bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A37: Tumor heterogeneity in SCLC: A role for endogenous Notch signaling
Authors: Lim Jing Shan , Ibaseta Alvaro , Yang Dian , Jahchan Nadine S. , Sage Julien
Published: May 2016

Small cell lung cancer (SCLC), a very aggressive neuroendocrine (NE) tumor of the lung, constitutes approximately 15% of all lung cancers and has a 5-year survival rate of only 5%. Resistance following initial chemotherapy and radiation treatments accounts for the high rate of recurrence and the overall poor prognosis of SCLC.

Through genomic sequencing of 100 human SCLC tumors, the group of Roman Thomas and Martin Peifer identified universal inactivation of RB and p53 and inactivating mutations in the NOTCH receptors in ~25% of the tumors. Accordingly, we found that activation of the Notch pathway in a pre-clinical mouse model for SCLC dramatically reduces the number of tumors and extends the survival of the mice. Acute Notch activation also inhibits NE gene expression and proliferation in SCLC tumor cells, providing further evidence for a tumor suppressive role for Notch in SCLC (George, Lim, et al., Nature, 2015).

Intriguingly, however, we recently identified a population of cells in mouse and human SCLC tumors that exhibit endogenous activation of the Notch pathway. This observation raises the question of why tumor cells would activate a tumor suppressive pathway. Consistent with the inhibitory role of the pathway in NE differentiation, these Notch-active SCLC cells comprise a slow-cycling, non-NE compartment within SCLC tumors. Lineage tracing experiments indicate that NE tumor cells generate these non-NE Notch-active cells during tumorigenesis. Importantly, our data suggest that these slow-growing Notch-active SCLC cells may function as tumor-derived stromal-like cells that confer a growth or protective advantage to the NE tumor cells under certain growth conditions.

In conclusion, Notch is a potent suppressor of SCLC. However, Notch may have pro-tumorigenic effects in SCLC, possibly under stress conditions. A better understanding of the molecular and cellular roles of Notch is required before therapeutic strategies manipulating the Notch pathway can be used in SCLC patients.

Citation Format: Jing Shan Lim, Alvaro Ibaseta, Dian Yang, Nadine S. Jahchan, Julien Sage. Tumor heterogeneity in SCLC: A role for endogenous Notch signaling. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A37.
Abstract A38: In vitro and in vivo interaction of Cdk6 and Eya2 indicate potential crosstalk
Authors: Kohrt Dawn , Hinds Philip , Ford Heide , Grossel Martha
Published: May 2016

We have identified a novel association of the developmentally significant protein, Eya2, with cyclin dependent kinase (cdk) 6. Eya2 is part of the conserved retinal determination network that has been shown to function in fly eye development (Rebay, 2005). In mammals, the EYA gene product has been implicated in gonadogenesis, myogenesis, neurognenesis, limb formation, thymus, and kidney development, in part through its ability to regulate cell proliferation (Zhang 2005). Eya2 is overexpressed in several types of cancers including epithelial ovarian (Zhang et al, 2005), cervical (Bierkens et al, 2013), lung adenocarcinoma (Guo et al, 2009), breast and hematopoietic (Patrick, 2013, Wang, 2011). Cdk6 knockout mice display defects in hematopoiesis, including decreased cellularity of the thymus, red blood cells and lymphocytes (Malumbres, 2004). Cdk6 kinase activity is required for thymocyte development (Hu et al, 2011) and this role is partially mediated by modulating Notch target gene expression.

The interaction of these two proteins, each important in both development and cancer, and both involved in regulation of cell proliferation and transcription, was first identified in a yeast two-hybrid analysis of a human fetal brain library. Subsequent results from our labs confirm the association of cdk6 and Eya2 in GST binding assays and co-immunoprecipitations. GST binding assays demonstrated that Six4, a cofactor of Eya2, competes with cdk6 for Eya2 binding. Co-immunoprecipitation of transfected cell lysates and native immunoprecipitations also demonstrate binding. Finally, co-expression of cdk6 with Eya2 reduces the half-life of the Eya2 protein in cell lysates. We propose that cdk6 and Eya2 interact to affect the function of cell proliferation and differentiation that is crucial to both the biology of cancer and development. This interaction could provide a mechanism to allow the expansion of the progenitor cell population prior to differentiation.

References:

Rebay I, Silver SJ, Tootle TL (2005) Trends Genet 21: 163-171.

Zhang L, et al. (2005). Cancer Research 65: 925-932.

Bierkens M, et al. (2013). Genes, Chromosomes & Cancer 52: 56-68.

Guo JT et al. (2009) Chinese journal of oncology 31: 528-531.

Patrick AN, et al. (2013) Nature Structural & Molecular Biology 20: 447-453.

Wang QF, et al. (2011) Blood 117: 6895-6905.

Malumbres et al. (2004). Cell 118: 493-504.

Hu MG, et al. (2011) Blood 117: 6120-6131.

Citation Format: Dawn Kohrt, Philip Hinds, Heide Ford, Martha Grossel. In vitro and in vivo interaction of Cdk6 and Eya2 indicate potential crosstalk. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A38.
Abstract B07: Tead and AP1 coordinate transcription and motility in cancer cells
Authors: Liu Xiangfan , Li Huapeng , Rajurkar Mihir , Cotton Jennifer , Mercurio Arthur , Davis Roger , Mao Junhao
Published: May 2016

The Tead family transcription factors are the major mediators of the Hippo-Yap pathway. Although misregulation of Hippo signaling has been implicated in many human cancers, Tead dependent downstream transcriptional programs in cancer cells remain poorly understood. Here we characterize Tead4-mediated transcriptional networks in diverse cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 factors to coordinate target gene transcription. We find that the interaction of AP1 and Tead4 is JNK independent, but engages the SRC coactivators to promote downstream transcription. Furthermore we show that Tead and AP1 drive the expression of a unique core set of target genes to direct cell motility and invasion. Together, our data unveil a critical regulatory mechanism coordinating AP1 and Tead -controlled transcriptional and functional output in cancer cells.

Citation Format: Xiangfan Liu, Huapeng Li, Mihir Rajurkar, Jennifer Cotton, Arthur Mercurio, Roger Davis, Junhao Mao. Tead and AP1 coordinate transcription and motility in cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B07.
Abstract B28: The stem cell gene ABCB5 mediates colorectal cancer resistance to apoptosis
Authors: Guo Qin , Berg Gretchen , Wilson Brian J. , Gonzalez Gabriel , Ma Jie , Gold Jason S. , Nandi Bisweswar , Huang Qin , Zhan Qian , Murphy George F. , Waaga-Gasser Ana Maria , Lian Christine G. , Frank Markus H. , Gasser Martin , Frank Natasha
Published: May 2016

Cancer stem cells (CSC) responsible for disease progression and therapeutic resistance have been identified in several human malignancies, including colorectal cancer (CRC). However, the molecular mechanisms through which CSC drive tumor growth are incompletely understood. ABCB5, a member of the ATP-binding cassette superfamily of active transporters, serves as a CSC-specific multidrug resistance mechanism in diverse human malignancies. Additionally, ABCB5 has recently been demonstrated to function as an anti-apoptotic gene in tissue-specific non-malignant stem cells. Here we demonstrate that ABCB5 also serves an anti-apoptotic role required for CSC maintenance in human cancer. Targeted inhibition of ABCB5, previously shown to be preferentially expressed on CD133-positive CRC stem cells, induced tumor cell apoptosis in vitro and in vivo and inhibited human CRC growth in NSG recipient mice. Mechanistically, ABCB5-positive tumor cell ablation through monoclonal antibody-mediated blockade or shRNA-mediated gene knockdown resulted in diminished production of the receptor tyrosine kinase AXL, a pro-tumorigenic molecule identified herein to be preferentially produced by CRC stem cells. Restoration of AXL expression through gene transfection in ABCB5 knockdown tumors partially restored tumor growth, demonstrating that ABCB5-positive CRC stem cells drive tumorigenicity at least in part through production of AXL. Our results establish a novel anti-apoptotic function of ABCB5 in human cancer and indicate that targeted blockade of ABCB5 represents a novel strategy for CSC eradication, independent of its previously established function as a multidrug resistance mediator.

Citation Format: Qin Guo, Gretchen Berg, Brian J. Wilson, Gabriel Gonzalez, Jie Ma, Jason S. Gold, Bisweswar Nandi, Qin Huang, Qian Zhan, George F. Murphy, Ana Maria Waaga-Gasser, Christine G. Lian, Markus H. Frank, Martin Gasser, Natasha Frank. The stem cell gene ABCB5 mediates colorectal cancer resistance to apoptosis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B28.
Abstract B38: Quiescence as a marker of treatment resistance and malignancy in GBM
Authors: Atkins Ryan J. , Stylli Stanley S. , Luwor Rodney B. , Ware Thomas MB , Kaye Andrew H. , Hovens Christopher M.
Published: May 2016

Glioblastoma multiforme (GBM) is a World Health Organization grade IV astrocytic tumor, and is the most common primary brain malignancy. GBM is characterized as being highly malignant and rapidly progressive with a high mitotic index, diffuse invasion, microvascular proliferation and pseudopalisading necrosis. Current best treatment for GBM involves maximal safe surgical resection, with radiotherapy (XRT) and temozolomide (TMZ), but even with this regime patients survive for an average of only ~15 months. GBM’s position within the brain and diffuse progression profile prevents a surgical cure, and the cells left behind following surgery contain a quiescent, treatment-resistant subpopulation of cells with a stem-like capacity for self-renewal which survive chemoradiotherapy and cause relapse. These resistant cells have been referred to as cancer stem cells, but while stem cell markers have been useful in enriching stem populations in some cancers, a marker that reliably defines the glioma stem cell has remained elusive. The critical feature that allows these resistant cells to survive treatment is their slow division rate, which helps them to avoid chemoradiotherapy-induced cell death by virtue of their condensed chromatin and reduced requirement for DNA replication. In the present study we use a pulse-chase assay to ubiquitously label glioma cell lines with the fluorescent dye Oregon Green and observe the label dilution as an indicator of cell division. Based on their slower division rates, quiescent cells retain the dye longer than rapidly-dividing cells and are easily identified by fluorescence imaging and FACS analysis. Once such a population is isolated it can then be compared to a rapidly-dividing (Oregon Green-diluting) subpopulation of cells to analyze differences in treatment resistance, migration, invasion, and gene expression between the two populations. It is hoped that by elucidating the molecular mechanisms that drive treatment resistance and migration/invasion we will be able to inform novel GBM treatments that improve patient outcomes.

We have shown that quiescent cells are innately resistant to the current gold standard GBM treatments and display more malignant features in vitro than rapidly dividing cells. We have developed a platform for quick, easy, and reliable isolation of this quiescent fraction of cells to facilitate its interrogation. This method has the potential to identify future treatment targets, and could, in principle, be extended to other malignancies.

Citation Format: Ryan J. Atkins, Stanley S. Stylli, Rodney B. Luwor, Thomas MB Ware, Andrew H. Kaye, Christopher M. Hovens. Quiescence as a marker of treatment resistance and malignancy in GBM. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B38.
Abstract IA12: Lgr5 stem cell-based organoids in human disease
Authors: Clevers Hans
Published: May 2016

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific and almost ‘generic’ marker for stem cells, including in hair follicles, kidney, liver, mammary gland, inner ear tongue and stomach epithelium.

Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids, or so called ‘mini-guts’ in 3D culture. The technology is based on the observation that Lgr5 is the receptor for a potent stem cell growth factor, R-spondin. Similar 3D cultures systems have been developed for the Lgr5+ve stem cells of human stomach, liver, pancreas, prostate and kidney. Using CRISPR/Cas9 technology, genes can be efficiently modified in organoids of various origins.

Citation Format: Hans Clevers. Lgr5 stem cell-based organoids in human disease. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA12.
Abstract IA15: The unique genomic and epigenomic landscape of pediatric high-grade glioma
Authors: Larson Jon D. , Silveira Andre B. , Kasper Lawryn H. , Diaz Alexander K. , Zhu Xiaoyan , Baker Suzanne J.
Published: May 2016

Diffuse high-grade gliomas (HGGs) of childhood are a spectrum of disease with devastatingly poor outcome. Despite similar histological features, pediatric HGGs arise from a broader distribution of anatomical locations when compared to adults, with approximately 50% arising in the brainstem as diffuse intrinsic pontine glioma (DIPG), a disease found almost exclusively in children. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation as well as developmental signaling pathways. The striking association between frequencies of specific mutations with spatiotemporal pattern of HGG formation in children further highlights context-dependent connections between developmental states and oncogenic drivers. Activating mutations in the BMP receptor ACVR1 are found exclusively in the youngest subgroup of DIPG patients, and not identified in HGGs outside the brainstem. Recurrent mutations in histone H3 establish a critical role for epigenetic regulation in disease pathogenesis of childhood HGG. H3K27M mutations occur in nearly 80% of DIPGs and more than half of HGGs arising in midline structures outside the brainstem such as the thalamus. In contrast, approximately 15% of HGGs arising in the cerebral cortex have an alternative H3 mutation, G34R/V, and are predominantly found in older adolescents and young adults. To study these mutations in the developing mammalian brain, we generated conditionally activated, epitope tagged H3f3a knock-in mice to express K27M, G34R or non-mutated H3.3 proteins from the endogenous H3f3a locus. We will present early analyses of these new oncohistone mouse models.

Citation Format: Jon D. Larson, Andre B. Silveira, Lawryn H. Kasper, Alexander K. Diaz, Xiaoyan Zhu, Suzanne J. Baker. The unique genomic and epigenomic landscape of pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA15.
Abstract IA28: Epigenetic heterogeneity in breast cancer
Authors: Polyak Kornelia
Published: May 2016

Heterogeneity of cancer cells between and within tumors is a major obstacle toward understanding and treatment of cancers. Variability of epigenetic states is one of the major contributor to both intertumor and intratumor heterogeneity. In breast cancer luminal and basal-like breast tumors have very different molecular and clinical profiles. However, even in individual tumors there is variability among cells for these features. The determinants of luminal cell phenotypes are fairly well understood and major transcriptional regulators have been identified. In contrast, transcriptional determinants of basal-like breast tumors are still poorly defined and high variability is observed among individual tumors. We have investigated molecular regulators of luminal and basal-like phenotypes by applying somatic cell genetics and cellular reprogramming approaches combined with comprehensive molecular profiling. We found that the basal-like state is predominantly dominant and it is defined mainly by epigenetic mechanisms. We have also identified candidate epigenetic and transcriptional regulators of basal-like cellular states. Modulation of epigenetic regulators may decrease intratumor heterogeneity and in combination with other agents could improve the efficacy of cancer therapies.

Citation Format: Kornelia Polyak. Epigenetic heterogeneity in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA28.
Abstract 22: Inferring regulatory element landscapes and transcription factor networks from cancer methylomes
Authors: Yao Lijing , Shen Hui , Laird Peter , Farnham Peggy , Benjamin Berman
Published: May 2016

Genome-wide DNA methylation studies have established that transcriptional enhancers can be detected from changes in methylation patterns. However, no systematic approach has been developed to infer the function of these elements within larger transcription factor networks. We developed ELMER (Enhancer Linking by Methylation/Expression Relationships), a computational tool that combines DNA methylation and gene expression data from tissue samples, along with annotations from epigenomic repositories, to infer multi-level cis-regulatory networks. ELMER uses DNA methylation to identify enhancers that differ between normal and disease tissues, and correlates these with gene expression to identify a target gene or genes (typically not the nearest gene). Transcription factor (TF) binding site analysis is then used in conjunction with TF expression patterns to infer the upstream regulators that drive enhancer changes. We applied ELMER to Infinium HM450k methylation and RNA-seq data for 2,000+ tumor samples and ten cancer types from The Cancer Genome Atlas (TCGA). Our multi-level analysis identified enhancer networks regulated by known cancer driver transcription factors, such as GATA3 and FOXA1 in breast cancer, FOXA2 and SOX17 in endometrial cancer, and NFE2L2, SOX2, and TP63 in squamous cell lung cancer. We also identified several novel networks with prognostic associations, including RUNX1 in kidney cancer, and putative target genes of these transcription factors in primary tumor.

Citation Format: Lijing Yao, Hui Shen, Peter Laird, Peggy Farnham, Berman Benjamin. Inferring regulatory element landscapes and transcription factor networks from cancer methylomes. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 22.
Concordant Patterns of Brain Structure in Mothers with Recurrent Depression and Their Never-Depressed Daughters
Authors: Foland-Ross Lara C. , Behzadian Negin , LeMoult Joelle , Gotlib Ian H.
Published: May 2016

Background: A growing body of research has demonstrated that having a mother with a history of major depressive disorder (MDD) is one of the strongest predictors of depression in adolescent offspring. Few studies, however, have assessed neural markers of this increased risk for depression, or examined whether risk-related anomalies in adolescents at maternal risk for depression are related to neural abnormalities in their depressed mothers. We addressed these questions by examining concordance in brain structure in two groups of participants: mothers with a history of depression and their never-depressed daughters, and never-depressed mothers and their never-depressed daughters. Method: We scanned mothers with (remitted; RMD) and without (control; CTL) a history of recurrent episodes of depression and their never-depressed daughters, computed cortical gray matter thickness, and tested whether mothers' thickness predicted daughters' thickness. Results: Both RMD mothers and their high-risk daughters exhibited focal areas of thinner cortical gray matter compared with their CTL/low-risk counterparts. Importantly, the extent of thickness anomalies in RMD mothers predicted analogous abnormalities in their daughters; this pattern was not present in CTL/low-risk dyads. Conclusions: We identified neuroanatomical risk factors that may underlie the intergenerational transmission of risk for MDD. Our findings suggest that there is concordance in brain structure in dyads that is affected by maternal depression, and that the location, direction, and extent of neural anomalies in high-risk offspring mirror those of their recurrent depressed mothers.
Typification of the name Astragalus vulnerarioides, basionym of Anthyllis vulneraria subsp. vulnerarioides (Fabaceae), and notes on its distribution
Authors: CONTI FABIO , GUGLIELMONE LAURA , PENNESI RICCARDO , BARTOLUCCI FABRIZIO
Published: May 2016

Astragalus vulnerarioides Allioni (1785a: 343) was first described from Mt. Cenis, between the Cottian and Graian Alps (western Alps, France), probably based on herbarium specimens collected by Allioni. The author cited two illustrations in the protologue, which are consequently original material for the name (Art. 9.3 of the ICN, McNeill et al. 2012). The illustrations were drawn by F. Peyrolery. The first was published in the third volume of Flora Pedemontana (T. XIX, Fig. 2, Allioni 1785b), while the second is an unpublished illustration from the Iconographia Taurinensis (Vol. XV, T. 79, Fig. 2, 1765), a collection of watercolours from the 18th and first half of the 19th centuries, housed in the Library of the Department of Plant Biology of the University of Torino (Forneris 2008). Both these illustrations match Allioni’s’ diagnosis, were cited in the protologue and correspond to the current concept of the species.
Changes in gene expression of neo‐squamous mucosa after endoscopic treatment for dysplastic Barrett’s esophagus and intramucosal adenocarcinoma
Authors: Levert‐Mignon Angelique , Bourke Michael J , Lord Sarah J , Taylor Andrew C , Wettstein Antony R , Edwards Melanie , Botelho Natalia K , Sonson Rebecca , Jayasekera Chatura , Fisher Oliver M , Thomas Melissa L , Macrae Finlay , Hussey Damian J , Watson David I , Lord Reginald V
Published: May 2016

Background

Endoscopic therapy, including by radiofrequency ablation (RFA) or endoscopic mucosal resection (EMR), is first line treatment for Barrett’s esophagus (BE) with high‐grade dysplasia (HGD) or intramucosal cancer (IMC) and may be appropriate for some patients with low‐grade dysplasia (LGD).

Objective

The purpose of this study was to investigate the molecular effects of endotherapy.

Methods

mRNA expression of 16 genes significantly associated with different BE stages was measured in paired pre‐treatment BE tissues and post‐treatment neo‐squamous biopsies from 36 patients treated by RFA (19 patients, 3 IMC, 4 HGD, 12 LGD) or EMR (17 patients, 4 IMC, 13 HGD). EMR was performed prior to RFA in eight patients. Normal squamous esophageal tissues were from 20 control individuals.

Results

Endoscopic therapy resulted in significant change towards the normal squamous expression profile for all genes. The neo‐squamous expression profile was significantly different to the normal control profile for 11 of 16 genes.

Conclusion

Endotherapy results in marked changes in mRNA expression, with replacement of the disordered BE dysplasia or IMC profile with a more “normal” profile. The neo‐squamous mucosa was significantly different to the normal control squamous mucosa for most genes. The significance of this finding is uncertain but it may support continued endoscopic surveillance after successful endotherapy.
A new glucocerebrosidase deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease
Authors: Westbroek Wendy , Nguyen Matthew , Siebert Marina , Lindstrom Taylor , Burnett Robert A. , Aflaki Elma , Jung Olive , Tamargo Rafael , Rodriguez-Gil Jorge L. , Acosta Walter , Hendrix An , Behre Bahafta , Tayebi Nahid , Fujiwara Hideji , Sidhu Rohini , Renvoise Benoit , Ginns Edward I. , Dutra Amalia , Pak Evgenia , Cramer Carole , Ory Daniel S. , Pavan William J. , Sidransky Ellen
Published: May 2016

Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. While induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba−/− mice and the control littermate (gba+/+) by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba−/− neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba+/+ neurons. This null allele gba−/− mouse neuronal model provides a much needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies.
Priorities of the state policy of ensuring national security and counteraction to terrorism in Russia
Authors: Берникова  , Bernikova Olga
Published: May 2016

In the article the authors cover a problem of formation of an effective state policy of counteraction to terrorism in the Russian Federation. Political and legal aspects of ensuring the state and public security in modern Russia are characterized. The objective reasons and factors of emergence of terrorism in the modern state are generalized. The main general directions and institutional mechanisms of realization of a state policy of counteraction to terrorism in system of ensuring national security in Russia are revealed.
Ten Things I Wish Someone Had Told Me When I Became a Health Officer
Authors: Frieden Thomas R.
Published: May 2016

Public health, like politics, is the art of the possible. To maximize effectiveness, public health officers in any jurisdiction should (1) get good data and ensure timely and effective dissemination; (2) prioritize and tackle more difficult initiatives first; (3) find, fight, and win winnable battles in areas where progress is possible but not ensured without focused, strategic effort; (4) support and hire great people and protect them so they can do their jobs; (5) address communicable diseases and environmental health effectively; (6) do not cede the clinical realm—public health programs depend on clinical care and on effective coordination between health care and public health; (7) learn and manage the budget cycle; (8) manage the context; (9) never surprise their boss; and (10) follow core principles.
A Dynamic Rabbit Model of Sinus Barotrauma and Its Related Pathology
Authors: Xu Xianrong , Wang Binru , Jin Zhanguo , Zhang Yang
Published: May 2016

BACKGROUND: This study was undertaken to establish a dynamic animal model of sinus barotrauma (SB).METHODS: The right nasal cavities of 65 rabbits were filled with sponges to obstruct the right ostiomeatal complex (OMC), while in the left nasal cavities, the left OMC
was kept clear. The rabbits were exposed to hypobaric chamber simulation. The right sinuses were assigned as the model group, randomly divided into 13 subgroups with 5 in each subgroup, while the left sinuses were assigned as the control group. The hypobaric chamber simulation involved 6 pairs
of ascending/descending speeds (100 m · s−1, 75 m · s−1, 50 m · s−1) to 2 altitudes (13,123 ft or 6562 ft). The ascending/descending speed for Model Group 13 was 15 m · s−1 to an altitude of 13,123
ft. The control group was not exposed to hypobaric chamber simulation or obstruction of the OMC. All rabbits were monitored for behavior and via nasal endoscopy, MRI, and mucosal pathology, and statistically analyzed.RESULTS: SB appeared at the ascending/descending speeds of 50
m · s−1, 75 m · s−1, and 100 m · s−1. SB was more obvious at 100 m · s−1 than at 50 m · s−1 and 75 m · s−1, and SB happened mainly at altitudes between
0-6562 ft. Based on behavior during hypobaric chamber simulation and the results of endoscopic morphology, imaging, and cell pathology, SB could be divided into mild, moderate, and severe.DISCUSSION: By obstructing the OMC and using hypobaric chamber simulation at high ascending/descending
speeds and altitude, a dynamic rabbit model of SB at various degrees was established. The severity of SB was proportional to the ascending/descending speeds and mainly seen below 6562 ft.Xu X, Wang B, Jin Z, Zhang Y. A dynamic rabbit model of sinus barotrauma and its related pathology. Aerosp Med Hum Perform. 2016; 87(6):521–527.
Performance Assessment in the PILOT Experiment On Board Space Stations Mir and ISS
Authors: Johannes Bernd , Salnitski Vyacheslav , Dudukin Alexander , Shevchenko Lev , Bronnikov Sergey
Published: May 2016

BACKGROUND: The aim of this investigation into the performance and reliability of Russian cosmonauts in hand-controlled docking of a spacecraft on a space station (experiment PILOT) was to enhance overall mission safety and crew training efficiency. The preliminary findings on
the Mir space station suggested that a break in docking training of about 90 d significantly degraded performance.METHODS: Intensified experiment schedules on the International Space Station (ISS) have allowed for a monthly experiment using an on-board simulator. Therefore, instead
of just three training tasks as on Mir, five training flights per session have been implemented on the ISS. This experiment was run in parallel but independently of the operational docking training the cosmonauts receive.RESULTS: First, performance was compared between the experiments
on the two space stations by nonparametric testing. Performance differed significantly between space stations preflight, in flight, and postflight. Second, performance was analyzed by modeling the linear mixed effects of all variances (LME). The fixed factors space station, mission phases,
training task numbers, and their interaction were analyzed. Cosmonauts were designated as a random factor. All fixed factors were found to be significant and the interaction between stations and mission phase was also significant.DISCUSSION: In summary, performance on the ISS was
shown to be significantly improved, thus enhancing mission safety. Additional approaches to docking performance assessment and prognosis are presented and discussed.Johannes B, Salnitski V, Dudukin A, Shevchenko L, Bronnikov S. Performance assessment in the PILOT experiment on board space stations Mir and ISS. Aerosp Med Hum Perform. 2016; 87(6):534–544.
Studies on the Synergetic Effects in Multi-Phase Metal Hydride Alloys
Authors: Young Kwo-hsiung , Ouchi Taihei , Meng Tiejun , Wong Diana
Published: May 2016

The electrochemical reactions of multi-phase metal hydride (MH) alloys were studied using a series of Laves phase-related body-centered-cubic (BCC) Ti15.6Zr2.1V43Cr11.2Mn6.9Co1.4Ni18.5Al0.3X (X = V, B, Mg, Y, Zr, Nb, Mo, La, and Nd) alloys. These alloys are composed of BCC (major), TiNi (major), C14 (minor), and Ti2Ni (minor) phases. The BCC phase was found to be responsible for the visible equilibrium pressure plateau between 0.1 MPa and 1 MPa. The plateaus belonging to the other phases occurred below 0.005 MPa. Due to the synergetic effects of other non-BCC phases, the body-centered-tetragonal (BCT) intermediate step is skipped and the face-centered-cubic (FCC) hydride phase is formed directly. During hydrogenation in both gaseous phase and electrochemistry, the non-BCC phases were first charged to completion, followed by charging of the BCC phase. In the multi-phase system, the side with a higher work function along the grain boundary is believed to be the first region that becomes hydrogenated and will not be fully dehydrided after 8 h in vacuum at 300 °C. While there is a large step at approximately 50% of the maximum hydrogen storage for the equilibrium pressure measured in gaseous phase, the charge/discharge curves measured electrochemically are very smooth, indicating a synergetic effect between BCC and non-BCC phases in the presence of voltage and charge non-neutrality. Compared to the non-BCC phases, the C14 phase benefits while the TiNi phase deteriorates the high-rate dischargeability (HRD) of the alloys. These synergetic effects are explained by the preoccupied hydrogen sites on the side of the hydrogen storage phase near the grain boundary.
Systematic Error Modeling and Bias Estimation
Authors: Zhang Feihu , Knoll Alois
Published: May 2016

This paper analyzes the statistic properties of the systematic error in terms of range and bearing during the transformation process. Furthermore, we rely on a weighted nonlinear least square method to calculate the biases based on the proposed models. The results show the high performance of the proposed approach for error modeling and bias estimation.
Competencies in Entrepreneurship
Authors: Baaken Thomas , Kiel Bert , Rossano-Rivero Sue , Baaken Marieke Cornelia , Maas Gideon
Published: May 2016

Entrepreneurial thinking and acting as well as innovation driving managers is a need for society. Companies need to speed up their efforts when facing competition, society need entrepreneurs and innovation driving members. Successful entrepreneurial acting requires particular competencies. Past research has mainly focused on evolving theories to enable an organization to manage innovation successfully by managers. However, it is not the organization but the people, united by a proactive and market-driven culture, that are innovative and which combine to populate and to equip the organization with the required competencies. Hence, the individual competencies in times of change and innovation need to be researched. This paper proposes a research methodology to close this research gap and to analyze the individual competencies that should be fostered by higher education programmes in order to provide graduates with the desired competencies for entrepreneurship and driving innovation.
Key Aspects to Develop Long-Term Microfinance and Financial Inclusion for Social Development
Authors: Castro Omar Alonso Patiño
Published: May 2016

This chapter presents the main guidelines for microfinance to be a successful financial model, mainly for who do not have any access to the traditional financial market. The model can be active for reaching one of its main objectives (to reach poverty eradication worldwide). This will be achieved only if the microcredit institutions do not consider the operating conditions that may oblige them to be part of the traditional financial system. Nowadays, governments, financial sectors, and multilateral agencies have focused their efforts on financial inclusion, as a first experience before using a broad portfolio of microcredit services.
Preservice Teachers' Knowledge Construction with Technology
Authors: Zhou George , Xu Judy
Published: May 2016

Today's teachers are expected to use digital technologies in their teaching. However, teacher education programs do not yet effectively develop teachers' capabilities to teach with technology. In order to search for best approaches, this chapter starts with an epistemological discussion on knowledge, and then moves to a more specific discussion about the nature of preservice teachers' learning about using technology to teach. Using the framework of Technological Pedagogical Content Knowledge, the chapter argues that methods courses of a teacher education program are the key space where preservice teachers can be trained to use technology in subject teaching. Particularly, the Microteaching Lesson Study approach in methods courses was considered an effective way for the development of technology proficiency. A small recent supports the arguments and articulates the success and challenges of the Microteaching Lesson Study approach.
Blended Learning in Teacher Education
Authors: Kim Jackie HeeYoung , Baylen Danilo M. , Leh Amy , Lin Lijia
Published: May 2016

This chapter acknowledges that there is sparse literature to consult about the pedagogical and empirical foundations of blended learning in teacher preparation programs because this field is in its infancy. This chapter will first define blended learning, identify the challenges in teacher preparation programs and indicate how blended-learning approaches will assist teacher educators to meet long-standing and newly emerged challenges, and help future teachers to be reflective practitioners, better problem-solvers, and critical thinkers. This chapter also will discuss pedagogical values of blended learning and factors affecting blended learning course designs, and then showcase best practices using blended learning in order to show the effectiveness of blended learning approaches in teacher education. Lastly, this chapter will discuss considerations when blending teacher education courses.
Leveraging Online Collaboration to Optimize Faculty Efficiency, Student Engagement, and Self-Efficacy
Authors: Matrix Sidneyeve
Published: May 2016

Using two large, blended communications courses as case studies, this chapter suggests that designing online courses that prioritize asynchronous collaboration and self-directed learning is key to increasing the productivity, efficiency, and wellness of students and faculty alike. Informed by insights from student feedback and research on social teaching strategies, the chapter discusses how to use technology to implement active learning opportunities that encourage and engage students. The chapter includes actionable ideas for leveraging the campus learning management system as a collaborative learning platform, to help online faculty manage the many demands on their time.
Assessment in the Online Classroom
Authors: Ryan Mark Patrick
Published: May 2016

This study used quantitative and qualitative data from more than 500 online learners who took secondary, undergraduate, and graduate level online courses during the period 2010 through 2014 and who provided feedback on multiple iterations of those two assessment forms during that period. Data from twelve online course instructors' perceptions were also gathered. Findings include recommendations that instructors of online courses plan discussion board prompts that are narrow in scope, require use of course materials, and are closely monitored by the instructors throughout the posting process. Online quizzes and tests should, whenever possible, allow students immediate access to feedback and results, as such feedback is very well received by students. Various important lessons for online instructors and course planners are shared.
Aerodynamic Characteristic Analysis of Flow Structure around the High-Speed Train Equipment Bay
Authors: Zhang Yong Chang , Xu Yu Gong , Zhang Le Le
Published: May 2016

An improved train model, which contributes to obtain the aerodynamic characteristic of the high-speed train equipment bay, is established. By building a VEB (vehicle equipment bay) model in it, this improved model can demonstrate air flow around the VEB. The result shows that pressure fluctuation appears around the VEB, which gives visible difference from the classical train model. Applying the spectral analysis, the influence factors (include position and train speed) of the pressure fluctuation is studied.
Structural Design of Groove and Micro-Blade of the End Mill Based on Bionics
Authors: Jiang Zhen Xi , Sun Jie , Li Jian Feng
Published: May 2016

The existing end mill is hard to balance the tool rigidity, heat dissipation and chip evacuation. In this study, the geometries of groove and micro-blade of the end mill machining titanium are optimized, through imitating the corn leaf’s tooth based on bionics. The peripheral cutting edge is composed of linear first rake, parabolic second rake and rear face. The chip-hold groove is composed of parabolic main groove and cubic curve vice groove. The cutting process of straight tooth and designed composite tooth are simulated by constructing the two-dimensional orthogonal cutting model using ABAQUS. The results show that: compared to the straight tooth, the designed composite tooth inhibits the generation of serrated chip, and the fluctuations of cutting force are smaller, the squeezing effect on the machined surface is weaker.
Investigation on the Metrology of Conical Thread Gauge
Authors: Zhao Yan , Qu Xing Hua , Tian Yong , Lu Rui Jun , Liu Hong Guang
Published: May 2016

This paper presents a new method for the calibration of conical thread gauges. The procedure involves scanning of conical thread profiles, extracting all the thread main parameters, reconstructing the conical thread model. The metrologies model compared to the Standard one that is established on the basis of theoretical data. Thereby, the actual state of the threads can be fully identified by means of Screwing into the threaded length, which is good for control of the thread quality
An Experimental Research on the Vibration Reduction of Ball Bearings by Superfinishing Process
Authors: Liu Wen Tao , Zhang Yun , Feng Zhi Jing , Wang Dong Feng
Published: May 2016

An experimental research on the reduction of vibration of ball bearings is provided in this paper. The waviness of inner race and outer race are decreased by superfinishing process, and their excitation frequencies are obtained. After the bearings’ vibration is tested, the powers of vibration distributed in different frequency regions are computed. The results reveal that the waviness excitations have a considerable influence on vibration of ball bearings in medium-frequency ranges, and the vibration can be reduced greatly by superfinishing process.
Pipe Thread-Intelligent Detection and Restoration Technology
Authors: Wang Ke , Dong Zhi Xu , Jing Wen Qing
Published: May 2016

Regarding the problem for the existing CNC machining tube tip with the old car exists thread groove, on the basis of the mechanism analysis and experimental study, the detection of inherent inter-spindle screw thread cutting tracks with old spiral phase angle technology is herein proposed. Detected by the advanced hardware and software data processing technology, and strive to achieve the alignment tool for automatic restoration of the old spiral grooves machined technological breakthroughs, innovation and invention of the NC system turning tool with new features slot. Pipe thread repair machining accuracy and efficiency is significantly improved, which savelots of manpower and material resources.
New Simulation System Applying Virtual Reality for AC Servo System
Authors: Liu You Yu , Li Jun , Huang De Yuan , Diao Jie Sheng , Dong Fang Fang
Published: May 2016

To change the empty talk phenomenon of the research of a current AC servo system, virtual reality technology is used to develop the virtual simulation system of an AC servo system. This article described the fundamental principle of the sinusoidal pulse width modulation, introduced the functional structure of the virtual system. The fundamental principle of a wave display and the treatment of the key detail problems were solved. In the end, an example of the AC servo system simulation was given. The simulation of the AC servo system can be used as a soft device instead of a real one, and provide a technology platform for the development of a new AC servo system.
Development of an Information Management System for NC Machine Tools Based on B/S Architecture
Authors: Xu He Nan , Wang Tai Yong , Zou Xiang Xiang , Sang Zhen , Liu Zhe
Published: May 2016

With the development of computer and Internet technology, enterprises need scientific and effective management of the available information resources to make full use of them. Traditionally, paper is used as the medium. However, information on paper is hard to edit, store, and check. Moreover, this way has a higher requirement for employees. This study adopts B/S architecture to build an information management system, which contains complete NC machine tools as well as components. The system uses a framework as the development platform, and uses SQL Server 2005 as the database. This application can fit most browsers.
Study on the Relationship Model between Information and Quality
Authors: Mou W.M.
Published: May 2016

After explaining the definition of accounting information quality and investment efficiency, the paper goes on analyzing the impact of accounting information quality on investment efficiency, puts forward the assumptions, and extracts the Shenzhen Stock Exchange A-share 99 listed companies from 2009 to 2011 sample data for empirical research. It is found that high quality accounting information can contribute to improving the under-investment and restraining over-investment, and thus improve the investment efficiency of the enterprises.
The Study of Offshore Wind Power Jacket Cutting Equipment
Authors: Zheng Zhong Min , Chen Jie , Liu Guo Qing , Qian Hai Dong
Published: May 2016

The current cutting equipment and methods cannot meet the demand of offshore wind cut jacket. In order to solve this problem, we develop a new suit of offshore wind jacket intersecting line cutting equipment. In this paper, detailed structure and operating guide of the equipment have been presented. The characteristics and application range are also included. The new equipment is simple and practical.
Design and Analysis of Conjugate Cam Beating-Up Motion Law
Authors: Li Zhi Jie , Wang Huai Ming
Published: May 2016

According to the special technology requirement of conjugate cam beating-up mechanism, this study introduce the motion law which acceleration curve is a combination of trigonometric functions and linear to mathematical model of cam pressure angle. With the help of computer software MATLAB programming, more detailed analysis and study on this motion law property were given and the variables great impact on the performance of beat-up motion were demonstrated clearly.