Long-Term Exposure to High Altitude Affects Voluntary Spatial Attention at Early and Late Processing Stages

The neurocognitive basis of the effect of long-term high altitude exposure on voluntary attention is unclear. Using event related potentials, the high altitude group (people born in low altitude but who had lived at high altitude for 3 years) and the low altitude group (living in low altitude only) were investigated using a voluntary spatial attention discrimination task under high and low perceptual load conditions. The high altitude group responded slower than the low altitude group, while bilateral N1 activity was found only in the high altitude group. The P3 amplitude was smaller in the high altitude compared to the low altitude group only under high perceptual load. These results suggest that long-term exposure to high altitudes causes hemispheric compensation during discrimination processes at early processing stages and reduces attentional resources at late processing stages. In addition, the effect of altitude during the late stage is affected by perceptual load

Human Hepatocytes with Drug Metabolic Function Induced from Fibroblasts by Lineage Reprogramming

SummaryObtaining fully functional cell types is a major challenge for drug discovery and regenerative medicine. Currently, a fundamental solution to this key problem is still lacking. Here, we show that functional human induced hepatocytes (hiHeps) can be generated from fibroblasts by overexpressing the hepatic fate conversion factors HNF1A, HNF4A, and HNF6 along with the maturation factors ATF5, PROX1, and CEBPA. hiHeps express a spectrum of phase I and II drug-metabolizing enzymes and phase III drug transporters. Importantly, the metabolic activities of CYP3A4, CYP1A2, CYP2B6, CYP2C9, and CYP2C19 are comparable between hiHeps and freshly isolated primary human hepatocytes. Transplanted hiHeps repopulate up to 30% of the livers of Tet-uPA/Rag2−/−/γc−/− mice and secrete more than 300 μg/ml human ALBUMIN in vivo. Our data demonstrate that human hepatocytes with drug metabolic function can be generated by lineage reprogramming, thus providing a cell resource for pharmaceutical applications

A two-step lineage reprogramming strategy to generate functionally competent human hepatocytes from fibroblasts

Terminally differentiated cells can be generated by lineage reprogramming, which is, however, hindered by incomplete conversion with residual initial cell identity and partial functionality. Here, we demonstrate a new reprogramming strategy by mimicking the natural regeneration route, which permits generating expandable hepatic progenitor cells and functionally competent human hepatocytes. Fibroblasts were first induced into human hepatic progenitor-like cells (hHPLCs), which could robustly expand in vitro and efficiently engraft in vivo. Moreover, hHPLCs could be efficiently induced into mature human hepatocytes (hiHeps) in vitro, whose molecular identity highly resembles primary human hepatocytes (PHHs). Most importantly, hiHeps could be generated in large quantity and were functionally competent to replace PHHs for drug-metabolism estimation, toxicity prediction and hepatitis B virus infection modeling. Our results highlight the advantages of the progenitor stage for successful lineage reprogramming. This strategy is promising for generating other mature human cell types by lineage reprogramming.</p

Long-term functional maintenance of primary human hepatocytes in vitro

The maintenance of terminally differentiated cells, especially hepatocytes, in vitro has proven challenging. Here we demonstrated the long-term in vitro maintenance of primary human hepatocytes (PHHs) by modulating cell signaling pathways with a combination of five chemicals (5C). 5C-cultured PHHs showed global gene expression profiles and hepatocyte-specific functions resembling those of freshly isolated counterparts. Furthermore, these cells efficiently recapitulated the entire course of hepatitis B virus (HBV) infection over 4 weeks with the production of infectious viral particles and formation of HBV covalently closed circular DNA. Our study demonstrates that, with a chemical approach, functional maintenance of PHHs supports long-term HBV infection in vitro, providing an efficient platform for investigating HBV cell biology and antiviral drug screening.</p

MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model

Human embryonic stem cells (hESCs) can potentially differentiate into any cell type, including dopaminergic neurons to treat Parkinson's disease (PD), but hyperproliferation and tumor formation must be avoided. Accordingly, we use myocyte enhancer factor 2C (MEF2C) as a neurogenic and anti-apoptotic transcription factor to generate neurons from hESC-derived neural stem/progenitor cells (NPCs), thus avoiding hyperproliferation. Here, we report that forced expression of constitutively active MEF2C (MEF2CA) generates significantly greater numbers of neurons with dopaminergic properties in vitro. Conversely, RNAi knockdown of MEF2C in NPCs decreases neuronal differentiation and dendritic length. When we inject MEF2CA-programmed NPCs into 6-hydroxydopamine—lesioned Parkinsonian rats in vivo, the transplanted cells survive well, differentiate into tyrosine hydroxylase-positive neurons, and improve behavioral deficits to a significantly greater degree than non-programmed cells. The enriched generation of dopaminergic neuronal lineages from hESCs by forced expression of MEF2CA in the proper context may prove valuable in cell-based therapy for CNS disorders such as PD

Photoplethysmography based psychological stress detection with pulse rate variability feature differences and elastic net

Detecting psychological stress in daily life is useful to stress management. However, existing stress-detection models with only heartbeat/pulse input are limited in prediction output granularity, and models with multiple prediction levels output usually require additional bio-signal other than heartbeat, which may increase the number of sensors and be wearable unfriendly. In this study, we took a novel approach of incremental pulse rate variability and elastic-net regression in predicting mental stress. Mental arithmetic task paradigm was used during the experiments. A total of 178 participants involved in the model building, and the model was verified with a group of 29 participants in the laboratory and 40 participants in a 14-day follow-up field test. The result showed significant median correlations between self-report and model-prediction stress levels (cross-validation: r=0.72 (p&lt;0.0001), laboratory verification: r=0.70 (p&lt;0.0001), field test r=0.56 (p&lt;0.0001)) with fine granularity ratings of 0-7 float numbers. The correct prediction took 86%-91% of the testing samples with error standard deviation of 0.68-0.81 in the label space of 14. By simplifying the process of prediction with a perspective of stress difference and handling the collinearity among pulse rate variability features with elastic net, we successfully built a stress prediction model with only pulse rate variability input source, fine granularity output and portable friendly sensor

Long-Term Exposure to High Altitude Affects Conflict Control in the Conflict-Resolving Stage

The neurocognitive basis of the effect of long-term high altitude exposure on conflict control is unclear. Event related potentials (ERPs) were recorded in a flanker task to investigate the influence of high altitude on conflict control in the high-altitude group (who had lived at high altitude for three years but were born at low altitude) and the low-altitude group (living in low altitude only). Although altitude effect was not significant at the behavioral level, ERPs showed cognitive conflict modulation. The interaction between group and trial type was significant: P3 amplitude was greater in the low-altitude group than in the high-altitude group in the incongruent trial. This result suggests that long-term exposure to high altitude affects conflict control in the conflict-resolving stage, and that attentional resources are decreased to resist the conflict control in the high-altitude group