The present invention relates to a method for increasing the embryo implantation rate in a mammalian uterus, by administering to the uterus of a mammal an effective amount of an extracellular matrix remodeling enzyme, as well as to a product comprising an extracellular remodeling enzyme.

The present invention relates to a method for increasing the embryo implantation rate in a mammalian uterus, by administering to the uterus of a mammal an effective amount of an extracellular matrix remodeling enzyme, as well as to a product comprising an extracellular remodeling enzyme.

Disclosed herein are methods of treating HIBM in a subject comprising identifying subject in need thereof; and administering to the subject a compound, or a pharmaceutically acceptable salt, ester, amide, glycol, peptidyl, or prodrug thereof, wherein the compound is a compound that is biosynthesized in a wild type individual along a biochemical pathway between glucose and sialic acid, inclusive. Also disclosed herein are vectors comprising a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2, recombinant cells comprising these vectors, and recombinant animals comprising the cells. In addition, methods of identifying a compound having therapeutic effect for HIBM are disclosed.

The present invention relates to a method of producing a non-human, mammalian oocyte carrying a modified target sequence in its genome, the method comprising the steps of introducing into a non-human, mammalian oocyte: (a) a clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated protein 9 (Cas9 protein) or a nucleic acid molecule encoding said Cas9 protein; and (b-i) a target sequence specific CRISPR RNA (crRNA) and a trans-activating crRNA (tracr RNA) or a nucleic acid molecule encoding said RNAs; or (b-ii) a chimaeric RNA sequence comprising a target sequence specific crRNA and tracrRNA or a nucleic acid molecule encoding said RNA; wherein the Cas9 protein introduced in (a) and the RNA sequence(s) introduced in (b-i) or (b-ii) form a protein/RNA complex that specifically binds to the target sequence and introduces a single or double strand break within the target sequence. The present invention further relates to the method of the invention, wherein the target sequence is modified by homologous recombination with a donor nucleic acid sequence further comprising the step: (c) introducing a nucleic acid molecule into the cell, wherein the nucleic acid molecule comprises the donor nucleic acid sequence and regions homologous to the target sequence. The present invention also relates to a method of producing a non-human mammal carrying a modified target sequence in its genome.

The present invention relates to a method of producing a non-human, mammalian oocyte carrying a modified target sequence in its genome, the method comprising the steps of introducing into a non-human, mammalian oocyte: (a) a clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated protein 9 (Cas9 protein) or a nucleic acid molecule encoding said Cas9 protein; and (b-i) a target sequence specific CRISPR RNA (crRNA) and a trans-activating crRNA (tracr RNA) or a nucleic acid molecule encoding said RNAs; or (b-ii) a chimaeric RNA sequence comprising a target sequence specific crRNA and tracrRNA or a nucleic acid molecule encoding said RNA; wherein the Cas9 protein introduced in (a) and the RNA sequence(s) introduced in (b-i) or (b-ii) form a protein/RNA complex that specifically binds to the target sequence and introduces a single or double strand break within the target sequence. The present invention further relates to the method of the invention, wherein the target sequence is modified by homologous recombination with a donor nucleic acid sequence further comprising the step: (c) introducing a nucleic acid molecule into the cell, wherein the nucleic acid molecule comprises the donor nucleic acid sequence and regions homologous to the target sequence. The present invention also relates to a method of producing a non-human mammal carrying a modified target sequence in its genome.

Single nucleotide polymorphic sites of the bovine MAP1B, PPP1R11, and DDX4 genes are associated with improved bull fertility as measured by e.g. sire conception rates. Nucleic acid molecules, arrays, kits, methods of genotyping and marker-assisted bovine breeding methods based on these SNPs are disclosed.

Single nucleotide polymorphic sites of the bovine MAP1B, PPP1R11, and DDX4 genes are associated with improved bull fertility as measured by e.g. sire conception rates. Nucleic acid molecules, arrays, kits, methods of genotyping and marker-assisted bovine breeding methods based on these SNPs are disclosed.

Methods and compositions directed to altering a population of sRNAs in a sperm using vesicles isolated from an epididymosome are provided. Methods and compositions directed to altering a population of sRNAs in an oocyte using vesicles isolated from an epididymosome are also provided. Methods for altering an sRNA population in a sperm or an oocyte can be used to prevent, or reduce the severity of, a disease, disorder, or condition that would otherwise be inherited by progeny. For example, certain epigenetic inherited conditions due to paternal effects, such as certain metabolic and stress disorders and conditions, can be ameliorated in progeny using sperm or oocytes having an altered sRNA population.

Methods and compositions directed to altering a population of sRNAs in a sperm using vesicles isolated from an epididymosome are provided. Methods and compositions directed to altering a population of sRNAs in an oocyte using vesicles isolated from an epididymosome are also provided. Methods for altering an sRNA population in a sperm or an oocyte can be used to prevent, or reduce the severity of, a disease, disorder, or condition that would otherwise be inherited by progeny. For example, certain epigenetic inherited conditions due to paternal effects, such as certain metabolic and stress disorders and conditions, can be ameliorated in progeny using sperm or oocytes having an altered sRNA population.

Novel benzamide derivatives of formula (I)

##STR00001##

wherein W.sup.1, W.sup.2, R.sup.1 to R.sup.10 and X have the meaning according to the claims, are positive allosteric modulators of the FSH receptor, and can be employed, inter alia, for the treatment of fertility disorders.