Hereditary cholestasis in childhood and infancy with normal serum gamma‐glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low‐GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow‐up. Liver biopsy specimens revealed giant‐cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP‐deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated‐cholestasis patients (11 of 38 vs. 0 of 13). Conclusion: MYO5B deficiency may underlie 20% of previously undiagnosed low‐GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655‐1669).

A simple layer-by-layer (LbL) self-assembly process of poly(acrylic acid) (PAA) and ZrO2 was applied to construct functional ultrathin multilayers on polyethylene (PE) separators without sacrificing the excellent porous structure of separators. Such PAA/ZrO2 LbL-modified PE separators possess good electrolyte wettability, excellent electrolyte uptake, high ionic conductivity and large Li(+) transference number. More importantly, the top layer of LbL self-assembly would affect the dissociation of electrolyte and the formation of solid electrolyte interphase (SEI) layer in half-cells. Compared with the pristine and (PAA/ZrO2)1PAA-modified PE separators, (PAA/ZrO2)3-modified PE separator shows a larger Li(+) transference number (0.6) and a faster tendency to form a stable SEI layer, endowing half-cells with excellent capacity retention at high C-rates and superior cycling performance. These fascinating characteristics will provide the LbL self-assembly with a promising method to improve the surface property of PE separators for high performance lithium-ion batteries.

This research develops a simple template assisted sol-gel process for preparing porous TiO2 for a high performance humidity sensor. Tetraethyl orthosilicate (TEOS) as a template was directly introduced into TiO2 sol formed by the hydrolysis and condensation of titanium alkoxide; the following calcination led to the formation of TiO2-SiO2 composite, and the selective removal of SiO2 by dilute HF solution led to the formation of porous structure in TiO2. The resulting porous TiO2-based sensor exhibits high sensitivity and linear response in the wide relative humidity (RH) range of 11%-95%, with an impedance variation of four orders of magnitude to humidity change. Moreover, it exhibits a rapid and highly reversible response characterized by a very small hysteresis of <1% RH and a short response-recovery time (5 s for adsorption and 8 s for desorption), and a 30-day stability test also confirms its long-term stability. Compared with pure TiO2 prepared by the conventional sol-gel method, our product shows remarkably improved performance and good prospect for a high performance humidity sensor. The complex impedance spectra were used to elucidate its humidity sensing mechanism in detail.

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SummaryHuman induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes (CMs) hold great promise for elucidating underlying cellular mechanisms that cause atrial fibrillation (AF). In order to use atrial-like hiPSC-CMs for arrhythmia modeling, it is essential to better understand the molecular and electrophysiological phenotype of these cells. We performed comprehensive molecular, transcriptomic, and electrophysiologic analyses of retinoic acid (RA)-guided hiPSC atrial-like CMs and demonstrate that RA results in differential expression of genes involved in calcium ion homeostasis that directly interact with an RA receptor, chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TFII). We report a mechanism by which RA generates an atrial-like electrophysiologic signature through the downstream regulation of calcium channel gene expression by COUP-TFII and modulation of calcium handling. Collectively, our results provide important insights into the underlying molecular mechanisms that regulate atrial-like hiPSC-CM electrophysiology and support the use of atrial-like CMs derived from hiPSCs to model AF.

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Objective Vascular endothelial (VE)-cadherin is the predominant component of endothelial adherens junctions essential for cell-cell adhesion and formation of the vascular barrier. Endocytic recycling is an important mechanism for maintaining the expression of cell surface membrane proteins. However, little is known about the molecular mechanism of VE-cadherin recycling and its role in maintenance of vascular integrity. Approach and Results Using calcium-switch assay, confocal imaging, cell surface biotinylation and flow cytometry, we showed that VE-cadherin recycling required Rab11a and Rab11-family interacting protein 2 (FIP2). Yeast 2-hybrid assay and co-immunoprecipitation demonstrated that direct interaction of VE-cadherin with FIP2 (at aa 453-484) formed a ternary complex with Rab11a in human endothelial cells. Silencing of Rab11a or FIP2 in endothelial cells prevented VE-cadherin recycling and VE-cadherin expression at endothelial plasma membrane. Further, inactivation of Rab11a signaling blocked junctional re-annealing following vascular inflammation. Selective knockdown of Rab11a in pulmonary microvessels markedly increased vascular leakage in mice challenged with lipopolysaccharide or polymicrobial sepsis. Conclusions Rab11a/FIP2-mediated VE-cadherin recycling is required for formation of adherens junctions and restoration of vascular endothelial barrier integrity and hence a potential target for clinical intervention in inflammatory disease.