Flow refers to a positive, activity-associated, subjective experience under conditions of a perceived fit between skills and task demands. Using functional magnetic resonance perfusion imaging, we investigated the neural correlates of flow in a sample of 27 human subjects. Experimentally, in the flow condition participants worked on mental arithmetic tasks at challenging task difficulty which was automatically and continuously adjusted to individuals' skill level. Experimental settings of "boredom" and "overload" served as comparison conditions. The experience of flow was associated with relative increases in neural activity in the left anterior inferior frontal gyrus (IFG) and the left putamen. Relative decreases in neural activity were observed in the medial prefrontal cortex (MPFC) and the amygdala (AMY). Subjective ratings of the flow experience were significantly associated with changes in neural activity in the IFG, AMY, and, with trend towards significance, in the MPFC. We conclude that neural activity changes in these brain regions reflect psychological processes that map on the characteristic features of flow: coding of increased outcome probability (putamen), deeper sense of cognitive control (IFG), decreased self-referential processing (MPFC), and decreased negative arousal (AMY).

Imiquimod treatment of AK resulted in superior sustained clearance and cosmetic outcomes compared with cryosurgery and 5-FU. It should be considered as a first line therapy for sustained treatment of AK.

Organoid models of early tissue development have been produced for the intestine, brain, kidney and other organs, but similar approaches for the heart have been lacking. Here we generate complex, highly structured, three-dimensional heart-forming organoids (HFOs) by embedding human pluripotent stem cell aggregates in Matrigel followed by directed cardiac differentiation via biphasic WNT pathway modulation with small molecules. HFOs are composed of a myocardial layer lined by endocardial-like cells and surrounded by septum-transversum-like anlagen; they further contain spatially and molecularly distinct anterior versus posterior foregut endoderm tissues and a vascular network. The architecture of HFOs closely resembles aspects of early native heart anlagen before heart tube formation, which is known to require an interplay with foregut endoderm development. We apply HFOs to study genetic defects in vitro by demonstrating that NKX2.5-knockout HFOs show a phenotype reminiscent of cardiac malformations previously observed in transgenic mice.

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Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs.