The dynamic relationships between the active and catabolic vitamin D metabolites, their ratios, and associations with PTH

Vitamin D status, assessed by serum concentration of 25(OH)D, is the prime candidate marker for many disease-association studies, but the interplay between the subsequent 1,25-dihydroxyvitamin D (1,25(OH)2D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) metabolites is unclear. In this study, we conducted an analysis from a large cohort of healthy, physically fit, young army recruits (n = 940). We found a significant, inverse relationship between serum 25(OH)D and 1,25(OH)2D:24,25(OH)2D vitamin D metabolite ratio (VMR) (r(2)Exp = 0.582, p /=35 to be the threshold value for vitamin D insufficiency, and >/=51 to be predictive of vitamin D deficiency. Our three-dimensional model provides mechanistic insight into the vitamin D-PTH endocrine system, and further substantiates the role of 24,25(OH)2D in human physiology. The model sets a new paradigm for vitamin D treatment strategy, and may help the establishment of vitamin D-adjusted PTH reference intervals. The study was approved by the UK Ministry of Defence research ethics committee (MODREC 165/Gen/10 and 692/MoDREC/15). ClinicalTrials.gov Identifier NCT02416895

Gene Expression Profiling Identified High-mobility Group AT-hook (HMGA2) as Being Frequently Upregulated in Esophageal Squamous Cell Carcinoma

Background: Esophageal cancer is one of the most deadly malignancies worldwide and esophageal squamous cell carcinoma (ESCC) is the most frequent type. Methods: We identified up-regulated genes from gene expression profiles of HKESC-4 cell line, its parental tumor tissues, non-tumoral esophageal epithelia and lymph nodes with metastatic carcinoma using Human Genome U133 Plus 2.0 microarray. Results: Four genes [High-mobility group AT-hook 2 (HMGA2), paternally expressed 10 (PEG10), SH3 and multiple ankyrin repeat domains 2 (SHANK2) and WNT1 inducible signaling pathway protein 3 (WISP3)] were selected for further validation with real-time quantitative polymerase chain reaction (qPCR) in a panel of ESCC cell lines and clinical specimens. HMGA2 was found to be overexpressed in the panel of ESCC cell lines tested. By using immunohistochemistry, HMGA2 was found to be up-regulated in 70% of ESCC tissues (21 out of 30 cases). Conclusion: This study demonstrates successful use of gene microarray to identify and reveal HMGA2 as a novel and consistently overexpressed gene in ESCC cell lines and clinical samples.published_or_final_versio

Do mutual funds have consistency in their performance?

Using a comprehensive data set of 714 Chinese mutual funds from 2004 to 2015, the study investigates these funds’ performance persistence by using the Capital Asset Pricing model, the Fama-French three-factor model and the Carhart Four-factor model. For persistence analysis, we categorize mutual funds into eight octiles based on their one year lagged performance and then observe their performance for the subsequent 12 months. We also apply Cross-Product Ratio technique to assess the performance persistence in these Chinese funds. The study finds no significant evidence of persis- tence in the performance of the mutual funds. Winner (loser) funds do not continue to be winner (loser) funds in the subsequent time period. These findings suggest that future performance of funds cannot be predicted based on their past performance.info:eu-repo/semantics/publishedVersio

The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells.

An open and decondensed chromatin organization is a defining property of pluripotency. Several epigenetic regulators have been implicated in maintaining an open chromatin organization, but how these processes are connected to the pluripotency network is unknown. Here, we identified a new role for the transcription factor NANOG as a key regulator connecting the pluripotency network with constitutive heterochromatin organization in mouse embryonic stem cells. Deletion of Nanog leads to chromatin compaction and the remodeling of heterochromatin domains. Forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin. NANOG associates with satellite repeats within heterochromatin domains, contributing to an architecture characterized by highly dispersed chromatin fibers, low levels of H3K9me3, and high major satellite transcription, and the strong transactivation domain of NANOG is required for this organization. The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG, and loss of Sall1 recapitulates the Nanog-null phenotype, but the loss of Sall1 can be circumvented through direct recruitment of the NANOG transactivation domain to major satellites. These results establish a direct connection between the pluripotency network and chromatin organization and emphasize that maintaining an open heterochromatin architecture is a highly regulated process in embryonic stem cells.We thank Ludovic Vallier for constitutive Nanog-EpiSC, Gabrielle Brons for 129S2 EpiSC, Prim Singh for H3K9me3 antibody, Maria Elena Torres Padilla for TALE-mClover and luciferase plasmids, Wellcome Trust Sanger Institute for pCyL43 plasmid and Andras Nagy for PB-TET and rtTA plasmids. We are grateful to David Oxley and Judith Webster Novo et al. for mass spectrometry support, Simon Walker for imaging support and Anne Segonds- Pichon for statistical advice. We thank Wolf Reik and Jon Houseley for comments on the manuscript and members of Wolf Reik’s group for helpful discussions. P.J.R.-G. is supported by the Wellcome Trust [WT093736], BBSRC [M022285] and the European Commission Network of Excellence EpiGeneSys [HEALTH-F4-2010-257082]. The work was also supported with funds from the Canadian Institutes of Health Research to J.E. [Team Grant EPS-129129] and D.P.B.-J. D.P.B-J. holds the Canada Research Chair in Molecular and Cellular Imaging. I.C. is supported by the MRC

Clinical correlation of nuclear survivin in esophageal squamous cell carcinoma

To examine the correlation of survivin (both total and nuclear survivin) with clinicopathological parameters of esophageal squamous cell carcinoma (ESCC) patients. Tumors and non-tumor tissues near the proximal resection margins were resected from ESCC patients undergone esophagectomy. Quantitative polymerase chain reaction (qPCR) was performed to detect survivin mRNA expression level in the 10 paired tumor and adjacent non-tumor tissues. To confirm with the clinical situation, survivin mRNA and protein expression were measured by qPCR and immunoblot, respectively, in 5 ESCC cell lines and a non-neoplastic esophageal epithelial cell line. Immunohistochemistry was employed to reveal the cellular localization of survivin in tumor tissues isolated from the 64 ESCC patients undergone surgery alone. Up-regulation of survivin mRNA and protein was found in 5 ESCC lines (HKESC-1, HKESC-2, HKESC-3, HKESC-4, and SLMT-1) when compared to a non-neoplastic esophageal epithelial cell line NE-1. In particular, HKESC-3, HKESC-4, and SLMT-1 cells demonstrated ~50-fold increase in survivin mRNA. High level of survivin mRNA in tumor tissues when compared to non-tumor tissues was found in 70 % (7 of 10) of clinical cases. The increase in expression ranged from ~twofold to ~16-fold. Immunohistochemistry results showed that survivin was found at the cell nuclei in all specimens examined. Nuclear expression of survivin was inversely associated with the likelihood of developing nodal metastasis (p = 0.021) and significantly associated with early-stage ESCC (p = 0.039). Nuclear survivin could serve as a marker for indicating disease status in ESCC patients. © 2012 The Author(s).published_or_final_versio

1.7eV Al0.2Ga0.8As solar cells epitaxially grown on silicon by SSMBE using a superlattice and dislocation filters

Lattice-mismatched 1.7eV Al0.2Ga0.8As photovoltaic solar cells have been monolithically grown on Si substrates using Solid Source Molecular Beam Epitaxy (SSMBE). As a consequence of the 4%-lattice-mismatch, threading dislocations (TDs) nucleate at the interface between the Si substrate and III-V epilayers and propagate to the active regions of the cell. There they act as recombination centers and degrade the performances of the cell. In our case, direct AlAs/GaAs superlattice growth coupled with InAlAs/AlAs strained layer superlattice (SLS) dislocation filter layers (DFLSs) have been used to reduce the TD density from 1×10^9cm^-2 to 1(±0.2)×10^7cm^-2. Lattice-matched Al0.2Ga0.8As cells have also been grown on GaAs as a reference. The best cell grown on silicon exhibits a Voc of 964mV, compared with a Voc of 1128mV on GaAs. Fill factors of respectively 77.6% and 80.2% have been calculated. Due to the lack of an anti-reflection coating and the non-optimized architecture of the devices, relatively low Jsc have been measured: 7.30mA.cm^-2 on Si and 6.74mA.cm^-2 on GaAs. The difference in short-circuit currents is believed to be caused by a difference of thickness between the samples due to discrepancies in the calibration of the MBE prior to each growth. The bandgap-voltage offset of the cells, defined as Eg/q-Voc, is relatively high on both substrates with 736mV measured on Si versus 572mV on GaAs. The non-negligible TD density partly explains this result on Si. On GaAs, non-ideal growth conditions are possibly responsible for these suboptimal performances

Supplementary Energy Increases Bone Formation during Arduous Military Training

Purpose: This study aimed to investigate the effect of supplementary energy on bone formation and resorption during arduous military training in energy deficit. Methods: Thirty male soldiers completed an 8-wk military combat course (mean ± SD, age = 25 ± 3 yr, height = 1.78 ± 0.05 m, body mass = 80.9 ± 7.7 kg). Participants received either the habitual diet (control group, n = 15) or an additional 5.1 MJ·d−1 to eliminate the energy deficit (supplemented group, n = 15). Circulating markers of bone formation and resorption, and reproductive, thyroid, and metabolic status, were measured at baseline and weeks 6 and 8 of training. Results: Bone-specific alkaline phosphatase decreased in controls (−4.4 ± 1.9 μg·L−1) and increased in the supplemented group (16.0 ± 6.6 μg·L−1), between baseline and week 8 (P < 0.001). Procollagen type 1 N-terminal propeptide increased between baseline and week 6 for both groups (5.6 ± 8.1 μg·L−1, P = 0.005). Beta carboxy-terminal cross-linking telopeptide of type 1 collagen decreased between baseline and week 8 for both groups (−0.16 ± 0.20 μg·L−1, P < 0.001). Prolactin increased from baseline to week 8 for the supplemented group (148 ± 151 IU·L−1, P = 0.041). The increase in adiponectin from baseline to week 8 was higher in controls (4.3 ± 1.8 mg·L−1, P < 0.001) than that in the supplemented group (1.4 ± 1.0 mg·L−1, P < 0.001). Insulin-like growth factor binding protein-3 was lower at week 8 than baseline for controls (−461 ± 395 ng·mL−1, P < 0.001). Conclusion: The increase in bone-specific alkaline phosphatase, a marker of bone formation, with supplementation supports a role of energy in osteoblastic activity; the implications for skeletal adaptation and stress fracture risk are unclear. The mechanism is likely through protecting markers of metabolic, but not reproductive or thyroid, function

Endocrine resistance in breast cancer: new roles for ErbB3 and ErbB4

Endocrine resistance is a major limitation to the successful treatment of estrogen receptor-positive (ER+) breast cancer, and the EGFR (epidermal growth factor receptor) and ErbB-2 receptor tyrosine kinases are involved in this process. A recent study now implicates the other two ErbB family members, ErbB-3 and -4. Exposure of ER+ breast cancer cells to the pure antiestrogen, fulvestrant, increased levels of ErbB-3 or ErbB-4 and sensitivity to the growth-stimulatory effects of heregulin ݱ, a potent ligand for these receptors. Thus, the initial growth-inhibitory effects of fulvestrant appear compromised by cellular plasticity that allows rapid compensatory growth stimulation via ErbB-3/4. Further evaluation of pan-ErbB receptor inhibitors in endocrine-resistant disease appears warranted

Self-assembly of highly symmetrical, ultrasmall inorganic cages directed by surfactant micelles

Nanometre-sized objects with highly symmetrical, cage-like polyhedral shapes, often with icosahedral symmetry, have recently been assembled from DNA(1-3), RNA(4) or proteins(5,6) for applications in biology and medicine. These achievements relied on advances in the development of programmable self-assembling biological materials(7-10), and on rapidly developing techniques for generating three-dimensional (3D) reconstructions from cryo-electron microscopy images of single particles, which provide high-resolution structural characterization of biological complexes(11-13). Such single-particle 3D reconstruction approaches have not yet been successfully applied to the identification of synthetic inorganic nanomaterials with highly symmetrical cage-like shapes. Here, however, using a combination of cryo-electron microscopy and single-particle 3D reconstruction, we suggest the existence of isolated ultrasmall (less than 10 nm) silica cages ('silicages') with dodecahedral structure. We propose that such highly symmetrical, self-assembled cages form through the arrangement of primary silica clusters in aqueous solutions on the surface of oppositely charged surfactant micelles. This discovery paves the way for nanoscale cages made from silica and other inorganic materials to be used as building blocks for a wide range of advanced functional-materials applications

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders