Overbearing Mom And Calling Dibs On The Holidays : JUSTNOMIL
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May 9, 2022 at 3:59 pm #118151hannahlombardoParticipant
<br> In functional assays, IC50 is the concentration that reduces a biological response, e.g., transcription of mRNA or protein expression, by 50% of the biological response that is achieved without the therapeutic molecule. In functional assays, EC50 is the concentration of a therapeutic molecule that produces 50% of the biological response, e.g., transcription of mRNA or protein expression. The term “transcript” as used herein can refer to a primary transcript that is synthesized by transcription of DNA and becomes a messenger RNA (mRNA) after processing, i.e., a precursor messenger RNA (pre-mRNA), and the processed mRNA itself. It includes, without limitation, transcription of the polynucleotide into messenger RNA (mRNA) and the translation of an mRNA into a polypeptide. It is well known that complementarity is the base principle of DNA replication and transcription as it is a property shared between two DNA or RNA sequences, such that when they are aligned antiparallel to each other, the nucleotide bases at each position in the sequences will be complementary, much like looking in the mirror and seeing the reverse of things. The term “design” or “oligomer design” or “ASO Sequence” as used herein refers to a pattern of nucleotides (e.g., DNA) and nucleotide analogs (e.g., LNA) in a given sequence.<br>
<br> The term “chemical structure” of an oligomer as used herein refers to a detailed description of the components of the oligomers, e.g., nucleotides (e.g., DNA), nucleotide analogs (e.g., beta-D-oxy-LNA), nucleotide base (e.g., A, T, G, C, U, or MC), and backbone structure (e.g., phosphorothioate or phosphorodiester). The term “transcript” can be interchangeably used with “pre-mRNA” and “mRNA.” After DNA strands are transcribed to primary transcripts, the newly synthesized primary transcripts are modified in several ways to be converted to their mature, functional forms to produce different proteins and RNAs such as mRNA, tRNA, rRNA, lncRNA, miRNA and others. Examples of assays measuring calcium oscillations are discussed in further detail below. FIGS. 2, 16B, and 20B lists non-limiting examples of chemical structures that can be applied to any one of the oligomers disclosed herein. Likewise, particularly in the case of oligonucleotides where one or more of the internucleoside linkage groups are modified, the term “nucleotide” can refer to a “nucleoside” for example the term “nucleotide” can be used, even when specifying the presence or nature of the linkages between the nucleosides. In one embodiment, the disclosure provides a method of testing, identifying, or determining in vivo acute neurotoxicity of a molecule comprising measuring calcium oscillations in vitro in neuronal cells which are in contact or have been in contact with the molecule.<br>
<br> In some embodiments, the molecule is considered to have an acceptable toxicity (e.g., in vivo acute neurotoxicity) if the molecule does not significantly reduce calcium oscillations in a cell exposed to the molecule compared to the calcium oscillations in a control cell. By “tolerable” is meant a molecule that is well tolerated by a live subject, e.g., a molecule that, when administered, causes no harmful effects that are either visible or can be tested for using general quality of life tests or by measuring in vivo tolerability scores as described herein. The percentage is calculated by counting the number of aligned bases that are identical between the two sequences, dividing by the total number of contiguous monomers in the oligomer, and multiplying by 100. In such a comparison, if gaps exist, it is preferable that such gaps are merely mismatches rather than areas where the number of monomers within the gap differs between the oligomer of the invention and the target region. In determining the degree of “complementarity” between oligomers of the invention (or regions thereof) and the target region of the nucleic acid which encodes the mammalian gene, such as those disclosed herein, the degree of “complementarity” (also, “homology” or “identity”) is expressed as the percentage identity (or percentage homology) between the sequence of the oligomer (or region thereof) and the sequence of the target region (or the reverse complement of the target region) that best aligns therewith.<br>
<br> Gene products described herein further include nucleic acids with post transcriptional modifications, e.g., polyadenylation or splicing, or polypeptides with post translational modifications, e.g., methylation, glycosylation, the addition of lipids, association with other protein subunits, or proteolytic cleavage. In certain embodiments, a subject is successfully “treated” for a disease or condition disclosed elsewhere herein according to the methods provided herein if the patient shows, e.g., total, partial, or transient alleviation or elimination of symptoms associated with the disease or disorder. Calcium oscillations can also regulate interactions of neurons with associate glia, in addition to other associated neurons in the network, to release other neurotransmitters in addition to glutamate. Networks of cortical neurons have been shown to undergo spontaneous calcium oscillations resulting in the release of the neurotransmitter glutamate. As used herein, the design of an oligomer is shown by a combination of upper case letters and lower case letters. Not being bound by any theory, the present disclosure identifies (i) a correlation between calcium oscillations of a molecule in vitro in neuronal cells and the sequence score of the molecule (e.g., polynucleotide comprising a sequence), (ii) a correlation between calcium oscillations of a molecule and the in vivo neurotoxicity of the molecule; (iii) a correlation between the sequence score of a molecule (e.g., polynucleotide comprising a sequence) and the in vivo neurotoxicity of the molecule, or (iv) any combination thereof.<br>
<br> For example, molecules can be assayed to determine if they have low toxicity (e.g., in vivo acute neurotoxicity), and if they are found to have low toxicity, the molecules are selected for use in further testing or administration to a subject such as a mammal. The present disclosure provides methods for testing or determining the toxicity (e.g., in vivo acute neurotoxicity) of a molecule by measuring certain characteristics of the molecule. Such methods are helpful to reduce unnecessary killing of animals during testing of the molecule’s toxicity and/or enhance the possibilities that the molecules will be safe for in vivo administration. Mammalian subjects include humans, domestic animals, farm animals, sports animals, and zoo animals including, e.g., humans, non-human primates, dogs, cats, camera Websex guinea pigs, rabbits, rats, mice, horses, cattle, bears, and so on. By “toxic side effect” is meant an effect that causes debilitation of a living subject, including, but not limited to, death, pain, tremors, convulsions, seizures, an inhibition of movement, or loss of memory.<br>
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