Generation of Human Striatal Neurons by MicroRNA-Dependent Direct Conversion of Fibroblasts

SummaryThe promise of using reprogrammed human neurons for disease modeling and regenerative medicine relies on the ability to induce patient-derived neurons with high efficiency and subtype specificity. We have previously shown that ectopic expression of brain-enriched microRNAs (miRNAs), miR-9/9∗ and miR-124 (miR-9/9∗-124), promoted direct conversion of human fibroblasts into neurons. Here we show that coexpression of miR-9/9∗-124 with transcription factors enriched in the developing striatum, BCL11B (also known as CTIP2), DLX1, DLX2, and MYT1L, can guide the conversion of human postnatal and adult fibroblasts into an enriched population of neurons analogous to striatal medium spiny neurons (MSNs). When transplanted in the mouse brain, the reprogrammed human cells persisted in situ for over 6 months, exhibited membrane properties equivalent to native MSNs, and extended projections to the anatomical targets of MSNs. These findings highlight the potential of exploiting the synergism between miR-9/9∗-124 and transcription factors to generate specific neuronal subtypes

Measuring the predictability of life outcomes with a scientific mass collaboration.

How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Cultural-Exchange or Economic-Opportunity? How Multicultural Attitude and Framing Affect Acceptance of Collaboration

Department of Management and MarketingRefereed conference pape

Biphasic regulation of ENaC by TGF-α and EGF in renal epithelial cells

The epithelial sodium channel (ENaC) is regulated by epidermal growth factor (EGF). We investigate whether ENaC is regulated by another EGF receptor (EGFR) ligand, transforming growth factor-α (TGF-α). We show that chronic (24 h) treatment with TGF-α inhibits ENaC in Xenopus laevis kidney cells 20 times more strongly than EGF. By using single-channel measurements, we show that TGF-α significantly reduces the number of ENaC per patch. The open probability (Po) is unchanged by 24-h treatment with TGF-α. α-, β-, and γ-ENaC mRNA levels are significantly reduced by TGF-α or EGF. TGF-α or EGF reduces α- and γ-ENaC proteins in the membrane; however, β-ENaC is unchanged. TGF-α or EGF inhibits ENaC by activating EGFR since the EGFR inhibitor AG1478 blocks the effects of both. The MAPK 1/2 inhibitor U0126 also blocks the effect of TGF-α or EGF on ENaC, indicating that the MAPK1/2 pathway is involved in the TGF-α- or EGF-induced inhibition of ENaC. Interestingly, acute treatment (<1 h) with TGF-α or EGF does not inhibit ENaC current; it enhances ENaC activity by increasing Po. Pretreatment of the cells with U0126 potentiates the acute TGF-α- or EGF-induced stimulation of ENaC. This TGF-α- or EGF-induced increase in sodium current is abolished by a phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor, LY294002, suggesting that PI-3 kinase is involved in the activation of sodium transport. In conclusion, chronic treatment with TGF-α or EGF inhibits ENaC by decreasing the number of channels in the membrane transcriptionally through MAPK1/2 pathways, but acute treatment with TGF-α or EGF activates ENaC by increasing Po via PI-3 kinase