Studies in embryonic development have guided successful efforts to direct the differentiation of human embryonic and induced pluripotent stem cells (PSCs) into specific organ cell types in vitro 1,2. For example, human PSCs have been differentiated into monolayer cultures of liver hepatocytes and pancreatic endocrine cells3–6 that have therapeutic efficacy in animal models of liver disease 7,8 and diabetes 9 respectively. However the generation of complex three-dimensional organ tissues in vitro remains a major challenge for translational studies. We have established a robust and efficient process to direct the differentiation of human PSCs into intestinal tissue in vitro using a temporal series of growth factor manipulations to mimic embryonic intestinal development 10 (Summarized in supplementary Fig. 1). This involved activin-induced definitive endoderm (DE) formation 11, FGF/Wnt induced posterior endoderm pattering, hindgut specification and morphogenesis 12–14; and a pro-intestinal culture system 15,16 to promote intestinal growth, morphogenesis and cytodifferentiation. The resulting three-dimensional intestinal “organoids” consisted of a polarized, columnar epithelium that was patterned into villus-like structures and crypt-like proliferative zones that expressed intestinal stem cell markers17. The epithelium contained functional enterocytes, as well as goblet, Paneth, and enteroendocrine cells. Using this culture system as a model to study human intestinal development, we identified that the combined activity of Wnt3a and FGF4 is required for hindgut specification whereas FGF4 alone is sufficient to promote hindgut morphogenesis. Our data suggests that human intestinal stem cells form de novo during development. Lastly we determined that NEUROG3, a pro-endocrine transcription factor that is mutated in enteric anendocrinosis 18, is both necessary and sufficient for human enteroendocrine cell development in vitro. In conclusion, PSC-derived human intestinal tissue should allow for unprecedented studies of human intestinal development and disease.

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The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a cognitive battery that contains scales of several cognitive abilities, but no scale in the instrument is exclusively dedicated to executive functioning. Although the subtests allow for observation of executive-type errors, each error is of fairly low base rate, and healthy and clinical normative data are lacking on the frequency of these types of errors, making their significance difficult to interpret in isolation. The aim of this project was to create an RBANS executive errors scale (RBANS EE) with items comprised of qualitatively dysexecutive errors committed throughout the test. Participants included Veterans referred for outpatient neuropsychological testing. Items were initially selected based on theoretical literature and were retained based on item-total correlations. The RBANS EE (a percentage calculated by dividing the number of dysexecutive errors by the total number of responses) was moderately related to each of seven established measures of executive functioning and was strongly predictive of dichotomous classification of executive impairment. Thus, the scale had solid concurrent validity, justifying its use as a supplementary scale. The RBANS EE requires no additional administration time and can provide a quantified measure of otherwise unmeasured aspects of executive functioning.