In response to stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and pathological growth of cardiomyocytes (hypertrophy), which contribute to heart failure. Alterations in microRNA (miRNA) levels are associated with dysfunctional gene expression profiles associated with many cardiovascular disease conditions; however, miRNAs have emerged recently as paracrine signaling mediators. Thus, we investigated a potential paracrine miRNA crosstalk between cardiac fibroblasts and cardiomyocytes and found that cardiac fibroblasts secrete miRNA-enriched exosomes. Surprisingly, evaluation of the miRNA content of cardiac fibroblast-derived exosomes revealed a relatively high abundance of many miRNA passenger strands ("star" miRNAs), which normally undergo intracellular degradation. Using confocal imaging and coculture assays, we identified fibroblast exosomal-derived miR-21_3p (miR-21*) as a potent paracrineacting RNA molecule that induces cardiomyocyte hypertrophy. Proteome profiling identified sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) as miR-21* targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of miR-21* in a mouse model of Ang II-induced cardiac hypertrophy attenuated pathology. These findings demonstrate that cardiac fibroblasts secrete star miRNA-enriched exosomes and identify fibroblast-derived miR-21* as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target.

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms † Correspondence to ; Email: mikeh@alleninstitute.org, ; Email: edl@alleninstitute.org 2 These authors contributed equally to this study. AUTHOR CONTRIBUTIONS HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure, and function. We applied a correlation-based metric of "differential stability" (DS) to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing meso-scale genetic organization. The highest DS genes are highly biologically relevant, with enrichment for brainrelated biological annotations, disease associations, drug targets, and literature citations. Using high DS genes we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components, and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely-patterned genes displayed dramatic shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry.The adult human brain is composed of many regions with distinct distributions of cell types and patterns of functional connectivity. Underlying this complexity is differential transcription, whereby different brain regions and their constituent cell types express unique combinations of genes during their developmental specification and maturation and in their mature functional state. Despite a range of brain sizes across individuals and variation in sulcal patterning in the neocortex, the general anatomical positioning of and connectivity between regions is highly stereotyped between individuals, suggesting that a significant proportion of the transcriptional coding for this common architecture is conserved across the human population.We aimed to identify the core or "canonical" transcriptional machinery conserved across individuals, in contrast to numerous studies that explore genetic variants associated with disease traits by analyzing enormous sample sizes in population studies 1 , 2 . If common expression relationships can be identified with high confidence in modest sample sizes and with good anatomical coverage of various brain regions, the resulting "default gene network" could provide a base template for understanding the genetic underpinnings of highly conserved features of brain organization and a b...

The rate of caesarean section delivery (CSD) is increasing worldwide. It remains unclear whether disruption of mother-to-neonate transmission of microbiota through CSD occurs and whether it affects human physiology. Here we perform metagenomic analysis of earliest gut microbial community structures and functions. We identify differences in encoded functions between microbiomes of vaginally delivered (VD) and CSD neonates. Several functional pathways are over-represented in VD neonates, including lipopolysaccharide (LPS) biosynthesis. We link these enriched functions to individual-specific strains, which are transmitted from mothers to neonates in case of VD. The stimulation of primary human immune cells with LPS isolated from early stool samples of VD neonates results in higher levels of tumour necrosis factor (TNF-α) and interleukin 18 (IL-18). Accordingly, the observed levels of TNF-α and IL-18 in neonatal blood plasma are higher after VD. Taken together, our results support that CSD disrupts mother-to-neonate transmission of specific microbial strains, linked functional repertoires and immune-stimulatory potential during a critical window for neonatal immune system priming.

Using a combination of in silico and experimental approaches, we present evidence that the G-quadruplex (G4) motif (an alternative higher-order DNA conformation) has regulatory potential. Genome-wide analyses of 99980 human, chimpanzee, mouse, and rat promoters showed enrichment of sequence with potential to adopt G4 (potential G4 or PG4) motifs near transcription start sites (TSS; P < 0.0001), supporting earlier findings. Interestingly, we found >700 orthologously related promoters in human, mouse, and rat conserve PG4 motif(s). The corresponding genes have enriched (z score > 4.0) tissue-specific expression in 75 of 79 human tissues and are significantly overrepresented in signaling and regulation of cell-cycle (P < 10(-05)). This is supported by results from whole genome expression experiments in human HeLa S3 cells following treatment with TMPyP4 [5,10,15,20-tetra(N-methyl-4-pyridyl) porphine chloride], which is known to bind the G4 motif inside cells. Our results implicate G4-motif mediated regulation as a more general mode of transcription control than currently appreciated.