text:
|Publication number
|Publication type
|Application number
|Publication date
|Mar 22, 2011
|Priority date
|Sep 28, 2007
|Fee status
|Also published as
|Publication number
|Cymbeline T. Culiat
|Original Assignee
|Ut-Battelle, Llc
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (9), Non-Patent Citations (39), Referenced by (3), Classifications (17), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
The United States Government has rights in this invention pursuant to contract no. DE-AC05-00OR22725 between the United States Department of Energy and UT-Battelle, LLC.
This application is related to U.S. application Ser. No. 11/192,813 to Cymbeline T. Culiat entitled "Cranial and Vertebral Defects Associated with Loss-of-Function of Nell1." This application is also related to U.S. Provisional Application Ser. Nos. 60/995,854 filed on Sep. 28, 2007 and 61/079,446 filed on Jul. 10, 2008 entitled "Treatment of Cardiovascular Disorders Using the Cell Differentiation Signaling Protein Nell1."
This application asserts the priority of U.S. Provisional Application Ser. No. 60/976,023 filed on Sep. 28, 2007, the contents of which are incorporated herein by reference.
This invention relates to the field of wound healing and muscle regeneration. In particular, the invention relates to the discovery that Nell1 protein promotes wound healing and muscle regeneration.
Wound healing involves a series of complex biological processes whereby injured tissue is repaired, specialized tissue is regenerated, and new tissue is reorganized. The healing of wounds is generally divided into three phases: the inflammatory phase, the proliferative phase, and maturation and remodeling phase.
In the inflammatory phase, the clotting cascade is initiated in order to stop blood loss. In addition, various factors, such as chemokines, cytokines, and growth factors, are released to attract and activate cells that phagocytize debris, bacteria, and damaged tissue.
The proliferative phase is characterized by angiogenesis and rebuilding of the extracellular matrix architecture which includes collagen deposition, granulation tissue formation, and epithelialization. The formation of new blood vessels, such as capillaries, and the formation of extracellular matrix enable activated satellite cell to proliferate, differentiate, and fuse into new muscle fibers.
Typically, the maturation and remodeling phase of wound healing is said to begin when the levels of collagen production and degradation equalize. During maturation, type III collagen, which is prevalent during proliferation, is gradually degraded and the stronger type I collagen is laid down in its place. The originally disorganized collagen fibers are rearranged, cross-linked, and aligned. In addition, the newly regenerated muscle matures and contracts with the reorganization of the scar tissue.
An impairment in any of these complex phases leads to complications in wound healing. Therefore, it would be beneficial to provide methods for promoting wound healing and/or muscle regeneration.
These and other objectives have been met by the present invention, which provides, in one aspect, a method for promoting healing of a wound in a mammal in need thereof. The method comprises administering to the mammal an effective amount of Nell1 protein or nucleic acid molecule.
In another aspect, the invention provides a method for treating skeletal muscle atrophy in a mammal in need thereof. The method comprises administering to the mammal an effective amount of Nell1 protein or nucleic acid molecule.
For a better understanding of the present invention, together with other and further advantages, reference is made to the following detailed description, and its scope will be pointed out in the subsequent claims.
The invention is based on the surprising discovery by the inventor that, Nell1 protein promotes wound healing and muscle regeneration. Throughout this specification, parameters are defined by maximum and minimum amounts. Each minimum amount can be combined with each maximum amount to define a range.
Method for Promoting Healing of a Wound
In one aspect, the present invention provides a method for promoting healing of a wound in a mammal in need thereof. As used herein, the term "promoting healing of a wound" refers to augmenting, improving, increasing, or inducing closure, healing, or repair of a wound. Wound healing is considered to be promoted, for example, if the time of healing a wound treated with Nell1 compared to a wound not treated with Nell1 is decreased by about 10%, preferably decreased by about 25%, more preferably decreased by about 50%, and most preferably decreased by about 75%. Alternatively, wound healing is considered to be promoted if the time and extent of re-acquisition of muscle contractility and function treated with Nell1 compared to a wound not treated with Nell1 is improved by about by about 10%, preferably improved by about 25%, more preferably improved by about 50%, and most preferably improved by about 75%. Conversely, the degree of scar formation can be used to ascertain whether wound healing is promoted.
The wound can be an internal wound or an external wound found in any location of a mammal. A wound is typically caused by physical means, such as mechanical, chemical, bacterial, or thermal means. Wounds can also be caused by accidents, such as a car accident, a fall, injuries sustained in battle (deep lacerations and amputations in soldiers), etc. or by surgical procedures, such as open heart surgery, organ transplants, amputations, and implantations of prosthetics, such as joint and hip replacement, etc. The wound can be an open wound or closed wound.
Open wounds refers to wounds in which the skin is broken. Open wounds include, for example, incisions (i.e., wounds in which the skin is broken by, for instance, a cutting instrument (e.g., knife, razor, etc.)), lacerations (i.e., wounds in which the skin is typically broken by a dull or blunt instrument), abrasions (e.g., generally a superficial wound in which the topmost layers of the skin are scraped off), puncture wounds (typically caused by an object puncturing the skin, such as nail or needle), penetration wounds (e.g., caused by an object such as a knife), and gunshot wounds.
Closed wounds are typically wounds in which the skin is not broken. An example of a closed wound is a contusion.
Any mammal suffering from a wound, such as those described above, is in need of promoting wound healing in accordance with the method of the present invention.
Mammals also in need of promoting wound healing further include any mammal with a disease or condition associated with impaired neovascularization and/or impaired angiogenesis. Neovascularization typically refers to the formation of functional microvascular networks with red blood cell perfusion. Angiogenesis refers generally to the protrusion and outgrowth of capillary buds and sprouts from pre-existing blood vessels. Examples of diseases or conditions associated with impaired neovascularization and/or impaired angiogenesis include diabetes, vascular diseases and aging
In one embodiment, the wound healing is promoted in the mammal by promoting regeneration of skeletal muscle. Muscle tissue generally regenerate from reserve myoblasts called satellite cells. The satellite cells are typically found distributed throughout muscle tissue. In undamaged muscle, the majority of satellite cells are quiescent in that they neither differentiate nor undergo cell division.
Following muscle injury or during recovery from disease, satellite cells re-enter the cell cycle, proliferate, and enter existing muscle fibers or undergo differentiation into multinucleate myotubes which form new muscle fiber. The myoblasts eventually yield replacement muscle fibers or fuse into existing muscle fibers, thereby increasing fiber girth.
Thus, the term "regeneration of skeletal muscle" refers to the process by which new skeletal muscle fibers form from muscle progenitor cells. The new skeletal muscle fibers can be new skeletal muscle fibers that replace injured or damaged muscle fibers or new skeletal fibers that fuse into existing muscle fibers.
Skeletal muscle regeneration is considered to be promoted if the number of new fibers is increased at least about 1%, more preferably at least by about 20%, and most preferably by at least about 50%.
In another embodiment, the wound healing is promoted in the mammal by promoting collagen production. Collagen is a fibrous structural protein and a major component of the extracellular matrix. Any type of collagen can be promoted in accordance with the method of the present invention. Examples of types of collagen include, but are not limited to, collagen types I-XXVIII. Preferably, the collagen is type I, collagen type III, collagen type IV, or collagen type VI.
The term "promoting collagen production" refers to an increase in the amount of collagen produced. Any method known to those skilled in the art can use used to determine whether the production of collagen is increased. For example, an increase in collagen production can be determined by analyzing for increased expression of collagen by using, for example, Northern Blot, real time RTPCR, etc. Typically, collagen production is considered to be promoted if the amount of collagen is increased by at least about 1%, more preferably at least by about 10%, and most preferably by at least about 20%.
In one aspect, the method for promoting healing of a wound comprises administering to the mammal in need thereof, an effective amount of a Nell1 protein. The Nell 1 protein useful in the methods of the present invention is described below.
In another aspect, the method for promoting healing of a wound comprises administering to the mammal a nucleic acid molecule encoding a Nell1 protein. The nucleic acid molecule useful in the methods of the present invention is described below.
Method for Treating Muscle Atrophy
In another aspect, the present invention provides a method for treating skeletal muscle atrophy in a mammal in need thereof. The term "muscle atrophy" refers to loss of skeletal muscle mass and strength. The atrophy can be found in any location of a mammal.
Skeletal muscle atrophy can be caused by, for example, genetic abnormalities (e.g., mutations or combinations of certain single nucleotide polymorphisms), poor nourishment, poor circulation, loss of hormonal support, disuse of the muscle due to lack of exercise (e.g., bedrest, immobilization of a limb in a cast, etc.), and aging.
Alternatively, skeletal muscle atrophy can be caused by loss of nerve supply to a target organ. Examples of such diseases and conditions include CMT (Charcot Marie Tooth syndrome) poliomyelitis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), and Guillain-Barre syndrome.
Conversely, skeletal muscle atrophy can be a disease of the muscle tissue itself. Examples of such diseases include, but are not limited to, muscular dystrophy, myotonia congenita, and myotonic dystrophy.
Similarly, certain diseases and conditions can also induce skeletal muscle atrophy. Examples of such diseases and conditions include congestive heart failure and liver disease.
Any mammal suffering from skeletal muscle atrophy, such as those described above, can be treated in accordance with the method of the present invention. In one aspect, the method for treating skeletal muscle atrophy includes administering to the mammal an effective amount of a Nell1 protein described below. The Nell1 protein promotes skeletal muscle regeneration, thereby treating the skeletal muscle atrophy.
In another aspect, the method for treating skeletal muscle atrophy comprises administering to the mammal a nucleic acid molecule encoding a Nell1 protein. The nucleic acid molecule useful in the methods of the present invention is described below.
Nell1 Protein
Nell1 protein is a protein kinase C (PKC) β-binding protein. The Nell1 protein useful in the methods of the present invention can comprise a polypeptide having the same amino acid sequence as Nell1 protein derived from nature, a recombinant Nell1 protein, a homolog thereof, or fragments thereof. Accordingly, a "Nell1 protein" as used herein, also refers to homologs and fragments thereof.
The amino acid sequence of Nell1 protein is highly conserved across species. For example, the mouse Nell1 protein shares about 93% sequence identity with the human Nell1 protein, which, in turn, shares about 90% sequence identity with the rat Nell1 protein.
Since the amino acid sequence of Nell1 protein is highly conserved, the naturally occurring amino acid sequence of Nell1 protein can be from any animal. For example, the Nell1 protein can be human Nell1, rat Nell1, or mouse Nell1.
The amino acid sequence of human Nell1 protein can be found at GenBank Accession No. AAH96102, and is shown in
The amino acid sequence of rat Nell1 protein can be found at GenBank Accession No. NP—112331, and is shown in
The amino acid sequence of mouse Nell1 protein can be found at GenBank Accession No. NP—001032995, and is shown in
The structure of Nell1 proteins has been characterized (see, e.g., Kuroda et al., 1999a; Kuroda et al., 1999b, Desai et al., 2006). For example, the mouse Nell1 protein (SEQ ID NO: 5) is a protein of 810 amino acids, having a secretion signal peptide (amino acids 1 to 16), an N-terminal TSP-like module (amino acids # 29 to 213), a Laminin G region (amino acids # 86 to 210), von Willebrand factor C domains (amino acids # 273 to 331 and 699 to 749), and a Ca2+-binding EGF-like domains (amino acids # 549 to 586).
The secretion signal peptide domain of Nell1 protein is an amino acid sequence in the protein that is generally involved in transport of the protein to cell organelles where it is processed for secretion outside the cell. The N-terminal TSP-like module is generally associated with heparin binding. von Willebrand factor C domains are generally involved with oligomerization of Nell1. Laminin G domains of Nell1 protein are generally involved in adherence of Nell1 protein to specific cell types or other extracellular matrix proteins. The interaction of such domains with their counterparts is generally associated with, for example, processes such as differentiation, adhesion, cell signaling or mediating specific cell-cell interactions in order to promote cell proliferation and differentiation. The Ca2+-binding EGF-like domains of Nell1 binds protein kinase C beta, which is typically involved in cell signaling pathways in growth and differentiation
Homologs of Nell1 protein include, for example, a substitution mutant, a mutant having an addition or insertion, or a deletion mutant of the protein. Substitutions in a sequence of amino acids are preferably with equivalent amino acids. Groups of amino acids known to be of equivalent character are listed below:
Any substitutions, additions, and/or deletions in an amino acid sequence are permitted provided that the Nell1 protein is functional. An amino acid sequence that is substantially identical to another sequence, but that differs from the other sequence by means of one or more substitutions, additions, and/or deletions, is considered to be an equivalent sequence.
In order to compare a first amino acid to a second amino acid sequence for the purpose of determining homology, the sequences are aligned so as to maximize the number of identical amino acid residues. The sequences of highly homologous proteins can usually be aligned by visual inspection. If visual inspection is insufficient, the amino acid molecules may be aligned in accordance with methods known in the art. Examples of suitable methods include those described by George, D. G. et al., in Macromolecular Sequencing and Synthesis, Selected Methods and Applications, pages 127-149, Alan R. Liss, Inc. (1988), such as formula 4 at page 137 using a match score of 1, a mismatch score of 0, and a gap penalty of −1.
Preferably, less than 15%, more preferably less than 10%, and still more preferably less than 5% of the number of amino acid residues in the sequence of Nell1 are different (i.e., substituted for, inserted into, or deleted from). More preferably still, less than 3%, yet more preferably less than 2% and optimally less than 1% of the number of amino acid residues in a sequence are different from those in a naturally occurring sequence.
Preferably, the substitutions, additions, and/or deletions are not made in the conserved regions of the protein or in the functional domain of the protein. Examples of conserved regions of Nell1 protein include the secretory signal, Willebrand like domain, thrombospondin-like domains and laminin-like domains. Examples of functional domains of Nell1 protein include the EGF like domains. Thus, substitutions, additions, and/or deletions in the non-conserved and/or non-functional regions of the protein can typically be made without affecting the function of Nell1 protein.
A Nell1 protein further includes Nell1 protein fragments that retain the ability to promote healing of wounds and skeletal muscle regeneration. Preferably, the Nell1 protein fragment contains one or more of the conserved regions and/or functional domains of the protein. For example, the Nell1 protein fragments can comprise the EGF like domains and/or the von Willebrand like domain of Nell1 protein.
The minimum length of a Nell1 functional fragment is typically at least about 10 amino acids residues in length, more typically at least about 20 amino acid residues in length, even more typically at least about 30 amino acid residues in length, and still more typically at least about 40 amino acid residues in length. As stated above, wild type Nell1 protein is approximately about 810 amino acid residues in length. A Nell1 functional derivative can be at most about 810 amino acid residues in length. For example, a Nell1 functional derivative can be at most at most about 820, 805, 800, 790, 780, 750, 600, 650 600, 550, etc. amino acid residues in length
Once a Nell1 functional protein homolog or Nell1 functional protein fragment is made, such protein can be tested to determine whether it retains substantially the activity or function of a wild type Nell1 protein. For example, the ability of a Nell1 homolog or fragment to bind PKC beta can be tested. Suitable assays for assessing the binding of Nell1 to PKC beta is described in e.g., Kuroda et al. (Biochemical Biophysical Research Comm. 265: 752-757 (1999b)). For example, protein-protein interaction can be analyzed by using the yeast two-hybrid system. Briefly, a modified Nell1 protein can be fused with GAL4 activating domain and the regulatory domain of PKC can be fused with the GAL4 DNA-binding domain.
In addition, the ability of a Nell1 protein homolog or fragment to stimulate differentiation of precursor cells, such as skeletal satellite cells, to maturity can be tested. Maturity of skeletal muscle cells can be assessed cellularly (histology) and molecularly (expression of skeletal muscle-specific proteins or extracellular matrix materials). Still further, a Nell1 protein homolog or fragment can be tested for its ability to drive osteoblast precursors to mature bone cells, by detecting expression of late molecular bone markers or mineralization (i.e., calcium deposits). By comparing the activity of a Nell1 protein homolog or fragment with that of a wild type Nell1 protein in one or more of the assays such as those described above, one can determine whether such homologs or fragments retain substantially the activity or function of a wild type Nell1 protein.
The Nell1 protein, functional homolog or functional fragment may be prepared by methods that are well known in the art. One such method includes isolating or synthesizing DNA encoding the Nell1 protein, and producing the recombinant protein by expressing the DNA, optionally in a recombinant vector, in a suitable host cell. Suitable methods for synthesizing DNA are described by Caruthers et al. 1985. Science 230:281-285 and DNA Structure, Part A: Synthesis and Physical Analysis of DNA, Lilley, D. M. J. and Dahlberg, J. E. (Eds.), Methods Enzymol., 211, Academic Press, Inc., New York (1992). Examples of suitable Nell1 nucleic acid sequences include SEQ. ID. NOs: 2, 4, and 6.
The Nell1 protein may also be made synthetically, i.e. from individual amino acids, or semisynthetically, i.e. from oligopeptide units or a combination of oligopeptide units and individual amino acids. Suitable methods for synthesizing proteins are described by Stuart and Young in "Solid Phase Peptide Synthesis," Second Edition, Pierce Chemical Company (1984), Solid Phase Peptide Synthesis, Methods Enzymol., 289, Academic Press, Inc, New York (1997). Examples of suitable Nell1 amino acid sequences include SEQ. ID. NOs: 1, 3, 5, homologs thereof, and fragments thereof.
Nell1 Nucleic Acid Molecules
Any nucleic acid sequence that encodes for Nell1 protein can be used in the methods of the present invention. Suitable nucleic acid molecules encoding Nell1 protein for use in the methods of the present invention include nucleic acid molecules having a nucleotide sequence as set forth in SEQ. ID. NOs: 2, 4 and 6, as well as degenerate sequences thereof. As used herein, the term "degenerate sequence" refers to a sequence formed by replacing one or more codons in the nucleotide sequence encoding wild type Nell1 protein with degenerate codes which encode the same amino acid residue (e.g., GAU and GAC triplets each encode the amino acid Asp). The nucleic acid molecules can be incorporated into recombinant vectors suitable for use in gene therapy.
Examples of vectors suitable for use in gene therapy may be any vector that comprises a nucleic acid sequence capable of expressing the Nell1 protein in a mammal, especially a human, in need of such therapy. The suitable vector may be for example a viral vector (e.g., such as an adenovirus vector, adeno-associated virus (AAV) vector, retroviral vector, herpes simplex viral vector, polio virues and vaccinia vectors), nonviral vectors (e.g., plasmid vectors), etc. See for example: Ledley 1996. Pharmaceutical Research 13:1595-1614 and Verma et al. Nature 1997. 387:239-242.
Examples of retroviral vectors include, but are not limited to, Moloney murine leukemia virus (MoMuLV), Harvey murine sarcoma virus (HaMuSV), murine mammary tumor virus (MuMTV), and Rous Sarcoma Virus (RSV)-derived recombinant vectors. A Nell 1-coding nucleotide sequence can be placed in an operable linkage to a promoter in the expression vector, wherein the promoter directs the expression of the Nell1 protein in the targeted tissue or cells, and includes both a constitutive promoter and a tissue or cell-specific promoter
The Nell1 protein or nucleic acid molecule is administered to a mammal in need thereof. The mammal may be a farm animal, such as a goat, horse, pig, or cow; a pet animal, such as a dog or cat; a laboratory animal, such as a mouse, rat, or guinea pig; or a primate, such as a monkey, orangutan, ape, chimpanzee, or human. In a preferred embodiment, the mammal is a human.
The Nell1 protein or nucleic acid molecule can be incorporated in a pharmaceutical composition suitable for use as a medicament, for human or animal use. The pharmaceutical compositions may be for instance, in an injectable formulation, a liquid, cream or lotion for topical application, an aerosol, a powder, granules, tablets, suppositories or capsules, such as for instance, enteric coated capsules etc. The pharmaceutical compositions may also be delivered in or on a lipid formulation, such as for instance an emulsion or a liposome preparation. The pharmaceutical compositions are preferably sterile, non-pyrogenic and isotonic preparations, optionally with one or more of the pharmaceutically acceptable additives listed below.
Pharmaceutical compositions of Nell1 protein or nucleic acid molecule are preferably stable compositions which may comprise one or more of the following: a stabilizer, a surfactant, preferably a nonionic surfactant, and optionally a salt and/or a buffering agent. The pharmaceutical composition may be in the form of an aqueous solution, or in a lyophilized form.
The stabilizer may, for example, be an amino acid, such as for instance, glycine; or an oligosaccharide, such as for example, sucrose, tetralose, lactose or a dextram. Alternatively, the stabilizer may be a sugar alcohol, such as for instance, mannitol; or a combination thereof. Preferably the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% weight for weight of the Nell1 protein.
The surfactant is preferably a nonionic surfactant, such as a polysorbate. Some examples of suitable surfactants include Tween20, Tween80; a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001% (w/v) to about 10% (w/v).
The salt or buffering agent may be any salt or buffering agent, such as for example, sodium chloride, or sodium/potassium phosphate, respectively. Preferably, the buffering agent maintains the pH of the pharmaceutical composition in the range of about 5.5 to about 7.5. The salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a human or an animal. Preferably the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM.
The pharmaceutical composition comprising Nell1 protein or nucleic acid molecule may additionally contain one or more conventional additive. Some examples of such additives include a solubilizer such as for example, glycerol; an antioxidant such as for example, benzalkonium chloride (a mixture of quaternary ammonium compounds, known as "quats"), benzyl alcohol, chloretone or chlorobutanol; anaesthetic agent such as for example a morphine derivative; or an isotonic agent etc., such as described above. As a further precaution against oxidation or other spoilage, the pharmaceutical compositions may be stored under nitrogen gas in vials sealed with impermeable stoppers.
An effective amount of the Nell1 protein or nucleic acid molecule, preferably in a pharmaceutical composition, may be administered to a human or an animal in need thereof by any of a number of well-known methods. For example, the Nell 1 protein or nucleic acid molecule may be administered systemically or locally, for example by injection.
The systemic administration of the Nell1 protein or nucleic acid molecule may be by intravenous, subcutaneous, intraperitoneal, intramuscular, intrathecal or oral administration. Alternatively, the Nel-1 protein or nucleic acid molecule may be applied topically in appropriate situations. Such situations include, for example, skin abrasions and surface wounds.
The Nell1 protein can be administered by a cell based gene therapy. For example, allogeneic or xenogenic donor cells are genetically modified in vitro to express and secrete Nell1 protein. The genetically modified donor cells are then subsequently implanted into the mammal in need for delivery of Nell1 protein in vivo. Examples of suitable cells include, but are not limited to, endothelial cells, epithelial cells, fibroblasts, myoblasts, satellite cells, and skeletal muscle cells, stem cells, such as adult stem cells, embryonic stem cells, and cord blood stem cells.
Alternatively, the genetically modified donor cells can be incorporated into a matrix containing an appropriate microenvironment to maintain, for a given time, the viability and growth of the genetically modified donor cells. The matrix can be applied to, for example, a surface wound. Expression and secretion of Nell1 by the genetically modified donor cells promotes healing of the wound. After the wound is healed, the matrix can be removed. Examples of suitable matrices include, but are not limited to, wound dressings, collagen matrix, patches, and hydrogels.
An effective amount of a pharmaceutical composition of the invention is any amount that is effective to achieve its purpose. The effective amount, usually expressed in mg/kg can be determined by routine methods during pre-clinical and clinical trials by those of skill in the art.
Sagittal sections of whole fetal bodies collected a day before birth were analyzed by immunohistochemical methods using an antibody for the Nell1 protein. The red/pink staining in the epidermis, dermis and underlying skeletal muscle of normal fetal mice (
Genes that are part of the Nell1 pathway during musculoskeletal development were determined by quantitative real time PCR (qRTPCR) assays and microarray analyses of fetal bodies (15 and 18 days of gestation). The role of Nell1 in muscle formation was revealed by the immunohistochemistry and microarray data. The genes in the Nell1 pathway associated with wound healing and muscle regeneration include Tenascin b (Tnxb), Tenascin C (Tnc), osteoblast specific factor (Osf2), periostin, Matrilin 2 (Matn2), Collagen VI a1 (Col6a1), protein kinase C(PKC), Notch 3, TAL/SCL, Bcap31, Collagen IV a1 (Col4a1).
Severe muscle injury is induced in adult SJL/J mice a strain, known to be a genetically poor wound healer. The ability of purified recombinant human Nell1 protein is tested in the wound healing of severely lacerated leg muscles of SJL/J mice. Wounding is induced by surgically removing a sliver of muscle (approximately 5 mm long�1 mm wide�2 mm deep) from the left gastrocnemius muscle of adult mice (4-5 months old) and the skin wound is sutured. On the third day after wounding, 5 mice are given phosphate buffered saline (PBS) solution to serve as controls, 5 mice are treated with 312 ng Nell1 protein (Dose I) and another 5 mice with 624 ng protein (Dose II). Nell1 Protein diluted in PBS (8 microliters) is administered directly along the entire length of the gaping muscle wound by dripping from a microinjector with a fine gauge needle. Wound healing is assessed one week post-treatment. Observations are made under a dissecting microscope.
Type I diabetes is induced in mice by streptozotocin (STZ), an alkylating agent that destroys the pancreatic islet cells. Commercially produced diabetic mice are purchased from The Jackson Laboratory. Diabetic mice are generated by the following method: At 8 weeks of age, one daily intraperitoneal injection of STZ for five consecutive days. Two weeks after the last STZ injection, mice are weighed and blood glucose levels are measured. Mice with at least 300-400 mg/dL blood glucose levels are considered diabetic. Wounding surgeries are performed as previously described in Example 3, but are done on younger adult mice (three months old) due to the severity of the induced diabetes (diabetic mice are already at 400-600 mg/dL at this stage). Four diabetic mice are given PBS as controls and four are given 312 ng of purified recombinant human Nell1 protein diluted in PBS. Protein is given two days after wounding and treatment effects are examined after one week.
Ten to twelve month old C57BL/6 mice are lacerated in the leg muscle as described Examples 3 and 4. Nell1 protein is injected or administered as described in Examples 3 and 4 directly into the wound site. The mice are euthanized at different time points, wounds are evaluated and their tissue is collected for histological analysis.
Mammals with chemically or heat-induced muscle damage are treated with Nell1 protein in the wound and areas immediately bordering the damaged tissue. This can be a single administration of the appropriate Nell1 protein level or can be incorporated into wound dressings, bandages or ointments to provide a lower dose but continuous/time release introduction of Nell1. In addition, tissue grafts can be implanted into the damaged area along with the Nell1 protein introduced in the boundaries of the graft in order to promote vascularization and success of the tissue grafts onto the damaged areas.
Thus, while there have been described what are presently believed to be the preferred embodiments of the invention, changes and modifications can be made to the invention and other embodiments will be know to those skilled in the art, which fall within the spirit of the invention, and it is intended to include all such other changes and modifications and embodiments as come within the scope of the claims as set forth herein below
|Cited Patent
|Filing date
|Publication date
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|May 30, 2006
|The Regents Of The University Of California
|NELL-1 enhanced bone mineralization
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|Mayo Foundation For Medical Education And Research, A Minnesota Corporation
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|The Regents Of The University Of California
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|The Regents Of The University Of California
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|The Regents Of The University Of California
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|Liu, L., et al., Characterizing the role of the Nell1 Gene in Cardiovascular Development, U.S. Department of Energy Jornal of Undergraduate Research, 2007 (Abstract).
|Liu, L.Y. et al., "Characterizing the Role of the Nell1 Gene in Cardiovascular Development" American Association for the Advancement of Science, San Francisco, CA, Presentation on Feb. 15-17, 2007 (Abstract).
|Lu, S.S., et al., "The Osteoinductive Properties of Nell-1 in a Rat Spinal Fusion Model," The Spine Journal, 2007, pp. 50-60, vol. 7, Issue 1.
|Luce, M.J., et al., "The Neuronal EGF-related genes NELL1 and NELL2 are Expressed in Hemopoietic Cells and Developmentally Regulated in the B Lineage," Gene, 1999, pp. 121-126, vol. 231, Issue 1-2.
|Maeda, K. et al., Brain Specific Human Genes, NELL 1 and NELL2, are Predominantly Expressed in Neuroblastoma and Other Embryonal neuroephithelial tumors, Neurol Med Chir (Tokyo), 2001, pp. 582-588, vol. 41, Issue 12.
|Ngo et al. (1994). Computational complexity, protein structure prediction, and the Levinthal paradox. In Merz and Le Grand (Eds.) The Protein Folding Problem and Tertiary Structure Prediction. Birkhauser:Boston, pp. 491-495.
|Orlic, D., et al., "Transplanted Adult Bone Marrow Cells Repair Myocardial Infarcts in Mice," Ann NY Acad Sci, 2001, pp. 221-230, vol. 938, Issue 1.
|Ott, H.C., et al., "From Cardiac Repair to Cardiac Regeneration-Ready to Translate?," Expert Opin Biol Ther., 2006, pp. 867-878, vol. 6, Issue 9.
|Pettit et al. (1998). The development of site-specific drug-delivery systems for protein and peptide biopharmaceuticals. Trends in Biotechnology. 16: 343-349.
|Rinchik, E.M., et al., "Functional Annotation of Mammalian Genomic DNA Sequence by Chemical Mutagenesis: A Fine-Structure Genetic Mutation Map of a 1- to 2-cM Segment of Mouse Chromosome 7 Corresponding to Human Chromosome 11p14p15," PNAS, 2002, pp. 844-849, vol. 99, Issue 2.
|Rosenthal, N., et al., "Growth Factor Enhancement of Cardiac Regeneration," Cell Transplant. 15 (Suppl1): S41-S45, 2006.
|Rubart, M., et al., "Cell-Based Approaches for Cardiac Repair," Ann NY Acad Sci, 2006, pp. 34-38, vol. 1080.
|Santini, M. P. et al., "Signalling Pathways in Cardiac Rengeneration," Novartis Found Symp, 2006, pp. 228-243, vol. 274.
|Schmitt, et al., "BMP2 Initiates Chondrogenic Lineage Development of Adult Human Mesenchymal Stem Cells in High-Density Culture," Differentiation, 2003, pp. 567-577, vol. 71, Issue 9-10.
|Shen, Y., et al., "Knock Down of NELL2 in Wilms' Tumor Cell Line," Journal of the William Jarvie Society, 2006, p. 41, vol. 49, Abstract.
|The Reporter, No. 78 (Jun. 2006), published by Oak Ridge National Laboratory, accessible on line at http:;//www.ornl.gov/info/reporter/no78/June06 dw.htm.
|Ting, K., et al., "Human NELL-1 Expressed in Unilateral Coronoal Synostosis," J Bone Miner Res, 1999, pp. 80-89, vol. 14, Issue 1.
|Tsutsumi, S., et al., "The Novel Gene Encoding a Putative Transmembrane Protein Is Mutated in Gnathodiaphyseal Dysplasia (GDD)," Am. J. Hum. Genet, 2004, pp. 1255-1261, vol. 74.
|Watanabe, T.K., et al., "Cloning and Characterization of Two Novel Human cDNAs (NELL1 and NELL2) Encoding Proteins with Six EGF-Like Repeats," Genomics, 1996, pp. 273-276, vol. 38.
|Wells, J.A. (1990). Additivity of mutational effects in proteins. Biochemistry. 29(37):8509-8517.
|Yamamoto, et al., "Regulation of Bone Morphogenetic Proteins in Early Embryonic Development," Naturwissenschaften, 2004, pp. 519-534, vol. 91.
|Zhang, X., et al., "Craniosynostosis in Transgenic Mice Overexpressing Nell-1," J Clin Invest, 2002, pp. 861-870, vol. 110, Issue 6.
|Zhang, X., et al., "Nell-1 Induces Acrania-Like Cranioskeletal Deformities During Mouse Embryonic Development," Lab Invest, 2006, pp. 633-644, vol. 86, Issue 7.
|Zhang, X., et al., "Overexpression of Nell-1, a Craniosynostosis-Associated Gene, Induces Apoptosis in Osteoblasts During Craniofacial Development," J Bone Miner Res. 2003, pp. 2126-2134, vol. 18, Issue 12.
|Citing Patent
|Filing date
|Publication date
|Sep 24, 2008
|May 13, 2014
|Ut-Battelle, Llc
|Treatment of cardiovascular disorders using the cell differentiation signaling protein Nell1
|Sep 24, 2008
|Apr 2, 2009
|Ut-Battelle, Llc
|Treatment of cardiovascular disorders using the cell differentiation signaling protein Nell1
|Sep 29, 2011
|NellOne Therapeutics, Inc.
|Methods to treat or prevent a skin condition using a nell1 peptide
|U.S. Classification
|514/1.1, 514/21.2, 530/350, 514/17.2, 514/18.6
|International Classification
|Cooperative Classification
|European Classification
|Oct 1, 2008
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text:
Police prevention strategy helps keep crime rates down
Relevant offers
The amount of crime in Queenstown and Central Otago has followed the downward trend in statistics throughout the country.
Figures issued by the New Zealand Police yesterday show the total recorded crime in rural Otago – which includes Queenstown Lakes, Central Otago, and Waitaki – fell by 17.3 per cent, with the total number of offences dropping from 5295 in 2010 to 4902 in 2011.
Otago Rural area commander Inspector Mike Cook said he was pleased with the results. "They represent some good hard work by our staff and by our communities, and so we're just looking build on those results as well."
This was the third year in a row Otago Rural had recorded a decrease in crime, and the recently-introduced Prevention First strategy, which took a more proactive approach rather than a reactive approach to policing, had played a role in that, he said.
"I think we're definitely starting to see some benefits from taking a proactive approach. Quite clearly if we can target our resources and people into the areas that need it ... that has that flow-on effect of stopping those crimes in the first place."
While crime was on the decrease, any crime involving violent offending was always a concern, and it was an area police would continue to target, he said.
The number of offences classed as acts intended to cause injury continued to decline, going from 648 in 2010 to 551 in 2011, a decrease of 15.0 per cent.
Theft rates and related offences also declined, falling by 15.5 per cent (1538 offences to 1299) as did offences related to property damage, which were down 12.7 per cent from the previous year (959 down from 1098).
Reported crime in the Dunedin-Clutha policing area also recorded a drop in 2011, with 13.0 per cent less than in the previous year.
Dunedin-Clutha area commander Inspector Greg Sparrow said more than 1500 fewer offences than in 2010 meant fewer victims of crime.
The number of reported assaults fell by 9.9 per cent, dropping from 1322 offences in 2010 to 1193 in 2011.
Although the total number of assaults had fallen, reported family violence still remained relatively high, he said.
"Our strategy is a positive action approach, meaning that we will always take action of some kind ... We will arrest and/or remove offenders for a `cooling-off' period and then work with other agencies and organisations to help develop sustainable solutions for families to move forward."
Southland also recorded a decrease in crime, with the total number of reported offences falling from 8790 in 2010 to 7874 in 2011 – a reduction of 10.4 per cent.
- The Southland Times
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subset: commoncrawl


text:
Celebs UncensoredSpring Break with the Kardashians!
Check out Kim, Kourtney and the rest of the clan in Miami in aspiring photographer Kendall's own big photos, taken with her new Nintendo DSi XL camera!
Credit: Courtesy Kendall Jenner
Updated: Friday Apr 09, 2010 | 11:00 AM EDT
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text:
65 Union Ave
Sudbury, MA 01776
730 Boston Post Rd
Sudbury, MA 01776
64 Union Ave
Sudbury, MA 01776
528 Boston Post Road
Sudbury, MA 01776
UGH this place is the best. as a student in cambridge, dickson bros never let me down when i needed some random thing. since...
I can't say enough about the staff here, always so friendly and waiting to help you find things in the store.
Good: They were here at the time they said they were going to be here.Their price was a bit less than what they had estimated.....
©2016 Cox Search, Inc. All rights reserved. Data provided in part by Localeze and Valpak.


text:
My name is Canon Andrew White and I am the founder and president of The Foundation for Relief and Reconciliation in the Middle East (FRRME). Before that, I was Chaplain of St George's Church in Baghdad.
FRRME provides emergency relief to Christians and other persecuted minorities in Northern Iraq, as well thousands of Iraqi refugees who have fled to Jordan to escape the sectarian violence. In addition to spiritual support we provide food, medicine and shelter. We work with partners on the ground, including churches, NGOs and the UN, to ensure that aid reaches the most vulnerable.
In Jordan we are looking after 500 Iraqi refugee families. Currently, the Jordanian government does not permit refugees to work so we provide them with shelter, food (via a weekly voucher scheme), and free health care (including prescriptions). We have also set up a school in Marka, a suburb of Amman, which has 175 pupils.
Our reconciliation work is focused on the peace process in Israel / Palestine. As well as supporting grassroots organisations, we run an annual summer school – The Jerusalem International School for Reconciliation (JISR) – which introduces a new generation to the power and methods of reconciliation. Former speakers at JISR include former Israeli Ambassador to the UK, Daniel Taub, and Sheik Imad Falouji, former-founding member of Hamas.
As I often say, we must pray for peace but we must also pay for peace. If you would like to find out more about us, please explore this website. If you would like to make a donation, you can do so by clicking here.
Grace and Peace,
Statement from the FRRME Board of Trustees regarding Canon Andrew White
The Rev. Canon Andrew White has been suspended with pay by the Foundation for Relief and Reconciliation in the Middle East pending the findings of a Charity Commission Statutory Enquiry.
The Foundation is cooperating fully with the appropriate authorities. It would be inappropriate to comment further on an active investigation other than to say that the Foundation believe at this stage that the alleged incident stemmed from a genuine desire by Canon White to help others.
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Security situation in Jordan worsens
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"Security situation in Jordan worsens" - please read / share this latest update ... See MoreSee Less
Security situation in Jordan worsens - Foundation for Relief and Reconciliation in the Middle East
The Hashemite Kingdom of Jordan was attacked two days ago by a suspected Islamic State suicide bomber who drove his car into an army checkpoint at the bord
3 days ago
Ibraheem Hasan, Heather Bryan and 19 others like this
An excellent article in the Wall Street Journal which explains the humanitarian consequences of the Battle of Falluja ... See MoreSee Less
Iraq Refugees Languish Outside Fallujah
Refugees who fled Fallujah as Iraqi forces fought to take the city back from Islamic State militants have flooded into camps that lack adequate shelter and supplies.
5 days ago
Miriam Millson, Sharon Ward and 9 others like this


text:
I am compiling a C++ application using GNU
g++. The project takes advantage of OpenSSL libraries.
On my machine (a 64 bit CentOS quad core) I compile and link my files.
g++ -g -c -L/usr/local/lib/ -L/usr/lib64/
-I/usr/local/include/ -I/usr/local/ssl/include/
-lcrypto mysrc1.cpp mysrc2.cpp mysrc3.cpp
g++ -L/usr/local/lib/ -L/usr/lib64/ -lcrypto
*.o -o ./myapp.out
My application uses function
MD5 which is contained in
libcrypto.so. As you can see I specify to
g++ the dirs where to search using the
-I options and which libraries to look for with the
-l<lib-name> option. There are some trivial paths like
/usr/local/lib which can be omitted of course, but I specified them because the makefile is parametric.
The problem
My problem is that I can successfully compile my stuff (first command), but linking fails (second command):
/usr/bin/ld: cannot find -lcrypto
collect2: ld returned 1 exit status
make: * [cppsims_par] Error 1
But I did check folders and everything...
libcrypto.so is inside
/usr/lib64/. What is going on?


text:
Kukla's Korner Hockey
Video- TSN Goes Hollywood
by Paul on 04/29/13 at 09:28 PM ET
Comments (3)
After a night of partying in LA, the NHL on TSN panel wakes up with a random stranger, and one less member of the panel. Follow their journey as they look to retrace their steps and find the lost Aaron Ward.
Filed in: NHL Media, | KK Hockey | Permalink
Tags: tsn
That was pretty funny. I'm impressed.
Posted by NHLJeff from Pens fan in Chicago, IL on 04/30/13 at 12:03 AM ET
Not bad. I liked the guy under the bench in the lockerroom. That was pretty funny
Posted by timbits on 04/30/13 at 09:33 AM ET
Good stuff. Dreger was tremendous.
Posted by Chris M on 04/30/13 at 09:44 AM ET
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Email Paul anytime at email@example.com


text:
CN X112 knocks down the light at Armstrong East with a long 173 platform intermodal ; CN 2642, 5715, 2561, 2153 provide the power
CN 303 slams on the binders for a permanent slow order; CN 2694 + CN 2426 provide the power for 96 cars.
CN M314 chugs along at 35mph across the NOZ (due to recent derailments, a 35mph speed restriction has been in effect for all trains with loaded dangerous goods) with a long 157 car freight. Provid... (more)
CN 8898 + IC 2705 have a 124 car 314 nicely stretched out through Wagaming
CP 5750, CP 8920, UP 3756 provide a nice mix of power for the Winnipeg to Toronto freight
CN's Winnipeg Transcona, MB - Toronto BIT, ON intermodal train pulls into Armstrong for a crew change behind a trio of GE's
CN 301 passes Lamaune proper, and our hi-rail truck in a good snow storm.
Unibrow 8808 east chugs along with a siding length 114.
A pair of CN's finest Dash 8's pull 301's freight into Auden, passing through a WILD (Wheel Impact Load Detector) off in the distance, no defects, not a key train, good for track speed!
Three new Liebherr Mammoet cranes ride on M303 towards Edmonton, AB
Down to 35mph, the new rule for crude oil trains, or loaded dangerous good between Winnipeg, MB and Capreol, ON on the CN line. It will be a long ride across the subdivision, just making it in the... (more)
A very faded looking SD70I and a ES44DC pull 152 platforms of the Roberts Bank, BC - Toronto, ON Q102 across the 799' Little Jackfish River bridge
CN 316 pulls through Ferland
CN 318 departs Armstrong, with a short train
After a slow trip over the hills West of Marathon, CP 420's horses bring their 8000ft train up to track speed.


text:
Time to Set the TableThursday, November 12, 2009
{Norman Rockwell, "Freedom From Want"}
Wow, I can't believe Thanksgiving is just 2 weeks away! So much to do in so little time. Does anyone else feel that way? Dinner parties will ensue and I know you will all want to make sure your table looks perfect. That's exactly how I feel so with that said, I found some great tables to get inspired by.
You might want to grab a snack before looking at these photos cause they just might make you hungry.
{Photo Credit: Country Living}
{Photo Credit: DwellStudio's Christiane Lemieux}
{Photo Credit: DwellStudio's Christiane Lemieux}
I love everything about this tablescape. The patterned table runner and napkins are a great way to add modern elements and I love that the flatware is gold.
{Photo Credit: Columbus Home and Garden}
Umm, can I just say this is like the pinnacle of chic in tablescapes?
{Photo Credit: Country Living}
{Photo Credit: Nicole De Lagrave}
I envy those of you who live in warmer climates; you can entertain outside year round!
{Photo Credit: Martha Stewart}
Don't feel that you have to have a variety of elements on your table to make things pop, repeating one element creates a big impact too.
{Photo Credit: Apartment Therapy: San Francisco}
You could probably find the pine cones and berry twigs right outside your house. And go to Michael's or any craft store to find some inexpensive glass vases.
{Photo Credit: Southern Living}
{Photo Credit: Midwest Living Magazine}
Great idea using pages of a book as place mats. Just make sure it's not a book you like! Or make photocopies of the pages. Also, I love the way they use books to create height in their tablescape. Varying heights provide points of interest and dimension.
{Photo Credit: Fine Living}
For those of you with kids, here are some cute ideas to dress up the kids table. Although, I think adults might appreciate these ideas too!
{Photo Credit: Martha Stewart}
{Photo Credit: Martha Stewart}
3 comments
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text:
Six Flags says it probably will reevaluate its employee screening process in the wake of an attack on a teenager on park property this past summer.
Three seasonal employees have been arrested for participating in the beating of a 19-year-old Marietta man just outside the park. The employees, ages 16, 17 and 18, have been suspended and will be fired if found guilty.
The attack, so severe it left a shoe print on the victim's face, involved as many as 25 participants and witnesses in what appeared to be an act of gang violence. One of the suspected employees is a member of a street gang called Young Gangster Living.
Six Flags says it conducts criminal background checks on all employees who are 18 and over. But Georgia law does not allow background checks on underage applicants. That leaves Six Flags, which hires many young seasonal workers, in a quandary.
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text:
A different presidentI first came into contact with Giani Zail Singh when he took up his phone as the home minister and directly dialled me at my home. He began the conversation with a friendly Nariman sahib, haal chaal kya hai? I came to know him better later but he ... Yahoo! India, 1 month ago
Giani Zail Singh remembered - Chandigarh Tribune, 1 month ago
Giani Zail Singh was a true 'giani': Pranab Mukherjee - Ani News, 1 month ago
2 images for "zail singh"
From the India Today archives: The untold story before Operation Bluestar
Indira Gandhi almost gave the go-ahead to a covert RAW mission to kidnap Jarnail Singh Bhindranwale months before she sent the Army into the Golden Temple in 1984. CRPF personnel take position for the siege of the Golden temple It was a ...India Today, 3 weeks ago
Remembering Operation Blue Star
Home Articles Remembering Operation Blue Star Like Dr Muhammad Khan Dr Gurnam Signh, a professor in the Coventry University, United Kingdom draws parallels between Operation Blue Star and Normandy Landing (Operation Neptune and Operation ...Pakistan Observer, 3 weeks ago
Modi's Qatar visit to bridge the remaining gulf with GCC
In his fourth visit to the Gulf starting today, the PM is expected to put in place an investment treaty to boost the country's economy, and ink pact on sharing intelligence on terror financing amid rising fears of the ISIS Prime Minister Narendra ...New Delhi Pioneer, 3 weeks ago
Where are such people?
Naresh Raj IT was mid-60s, my father asked me to accompany him to Chandigarh, where he was to attend a meeting of the Board of Studies of Economics at Panjab University. He was the HoD at Government College, Rohtak, and being the seniormost in the ...Chandigarh Tribune, 1 month ago
Ekta Dal criticises Modi Govt on NEET issue
Dharamshala, May 23 (UNI) Navbharat Ekta Dal today criticised the central government for adopting the ordinance to defuse the Supreme Court order for common National Eligibility Entrance Test (NEET) for the admissions to the medical courses. The ...United News of India, 1 month ago
In spite of uncompromising Modi, Augusta set to go Bofors way
Experienced bribe-takers know how to cover the money trail Despite the Italian court convicting the bribe-givers in the Augusta-Westland deal there is hardly any progress at the Indian end to track down the bribe-takers. Yes, former Air Force ...Afternoon Despatch & Courier, 1 month ago
A Funeral at St Inez
The gentleman, a retired colonel, at whose funeral I was, had left the planet early that morning. At 3 a.m., he went to use the bathroom and slumped as he stepped out. His heart had been beating 72 times per minute 60 times every hour, 24 hours per ...Navhind Times, 1 month ago
AICTE notice to 5 govt engg colleges over ineligibleheads
The All India Council for Technical Education (AICTE) has issued notices to five Punjab government engineering college for allegedly hiring ineligible principals. The AICTE, the governing body for technical education in the country, in a gazette ...Yahoo! India, 1 month ago
Exhibition of neglect
With unkempt building and damaged artefacts, Pune's Aga Khan Palace is another shameful example of how we handle heritage There are ways of seeing and then there are ways of seeing a museum. Historian Vinay Lal taught me the latter. During a ...The Hindu, 1 month ago
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text:
Angels general manager Jerry Dipoto, on with Steve Mason and John Ireland, talked about the team's addition of Zack Greinke, rookie star Mike Trout and the division race.
Cubs, Dodgers top MLB Future Power Ranks
4hDan Szymborski
Ball go far: Hitters mashing home runs at near record pace
22hDavid Schoenfield
MLB trade deadline preview: Buyers and sellers
14hJim Bowden
MLB Rumor Central: Angels pitchers face uncertain future
2dIsaac Chipps
Good luck picking your American League All-Star pitchers
2dDavid Schoenfield
George Springer leading Astros revival
3dTodd Wills, ESPN Stats & Information
MLB Rumor Central: Interest building in Yunel Escobar?
3dKyle Brasseur


text:
Ingram Micro takes out global Microsoft distie of the year award
Ingram Micro has been named Microsoft's Distributor Partner of the Year for 2016.
Ingram Micro has been named Microsoft's Distributor Partner of the Year for 2016.
Businesses that want to get their files out of on-premises data centers and into the cloud have a new option with Box Shuttle.
Facebook can resume tracking Belgians online even if they don't have an account with the social network, an appeals court ruled Wednesday.
A database described by some as a "terrorism blacklist" has fallen into the hands of a white-hat hacker who may decide to leak it online.
The digital transformation imperative is becoming increasingly urgent for companies large and small, and SAP wants to help. On Wednesday, the ERP giant set its sights squarely on SMBs with an updated app that's been enriched with analytics and other key features.
Mobile ransomware is on the rise, with the infection rate skyrocketing, according to new research.
Microsoft today pegged the number of Windows 10 devices at 350 million, an increase of about 50 million since early May.
As the Wi-Fi Alliance starts certifying the latest gigabit-speed products to work together, users may not get as excited as they did for some earlier standards. But the new technology adds a few features with real advantages, at least for some users.
The infrastructure used by an Iranian cyberespionage group to control infected computers has been hijacked by security researchers.
A survey by Volvo of more than 50,000 drivers shows that autonomous cars are more popular in some states than others -- but Americans in general are reluctant to let go of the steering wheel.
Following an extended preview period, Amazon's Elastic File System is now generally available in three geographical regions, with more on the way.
He's also asking for 1.5 percent of all future iPhone sales—around $3.5 billion per year.
The American Civil Liberties Union has filed a lawsuit challenging a 30-year-old hacking crimes law, with the civil liberties group saying the law inhibits research about online discrimination.
A key specification for exchanging sensor data between vehicles has found a new home, in a move that may help future drivers avoid dangers before they see them.
A Google security researcher has found high severity vulnerabilities in enterprise and consumer products from antivirus vendor Symantec that could be easily be exploited by hackers to take control of computers.
Oracle launched a new family of servers and a new Sparc chip on Wednesday, both aimed at customers considering x86 servers for a scale-out cloud infrastructure.
Microsoft officially confirmed Wednesday morning that its latest major refresh of Windows 10 will be released publicly in a little over a month on August 2.
Version 0.9 of the open source library includes backing for iOS and Raspberry Pi and Python 3.5 support
KPMG Australia will improve its professional services offerings by adding further integration to IBM's Watson cognitive computing platform.
Australian IT solutions and services provider and IPMG company, Blue Central, has named Peter Ikladios as its new managing director. Ikladios replaces George Kazangi, who recently launched a partner-focused technical services business named Four Nines.
To meet the challenges of digital disruption and drive competitive advantage your clients need fast, agile, and reliable applications. The proactive monitoring and management of application performance can ensure the delivery of efficient, integrated and reliable business applications and services. Alternatively, poor application performance will lead to lost productivity, poor customer service and lost business.. Read more


text:
Securing Your Asterisk Server, Part 2 - page 4
Locking Down OpenSSH
Any server administration done over a Web interface is transmitted in cleartext, unless you enable HTTPS. HTTPS is SSL over HTTP; a nice easy way to encrypt HTTP traffic. To activate it on your Asterisk server all you need to do is install the Apache SSL module, then restart Apache (Apache is the Web server included in Asterisk@Home):
# yum -y install mod_ssl # /etc/init.d/httpd restart
Then all you have to do is remember to point your Web browser to https://[asterisk-server].
Asterisk@Home is a complex package, so there may yet be the odd security hole somewhere. But you should be in pretty good shape now.
This article originally appeared on VoIPPlanet, a JupiterWeb site.
- Skip Ahead
- 1. Locking Down OpenSSH
- 2. Locking Down OpenSSH
- 3. Locking Down OpenSSH
- 4. Locking Down OpenSSH
- 1Linux Top 3: Fedora 24, Peppermint 7 and Solus 1.2
- 2Linux Top 3: Alpine Linux 3.4, deepin 15.2 and Linux Lite 3.0
- 3Linux 4.7 Set to Boost Live Patching, Security and Power Management
- 4Linux 4.6 Charred Weasel adds USB 3.1 Support
- 5Linux Top 3: OpenIndiana 2016.04, Ubuntu 16.04 and Debian's New Leader


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After a timely repeat of the Santa Ponsa special at 10.00pm, we're being graced with its 'companion show.' Yep, it's a new series devised to accompany Tallafornia, featuring the latest from the cast, and interviews with 'celebrity guests.' Given the line-up gracing Monday's Celebrity Come Dine With Me Ireland, you can expect Geraldine off The Apprentice years ago to make an appearance. Plus, we're being promised all the inside news from the resort of Santa Ponsa and a chance for fans to enjoy exclusive behind-the-scenes footage. Listen, you've only yerselves to blame, the ratings don't lie, you all watch it.
Tallafornia: The After Party. TV3: 10.40pm
Story by Sheena McGinley | 16:31 | Friday 4th January 2013 | TV Highlights
Today's Highlights
Live Euro 2016: Belgium v Wales
TV3: 7.00pm
The second quarter-final, which takes place at Stade Pierre-Mauroy in Lille will be contested between Wales and Belgium....TV3 |
Big Brother: Live Eviction
TV3: 9.00pm
It's another live eviction tonight as Georgina, Jayne, Andy and Evelyn have been facing the public vote the past few days....TV3 |
Hardy Bucks: The Movie
RTE2: 11.35pm
Somebody went and gave the Castletown lads a movie there a couple years ago and you can see the fruits of their labour on...RTE 2 |
Tara Road
RTE 1: 9.35pm
Nothing like a Maeve Binchy movie of a Friday night, and this one is almost like the premise of that Cameron Diaz/Kate...RTE One |
The Graham Norton Show
BBC1: 10.35pm
Unfortunately The Graham Norton Show has finished for another season, but you do have a 'Best Of' to entertain yourself with...BBC One |
Gogglebox: The Best Bits
Channel 4: 9.00pm
Like Graham Norton, Gogglebox also just has a 'Best Of' show tonight, where we can look back at some of the most memorable...


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GREEN, Eileen (Brennan) Of Swampscott, age 49, on Jan. 30, 2013. Wife of Lloyd Green. Mother of Emery, a student of Swampscott High School, and Elizabeth a student of Clarke Elementary School. Sister of Kathleen Shea of Walpole and Patricia Dresselaers of Littleton, Colorado, aunt of Kristen Shea. She was the sister-in-law of Wayne and Lauren Green of Franklin and Marsha and Jim Hastings of Bellingham. She also leaves many loving friends, cousins, aunts and uncles. Her funeral will be held from the Solimine, Landergan & Richardson Funeral Home, 67 Ocean St. (Rt 1A) LYNN on Monday at 9AM, followed by a Funeral Mass in St. John the Evangelist Church, Swampscott at 10AM. Interment will be private. Visiting hours will be Sunday 3-7 p.m. In lieu of flowers, memorial donations may be made to The Emery and Elizabeth Scholarship Fund c/o Salem Five Bank, Swampscott, MA 01907. Directions & guestbook
Funeral Home
Solimine Funeral Homes
67 Ocean Street
Lynn, MA 01902
(781) 595-1116
Published in The Boston Globe on Feb. 1, 2013


text:
Teghout CJSC to hold meetings on Teghout project on July 14
Yair Auron: Israeli Knesset will hold discussion on Armenian Genocide on July 5
Gagik Beglaryan considers that good roads will make Armenia attractive for Iranian business
Beeline Armenia holds a Digithon to reveal most promising and innovative solutions for development of the company
Armenian minister of transport and communication urges Yandex Taxi management to sign contracts with licensed drivers only
Armenia holds negotiations with Georgia and Russia for opening alternative road to Russia
Azerbaijani FM: Time has come to start serious work on settlement of Nagorno-Karabakh conflict
Anelik Bank and Ria Money Transfers launch a joint campaign on July 1, with the fee for money transfers to Ukraine, Georgia and Moldova halved
NKR Prosecutor General's Office completes investigation of murders of Armenian servicemen during April war: ears and fingers of many of them were cut off by Azeris
Forecast: Russia would oppose any deeper cooperation of Armenia with NATO by putting pressure on government in Yerevan
John Evans: It is time for Artsakh to take its place directly at the table of negotiations
Alexander Lukashevich does not anticipate any breakthrough solutions in Karabakh peace process with Steinmeier's visit to region
Baku reacts to Frank-Walter Steinmeier's meeting with Bako Sahakyan
Frank-Walter Steinmeier visits Armenian Genocide Memorial in Yerevan
Nalbandian about Brexit: Armenia will continue efforts towards enhancement of cooperation with Great Britain
Armenia and Germany sign intergovernmental agreement to avoid double taxation
Armenian Emergency Ministry: Russian rescue plane transporting Armenian citizens from Upper Lars border crossing makes emergency landing in Mineralniye Vody
Ambassador Mills says fighting corruption is not just a point in the list of contemplated actions that can be marked as done
Nouvelles d`Armenie: French government presents text of draft law criminalizing denial of Armenian Genocide
Former US ambassador to be included in black list of Azerbaijani Foreign Ministry for his visit to Artsakh
Nalbandian: Issue of giving Nagorno-Karabakh a status of autonomy within Azerbaijan has not been discussed
Steinmeier: Status quo in Karaabkh settlement may lead to new outbreak of violence
Rostelecom discussed with Armenian radio companies possibilities of using modern technological solutions in radio broadcasting
Orientalist: German Bundestag's recognition of the Armenian Genocide is logical continuation of Pope Francis' statement during the mass in 2015
Seyran Ohanyan: Army leadership knows what and where to plan
MP: Ratification of agreement on Joint Air Defense will affect Armenia's independence
Russian Ministry of Emergency Situations to evacuate Armenian citizens trapped on Upper Lars checkpoint
Naira Zohrabyan. Joint Air Defense system will upgrade security of Armenia's airspace
Batu Kutelia: Warsaw Summit will give definite political and military answers to Russia's attempted aggressive revisionism
Azerbaijani armed forces use DShK heavy machine gun on Line of Contact
Foreign Ministry: There are no citizens of Armenia among victims of explosion at Istanbul airport
Eduard Sharmazanov: Russia and Turkey will remain rivals and competitors
Zakharova about Karabakh peace process: There are issues that should be hushed up
Naira Zohrabyan to Serzh Sargsyan: Prosperous Armenia Party will win in upcoming parliamentary elections
Masis Mailyan : Baku intends to continue its "military diplomacy" with impunity
Deputy minister: Creation of a joint air defense system with Russia will only strengthen combat ability of Armenian armed forces
South Caucasus Railway CJSC sets car to auction
Beeline improves Smart tariff plans
Armenian political forces express different opinions about influence of possible Moscow-Ankara normalization on Armenia
Areximbank-Gazprombank Group offers 50% discount for renting safe deposits boxes during summer holidays
Sergey Lavrov to travel to Yerevan
Ban Ki-moon: UN concerned over violations of ceasefire in Karbakh conflict zone
Defense sure Zhirayr Sefulyan's arrest is a political order
Sharmazanov explains Serzh Sargsyan's interview: If Armenia's citizens are reluctant to vote for RPA, no one will make them do it
Rostelecom holds two seminars on sidelines of Hartak Festival
Paul Stronski: Yerevan's security alliance with Moscow will not impede Armenia's good ties with NATO
Armenian President: Armenia expects wider recognition of Genocide after German vote and pope's remarks
Nikol Pashinyan: Consensus on Electoral Code is ridiculous
Turkey's foreign ministry reacts to Pope Francis' visit to Armenia
By beginning of tourism season Areximbank-Gazprombank Group offers significant discounts of premium class chip cards
Batu Kutelia: Warsaw Summit will give definite political and military answers to Russia's attempted aggressive revisionism
Masis Mailyan : Baku intends to continue its "military diplomacy" with impunity
Paul Stronski: Yerevan's security alliance with Moscow will not impede Armenia's good ties with NATO
Alekper Aliyev: Nothing can justify our protracted fratricidal war
Giorgi Kanashvili: In case Karabakh conflict is settled, Armenia is able to make a U-turn and join NATO even sooner than Georgia will do
Sargis Hatspanyan: Our soldiers carried out their obligations and slapped not only the Azerbaijani but also Armenian authorities in the face
Vladimir Yevseyev: Updated Madrid Principles will not be implemented until the armed conflict is frozen
Polish Ambassador: Armenia is an ancient Christian country with European mentality and quite good prospects for European integration
It is necessary to lay down logical demands to Moscow instead of blaming it for all deadly sins
Lithuania's Ambassador: Extension of relations with EU is priority and future for Armenia
Arman Melikyan: Without Aliyev in power in Baku, Moscow will have to forget about its control over South Caucasus
ArmInfo's interview with President the KyIv-based Center for European and Transatlantic Studies Alexey Kolomiyets
by David Stepanyan
The West-Russia confrontation in Ukraine is growing, with the West already showing tough attitudes even towards its own companies working in Russia. As a result, a lot of money and technologies are flowing out of Russia. Can these measures sober the Kremlin and to give start to a real dialogue on Ukraine?
It is high time to realize fundamentally that the ongoing global conflict will have global consequences. It is not a new 'cold war.' What we have now is "a return of history," a direct confrontation of the West, or what has remained from the West, and 'a coalition of dark forces and evil' headed by Russia. And Ukraine proved on the front line of that confrontation. It seems that the West is late. The economic sanctions against Russia and the Kremlin's regime were to be imposed immediately after occupation of Crimea. Now, these sanctions will not be as efficient as necessary. In addition, the EU has already played its role, and did it poorly and cowardly. After all, it would be naive expecting more from the EU. In this light, there is need for new forces and structures in the geopolitical arena. It will hardly be NATO. Apparently, it will be a coalition that can be conventionally called 'a coalition of liberty.' Putin and the Kremlin will hardly sober up with such measures. "Quite the contrary, Putin's mad regime destroys the entire architecture of the post-WWII and 'cold war' policy. Putin's cabal does it consciously and providently. Only a power that seeks to destroy and change power in Russia without splitting it is able to stop Putin's strategy.
Can the West's sanctions against Russia are able to affect formation of the Customs Union and the Eurasian Economic Union?
Russia's leadership will ramp up pressure on the Customs Union members to stop 'abandonment,' which is quite possible, indeed. The strange irony of it all is that the West's sanctions may prove more disastrous for the CU and Eurasian Union members rather than for Russia. No one knows if it will spark a new more powerful wave of 'abandonment' or not. However, Putin's regime has already launched an open economic war against Moldova, Ukraine, and Georgia, which will collapse the CIS. Putin's Kremlin unleashed an economic war against Poland. Baltic States are the next. In Ukraine they have been waiting for the Government's decision to start an economic war against Russia for a long time already. Ukraine's Government has already made a decision to immediately prepare sanctions against Russia. If Ukraine imposes sanctions against Putin and his cabal, Moldova, Poland, the Baltic and other states will follow its example. I am sure that Ukraine must join the sanctions of the EU and the U.S. against Russia.
The Supreme Rada's refusal to accept Arseniy Yatsenyuk's resignation. Was it a protest against his Cabinet's unpopular measures?
This is a political game and its goal is to organize mid-term parliamentary elections. This goal has almost been achieved: in Oct we will reelect the parliament. I can't predict the results. It will be a military election but we have no other way but to hold it. Poroshenko and Yatseyuk have assumed the whole responsibility for Ukraine. The Ukrainians will reward them for this during the elections. And their fundamental criteria will be a victory over Russia and its bandits.
Concerning the crash of the Malaysian Boeing we still have more questions than answers, with the charges against Russia being as unproved as the ones against Ukraine and the United States. What is your version of this accident?
The crash was part of President Putin's strategy. The plane was hit by a Russian missile. Putin had a clear strategic plan but he made a mistake. And now, the only concern of the world community must be to make the Russian organizers of this tragedy answer before the Hague Tribunal.
The southeast of Ukraine is heading for a humanitarian disaster. Isn't it time for Ukraine to sober up and to stop being a laboratory rat for Russia and the West?
In order to prevent a real humanitarian disaster in the southeast of Ukraine, the Ukrainian authorities must destroy the aggressor by all existing means. They have enough means to do it, they simply lack political will and courage. The Ukrainian people want their authorities to be tougher in their military actions.
Apparently, Crimea has already turned into another 'black hole' for Russia, like Chechnya, where Russian taxpayers' billions are pumped in. Isn't this why the Kremlin is more careful in its calls for reintegration with the separatist regimes in the southeast of Ukraine? Or are there more serious factors?
Such developments were predictable. The Kremlin sought to create a fortress in Crimea and is doing it now, being absolutely unaware that in Crimea there are people, and many are not reliable from the political point of view. Developments in Crimea are a powerful geopolitical challenge to the entire Black Sea region and the regions bordering it. Military attacks on Ukraine's eastern regions are part of a wide conception. Even in case of failure in the east of Ukraine, other mechanisms will be included in that concept in other European regions that have already been 'targeted' by the Kremlin.
Central Valley Congressmen urge US to follow Pontiff's lead in reaffirming Armenian Genocide
Germany recognizes Armenian Genocide
Timur Urazayev: Initiative to recognize genocide should be addressed to those accused of committing genocide
"We are the Owners of Our Country": Arrested officers of Defense Ministry involved in criminal schemes were instructed by higher echelons
Official Baku comments on Nagorno Karabakh's President visit to Brussels


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Exploring the lesser-known graphic side of the iconic Eames furniture studio at fascinating new show
It's always interesting to see the less famous work of iconic creatives and they don't come much more iconic that husband and wife duo Charles and Ray Eames. The pair are synonymous with furniture design but a new show in west London explores the graphic design work that came out of their California studio.
Addressing the Need: The Graphic Design of the Eames Office which opens at the PM Gallery tomorrow includes adverts, packaging, invitations, posters and pamphlets as well as film, photography, toys and some of their exhibition work, much of which has never been displayed to the public in this way.
The Eames products are so familiar that it's fascinating to see how they marketed, explained and presented them, and how their design philosophy informed every part of the process rather than just the end result.
I Bernard Cohen, an expert in Eames, said: "Charles thought graphically, he would think in terms of what an idea meant—in terms of communication. And for him, communication always had to be graphic… he wasn't interested in the idea as ideas but ideas as challenges to communication, whether in lectures, films or exhibitions."
It is interesting that the last couple of years has seen a resurgence in in-depth interest in the ideas, processes and relationships that made the Eames phenomenon what it was. From an exhibition recreating their living space to the James Franco-narrated film The Architect and The Painter even a slightly surreal Ice Cube video tribute the pair have come in for closer attention, perhaps because the challenges of building an enduring design legacy seem starker than ever in a digital-first, economically depressed world.
The show runs until November 3.
- Photographer Benedetta Ristori documents cultural juxtapositions on the Baltic peninsula
- June Korea's photographic fantasy: one man's relationship with his sex doll
- Smart, funny and expertly executed party posters from German designer Mark Bohle
- Vice, despair and a bafflingly fertile imagination from Brooklyn-based Milton Melvin Croissant III
- A focus on typography in Ghent-based designer Corbin Mahieu's updated portfolio
- The joyously risqué work of Toronto-based illustrator Ness Lee
- Don't Hug Me I'm Scared - an exclusive interview with Duck, Red Guy and Yellow Guy
- World's "ugliest" Pantone colour 448C is being used to deter smokers
- North evolves Tate identity to be more adaptable
- Babak Ganjei paints 90s sitcom sitting rooms. But which one's which?
- More bonkers and surreal selfies from Izumi Miyazaki
- Reactions to the referendum and our weekly Best of the Web


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A pair of southern Kansas earthquakes whose effects reportedly were felt as far north as Manhattan didn't register with Tuttle Creek officials. The U.S. Geological Survey reported that the first earthquake to hit Harper County was at 7:30 a.m. Tuesday and was measured 3.3
The state revenue report released Tuesday gave Paul Davis, the Democratic candidate for governor, more campaign fodder than it gave Gov. Sam Brownback. But even the administration can point to a bright spot in otherwise troubling news. That involves corporate tax revenue, which was conspicuous
Francis Jay Lovell, 88, died at his home in Wichita on Tuesday, Sept. 23, 2014. The family provided the following information. He was born on Oct. 6, 1925, in Pittsburg to Cloral and Ruth Aiman Lovell. He graduated from Manhattan High School in 1944 and from Kansas State University in 1950 with
Patricia Joan Cunningham, 81, of Leonardville, died Tuesday, Sept. 30, 2014, at the Leonardville Nursing Home. The family provided the following information. She was born on March 25, 1933 in Anthony, the daughter of John E. and Mabel V. (Martin) Whittle. She graduated from Kiowa High School. She was married
David M. Wataha, 59, of Manhattan, died Tuesday, Sept. 30, 2014, at his residence. He was born on March 7, 1955, in Manhattan, the son of Clay J. and Janet R. Wataha. Additional obituary and service information will be announced later by the Yorgensen- Meloan-Londeen Funeral Home, 1616 Poyntz Avenue, Manhattan,
Helen C. Hannagan, 73, of the McDowell Creek Community in Manhattan, died Saturday, Sept. 27, 2014, at the Via Christi Village in Manhattan. The family provided the following information. She was born on March 28, 1941, in Manhattan, the daughter of Frank P. and Catherine A. (Otnes) Heidel. She was
Terry L. Bills, 64, of Manhattan, died Tuesday, Sept. 30, 2014, at the Good Shepherd Hospice House in Manhattan. The family provided the following information. Terry was born on April 20, 1950 in Wichita, the son of Ludie and Dortha (Adams) Bills. Terry enlisted in the Marines in 1967. He served
Frances Moyer, 97, of Manhattan, died Wednesday, Oct. 1, 2014, at Meadowlark Healthcare. Services are pending with Irvin-Parkview Funeral Home.
Jonathan Truman didn't need anyone to tell him what to do. He already knew what he was doing wasn't good enough. He had to be better. The Kansas State senior clearly wasn't at his best in Week 2 at Iowa State when he
Last year, the Manhattan High boys' soccer team beat Wichita South twice in the season, outscoring the Titans 19-0 in total. Tuesday night's game went much differently, as South stunned Manhattan with a 3-1 victory in Wichita. 'It's a very poor result for
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Talking Monkey
Talking Baby
- April 26, 2016
( 22,932)
**Talking Monkey repeats everything you say with a funny voice.
**Play with Monkey:
**Enjoy hours of fun and laughter with Talking Monkey. She is especially fun for children of all ages.
**Play with Monkey:
- Talk to Monkey and she will repeat everything you say with a funny voice.
- Ah! turn dizzy.
- really sweet.
- look at my dancing.
- have a sleep.
- It's the taste of bananas.
- Poke her head, Arm or feet.
Why are there games so cute?
Talking monekey Your pretty
Love love this. Game
I Love Lilly The Monkey SO!!!!!!!! Cute !!!!!
It is really very funny . I like it
What's New
Fix memory error bug.
Includes: sweet talking princess, horse feeding, music, baby care and more!


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category Earnings , Technology
category Stocks
from Market News Video
category Dividends
from Dividend Channel
Cramer: I have loved this stock for 30 years
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category Seres Therapeutics Inc , California Resources Corp , Mad Money , and 6 more.
from CNBC.com News
Benzinga's Top Initiations
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category Analyst Ratings , Top Initiations , INFN , and 9 more.
from Benzinga
8x8 to Present at Upcoming Investor Conferences
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