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Table of contents

Such a library may contain 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , or over 10 9 possible variants including substitutions, deletions of one or more residues, and insertion of one or more residues. Proper protein translation involves the physical aggregation of a number of polypeptides and nucleic acids associated with the mRNA. Provided by the present disclosure are protein-nucleic acid complexes, containing a translatable mRNA having one or more nucleoside modifications e. Generally, the proteins are provided in an amount effective to prevent or reduce an innate immune response of a cell into which the complex is introduced.

As described herein, provided are mRNAs having sequences that are substantially not translatable. Such mRNA is effective as a vaccine when administered to a mammalian subject.

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Also provided are modified nucleic acids that contain one or more noncoding regions. Such modified nucleic acids are generally not translated, but are capable of binding to and sequestering one or more translational machinery component such as a ribosomal protein or a transfer RNA tRNA , thereby effectively reducing protein expression in the cell. Nucleic acids for use in accordance with the present disclosure may be prepared according to any available technique including, but not limited to chemical synthesis, enzymatic synthesis, which is generally termed in vitro transcription, enzymatic or chemical cleavage of a longer precursor, etc.

Material Information

Methods of synthesizing RNAs are known in the art see, e. Oligonucleotide synthesis: methods and applications , Methods in Molecular Biology, v. Totowa, N. Modified nucleic acids need not be uniformly modified along the entire length of the molecule.

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One of ordinary skill in the art will appreciate that the nucleotide analogs or other modification s may be located at any position s of a nucleic acid such that the function of the nucleic acid is not substantially decreased. For example, the nucleic acids may contain a modified pyrimidine such as uracil or cytosine. The modified uracil can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures e. The modified cytosine can be replaced by a compound having a single unique structure, or can be replaced by a plurality of compounds having different structures e.

Generally, the shortest length of a modified mRNA of the present disclosure can be the length of an mRNA sequence that is sufficient to encode for a dipeptide. In another embodiment, the length of the mRNA sequence is sufficient to encode for a tripeptide. In another embodiment, the length of an mRNA sequence is sufficient to encode for a tetrapeptide. In another embodiment, the length of an mRNA sequence is sufficient to encode for a pentapeptide. In another embodiment, the length of an mRNA sequence is sufficient to encode for a hexapeptide.


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In another embodiment, the length of an mRNA sequence is sufficient to encode for a heptapeptide. In another embodiment, the length of an mRNA sequence is sufficient to encode for an octapeptide. In another embodiment, the length of an mRNA sequence is sufficient to encode for a nonapeptide. In another embodiment, the length of an mRNA sequence is sufficient to encode for a decapeptide. Examples of dipeptides that the modified nucleic acid sequences can encode for include, but are not limited to, carnosine and anserine. In a further embodiment, the mRNA is greater than 30 nucleotides in length.

In another embodiment, the RNA molecule is greater than 35 nucleotides in length. In another embodiment, the length is at least 40 nucleotides. In another embodiment, the length is at least 45 nucleotides. In another embodiment, the length is at least 55 nucleotides. In another embodiment, the length is at least 60 nucleotides. In another embodiment, the length is at least 80 nucleotides. In another embodiment, the length is at least 90 nucleotides.

In another embodiment, the length is at least nucleotides. In another embodiment, the length is at least nucleotides, or greater than nucleotides. For example, the modified nucleic acids described herein can be prepared using methods that are known to those skilled in the art of nucleic acid synthesis. In some embodiments, the present disclosure provides methods, e. In some embodiments, the methods further comprise a nucleotide selected from the group consisting of adenosine, cytosine, guanosine, and uracil.

In another aspect, the present disclosure provides for methods of amplifying a nucleic acid sequence, the method comprising: reacting a compound of Formula XI-d:. In some embodiments, the present disclosure provides for methods of synthesizing a pharmaceutical nucleic acid, comprising the steps of:. In still a further aspect of the present disclosure, the modified nucleic acids can be prepared using solid phase synthesis methods.


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In some embodiments, the present disclosure provides methods of synthesizing a nucleic acid comprising a compound of Formula XI-a:. Modifications to the nucleic acids of the present invention may generate a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. WO, WO , and WO , each of which is incorporated herein by reference in its entirety. Cap analogs, which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural i.


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Cap analogs may be chemically i. In one embodiment, the cap is a dinucleotide cap analog. As a non-limiting example, the dinucleotide cap analog may be modified at different phosphate positions with a boranophosphate group or a phophoroselenoate group such as the dinucleotide cap analogs described in U. Such a structure is termed the Cap1 structure. This cap results in a higher translational-competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e. In another non-limiting example, of the modified capping structure substrates CAPCAP could be added in the presence of vaccinia capping enzyme with a component to create enzymatic activity such as, but not limited to, S-adenosylmethionine AdoMet , to form a modified cap for mRNA.

In one embodiment, the replacement of the sugar ring oxygen that produced the carbocyclic ring with a methylene moiety CH 2 could create greater stability to the C—N bond against phosphorylases as the C—N bond is resistant to acid or enzymatic hydrolysis. The methylene moiety may also increase the stability of the triphosphate bridge moiety and thus increasing the stability of the mRNA. This modification could increase the stability of the mRNA towards decapping enzymes.

The thioguanosine analog may comprise additional modifications such as, but not limited to, a modification at the triphosphate moiety e. In another embodiment, the triphosphate bridge of any of the cap structures described herein may be replaced with a tetraphosphate or pentaphosphate bridge.

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Examples of tetraphosphate and pentaphosphate containing bridges and other cap modifications are described in Jemielity, J. Methods Mol. RNA, , each of which is incorporated herein by reference in its entirety. In one embodiment, the nucleic acids of the present invention may include a stem loop such as, but not limited to, a histone stem loop. WO, incorporated herein by reference in its entirety. In one embodiment, the stem loop may be located in the second terminal region.

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As a non-limiting example, the stem loop may be located within an untranslated region e. In one embodiment, the nucleic acid such as, but not limited to mRNA, which comprises the histone stem loop may be stabilized by the addition of at least one chain terminating nucleoside. Not wishing to be bound by theory, the addition of at least one chain terminating nucleoside may slow the degradation of a nucleic acid and thus can increase the half-life of the nucleic acid.

In one embodiment, the chain terminating nucleoside may be, but is not limited to, those described in International Patent Publication No.

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The nucleic acids comprising the histone stem loop and a polyA tail sequence may include a chain terminating nucleoside described herein. In one embodiment, the conserved stem loop region may comprise a miR sequence described herein. As a non-limiting example, the stem loop region may comprise the seed sequence of a miR sequence described herein. In another non-limiting example, the stem loop region may comprise a miR seed sequence.

In another embodiment, the conserved stem loop region may comprise a miR sequence described herein and may also include a TEE sequence. Nature Cell Biology. In one embodiment, the modified nucleic acids described herein may comprise at least one histone stem-loop and a polyA sequence or polyadenylation signal.

Non-limiting examples of nucleic acid sequences encoding for at least one histone stem-loop and a polyA sequence or a polyadenylation signal are described in International Patent Publication No. In one embodiment, the nucleic acid encoding for a histone stem loop and a polyA sequence or a polyadenylation signal may code for a pathogen antigen or fragment thereof such as the nucleic acid sequences described in International Patent Publication No WO and WO, the contents of both of which are incorporated herein by reference in their entirety. In another embodiment, the nucleic acid encoding for a histone stem loop and a polyA sequence or a polyadenylation signal may code for a therapeutic protein such as the nucleic acid sequences described in International Patent Publication No WO and WO, the contents of both of which are incorporated herein by reference in their entirety.