Provided is a method including detecting an incorporation of a labelled nucleotide into a nascent polynucleotide strand complementary to a template polynucleotide strand by a polymerase, wherein the polymerase is tethered to a solid support conductive channel by a tether and the labelled nucleotides is a compound of Formula I: ##STR00001##

Provided is a method including detecting an incorporation of a labelled nucleotide into a nascent polynucleotide strand complementary to a template polynucleotide strand by a polymerase, wherein the polymerase is tethered to a solid support conductive channel by a tether and the labelled nucleotides is a compound of Formula I: ##STR00001##

An oligo- or polynucleotide analogue having one or more structures of the general formula: where B is a pyrimidine or purine nucleic acid base, or an analogue thereof, is used for treating obesity-related metabolic diseases.

Provided are compounds, methods, and pharmaceutical compositions for modulating SCN1A RNA and/or protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a developmental or epileptic encephalopathic disease, such as Dravet Syndrome. Such symptoms include seizures, sudden unexpected death in epilepsy, status epilepticus, behavioral and developmental delays, movement and balance dysfunctions, orthopedic conditions, motor and cognitive dysfunctions, delayed language and speech issues, visual motor integration dysfunctions, visual perception dysfunctions, executive dysfunctions, growth and nutrition issues, sleeping difficulties, chronic infections, sensory integration disorders, and dysautonomia.

Provided are compounds, methods, and pharmaceutical compositions for modulating SCN1A RNA and/or protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a developmental or epileptic encephalopathic disease, such as Dravet Syndrome. Such symptoms include seizures, sudden unexpected death in epilepsy, status epilepticus, behavioral and developmental delays, movement and balance dysfunctions, orthopedic conditions, motor and cognitive dysfunctions, delayed language and speech issues, visual motor integration dysfunctions, visual perception dysfunctions, executive dysfunctions, growth and nutrition issues, sleeping difficulties, chronic infections, sensory integration disorders, and dysautonomia.

The present invention relates to the field of oligonucleotide conjugates and to methods of synthesis thereof. In the present method a low-water content solvent environment allows a more efficient conjugation, reducing the amount of conjugate moiety needed and increasing the conjugation reaction speed.

The present invention relates to the field of oligonucleotide conjugates and to methods of synthesis thereof. In the present method a low-water content solvent environment allows a more efficient conjugation, reducing the amount of conjugate moiety needed and increasing the conjugation reaction speed.

Provided is a nucleoside derivative represented by the following formula (1):

##STR00001##

or a salt thereof, wherein R.sup.1 represents an alkoxy group, a hydrogen atom or a halogen atom; R.sup.2 and R.sup.4, which may be the same as or different from each other, each represents a hydrogen atom, a protective group for a hydroxyl group, a phosphate group, a protected phosphate group, or —P(═O).sub.nR.sup.5R.sup.6 in which n represents 0 or 1, R.sup.5 and R.sup.6, which may be the same as or different from each other, each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group, a mercapto group, a protected mercapto group, an alkoxy group, a cyanoalkoxy group, an amino group, or a substituted amino group, provided that when n is 1, both R.sup.5 and R.sup.6 cannot be the hydrogen atom at the same time; R.sup.3 represents —(CH.sub.2).sub.mNHR.sup.7 in which m represents an integer of 1 to 6, R.sup.7 represents a hydrogen atom, an alkyl group, an alkenyl group or a protective group for an amino group; and B represents a purin-9-yl group, a 2-oxo-pyrimidin-1-yl group, a substituted purin-9-yl group, or a substituted 2-oxo-pyrimidin-1-yl group.

The invention provides a composition comprising a proteinase or an enzymatically active fragment thereof, said proteinase comprising the amino acid sequence of SEQ ID NO: 1 or comprising an amino acid sequence which is at least about 70% identical to SEQ ID NO: 1, wherein i) the concentration of free calcium in said composition is ≤about 80 μM; or ii) the concentration of monovalent salt in said composition is ≥about 20 mM. Under such conditions, the proteinases and enzymatically active fragments thereof are inducibly thermolabile. The invention further provides samples comprising one or more polypeptides and a proteinase or an enzymatically active fragment thereof, said proteinase comprising the amino acid sequence of SEQ ID NO: 1 or comprising an amino acid sequence which is at least about 70% identical to SEQ ID NO: 1, wherein i) the concentration of free calcium in said sample is ≤about 80 μM; or ii) the concentration of monovalent salt in said sample is ≥about 20 mM. The invention further provides methods comprising the inactivation of such proteinases or enzymatically active fragments thereof, wherein said method comprises the step of heating the sample to inactivate said proteinase or enzymatically active fragment, and wherein i) the concentration of free calcium in said sample is ≤about 80 μM; or ii) the concentration of monovalent salt in said sample is ≥about 20 mM.

The invention provides a composition comprising a proteinase or an enzymatically active fragment thereof, said proteinase comprising the amino acid sequence of SEQ ID NO: 1 or comprising an amino acid sequence which is at least about 70% identical to SEQ ID NO: 1, wherein i) the concentration of free calcium in said composition is ≤about 80 μM; or ii) the concentration of monovalent salt in said composition is ≥about 20 mM. Under such conditions, the proteinases and enzymatically active fragments thereof are inducibly thermolabile. The invention further provides samples comprising one or more polypeptides and a proteinase or an enzymatically active fragment thereof, said proteinase comprising the amino acid sequence of SEQ ID NO: 1 or comprising an amino acid sequence which is at least about 70% identical to SEQ ID NO: 1, wherein i) the concentration of free calcium in said sample is ≤about 80 μM; or ii) the concentration of monovalent salt in said sample is ≥about 20 mM. The invention further provides methods comprising the inactivation of such proteinases or enzymatically active fragments thereof, wherein said method comprises the step of heating the sample to inactivate said proteinase or enzymatically active fragment, and wherein i) the concentration of free calcium in said sample is ≤about 80 μM; or ii) the concentration of monovalent salt in said sample is ≥about 20 mM.