In this issue of Cell, Tan et al. report the first injection of human stem cells into in vitro non-human primate blastocysts with significant survival of the human cells, raising new scientific possibilities but also important ethical issues.Chromatin-modifying lysine acetyltransferases employ multiple protein domains to regulate transcription.  https://www.selleckchem.com/products/vu0463271.html  In this issue, Vannam et al. (2021) describe dCBP-1, a small molecule degrader of the multidomain acetyltransferases EP300 and CREBBP. This provides a new tool for interrogating EP300/CREBBP function and also suggests a strategy for pharmacological differentiation of acetyltransferase paralogs.In this issue of Cell Chemical Biology, Chen et al. (2020) expand the target repertoire of rocaglamide A (RocA) to now include eIF4A2 and DDX3X, converting DEAD-box helicases into dominant-negative translation repressors. These results also highlight how cancer cell sensitivity to RocA is dependent on eIF4A and DDX3X levels.JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.Significant evidence supports the view that dopamine shapes learning by encoding reward prediction errors. However, it is unknown whether striatal targets receive tailored dopamine dynamics based on regional functional specialization. Here, we report wave-like spatiotemporal activity patterns in dopamine axons and release across the dorsal striatum. These waves switch between activational motifs and organize dopamine transients into localized clusters within functionally related striatal subregions. Notably, wave trajectories were tailored to task demands, propagating from dorsomedial to dorsolateral striatum when rewards are contingent on animal behavior and in the opponent direction when rewards are independent of behavioral responses. We propose a computational architecture in which striatal dopamine waves are sculpted by inference about agency and provide a mechanism to direct credit assignment to specialized striatal subregions. Supporting model predictions, dorsomedial dopamine activity during reward-pursuit signaled the extent of instrumental control and interacted with reward waves to predict future behavioral adjustments.Cognitive flexibility, the ability to alter strategy according to changing stimulus-response-reward relationships, is critical for updating learned behavior. Attentional set-shifting, a test of cognitive flexibility, depends on the activity of prefrontal cortex (PFC). It remains unclear, however, what role PFC neurons play to support set-shifting. Using optogenetics and two-photon calcium imaging, we demonstrate that medial PFC activity does not bias sensorimotor responses during set-shifting, but rather enables set-shifting by encoding trial feedback information, a role it has been known to play in other contexts. Unexpectedly, the functional properties of PFC cells did not vary with their efferent projection targets. Instead, representations of trial feedback formed a topological gradient, with cells more strongly selective for feedback information located further from the pial surface, where afferent input from the anterior cingulate cortex was denser. These findings identify a critical role for deep PFC projection neurons in enabling set-shifting through behavioral feedback monitoring.The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.Yu et al. (2021) demonstrate that a subset of X-linked immune genes is repressed on the inactive X chromosome (Xi) in a manner dependent on XIST RNA in B cells, and derepression of these genes upon XIST depletion could bias differentiation of naive B cells and be involved in etiology of female-biased autoimmune diseases.