Adult neurogenesis represents a unique form of plasticity in the dentate gyrus requiring the presence of long-lived neural stem cells (LL-NSCs). However, the embryonic origin of these LL-NSCs remains unclear. The prevailing model assumes that the dentate neuroepithelium throughout the longitudinal axis of the hippocampus generates both the LL-NSCs and embryonically produced granule neurons. Here we show that the NSCs initially originate from the ventral hippocampus during late gestation and then relocate into the dorsal hippocampus. The descendants of these cells are the source for the LL-NSCs in the subgranular zone (SGZ). Furthermore, we show that the origin of these cells and their maintenance in the dentate are controlled by distinct sources of Sonic Hedgehog (Shh). The revelation of the complexity of both the embryonic origin of hippocampal LL-NSCs and the sources of Shh has important implications for the functions of LL-NSCs in the adult hippocampus.

Sequencing key cancer-driver genes using formalin-fixed, paraffin-embedded (FFPE) cancer tissues is becoming the standard for identifying the best treatment regimen. However, about 25% of all samples are rejected for genetic analyses for reasons that include too little tissue to extract enough high quality DNA. One way to overcome this is to do whole-genome amplification (WGA) in clinical samples, but only limited studies have tested different WGA methods in FFPE cancer specimens using targeted next-generation sequencing (NGS). We therefore tested the two most commonly used WGA methods, multiple displacement amplification (MDA-Qiagen REPLI-g kit) and the hybrid or modified PCR-based method (Sigma/Rubicon Genomics Inc. GenomePlex kit) in FFPE normal and tumor tissue specimens. For the normalized copy number analysis, the FFPE process caused none or very minimal bias. Variations in copy number were minimal in samples amplified using the GenomePlex kit, but they were statistically significantly higher in samples amplified using the REPLI-g kit. The pattern was similar for variant allele frequencies across the samples, which was minimal for the GenomePlex kit but highly variable for the REPLI-g kit. These findings suggest that each WGA method should be tested thoroughly before using it for clinical cancer samples.

Objectives

The rapid emergence, spread, and disease severity of avian influenza A (H7N9) in China has prompted concerns about a possible pandemic and regional spread in the coming months. The objective of this study was to predict the risk of future human infections with H7N9 in China and neighboring countries by assessing the association between H7N9 cases at sentinel hospitals and putative agricultural, climatic, and demographic risk factors.

Methods

This cross-sectional study used the locations of H7N9 cases and negative cases from China's influenza-like illness surveillance network. After identifying H7N9 risk factors with logistic regression, we used Geographic Information Systems (GIS) to construct predictive maps of H7N9 risk across Asia.

Results

Live bird market density was associated with human H7N9 infections reported in China from March-May 2013. Based on these cases, our model accurately predicted the virus' spread into Guangxi autonomous region in February 2014. Outside China, we find there is a high risk that the virus will spread to northern Vietnam, due to the import of poultry from China.

Conclusions

Our risk map can focus efforts to improve surveillance in poultry and humans, which may facilitate early identification and treatment of human cases.

Adipose tissue is a key endocrine organ that governs systemic homeostasis. PPARγ is a master regulator of adipose tissue signaling that plays an essential role in insulin sensitivity, making it an important therapeutic target. The selective PPARγ agonist rosiglitazone (RSG) has been used to treat diabetes. However, adverse cardiovascular effects have seriously hindered its clinical application. Experimental models have revealed that PPARγ activation increases cardiac hypertrophy. RSG stimulates cardiac hypertrophy and oxidative stress in cardiomyocyte-specific PPARγ knockout mice, implying that RSG might stimulate cardiac hypertrophy independently of cardiomyocyte PPARγ. However, candidate cell types responsible for RSG-induced cardiomyocyte hypertrophy remain unexplored. Utilizing cocultures of adipocytes and cardiomyocytes, we found that stimulation of PPARγ signaling in adipocytes increased miR-200a expression and secretion. Delivery of miR-200a in adipocyte-derived exosomes to cardiomyocytes resulted in decreased TSC1 and subsequent mTOR activation, leading to cardiomyocyte hypertrophy. Treatment with an antagomir to miR-200a blunted this hypertrophic response in cardiomyocytes. In vivo, specific ablation of PPARγ in adipocytes was sufficient to blunt hypertrophy induced by RSG treatment. By delineating mechanisms by which RSG elicits cardiac hypertrophy, we have identified pathways that mediate the crosstalk between adipocytes and cardiomyocytes to regulate cardiac remodeling.

Objective

Many adults with serious mental illness are sedentary and experience significant medical illness burden. This study examined the effectiveness of online weight management with peer coaching (WebMOVE) for increasing general physical activity among adults with serious mental illness.

Methods

Using quantitative and qualitative data from a randomized controlled trial (N=276), this study compared WebMOVE, in-person weight management for adults with serious mental illness (MOVE SMI), and usual care. Participants completed assessments of general physical activity (baseline, three months, and six months) and a qualitative assessment (six months). Mixed-effects models examined group × time interactions on general physical activity.

Results

There were significant differences between MOVE SMI and usual care for total physical activity at three (t=3.06, p=.002) and six (t=3.12, p=.002) months, walking at six months (t=1.99, p=.048), and moderate (t=2.12, p=.035) and vigorous (t=2.34, p=.020) physical activity at six months. There was a significant difference between WebMOVE and usual care for total physical activity at six months (t=2.02, p=.044) and a trend for a group difference in walking at six months (t=1.78, p=.076). These findings reflected a decline in physical activity among participants in usual care and an increase in physical activity among participants in MOVE SMI or WebMOVE.

Conclusions

In-person weight management counseling increased total physical activity and led to initiation of moderate and vigorous physical activity among adults with serious mental illness. Computerized weight management counseling with peer support led to more gradual increases in total physical activity.

BACKGROUND: Gremlin, a member of the Dan family of BMP antagonists, is a glycosylated extracellular protein. Previously Gremlin has been shown to play a role in dorsal-ventral patterning, in tissue remodeling, and recently in angiogenesis. Evidence has previously been presented showing both over- and under-expression of Gremlin in different tumor tissues. Here, we sought to quantify expression of Gremlin in cancers of the lung and performed in vitro experiments to check whether Gremlin promotes cell growth and proliferation. METHODOLOGY/PRINCIPAL FINDINGS: Expression of Gremlin in 161 matched tumor and normal lung cancer specimens is quantified by quantitative real-time PCR and protein level is measured by immunohistochemistry. GREM1 was transfected into lung fibroblast and epithelial cell lines to assess the impact of overexpression of Gremlin in vitro. RESULTS: Lung adenocarcinoma but not squamous cell carcinoma shows a significant increase in Gremlin expression by mRNA and protein level. Lung fibroblast and epithelial cell lines transfected with GREM1 show significantly increased cell proliferation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that Gremlin acts in an oncogenic manner in lung adenocarcinoma and could hold promise as a new diagnostic marker or potential therapeutic target in lung AD or general thoracic malignancies.

Objective

Many adults with serious mental illness are sedentary and experience significant medical illness burden. This study examined the effectiveness of online weight management with peer coaching (WebMOVE) for increasing general physical activity among adults with serious mental illness.

Methods

Using quantitative and qualitative data from a randomized controlled trial (N=276), this study compared WebMOVE, in-person weight management for adults with serious mental illness (MOVE SMI), and usual care. Participants completed assessments of general physical activity (baseline, three months, and six months) and a qualitative assessment (six months). Mixed-effects models examined group × time interactions on general physical activity.

Results

There were significant differences between MOVE SMI and usual care for total physical activity at three (t=3.06, p=.002) and six (t=3.12, p=.002) months, walking at six months (t=1.99, p=.048), and moderate (t=2.12, p=.035) and vigorous (t=2.34, p=.020) physical activity at six months. There was a significant difference between WebMOVE and usual care for total physical activity at six months (t=2.02, p=.044) and a trend for a group difference in walking at six months (t=1.78, p=.076). These findings reflected a decline in physical activity among participants in usual care and an increase in physical activity among participants in MOVE SMI or WebMOVE.

Conclusions

In-person weight management counseling increased total physical activity and led to initiation of moderate and vigorous physical activity among adults with serious mental illness. Computerized weight management counseling with peer support led to more gradual increases in total physical activity.

Background

The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance and its activation is aberrant in several types of cancer including mesothelioma. Protein kinase CK2 affects several cell signaling pathways through the mechanism of phosphorylation.

Methods

Protein and mRNA levels of CK2α and Gli1 were tested by quantitative RT-PCR and immunohistochemistry staining in mesothelioma samples and cell lines. Down-regulated Gli1 expression and transcriptional activity were demonstrated by RT-PCR, Western blot and luciferase reporter assay.

Results

In this study, we show that CK2α is over-expressed and a positive regulator of Hegdehog/Gli1 signaling in human malignant pleural mesothelioma. First of all, we found that the mRNA levels of CK2α and Gli1 were broadly elevated and correlated (n = 52, r = 0.401, P < 0.05), compared with LP9 (a normal mesothelial cell line). We then investigated their expression at the protein level, and found that all the 7 mesothelioma cell lines tested showed positive staining in CK2α and Gli1 immunohistochemistry. Correlation analysis by Pearson test for CK2α and Gli1 expression in the 75 mesothelioma tumors and the 7 mesothelioma cell lines showed that the two protein expression was significantly correlated (n = 82, r = 0.554, P < 0.01). Furthermore, we demonstrated that Gli1 expression and transcriptional activity were down-regulated after CK2α was silenced in two mesothelioma cell lines (H28 and H2052). CK2α siRNA also down-regulated the expression of Hh target genes in these cell lines. Moreover, treatment with a small-molecule CK2α inhibitor CX-4945 led to dose-dependent inhibition of Gli1 expression and transcriptional activity. Conversely, forced over-expression of CK2α resulted in an increase in Gli1 transcriptional activity in H28 cells.

Conclusions

Thus, we report for the first time that over-expressed CK2α positively regulate Hh/Gli1 signaling in human mesothelioma.

Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM.