Aims/hypothesis Morphological changes that occur during pancreatic endocrine cell differentiation have been shown in rodent systems to be dependent on sequential alterations in transcription factor expression. However, similar data for humans have been limited. The aim of the present study was to provide a connection between pancreatic morphology, transcription factor gene expression and protein localisation during human fetal development. Methods Human fetal pancreases were examined at early (8-12 weeks of fetal age), middle (14-16 weeks) and late (19-21 weeks) stages, using immunohistological, microarray and qRT-PCR analyses. Results We observed a significant decrease in pancreatic duodenal homeobox 1 (PDX-1) + /cytokeratin 19 + cells (p<0.001), with a simultaneous increase in PDX-1 + /insulin + cells from 8 to 21 weeks (p<0.05). Increased PDX-1/ insulin co-localisation within islet clusters was noted, while no co-expression of PDX-1 with glucagon was found, suggesting that loss of PDX-1 is essential for alpha cell formation. Given that neurogenin 3 (NGN3) expression is critical for establishing the endocrine cell programme in the rodent pancreas, we examined its expression pattern and colocalisation in PDX-1 + , insulin + and glucagon + cells. Colocalisation of NGN3 with PDX-1, insulin and glucagon was noted during early development, with significant decreases in middle and late stages (p<0.001). Our microarray and co-localisation analyses of transcription factors linked to NGN3 demonstrated that ISL1 transcription factor (ISL1), neurogenic differentiation 1 (NEUROD1), NK2 related transcription factor related, locus 2 (NKX2-2) and paired box gene 6 (PAX6) were upregulated during development and present in all four endocrine cell types, while NK6 related transcription factor related, locus 1 (NKX6-1) was expressed exclusively in beta cells. Conclusions/interpretation This study is an important step towards identifying key molecular factors involved in development of the human fetal endocrine pancreas.

No abstract

The electrochemical reduction of carbon monoxide is a promising approach for the renewable production of carbon-based fuels and chemicals. Copper shows activity toward multi-carbon products from CO reduction, with reaction selectivity favoring two-carbon products; however, efficient conversion of CO to higher carbon products such as n-propanol, a liquid fuel, has yet to be achieved. We hypothesize that copper adparticles, possessing a high density of under-coordinated atoms, could serve as preferential sites for n-propanol formation. Density functional theory calculations suggest that copper adparticles increase CO binding energy and stabilize two-carbon intermediates, facilitating coupling between adsorbed *CO and two-carbon intermediates to form three-carbon products. We form adparticle-covered catalysts in-situ by mediating catalyst growth with strong CO chemisorption. The new catalysts exhibit an n-propanol Faradaic efficiency of 23% from CO reduction at an n-propanol partial current density of 11 mA cm−2.

A high density of homogeneously dispersed atomic defects has long been believed to be a promising strategy for improving catalytic activity. Taking the defective nature of quantum dots, Liu et al. synthesize vacancy-rich metal nanocrystals through in situ electrochemical reduction of quantum dots. This maximizes the density and stability of vacancies in metallic nanocrystals and achieves record current densities with high faradic efficiencies in the electrosynthesis of formate, carbon monoxide, and ethylene at low applied potentials.

Aims/hypothesis The receptor tyrosine kinase, c-Kit, and its ligand, stem cell factor, control a variety of cellular processes, including pancreatic beta cell survival and differentiation as revealed in c-Kit Wv mice, which have a point mutation in the c-Kit allele leading to loss of kinase activity and develop diabetes. The present study further investigated the intrinsic role of c-Kit in beta cells, especially the underlying mechanisms that influence beta cell function. Methods We generated a novel transgenic mouse model with c-KIT overexpression specifically in beta cells (c-KitβTg) to further examine the physiological and functional roles of c-Kit in beta cells. Isolated islets from these mice were used to investigate the underlying molecular pathway of c-Kit in beta cells. We also characterised the ability of c-Kit to protect animals from high-fat-diet-induced diabetes, as well as to rescue c-Kit Wv mice from early onset of diabetes. Results c-KitβTg mice exhibited improved beta cell function, with significantly improved insulin secretion, and increased beta cell mass and proliferation in response to high-fat-dietinduced diabetes. c-KitβTg islets exhibited upregulation of: (1) insulin receptor and IRSs; (2) Akt and glycogen synthase kinase 3β phosphorylation; and (3) transcription factors important for islet function. c-KIT overexpression in beta cells also rescued diabetes observed in c-Kit Wv mice. Conclusions/interpretation These findings demonstrate that c-Kit plays a direct protective role in beta cells, by regulating glucose metabolism and beta cell function. c-Kit may therefore represent a novel target for treating diabetes.

Dysregulation of lipid metabolism is common in breast cancer. However, the underlying mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of breast cancer is poorly understood. Here, we show that the nuclear protein p54(nrb)/Nono is highly expressed in breast cancer tissues as compared with the adjacent normal tissues in human patients. To determine the functions of p54(nrb) in breast cancer, we performed a biochemical screen and identified SREBP-1a, a master activator for genes involved in lipid biosynthesis, as a novel interacting protein of p54(nrb). In human breast cancer tissues, the levels of p54(nrb) and SREBP-1a proteins were positively correlated with each other. Our biochemical analyses showed that the conserved Y267 residue of p54(nrb) was required for its binding to the nuclear form of SREBP-1a. Interestingly, p54(nrb) binding to nuclear SREBP-1a caused an increase of nuclear SREBP-1a protein stability. As a result, p54(nrb) stimulates SREBP-1-meidated transcription of lipogenic genes and lipid production in breast cancer cells. Moreover, both p54(nrb) and SREBP-1a were required for breast cancer cell growth in vitro, and p54(nrb) binding to nuclear SREBP-1a was also critical for breast tumor development in vivo. Together, we conclude that p54(nrb) is a novel regulator of SREBP-1a in the nucleus, and our data suggest that p54(nrb) regulation of SREBP-1a supports the increased cellular demand of lipids for breast cancer growth. Thus, the SREBP pathway may represent a novel target for treating breast cancer.

This work reports a study of the anatase-to-rutile phase transition (ART) in a highly ordered TiO2 nanotube (NT) specimen fabricated using an electrochemical process followed by thermal annealing at 750 °C (NT750). Two-dimensional X-ray absorption near-edge structure–X-ray excited optical luminescence spectroscopy reveals the hierarchically two-layered structure of NT750 by resolving the surface anatase luminescence and bulk rutile optical emission. Scanning transmission X-ray microscopy analysis of a sliced NT750 lamella spatially differentiates the top nanotubular anatase structure from the denser rutile bottom layer with a gradual ART interface layer. On the basis of these results together with the known behavior of size and anisotropy dependence of ART in TiO2 nanocrystal, we propose the “bottom-up” mechanism for ART in anodic TiO2 NTs. This result is particularly relevant to the fundamental understanding of phase transition in nanostructures as well as the fabrication of desired TiO2 NT mixed-phase composite with an excellent control of the anatase/rutile phase ratio.