is between 0.5 and 15 meters, the field of view is between 1 and 20 degrees, each strip comprises a line of 5,000 to 50,000 sensitive cells, the scanning speed is between 6.5 and 6.8 kilometers per second, the acquisition frequency is between 500 and 5,000 Hertz; the swath (length of the linear portion covered by one image line on the Earth's surface) is between 10 and 100 kilometers, the dimension of an area imaged by one pixel is between 0.5 and 20 meters on the Earth's surface. The strips are generally 5 to 50 centimeters apart in the focal plane; the time gap between the image of a point on the earth's surface being captured by the first strip and its image being captured by the second strip is between 0.05 to 5 seconds.
The successive image lines acquired by a single strip form a pixel matrix called "composite image", which represents the scene observed during image capture. It can be seen that, because the image lines are acquired at different times and because of the instrument's movements during image capture, the composite image distributed in a plane according to a regular grid does not represent the scene exactly as it would ideally be seen by an observer overlooking said scene. For example, because of these movements, a perfectly straight road may be curved in the composite image.
In the most general case, during image capture, two different strips will provide two different composite images whose pixels, acquired at a given time, represent different areas of the observed scene. In general, the layout of the strips, e.g. parallel in the focal plane of the observation instrument, is such that these composite images have a large amount of spatial overlap when the vehicle travels above the scene to be observed.
The differences between the two composite images are due to the fact that the lines of sight associated with the two strips are different. As a result, the composite images do not overlap completely at the beginning and the end of image capture. But the differences between the two composite images are mainly due to the movements of the instrument, since they can affect, at any given instant, different pixels in each composite image, specifically because of the gap between the two strips' lines of sight.
From patent FR 2 899 344, a method is known for reconstructing the line of sight, in which homologous characteristic areas between the composite images of a single scene acquired by two different strips are determined by correlation, and the angular variations of the line of sight are reconstructed according to the geometric distances between the positions (i.e. the pixel indices) of the characteristic areas in each of said composite images.
However, this method has many limitations.
For example, the ability to determine, or not, homologous characteristic areas in the two composite images very much depends on the nature of the observed scene. For example, for weakly textured scenes, such as sea/ocean and/or snowy mountain scenes, it will be impossible in practice to determine a sufficient number of homologous characteristic areas to achieve good performance in reconstructing the line of sight.
In addition, the method of patent FR 2 899 344 is sensitive to the effects of parallax and/or to the presence of clouds, which can distort or prevent the correlation of the homologous characteristic areas.
In the method of patent FR 2 899 344, the relative angular variations from one sampling instant to another are the parameters estimated by correlation between the homologous characteristic areas; this requires an additional step of filtering and integration to reconstruct the absolute angular variations, which step may be detrimental in terms of computation complexity.
In addition, the method of patent FR 2 899 344, which is very suitable for a pair of composite images, cannot be easily generalized to processing simultaneously more than two composite images with different time shifts or even different acquisition frequencies.

Method for estimating the movement of a traveling observation instrument flying over a celestial body


A graphite electrode joint, where the male tang has a tang factor, defined as the ratio of male tang length to electrode diameter, of at least about 0.60.

1. Technical Field
The present invention relates to the male tang used to join graphite electrodes, and especially to a male-female joint for graphite electrodes. More particularly, the invention concerns a unique design for a male-female electrode joint, and the electrodes from which the joint is formed.
2. Background Art
Graphite electrodes are used in the steel industry to melt the metals and other ingredients used to form steel in electrothermal furnaces. The heat needed to melt metals is generated by passing current through one or a plurality of electrodes, usually three, and forming an arc between the electrodes and the metal. Electrical currents in excess of 100,000 amperes are often used. The resulting high temperature melts the metals and other ingredients. Generally, the electrodes used in steel furnaces each consist of electrode columns, that is, a series of individual electrodes joined to form a single column. In this way, as electrodes are depleted during the thermal process, replacement electrodes can be joined to the column to maintain the length of the column extending into the furnace.
Conventionally, electrodes are joined into columns via a pin (sometimes referred to as a nipple) that functions to join the ends of adjoining electrodes. Typically, the pin takes the form of opposed male threaded sections or tangs, with at least one end of the electrodes comprising female threaded sections capable of mating with the male threaded section of the pin. Thus, when each of the opposing male threaded sections of a pin are threaded into female threaded sections in the ends of two electrodes, those electrodes become joined into an electrode column. Commonly, the joined ends of the adjoining electrodes, and the pin therebetween, are referred to in the art as a joint.
Alternatively, it has in the past been suggested that the electrodes be formed with a male threaded protrusion or tang machined into one end and a female threaded socket machined into the other end, such that the electrodes can be joined by threading the male tang of one electrode into the female socket of a second electrode, and thus form an electrode column. The joined ends of two adjoining electrodes in such an embodiment is referred to in the art as a male-female joint.
Given the extreme thermal stress that the electrode and the joint (and indeed the electrode column as a whole) undergoes, mechanical/thermal factors such as strength, thermal expansion, and crack resistance must be carefully balanced to avoid damage or destruction of the electrode column or individual electrodes. For instance, longitudinal (i.e., along the length of the electrode/electrode column) thermal expansion of the electrodes, especially at a rate different than that of the pin, can force the joint apart, reducing effectiveness of the electrode column in conducting the electrical current. A certain amount of transverse (i.e., across the diameter of the electrode/electrode column) thermal expansion of the pin in excess of that of the electrode may be desirable to form a firm connection between pin and electrode; however, if the transverse thermal expansion of the pin greatly exceeds that of the electrode, damage to the electrode or separation of the joint may result. Again, this can result in reduced effectiveness of the electrode column, or even destruction of the column if the damage is so severe that the electrode column fails at the joint section. Thus, control of the thermal expansion of an electrode, in both the longitudinal and transverse directions, is of paramount importance.
As a consequence, if the pin can be eliminated from the electrode/electrode column system, the need to balance the thermal expansion of the different system components (i.e., pin and electrode) is reduced. Prior attempts to eliminate the pin have been attempted, where a threaded electrode end or other electrode mating means have been employed. Industry acceptance has lagged, however, since it is felt that the strength of the joint is not sufficient to maintain the integrity of the electrode column without a pin.
What is desired, therefore, is a male-female electrode joint having sufficient strength and integrity to permit elimination of the pin, without a significant reduction in electrode performance. It is also highly desirable to achieve these property benefits without using high quantities of expensive materials.


An access point can include an array of antennas and a smart antenna selector. The smart antenna selector is configured to select a subset of antennas from the antenna array for use in multi-user multiple-input multiple-output (MU MIMO) data transmissions. Stations that are communicatively coupled to the access point can be selected for inclusion in a multi-user group based, at least in part, on performance measurements of the stations. Performance measurements are determined directly and indirectly from data transmissions sent in response to sounding packets. Antennas for use in MU MIMO data transmissions are selected for the antenna array based, at least in part, on previous antenna selections used for single user data transmissions.

Embodiments of the inventive subject matter generally relate to the field of communication systems and, more particularly, to selecting antennas from an array of antennas for use in multi-user multiple-input multiple-output data transmissions.
Multi-user multiple-input multiple-output (MU MIMO) data transmissions are described in some IEEE 802.11 draft specifications (e.g., IEEE 802.11ac). In brief, multiple data streams are transmitted from an Access Point (AP) to two or more stations (STAs) contemporaneously. For example, beamforming can be used to transmit a first data stream from the AP to a first STA and a second data stream from the AP to a second STA at approximately the same time. Some APs can include an array of antennas that can be used to transmit and/or receive wireless signals to and from the STAs. Beamforming techniques can be used to formulate multiple signals for transmission through multiple antennas to a STA. A beam of data is formed to the STA as the multiple signals constructively and destructively interfere with each other. MIMO techniques can also take advantage of multipath interference to increase data throughput by using additional pathways defined by the multipath interference. Although beamforming is relatively well understood, selecting antennas from the antenna array, particularly for use in MU MIMO data transmissions, can be less straightforward.

Smart antenna array configuration for multiple-input multiple-output communications


In one embodiment, a method of filling a container with a liquid drug from a drug reservoir may include: a) connecting a container and a drug reservoir with a cannula such that the drug reservoir and the container fluidically communicate with each other via the cannula, while being hermetically sealed; b) reducing a first volume contained within the container to displace a gaseous medium from the first volume of the container via the cannula into a second volume contained within the drug reservoir; c) increasing the first volume of the container to displace the liquid drug from the second volume of the drug reservoir into the first volume of the container to fill the container; and d) disconnecting the container and the drug reservoir. Before performing action d), action b) and action c) can be successively performed more than once to stepwise increase an amount of liquid drug displaced.

In the medical field, liquid drugs, such as insulin, can be supplied from a reservoir container that contains an amount of the liquid drug. The liquid drug can be transferred from the reservoir container to a container that receives a single dose of the drug, or an amount of the drug, which is suitable for a limited time of therapy of a patient. For example, doctors and nurses can draw medications from vials into syringes in order to inject the medications into patients. Patients can also inject themselves in a similar manner. For example, diabetes can be treated with the use of an insulin pump that supplies insulin from insulin ampoules. The insulin ampoules can be purchased without being filled with medication, i.e., as empty ampoules. Accordingly, patients may fill the empty ampoules from a vial containing an amount of insulin prior to use.
Some of the patients that fill the empty ampoules may suffer from movement disorders due to their disease and/or age. Thus, some patients may have difficulties in safely handling standard syringe assemblies or the like. Filling systems have been developed to assist with the process of filling ampoules from vials.
One example system is shown and described in EP 1 820 485 A1. The system provides a number of empty, single use ampoules made of plastic. Each of the ampoules can be formed by a container and a piston arranged therein in displaceable manner. A multi use piston rod can have a thread arranged at one end of the piston rod that is coupled to the piston of the ampoules. At the end of the ampoule facing away from the end of the ampoule where the piston rod can be coupled to the piston, each ampoule can include a connector with a cannula. The ampoule can be connected to a commercially available vial in via the connector such that the ampoule and the vial fluidically communicate with each other via the cannula, while the ampoule and the vial are structurally connected with each other.
One of the ampoules can be filled with insulin from a vial. Specifically, the piston rod is connected with the piston of the ampoule by screwing it with its threaded end into a corresponding thread formed in the piston. After that, the piston is pulled back with the piston rod, which can cause the inside of the ampoule is filled with air. The ampoule can then be coupled with the connector facing downwards to a vial. Next, the piston can be pushed into the container of the ampoule with the piston rod in order to displace the air contained inside the ampoule into the vial, and create an overpressure in the vial. In this state, the assembly can be turned upside down such that the vial is now on top. Then, the piston rod can be released. The overpressure in the vial can cause insulin to flow through the connector into the ampoule, and the piston to be displaced. Once the overpressure has dissipated, the displacement of the piston is stopped. The piston can be displaced until it reaches its original position via the piston rod to draw additional insulin into the ampoule. In this state the vial, the connector and the piston rod can be removed from the ampoule, which leaves the ampoule full of insulin and ready for use.
Accordingly, the example system can be utilized for filling ampoules from vials without needles. Thus, the risk of accidental needle sticks can be reduced compared filling a syringe arrangement. However, proper use of the system is required to avoid formation of foam and air bubbles within the ampoule. Furthermore, when the ampoule is filled with insulin from a smaller pen cartridge instead of from a vial, there is the risk that insulin may be spilled. Specifically, when the piston is fully pushed into the container of the ampoule with the piston rod, a piston of the pen cartridge can be pushed out of the cartridge causing the insulin contained therein to be spilled.
Another example of an ampoule filling system having similar functionality and shortcomings is disclosed in US 2002/0189712 A1.
Accordingly, additional methods, apparatuses and systems for filling containers with liquid drugs are needed.

Apparatuses, systems, and methods for filling a container with a liquid drug


An intermediate transfer media, such as a belt, that includes a polymer blend of a polymethacrylimide and a polysulfone, a polymethacrylimide and a polyphenylsulfone, or a polymethacrylimide and a polyethersulfone and optionally a conductive component.

Disclosed are intermediate transfer members, and more specifically, intermediate transfer members selected for the transfer of developed images in for example, an electrostatographic, for example xerographic, including digital, image on image, and the like, machines or apparatuses, and printers, inclusive of office printers, production printers, and the like. In embodiments, there are selected intermediate transfer members comprised of a polymer blend of a polymethacrylimide (PMMI) and a polysulfone (PSU), a polymethacrylimide and a polyphenylsulfone (PPSU), or a polymethacrylimide and a polyethersulfone (PESU), which individual polymers are commercially available. In embodiments thereof, the polymer blend of a polymethacrylimide and a polysulfone, a polymethacrylimide and a polyphenylsulfone, or a polymethacrylimide and a polyethersulfone are dispersed in or mixed with a conductive component such as a carbon black and a suitable solvent, such as N-methylpyrrolidinone (NMP), N,N′-dimethylformamide (DMF), or N,N′-dimethylacetaimide (DMAc), and subsequently the resulting dispersion is subjected to known casting methods, to form the intermediate transfer member. Also, in embodiments, the polymer blend of a polymethacrylimide and a polysulfone, a polymethacrylimide and a polyphenylsulfone, or a polymethacrylimide and a polyethersulfone together with a carbon black are extruded by a known extrusion device to form the intermediate transfer members or the intermediate transfer members can be generated by known solution casting processes.
A number of advantages are associated with the intermediate transfer members, such as belts (ITB) of the present disclosure such as excellent toner transfer efficiency, for example from about 90 to about 95 percent of the developed image can be transferred from the ITB to a substrate, like paper; functional resistivity, excellent modulus, and excellent break strength; an acceptable thermal expansion coefficient (CTE) and an acceptable hygroscopic expansion coefficient (CHE); wear and abrasion resistance; and low and acceptable surface friction characteristics for aiding in the transfer of developed xerographic images.
In electrostatographic printing machines wherein the toner image is electrostatically transferred by a potential difference between the imaging member and the intermediate transfer member, the transfer of the toner particles to the intermediate transfer member and the retention thereof should be substantially complete so that the image ultimately transferred to the image receiving substrate will have a high resolution. Substantially about 100 percent toner transfer occurs when most or all of the toner particles comprising the image are transferred, and little residual toner remains on the surface from which the image was transferred.
Intermediate transfer members may possess a number of advantages, such as enabling high throughput at modest process speeds; improving registration of the final color toner image in color systems using synchronous development of one or more component colors and using one or more transfer stations; and increasing the number of substrates that can be selected. However, a disadvantage of using an intermediate transfer member is that a plurality of transfer operations is usually needed allowing for the possibility of charge exchange occurring between toner particles and the transfer member which ultimately can lead to less than complete toner transfer, resulting in low resolution images on the image receiving substrate, and image deterioration. When the image is in color, the image can additionally suffer from color shifting and color deterioration.
In a typical electrostatographic reproducing apparatus, such as xerographic copiers, printers, multifunctional machines, and the like a light image of an original to be copied is recorded in the form of an electrostatic latent image upon a photosensitive member or a photoconductor, and the latent image is subsequently rendered visible by the application of electroscopic thermoplastic resin particles and colorant. Generally, the electrostatic latent image is developed by contacting it with a developer mixture comprised of carrier granules having toner particles adhering triboelectrically thereto, or a liquid developer material, which may include a liquid carrier having toner particles dispersed therein. The developer mixture is advanced into contact with the electrostatic latent image, and the toner particles are deposited thereon in image configuration. Subsequently, the developed image is transferred to a document, such as paper and fixed or fused by for example heat and pressure. It is advantageous in some instances to transfer the developed image to a intermediate transfer web, belt or component, and subsequently, transfer with a high, for example about 90 to about 100, transfer efficiency the developed image from the intermediate transfer member to a substrate, like paper, cardboard, transparencies, and the like.
It has been reported in several U.S. patents that intermediate transfer members enable acceptable registration of the final color toner image in color systems using synchronous development of one or more component colors, and using one or more transfer stations; and all for an increase the number of substrates that can be selected. However, a disadvantage of using an intermediate transfer member is that a plurality of developed toner transfer operations is utilized thus causing charge exchange between the toner particles and the transfer member, which ultimately can cause less than complete toner transfer, resulting in low resolution images on the image receiving substrate, like paper, and image deterioration. When the image is in color, the image can additionally suffer from color shifting and color deterioration.
In embodiments, it is desired to provide an intermediate transfer member, which has excellent transfer capabilities, for example, as compared to an intermediate transfer member where a polymer blend of a polymethacrylimide and a polysulfone, a polymethacrylimide and a polyphenylsulfone, or a polymethacrylimide and a polyethersulfone is absent; and possesses excellent release properties from a metal substrate permitting manufacturing simplicity. It is also desired to provide a weldable intermediate transfer belt that may not, but could, have puzzle cut seams, and instead, has a weldable seam, thereby providing a belt that can be manufactured without labor intensive steps, such as manually piecing together the puzzle cut seam with fingers, and without the lengthy high temperature and high humidity conditioning steps. It is also desired to provide an intermediate transfer member, which has excellent wear and abrasion resistance, and more specifically, has excellent mechanical properties as compared, for example, to an intermediate transfer member where a polymer blend of a polymethacrylimide and a polysulfone, a polymethacrylimide and a polyphenylsulfone, or a polymethacrylimide and a polyethersulfone are absent.

Polymer blend containing intermediate transfer members


A multi-sensor electromagnetic (EM) system and method for measuring gradients of EM signals. The multi-sensor EM system includes a frame; a transmitter device attached to the frame and configured to generate a primary EM field; a receiver device attached to the frame and configured to record a secondary EM field generated by the earth after being excited by the primary EM field; and a gradient sensor device attached to the frame and configured to record a gradient of the secondary EM field.

Technical Field
Embodiments of the subject matter disclosed herein generally relate to methods and systems for generating and/or measuring electromagnetic (EM) fields and, more particularly, to mechanisms and techniques for enhancing detection of near surface, lateral or vertical conductive targets.
Discussion of the Background
EM surveying is a method of geophysical exploration to determine the properties of a portion of the earth's subsurface, information that is especially helpful in the oil and gas industry and the mining industry. EM surveys may be based on a controlled source that generates a primary EM field which carries EM energy into the earth, which induces eddy currents in the earth. The eddy currents generate a secondary EM field or ground response. By measuring the secondary field with an EM receiver, it is possible to estimate the depth and/or composition of the subsurface features. These features may be associated with subterranean hydrocarbon deposits.
A schematic airborne EM survey system 100 generally includes, as illustrated in FIG. 1, a transmitter 102 for generating the primary EM field 104 that is directed toward the earth. When primary EM field 104 enters the ground 108, it induces eddy currents 106 inside layers 116 and 118 of the earth. These eddy currents 106 generate a secondary electromagnetic field or ground response 110. An EM receiver 112 then measures the response 110 of the ground. Transmitter 102 and receiver 112 may be connected to an aircraft 114 so that a large area of the ground is swept. Receiver 112 may be located concentric and/or coplanar with transmitter 102. A second receiver 113 may also be added.
However, the existing EM surveying systems are not sensitive to near surface formation detection as the signals usually associated with such formation are buried in either ambient or geologic noise. Thus, there is a need to have a new system that is capable of measuring signals associated with near surface formation detection.

Multi-sensor system for airborne geophysical prospecting and method


A web based desktop environment is disclosed. The desktop environment comprises a work area configured to display application windows in a web browser operating on a computer server. A resident application bar is displayed adjacent the work area and configured to display only icons for resident desktop applications. A power bar resident desktop application is configured to launch web applications to be displayed in the work area. A task board operating in the power bar resident desktop application comprises a vertically resizable two dimensional window located at a selected edge of the work area. The task board is configured to display a web application icon for each web application launched in the power bar resident desktop application.

A web desktop is a desktop environment that can be embedded in a web browser or similar client application. The web desktop can be used to integrate web applications, web services, client-server applications, application servers, and applications on a local client into a desktop environment using the desktop metaphor. A web desktop can be a virtual desktop running in a web browser. The applications, data, files, configuration, settings, and access privileges can reside remotely over the network. This allows much of the computing to take place remotely.
As the desktop metaphor has evolved over the years, the abilities of the desktop have advanced. Unfortunately, with the advances has come a certain amount of feature bloat. Superfluous and unnecessary features in many types of desktops can require excessive amounts of processor power and memory use. In addition, in a web desktop feature bloat can cause an undesirable amount of information to be communicated over a network. When a large number of computing devices connected to a network are using a web desktop, this excess communication can be a burden to the network.
Reference will now be made to the exemplary embodiments 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.

This patent is subject to a terminal disclaimer.


A method of producing dried cellulose nanofibrils includes atomizing an aqueous suspension of cellulose nanofibrils and introducing the atomized aqueous suspension into a drying chamber of a drying apparatus. The aqueous suspension is then dried, thereby forming substantially non-agglomerated dried cellulose nanofibrils.

Various embodiments of a method of producing dried cellulose nanofibrils are described herein. In particular, the embodiments described herein relate to an improved method of producing dried cellulose nanofibrils.
Cellulose nanoscale products, such as cellulose nanofibrils (CNF), nano-fibrillated cellulose (NFC), and cellulose nano-crystals (CNC) may be produced from mechanical or chemo-biological processing. Because of the processing methods, all the intermediate cellulose products exist in aqueous medium, which requires additional processes for production of dry products. Dehydrolysis of wet cellulose products poses a challenge since a number of hydroxyls from cellulose contribute to hydrophilicity that holds together water molecules, as well as other cellulose chains. Drying cellulose affects the final dimensions of cellulose crystals and fibrils due to the aggregation of individual fibrils. The cellulose fibrils or crystals in CNF, NFC, and CNC agglomerate with other fibrils or crystals as water is removed from the aqueous medium in drying processes such as freeze drying, critical point drying, spray drying, oven drying, and air drying.
It is desirable to provide an improved method of drying an aqueous suspension of cellulose nanofibrils to produce dry cellulose nanofibrils that may be used in non-aqueous applications, such as in non-polar polymer matrices used in forming non-polar polymer composites.

University of Maine System  Board of Trustees


A method of compressing an image data block is provided that includes computing a pixel residual for each pixel in the image data block except a non-residual pixel, computing a compression level for the image data block based on a minimum pixel residual value and a maximum pixel residual value of the pixel residuals, encoding a compression flag for the image data block, wherein the compression flag includes an indicator identifying the compression level and a first portion of bits from the non-residual pixel, and generating a compressed block comprising a second portion of bits from the non-residual pixel and the pixel residuals encoded using fixed length coding based on the compression level.

The demand for digital video products continues to increase. Some examples of applications for digital video include video communication, security and surveillance, industrial automation, and entertainment (e.g., DV, HDTV, satellite TV, set-top boxes, Internet video streaming, digital cameras, cellular telephones, video jukeboxes, high-end displays and personal video recorders). Further, video applications are becoming increasingly mobile as a result of higher computation power in handsets, advances in battery technology, and high-speed wireless connectivity.
Video compression is an essential enabler for digital video products. Compression-decompression (CODEC) algorithms enable storage and transmission of digital video. Codecs may be, for example, industry standards such as MPEG-2, MPEG-4, H.264/AVC, etc. and the standard currently under development, HEVC. At the core of all of these standards is the hybrid video coding technique of block motion compensation (prediction) plus transform coding of prediction error. Block motion compensation is used to remove temporal redundancy between successive pictures (frames or fields) by prediction from prior pictures, whereas transform coding is used to remove spatial redundancy within each block.
In many digital video products (e.g., a digital still camera, a digital video camera, a cellular telephone, etc.), raw video data is captured by a sensor and fed into a preview engine for processing. After processing, the resulting video sequence is stored in an external (i.e., off-chip) memory. A video encoder then fetches the video sequence from the external memory to encode it. In addition, during encoding, the video encoder both encodes a picture and stores a decoded copy of the picture in the external memory for use in prediction of a subsequent picture. The video encoder then fetches the decoded copy from the external memory when needed to perform prediction. Thus, the video encoder is fetching both pictures to be encoded and prior pictures from external memory to perform the encoding, and storing prior pictures in the external memory.
In a similar fashion, a video decoder both decodes an encoded picture and stores a decoded copy of the picture in external memory for use in decoding of a subsequent encoded picture. The video decoder then fetches the decoded copy from the external memory to perform the decoding. Thus, the video decoder is fetching both pictures to be decoded and prior decoded pictures from external memory to perform the decoding, and storing prior decoded pictures in external memory.
The real-time video data transfer to external memory and to and from external memory to the video encoder or video decoder requires a lot of memory bandwidth, especially if the video resolution is D1 (720×480) or higher. However, memory bandwidth is limited in many digital video products due to both cost and power constraints. Accordingly, reducing memory bandwidth requirements for processing video data is desirable.

Fixed length coding based image data compression


A practice sword simulating a Katana. The practice sword provides an affordable, safe practice weapon that correctly simulates the size, weight and curve of the Japanese sword with both simulated cutting and thrusting capabilities. The practice sword includes generally a handle, a handle guard, and a simulated blade. The blade is comprised of a plurality of flexible limbs. The limbs are interconnected at a proximal end, proximate the handle and handle guard. The distal end of each limb is limited to axial movement with respect to each other limb. The blade includes a plurality of flexible limbs. The proximal end of each flexible limb is fixed relative to each other proximate the handle guard. The distal end of each flexible limb is limited to axial movement with respect to each other flexible limb.

1. Field of Invention
The present invention pertains to the field of martial arts. More particularly, this invention is related to a practice Samurai sword for simulating combat with a safe weapon closely emulating the size, weight and shape of a Samurai sword.
2. Description of the Related Art
In the field of martial arts, it is well know that many forms of combat use weapons of one fashion or another. Many of the martial arts use swords in hand-to-hand combat. However, it is also well known that many of the martial arts are practiced as an art form and not as a means for actual combat.
In order to reduce the danger associated with authentic weaponry, it is well-known to use practice weaponry. For example, a Shinai is used to simulate a Japanese sword. A Shinai, from the verb "shinau" meaning "to bend" or "to be flexible", is a bamboo Kendo sword that allows a Kendoist to practice freely without fear of serious injury to his self or others. The modern Shinai is constructed of four staves of bamboo fitted together into a cylinder and held together by leather and a string.
The first Shinai were made of split bamboo and completely covered in a cloth or leather bag known as a Fukuro Shinai or bag Shinai. Shinai were of many different lengths and weights. Today, the Shinai is made from bamboo that is cut from the bottom of the culm, or stem, about four inches above ground. The stem is split vertically into six to eight pieces. The bamboo is then dried and four pieces are selected, straightened, and then planed and shaped into a Shinai. As will be understood, there are deliberate methods used to produce each Shinai.
In addition to the four bamboo slats, the Shinai includes a leather handgrip called the Tsuka-gawa covering the tsuka, or handle, a leather cup called the sakigawa on the tip, or kissaki, and a tsuba, or hand guard. The tsuba is fabricated from resin or leather and is held in place by a tsuba-dome, which is a rubber disk. The whole is kept together under tension by a string, called a tsuru, connecting the leather parts at each end, and by a leather binding, or Nakayui, around the Shinai marking out the Datotsubu (the valid strike area of the Shinai) or the Monouchi, which is the top part of the blade toward the tip, which is the most effective cutting area of the Shinai.
The Shinai allows full strength cuts to be made without the risk of injuring the training partner as would an authentic sword or a solid wooden dummy sword. The force of the blow is dissipated by the bamboo sections spreading out on contact. However, the force is often painful. A Shinai strike does not feel like a sword and a thrust can be dangerous, as there is no give in the blade.
In Kendo the solid wooden sword, or boken, is still used in the Kendo Kata, and more rarely in Waza, practice in order to gain a better understanding of how the technique works with a sword. However it is not used for free-sparring. The steel Katana, or alloy Iaito are used by high grades in Kata demonstrations and are the standard weapon used in Iaido.
Other devices have been developed to overcome these and similar problems associated with practice swords. Typical of the art are those devices disclosed in the following U.S. patents:
U.S. Patent No.Inventor(s)Issue Date5,295,926T. TanabeMar. 22, 19945,324,227C. Yuh-ChingJun. 28, 19945,598,596M. R. Jones et al.Feb. 4, 19975,630,998K. L. ParsonsMay 20, 19976,036,602D. G. AbbottMar. 14, 20006,497,619D. D. Dowdy et al.Dec. 24, 2002
Of these patents, Tanabe ('926) discloses a soft sword. The '926 device includes a core rod which comprises a short flexible center core having a grip and a guard constructed in one body and a soft core mounted coaxially around said flexible center core. A bag is disposed on the core rod by engaging at both ends of the core rod. A grip tape is wrapped onto the grip and over the bag. The '926 device is configured such that neither participants nor spectators will be injured during a match, whether by a strike using the device or by a portion of the device becoming dislodged from the device and being flung through the air.
U.S. Pat. No. 5,324,227, issued to C. Yuh-Ching, discloses a toy hitting rod. The '227 device includes a main hitting rod made of resilient material and formed with a longitudinal hole at the center. Two aligned holes are formed at one end thereof. An inner hitting rod is fabricated from resilient material and inserted into the longitudinal hole of the main hitting rod. A spring is sleeved on one end of the inner hitting rod. A hand grip is fabricated from a hard material and defines a recess for grasping. The grip has a connecting rod having a through hole in alignment with the aligned holes of the main hitting rod. The connecting rod defines two protuberances engageable with the other end of the spring. The '227 device is configured for safe use as a "weapon" in hand-to-hand combat. Upon impact, the main hitting rod is deformed to reduce the impact. After impact, the resiliency of the main hitting rod causes the device to return to its original state.
Jones et al., in the '596 patent, disclose a club shaped device having a removable cover. The cover encloses a substantial portion of the club and is fastened thereto. In one embodiment, the '596 device is composed of a head and a handle both constructed from a resilient material, such as dense foam rubber. The handle has a hollow interior area which has an opening at its bottom. The edges of the removable covering are placed into the opening and a removable plug is inserted into the opening to steadfastly hold the edges of the cover against the inner wall of the handle. In one embodiment, the '596 device is used as a soft club novelty item without causing injury to items struck by the club.
In his '998 patent, Parsons discloses a mock training baton including a flexible rod covered by a cushioning material secured to the rod by a removable cover. The '998 device may include a protective resilient disk at the ends of the rod and a means for securing the baton to the belt of trainee. The diameter, configuration and material of the handle of the mock training baton are identical to those of the handle of the actual standard issue baton. The mock baton may include a resilient ring for securing the cover to the baton and a fixed collar for anchoring the resilient disk in place.
Abbot, in the '602 patent, discloses a sparring instrument which is described as allowing for safe, pain free, full contact training. The sparring instrument comprises a handle and a striking portion having a bushing armature mounted thereto. The bushing armature comprises a tip rod telescopically received within a plurality of telescopically mounted cylinders. The bushing armature is covered by a sheath extending beyond the tip rod. The sheath is covered by a soft, flexible material to its end. The sheath is made of a soft, resilient material whereby the sheath extends from the end of the soft, flexible material when the instrument is bent.
Finally, Dowdy et al., in their '619 patent, disclose A scoring system is disclosed which allows for safe, accurate scoring during simulated combat situations. The scoring system includes a simulated striking apparatus having a marking means to safely deliver an erasable marking agent when the striking apparatus contacts an opponent. The striking sections of the apparatus are buffered by a soft, resilient material to reduce the impact from a striking type blow.


This invention provides an isolated vertebrate nucleic acid molecule which encodes dorsalin-1. This invention also provides a nucleic acid probe capable of specifically hybridizing with a sequence included within the sequence of a nucleic acid molecule encoding a dorsalin-1. The invention also provides a vector and host vector system for the production of a polypeptide having the biological activity of dorsalin-1 which comprises the above-described vector in a suitable host. This invention also provides a purified vertebrate dorsalin-1. This invention provides a method for stimulating neural crest cell differentiation, a method for regenerating nerve cells, a method for promoting bone growth, a method for promoting wound healing and a method for treating neural tumor using purified dorsalin-1. This invention further provides a pharmaceutical composition comprising purified dorsalin-1 and a pharmaceutically acceptable carrier. Finally, this invention provides an antibody capable of binding to dorsalin-1.

Throughout this application various publications are referenced by the names of the authors and the year of the publication within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Inductive interactions that define the fate of cells within the neural tube establish the initial pattern of the embryonic vertebrate nervous system. In the spinal cord, the identity of cell types is controlled, in part, by signals from two midline cell groups, the notochord and floor plate which induce neural plate cells to differentiate into floor plate, motor neurons and other ventral neuronal types (van Straaten et al. 1988; Placzek et al. 1990, 1993; Yamada et al. 1991; Hatta et al. 1991). The induction of floor plate cells appears to require a contact-mediated signal (Placzek et al. 1990a, 1993) whereas motor neurons can be induced by diffusible factors (Yamada et al., 1993). Thus, the fate of different ventral cell types may be controlled by distinct signals that derive from the ventral midline of the neural tube.
The specification of dorsal cell fates appears not to require ventral midline signals since the neural tube still gives rise to dorsal cell types such as sensory relay neurons and neural crest cells after elimination of the notochord and floor plate (Yamada et al. 1991; Placzek et al. 1991; Ericson et al. 1992). Moreover, dorsal cell types are found at more ventral positions in such embryos (Yamada et al. 1991; Placzek et al. 1991) suggesting that many or all cells in neural tube have acquired dorsal characteristics. The acquisition of a dorsal fate could represent a default pathway in the differentiation of neural plate cells or a response to inductive factors that are distinct from the ventralizing signals that derive from the notochord and floor plate.
To identify signals that might regulate cell differentiation within the neural tube, genes encoding secreted factors that are expressed in a restricted manner along the dorsoventral axis of the neural tube have been searched. In this application, the transforming growth factor .beta. (TGF .beta.) family have been focused since some of its members have been implicated in the control of cell differentiation and patterning in non-neural tissues. In frog embryos, for example, the differentiation and patterning of mesodermal cell types appears to be controlled, in part, by the action of activin-like molecules (Ruiz i Altaba and Melton, 1989; Green and Smith, 1990; Thomsen et al. 1990; Green et al. 1992). In addition, the dorsoventral patterning of cell types in Drosophila embryos is regulated by the decapentaplegic (dpp) gene (Ferguson and Anderson, 1992a,b). The dpp protein is closely related to a subgroup of vertebrate TGF .beta.-like molecules, the bone morphogenetic proteins (BMPs) (Wozney et al. 1988), several members of which are expressed in restricted regions of the developing embryos (Jones et al. 1991). In this application, the cloning and functional characterization of the dorsalin-1 (dsl-1) gene, which encodes a novel BMP-like member of the TGF-.beta. superfamily are described. Dsl-1 is expressed selectively by cells in the dorsal region of the neural tube and its expression in ventral regions appears to be inhibited by signals from the notochord. Dsl-1 promotes the differentiation or migration of neural crest cells and can prevent the differentiation of motor neurons in neural plate explants. The combined actions of dsl-1 and ventralizing factors from the notochord and floor plate may regulate the identity of neural cell types and their position along the dorsoventral axis of the neural tube.

Cloning, expression and uses of dorsalin-1

The Trustees of Columbia University in the City of New York