E86. In the methods of Embodiments 81 to 85, the improvement further comprising measuring reduction of in vitro expression of a target protein of the molecule. In certain embodiments, the therapeutic molecules (e.g., oligomers) target a pre-mRNA encoding an amyloid precursor protein. Chemokines, chemotactic proteins which stimulate the migration of leucocytes towards a site of infection, can also be incorporated into a fusion protein of the invention. You can start to get acquainted by applying a search filter based on geolocation, and after the program will give the results to proceed to the selection of candidates through swipe. International Search Report and Written Opinion for International Application No. PCT/US2015/041722, dated Jan. 6, 2016, 11 pages. E82. In a method of selecting or identifying a molecule having tolerable in vivo neurotoxicity, the improvement comprising measuring calcium oscillations in vitro in neuronal cells which are in contact with the molecule, wherein the neuronal cells in contact with the molecule exhibit calcium oscillations at a level comparable to or higher than that of vehicle control cells.



E87. In the method of any one of Embodiments 81 to 85, the improvement further comprising measuring an in vivo tolerability of the molecule. E36. A method of testing or determining in vivo tolerability of a molecule comprising administering the molecule to a mammal and grading the mammal's tolerability in a tolerability category. E34. The method of embodiment 33, wherein the in vivo tolerability is measured by administering the molecule to a mammal and Watch Live Sexcam grading the mammal's tolerability in a tolerability category. E45. The method of any one of embodiments 1 to 44, further comprising measuring tubulin intensity of the molecule in a culture of neuronal cells. E69. The method of any one of Embodiments 63 to 68, wherein the molecule comprises a small molecule, a polynucleotide, a protein, a peptide, or any combination thereof. E59. The method of any one of embodiments 1 to 58, wherein when the molecule is administered to laboratory animals, more than 85% of the animals survive.



E75. The method of any one of Embodiments 63 to 74, wherein when the molecule is administered to laboratory animals, more than 50% of the animals survive. E76. The method of any one of Embodiments 63 to 74, wherein when the molecule is administered to laboratory animals, more than 85% of the animals survive. E58. The method of any one of embodiments 1 to 57, wherein when the molecule is administered to laboratory animals, more than 50% of the animals survive. E57. The method of any one of embodiments 1 to 56, wherein when the molecule is administered to laboratory animals, more than 20% of the animals survive. 1992) Molecular Cloning: A Laboratory Manual, (Cold Springs Harbor Laboratory, NY); D. N. Glover ed., (1985) DNA Cloning, Volumes I and II; Gait, ed. E42. The method of any one of embodiments 1 to 41, further comprising measuring a behavioral test score of the molecule.



FIG. 3: Correlation analysis of sequence score vs. FIG. 1: Graph demonstrating primary neuronal spontaneous calcium oscillations. Primary neuronal spontaneous calcium oscillations were measured as described previously (Murphy et. E64. The method of Embodiment 63, further comprising comparing the calcium oscillations in the neuronal cells with the calcium oscillations in neuronal cells that are not exposed to the molecule ("control cells"). E88. In the method of Embodiment 87, wherein the in vivo tolerability is measured by administering the molecule to a mammal and grading the mammal's tolerability in a tolerability category. E43. The method of embodiment 42, wherein the behavioral test score is measured by administering the molecule to a mammal and grading the mammal's` behavioral performance. Sequence score for each oligomer was calculated by inserting appropriate numbers in the formula: ((number of C nucleotides or the analogs-number of G nucleotides)/nucleotide length (number) in the oligomer). E39. The method of embodiment 38, wherein the molecule exhibits an in vivo tolerability score of 0 to 4 in each of the tolerability category.



E74. The method of any one of Embodiments 63 to 73, wherein the molecule is an antisense oligonucleotide. E53. The method of any one of embodiments 16 to 52, wherein the polynucleotide comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten nucleotide analogs. E52. The method of any one of embodiments 16 to 51, wherein the polynucleotide comprises at least one nucleotide analog. E51. The method of any one of embodiments 16 to 50, wherein the polynucleotide is an antisense oligonucleotide. E55. The method of any one of embodiments 23 to 54, wherein the antisense oligonucleotide comprises an internucleoside linkage selected from: a phosphodiester linkage, a phosphotriester linkage, a methylphosphonate linkage, a phosphoramidate linkage, a phosphorothioate linkage, and combinations thereof. E37. The method of any one of embodiments 34 to 36, wherein the tolerability category comprises at least one, at least two, at least three, at least four, or at least five tolerability categories. 0.5 mM, at least about 0.6 mM, at least about 0.7 mM, at least about 0.8 mM, at least about 0.9 mM, at least about 1 mM, at least about 1.5 mM, at least about 2.0 mM, at least about 2.5 mM, at least about 3.0 mM, at least about 4 mM, at least about 5 mM, or at least about 10 mM.