Significance: The X-chromosome harbors hundreds of disease genes, a subset of which gives rise to neurodevelopmental disorders such as Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome. There is presently no disease-specific treatment. Here, we work toward a therapeutic program based on reactivation of the silent X chromosome to restore expression of the missing protein. We develop a mixed modality approach that combines a small-molecule inhibitor of DNA methylation and an antisense oligonucleotide against Xist RNA. This combination achieves up to 30,000-fold methyl-CpG binding protein 2 upregulation in cultured cells. In vivo modeling using a conditional Xist knockout and 5-aza-2′-deoxycytidine recapitulates inactive X reactivation. These findings provide proof of concept for the mixed modality approach to treat X-linked disorders, including RTT.

The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc.Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions throughhttps://www.cocainebiobank.org/andhttps://www.oxycodonebiobank.org/.

The coming of age story of furan oxidation cross-linking.

Significance: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in MECP2 . To treat RTT, reactivating the dormant copy of MECP2 on the inactive X has been of considerable interest. Although potential therapeutics have been identified, their development has been hampered by the lack of a suitable female mouse model and uncertainty regarding how much MECP2 needs to be restored. Here, we create a female model with a more severe phenotype, including a short lifespan, neuromotor impairment, and repetitive behaviors often seen in human RTT. Significantly, 5–10% MECP2 restoration in brain extends lifespan by eightfold and improves RTT phenotypes. Our study thus provides a much-needed female model and implies potential therapeutic benefit with low-level MECP2 expression.