text:
About Us
Policy on Financial Support
Contact Us
Subscribe for Free!
Ruthie Cohen
Michael G. Glab
Laurie D. Borman
Ellen Wu
M.J. Bower
Eastina Taylor
Academy of Science and Entrepreneurship English 11
Diane Walker
Stella H.
Josephine McRobbie
Jeremy Hogan
Patti Danner
Hayley Miller
Nicole McPheeters
Paul Bean
Harriet Castrataro
Anne Laker
Amanda Boyer
Jared Posey
Troy Maynard
Jennifer Pacenza
Ann Georgescu
Sean Starowitz
C. D. Culper
Amelia Brown
Samuel Welsch Sveen
Tomi and Jim Allison
Rob Stone
Jennifer Richler
Michelle Gottschlich
Sara Sheikh
Francis Shok Mweze
Alexandria Hollett
Chaz Mottinger
Rachel Glago
Jonah Chester
Erin Martoglio
Claude Cookman
Jim Manion
Megan Betz
Mark Blaney
John Mikulenka
Allison Yates
Erin Hollinden
Jenny Elig
Adam Reynolds
Benjamin Beane
Matt Flaherty
Susan M. Brackney
Luke Wood
Forrest Gilmore
Seth Teeters
Dason Anderson
Grayson Pitts
Duane Busick
Jim Allison
Laura Reagan
Yaël Ksander
Sierra Vandervort
April McKay
Devta Kidd
Doug Storm
Brian Hartz
Lindsay Welsch Sveen
TJ Jaeger
Miller Susens
Mark Anthony Kathurima
Sarah Gordon
Natasha Komoda
Michael Waterford
Richard Koenig
Elijah Pouges
Samantha Eibling
Chris Green
Paulina Guerrero
Andrew Cary
Miles Reiter
Penina Gal
Chris Sims
Ben Meraz
Matthew Fowler
Jen Hockney Bratton
Zak Szymanski
Jonna Mary Yost
Nathan Clark
Daniel Bingham
Justin Banks
Will Reed
Trent Deckard
Dave Torneo
J.D. Gray
Fine Art
Forests / Preserves
Rivers / Lakes
Food & Drink
Organic Farms
Vegetarian / Vegan
Education / Schools
Healthy Living
Exercise / Fitness
Explore / Discover
Animals / Pets
Beyond Bloomington
Indiana University
Religion / Spirituality
Science / Technology
About Us
About Us
Contact Us
Business Underwriting
Fundraising Policy
Sponsored Content
Business Underwriting
A Sense of Place
Purchase Locations
Community Notice
28 results
Grants for Nonprofits, Co-ops, and Independent Contractors in CARES Act
Limestone Post
The Coronavirus Aid, Relief, and Economic Security (CARES) Act that was recently passed by Congress offers programs and initiatives to offer economic relief caused by the COVID-19 pandemic. The program called Economic Injury Disaster Loans & Emergency Economic Injury Grants offers help specifically for nonprofits, cooperatives, and independent contractors.
Click here to learn more about the program.
Read More
April 3, 2020
List of COVID-19 Resources for Bloomington and Monroe County
Limestone Post
Bloomington and Monroe County officials, organizations, and individuals have responded to the COVID-19 crisis by developing programs and resources to help people trying to cope in the pandemic. Limestone Post has compiled this list for people who need help, who want to help, or who just want more information.
Click here for the list.
Read More
March 27, 2020
Community Notice
Monroe County Commission Plans Limestone Quarry Heritage Park
Laurie D. Borman
Writer Laurie D. Borman reports on a project by the Monroe County Plan Commission to turn a 100-acre former quarry property into a limestone heritage park that would highlight the history of the local limestone industry and the art of stonecutting, as well as provide an arts venue open to the public. (Posted: No Swimming.)
Click here to read the full story.
Read More
January 21, 2020
Bloomington 2019: 'The Year of the Farmers' Market Controversy'
Ellen Wu
Media coverage and discussions about the Bloomington Farmers' Market have dismissed the voices of Bloomington's people of color, says historian Ellen Wu. "This is a major omission, considering that African American, Latinx, and Asian American women have made integral interventions into the debate." For this article, Wu interviewed eight women of color to get their perspectives on the controversy.
Click here to read the article.
Read More
December 30, 2019
Big Mike's B-town: Adam Nahas, Artist's Artist
Michael G. Glab
The concept of Artisan Alley — the collective art space, studio, workshop, computer lab, gallery, and other projects — began in Adam Nahas's basement more than a decade ago. But the path from home workshop to one of Bloomington's largest art collectives was not a straight line. Writer Michael G. Glab maps out Nahas's journey.
Click here for the story.
Read More
August 6, 2019
Community Notice
High Cost of Living Among Factors in Local Gender Pay Gap
Hayley Miller
Nicole McPheeters
Indiana has the 49th largest gender wage gap in the nation. And the cost of living in Monroe County compounds the problem. While strides have been made, at the current rate it will take decades to achieve equal pay. Writer Hayley Miller looks at the data and gets the perspectives of three local experts.
Click here to read the story.
Read More
March 19, 2019
Guest Column: CDFI Friendly Bloomington Funds Overlooked Projects
Rachel Glago
Banking rules and regulations often prevent underserved communities from getting financing for needed programs. Without investments, projects to assist in affordable housing, develop small businesses, create community facilities, and support the arts go unrealized. Writer Rachel Glago explains how an innovative financial model, a nonprofit called CDFI Friendly Bloomington, expands opportunities for low-wealth communities.
Click here to read more.
Read More
March 13, 2019
Guest Column: Protecting Indiana Forests, the Bad News and the Good
Anne Laker
Since 2012, the Indiana Division of Forestry has increased logging of state forests by 400 percent, says Anne Laker of the Indiana Forest Alliance. In this guest column, Laker talks about the dangers facing our publicly owned forests and an Indiana Senate bill that could protect them. She also previews the upcoming Wild & Scenic Film Festival in Bloomington.
Click here to read the full story
Read More
February 12, 2019
Community Notice
Small Farms Are Putting the 'Community' in CSAs
Jared Posey
Local farms that participate in Community Supported Agriculture (CSA) programs offer more than just fresh produce. Not only do they make us feel better about how our food is produced, they also create community and enforce a sense of purpose, writes Jared Posey. While CSAs give us far more than we pay for, are they at risk?
Click here to read the full story.
Read More
October 30, 2018
'Benefit Corporations' Reflect New Vision of What Businesses Can Be
Erin Martoglio
Chaz Mottinger
Social impact startups — for-profit businesses that also strive to create a general public benefit — can make their intentions official by forming as benefit corporations, or "B corps." Writer and attorney Erin Martoglio shows how two trailblazing B corps in Bloomington, Green Camino and The Bee Corp, can do more than just turn a profit.
Click here to read the full story.
Read More
August 21, 2018
Stirring the Pot: Flour, Yeast, Salt, Water, and Love — Bloomington Bakers
Ruthie Cohen
Among the many talented people in B-town, some nurture our minds, some our souls, some our bellies, writes Ruthie Cohen. Surround a creative person with "caring mentors and a supportive community, and watch her grow." In her column, Stirring the Pot, Ruthie profiles a few of the nurturing souls in kitchens across town.
Click here to read the full story.
Read More
August 7, 2018
Delinquent and Twisted — New Homes to 'Lowbrow' and Edgier Art Scene
Samuel Welsch Sveen
New spaces — Delinquent Gallery & Tattoo KAIJU and Artisan Alley's Twisted — offer "lowbrow" and boundary-pushing art in Bloomington, says writer Samuel Welsch Sveen. Comics, video-game-themed artwork, cult movies, and tattoos can be found at one; artist studios, a healing shaman, and a retail store for edgier artwork at the other.
Click here to read the full story.
Read More
July 31, 2018
Community Notice


text:
Manglik Dosh, Kuja Dosha, Bhom Dosha, Angaraka Dosha According Vedic Astrology Whenever Mars is situated in 1, 4, 7, 8 or 12 th house of a natal chart or lunar chart {Moon chart} or navmansha horoscope it is called as[…]Read more
Author: mangliks
Get Astrology Remedies for Manglik Dosha
If you are Manglik then you must consider a Manglik life partner for Shaadi/Marriage. Due to the delay in marriage and shaadi, people tend to get more time to finding the right life partner, and also assess whether they have[…]Read more
How Mangal Dosha Can Affect a shaadi
How Mangal Dosha and Manglik Dosh Can Affect a Shaadi/Marriage Be it from our parents, we have been hearing a lot about Mangal Dosh and its powers to disrupt a relationship or shaadi/marriage. The common dosh found in Kundli is[…]Read more
Free kundli online and kundali matching
Online free manglik kundli and kundali matching Traditionally among the Hindus in India, a 'vivah' or a wedding is regarded as a tie for seven births and very sacred. Therefore, to ward off all possible evil influences and ensure a[…]Read more
Looking for boy or girl for marriage
Looking for brides or grooms for marriage India's No #1 and Most Trusted Shaadi Website For Manglik Brides and Grooms | Best Marriage Site In India. They say marriages are made in heaven and we at Mangliks.com strive to mix the right-minded[…]Read more
Are you a bride searching for a groom?
Are you a girl searching for a boy? Have you decided to get married? And, you want to look for your life partner yourself. Go for it. You are the new age woman who knows her mind and is confident. […]Read more
How to Choose the Right Profile for marriage
How to Choose the Right Profile for marriage Search for a life partner is serious business. You could be a guardian wanting to get your ward married. You could be searching a life partner for yourself. Either which way, you[…]Read more
Find your matrimonial partner in just a few clicks
Find your matrimony partner in few clicks Marrying the right person is of paramount importance in any person's life. India lays a lot of emphasis on marriage as having a family and taking one's family name forward is considered to[…]Read more
Being born a Manglik
Being born a Manglik, Manglik and Mangal Dosh When Mangal or Mars, is situated in the 1st, 2nd, 4th, 7th, 8th and 12th house of a person's Kundali or Horoscope (natal charts), it is called Mangal Dosha. Basically, it is[…]Read more
India's free matrimonial sites – the new age matchmakers
India's free matrimonial sites – the new age matchmakers Marriage is a big, big thing in India. India has a unique tradition of arranged marriages that typically follow some patterns while solemnizing. We have a tradition of matchmakers getting life[…]Read more

subset: commoncrawl


text:
Porsche Boxster Build- Encouraged to help my weblog, on this occasion I am going to provide you with with regards to Porsche Boxster Build. And from now on, this is the 1st picture.
Think about image over? is actually that will remarkable???. if you feel and so, I'l t explain to you many photograph once more beneath.
So, if you wish to secure these outstanding pics related to (Porsche Boxster Build), click on save button to store these photos in your personal pc. There're prepared for save, if you'd prefer and wish to grab it, simply click save logo on the web page, and it'll be instantly downloaded to your desktop computer. At last if you desire to grab unique and recent photo related with (Porsche Boxster Build), please follow us on google plus or bookmark this blog, we attempt our best to offer you regular up-date with fresh and new pics. We do hope you love keeping right here. For some up-dates and recent news about (Porsche Boxster Build) graphics, please kindly follow us on twitter, path, Instagram and google plus, or you mark this page on bookmark section, We try to present you up-date regularly with all new and fresh photos, love your surfing, and find the best for you.
Thanks for visiting our site, contentabove (Porsche Boxster Build) published by at . Nowadays we're pleased to declare that we have found an awfullyinteresting nicheto be discussed, that is (Porsche Boxster Build) Many people searching for details about(Porsche Boxster Build) and definitely one of them is you, is not it?


text:
Mini Review ARTICLE
What are the macrophages and stellate cells doing in pancreatic adenocarcinoma?
- 1Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- 2Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, Los Angeles, CA, USA
Pancreatic ductal adenocarcinoma is a devastating disease characterized by a dense desmoplastic stroma. Chemo- and radio-therapeutic strategies based on targeting cancer cells have failed in improving the outcome of this cancer suggesting important roles for stroma in therapy resistance. Cells in the tumor stroma have been shown to regulate proliferation, resistance to apoptosis and treatments, epithelial to mesenchymal transition (EMT) and stemness of cancer cells. Stellate cells in their activated state have been thought over the past decade to only have tumor promoting roles. However, recent findings suggest that stellate cells may have protective roles as well. The present review highlights the latest findings on the role of two major components of tumor stroma, pancreatic stellate cells and macrophages, in promoting or inhibiting pancreatic cancer, focused on their effects on EMT and cancer stemness.
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States. The 5-year survival rate remains at 5% making it one of the worst outcomes among cancers (Siegel et al., 2012).
PDAC is unique among solid tumors because of the extremely dense desmoplastic stroma that surrounds the cancer cell glands of this tumor. In fact, the majority of the tumor volume is made of stroma compared to a much smaller volume occupied by the cancer cells. Understanding of the populations of the cells present in the stroma is needed to better target the correct sub-populations.
Stellate Cells in the Context of Pancreatic Cancer
Pancreatic stellate cells (PSCs) were first isolated in 1998 by two groups- one from Australia and one Germany (Apte et al., 1998; Bachem et al., 1998). Since then extensive work has been done to understand the role of PSC in promoting pancreatic fibrosis and cancer. There has been general agreement for over a decade that the PSCs promote pancreatic cancer growth, metastasis and resistance to treatment, with observed association between strong stroma and worse outcome (Erkan et al., 2008; Beatty et al., 2011). Indeed, stellate cells promote the growth of cancer cells in sub-cutaneous mouse models of pancreatic cancer (Bachem et al., 2005). One mechanism through which PSCs mediate their pro-cancer effect is through secretion of large amounts of extracellular matrix proteins, responsible in large part for the fibrotic reaction characterizing human PDAC (Apte et al., 2004) as well as for inducing resistance to apoptosis in the cancer cells (Edderkaoui et al., 2005). Activated PSCs secrete growth factors, metallo-proteases, and cytokines shown to stimulate cancer cell proliferation, migration and metastasis of the pancreatic cancer cells (Wehr et al., 2011).
Stellate Cells Regulate Epithelial-Mesenchymal Transition (EMT) and Stemness of the Cancer Cells
A major cause of the poor outcome for patients with pancreatic cancer is the ability of the cancer cells to metastasize and to develop resistance to treatments mainly through development of cancer stemness characteristics. EMT is a process by which epithelial cells lose their cell polarity and cell-cell adhesion while gaining migratory and invasive properties to become mesenchymal stem cells. The importance of the process of EMT is that it is responsible for both metastasis and therapy resistance through development of cancer stemness (Mani et al., 2008; Arumugam et al., 2009). Cancer stem cells markers such as ALDH1A1, ABCG2, and nestin are highly expressed in metastatic cancer cells compared to non-metastatic cancer cells in animal models of pancreatic cancer. The metastatic cells show strong expression of EMT markers indicating the association between EMT, cancer stemness and metastasis (Matsuda et al., 2014).
Recently, the role of PSCs in up-regulating EMT has become more evident. Co-culture of cancer cells with PSCs induces a fibroblast-like appearance of the cancer cells (Kikuta et al., 2010). The cancer cells assume fibroblast characteristics such as increased migration; and expression of mesenchymal markers Vimentin, Snail-1 and Zeb; and decrease expression of epithelial markers in the cancer cells (Kikuta et al., 2010; Mizuuchi et al., 2014). The mechanisms underlying the promotion of EMT are still under investigation and are not established. Because PSCs produce significant amounts of Transforming growth factor-beta (TGF-β) (Shek et al., 2002), there has been interest in the role of TGF-β in EMT. In one study, the PSC-induced EMT induction was not altered by treatment with anti-TGF-β-neutralizing antibody, suggesting no role of TGF-β in this process (Kikuta et al., 2010). Differently, another study showed that specific neutralizing anti-TGF-β prevented EMT, cancer stem cells phenotype, and tumorigenicity (Al-Assar et al., 2014).
There is accumulating evidence that small non-coding microRNAs (miRNAs) mediate the interaction between PSCs and cancer cells. Co-culture of pancreatic cancer cells with PSCs led to increased expression of miR-210. PSCs-induced miR-210 up-regulation was inhibited by inhibitors of ERK and PI3K/Akt pathways. Inhibition of miR-210 expression decreased the expression of Vimentin and Snail-1 as well as cell migration, and increased the membrane-associated expression of β-catenin in Panc-1 cells co-cultured with PSCs indicating its role in regulating EMT and migration of the pancreatic cancer cells (Takikawa et al., 2013).
The role of hypoxia, which is highly present in solid tumors, on tumor promotion was highly investigated in the last few years, Hypoxia increases the activity of PSCs in vitro leading to its migration, secretion of collagen I and VEGF (Masamune et al., 2008; Erkan et al., 2009). The fibrosis-related gene connective tissue growth factor (CTGF/CCN2) protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CTGF/CCN2. Indeed, CTGF/CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and co-localized with hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas (Bennewith et al., 2009).
PSCs enhance the cancer stem cell phenotype of pancreatic cancer cells by inducing the expression of genes such as ABCG2, Nestin and LIN28 leading to an enhanced radio-resistance of pancreatic cancer cells in in vitro and in vivo systems of pancreatic cancer (Hamada et al., 2012; Al-Assar et al., 2014). The expression of several EMT and cancer stem cell markers is associated with significant in vivo tumorigenicity.
Very importantly, PSCs show greater activity when isolated from patients after undergoing chemo-radiation therapy as measured by the ability of PSCs to migrate, expand and contract (Cabrera et al., 2014). This data together with the high level of resistance to treatments developed in pancreatic cancer patients suggest that PSC activity may contribute to the development of resistance to therapy in the cancer cells. Indeed, PSCs were found to promote in vitro sphere formation and invasiveness of pancreatic cancer stem cells in an activin/Alk4 receptor -dependent manner (Lonardo et al., 2012). They also stimulated metastasis and the ability to form colonies in mouse orthotopic model of pancreatic cancer (Hwang et al., 2008). In another study, PSCs mediated radioprotection of pancreatic cancer cells in a β1 integrin dependent manner (Mantoni et al., 2011).
Clinical treatment of pancreatic cancer patients with Nab-paclitaxel combined with gemcitabine significantly decreased tumor growth and collagen staining as well as decreased the level of activated stellate cells (Alvarez et al., 2013). There was no association between the level of the secreted protein acidic and rich in cysteine (SPARC) and metastasis or the effect of Nab-paclitaxel (Schneeweiss et al., 2014).
Controversial Role of Stellate Cells
More recently, emerging data is challenging the established PSC pro-cancer role and provides strong evidence for an anti-cancer role of PSCs.
Ozdemir et al. (2014) showed that deletion of activated stellate cells in transgenic mice led to invasive and undifferentiated tumors, enhanced EMT, cancer stemness and decreased survival. The deletion of stellate cells resulted in decreases in both non-invasive precursor pancreatic intraepithelial neoplasia (PanIN) and the PDAC stage of the disease. Importantly, the authors observed an association between fewer activated stellate cells in the tumors with reduced survival in PDAC patients confirming their animal observations (Ozdemir et al., 2014). Finally, depletion of PSCs induced suppression of immune surveillance with increased CD4+Foxp3+Tregs in mouse tumors (Ozdemir et al., 2014). Of note, CD4+Foxp3+Tregs are cells of the immune system that suppress immune responses allowing the cancer cells to survive the immune checkpoint.
Simultaneously with this study, another study confirmed this data showing that depletion of stromal cells from pancreatic tumors, through genetic or pharmacological targeting of the Sonic hedgehog (SH) pathway, results in a reduced stromal content as expected, but led to a poorly differentiated histology, increased vascularity and proliferation, and reduced survival in an animal model of pancreatic cancer. Of note, SH drives the formation of a fibroblast-rich desmoplastic stroma in the tumor (Rhim et al., 2014).
Very importantly, the secretory protein periostin that has been suggested to function as a cell adhesion molecule and promote the invasiveness or growth rate of tumors is highly expressed by PSCs compared to cancer cells in humans (Erkan et al., 2007; Kanno et al., 2008). In addition, Recombinant periostin increased activation of the PSCs. These effects were reversed by silencing periostin expression and secretion by small interfering RNA transfection. Periostin stimulated cancer cell growth and induced their chemoresistance as well as resistance to starvation and hypoxia (Erkan et al., 2007).
This data suggest that PSC activation is a response by the body to prevent cancer development. The mechanism mediating this effect is not well known.
However, data from Kanno et al. (2008) showed that high concentration of recombinant periostin promoted cell migration of the cancer cells mediated by Akt kinase activation. They also found that lower doses of periostin had opposite effect causing expression of epithelial phenotype markers and reduction in mesenchymal markers resulting in reduced cell migration. The findings suggest that periostin has concentration-dependent dual effects on the development of pancreatic cancer (Kanno et al., 2008), especially on EMT and migration of the cancer cells. In the Erkan et al. study, periostin induced activation of the PSCs but decreased their invasiveness (Erkan et al., 2007). Periostin is highly expressed by PSC and its level may be a key regulator of the pro-EMT/cancer and the anti-EMT/cancer effects of PSC. That is, high expression of periostin by PSC will induce EMT, migration metastasis and stemness of the cancer cells; whereas, low doses of periostin will do the opposite.
The findings listed above indicate that there are potentially divergent roles for stellate cells in pancreatic cancer. That is, there may be pro-cancer, neutral, and anti-cancer effects of this stromal component. One possibility is that there are sub-populations and/or sub-phenotypes of PSCs that play different roles in the promotion or prevention of PDAC. The level of periostin expressed by PSC could be a good marker to start with. The different sub-phenotypes of PSCs may be affected by the other tumor microenvironment components. Targeting all of the PSCs together may not necessarily lead to an anti-cancer effect. Further studies are needed to better understand the potential divergent roles of PSCs before defining a treatment strategy based on targeting PSCs.
Role of Macrophages in Promoting Pancreatic Cancer
In addition to the PSCs, macrophages are a major component of the pancreatic tumor microenvironment. The link between inflammation and pancreatic cancer pathogenesis is well established (Yadav and Lowenfels, 2013).
Recently published studies suggest that the macrophages infiltrating the pancreas drive the acinar to ductal metaplasia, a key early process in pancreas carcinogenesis. Pancreatic acinar cells have the capacity to undergo metaplasia to a ductal cell phenotype in the setting of acute or chronic inflammation, representing an important link to PDAC. The process involves inflammatory cytokines such as RANTES and tumor necrosis factor-alpha (TNF-α) and inflammatory intracellular signals such as nuclear factor-κB (NF-κB) as well as growth factors such as TGF-α and epidermal growth factor-receptor (EGFR) (De Lisle and Logsdon, 1990; Sandgren et al., 1990; Song et al., 1999; Means et al., 2003). Genetically engineered mouse models using mutant Kras support the concept that acinar to ductal metaplasia precedes PanIN and PDAC development (Song et al., 1999; Means et al., 2005). Importantly, induction of KrasG12D mutation in acinar cells in mice leads to their transformation to PanIN lesions even in the absence of pancreas injury (Habbe et al., 2008).
Expression of mutant Kras in pancreatic acinar cells expedites their transformation to a duct-like phenotype by inducing local inflammation. Specifically, KrasG12D induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemo-attractant for macrophages.
Infiltrating macrophages amplify the formation of KrasG12D-caused abnormal pancreatic structures by re-modeling the extracellular matrix and providing cytokines such as TNF-α. Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell-specific promoter both resulted in a decreased formation of abnormal structures and decreased progression of acinar to ductal metaplasia to PanIN lesions (Liou et al., 2014). Of note, we have shown before that ICAM-1 is also expressed in acinar cells during pancreatitis (Zaninovic et al., 2000).
Both M1 and M2 macrophage phenotypes were found in the pancreatic tumor microenvironment. M1 macrophages are characterized by high expression of inducible nitric oxide synthase (iNOS), IL-10, major histocompatibility complex II (MHC-II), and low IL-12 among others. M2 macrophages express low level or no iNOS, IL-10, and MHC-II, and high levels of Arginase1, CD206, and C-C chemokine receptor 3 (CCR3). Greater levels of tumor-infiltrating M2 macrophages are significantly associated with shorter survival, whereas M1high/M2low correlated significantly with longer survival and suggested using the M1/M2 ratio as independent prognosticator (Ino et al., 2013). Analysis of pancreatic cancer tissues from 36 patients showed that the number of infiltrating macrophages in tumor tissue was significantly greater in patients with metastases to lymph nodes compared to tumor tissue without metastasis (Gardian et al., 2012).
Co-culture with macrophages or with tumor associated macrophage-conditioned media significantly reduced apoptosis and activation of the caspase-3 pathway during gemcitabine treatment of pancreatic cancer cells pointing to a survival effect that the macrophages provide to cancer cells (Weizman et al., 2014). Also, reducing macrophage recruitment and activation in PDAC models in mice demonstrated improved response to gemcitabine compared with controls (Weizman et al., 2014). The data by Weizman et al. showed that decreasing macrophage recruitment augmented the response of PDAC to chemotherapy and that tumor associated macrophages induced up-regulation of cytidine deaminase (CDA), the enzyme that metabolizes gemcitabine following its transport into the cell (Weizman et al., 2014).
Liu et al. showed recently that co-culture with M2-polarized tumor associated macrophages up-regulated the expression of mesenchymal markers Vimentin and Snail and decreased the epithelial marker E-cadherin in pancreatic cancer cells (Liu et al., 2013). Furthermore, co-culture of tumor associated macrophages with pancreatic cancer cells increased proliferation and migration of the cancer cells. They demonstrated that TLR4 and IL-10 mediate the cross talk between tumor associated macrophages and cancer cells (Liu et al., 2013).
All these data indicate that a bidirectional interaction between cancer cells and macrophages determines the fate of their phenotypes, more or less metastatic and resistant to treatment for cancer cells, and pro-inflammatory or pro-cancer for macrophages.
Interaction between Macrophages and Stellate Cells
When quiescent pancreatic stellate cells are co-cultured with macrophage cell lines, the stellate cells showed morphological changes consistent with myofibroblast morphology (Shi et al., 2014). In the presence of Heparin-binding EGF (HB-EGF) many of the stellate cells co-cultured with macrophages were positive for their activation marker αSMA (Shi et al., 2014).
In the same study they found that PSCs have the potential to regulate macrophage function, inducing the production of multiple cytokines, partially through PSC production of IL-6 (Shi et al., 2014). However, caution should be taken as these studies were performed in cell lines and not in cells freshly isolated from animals or humans (Shi et al., 2014).
In a different study, culture of peripheral blood mononuclear cells (PBMC) with PSCs supernatants or IL-6 promoted PBMC differentiation into Myeloid-derived suppressor cells MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells (Mace et al., 2013). IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation (Mace et al., 2013). Importantly, the level of cytokines produced by different PSCs was different suggesting different phenotypes of the PSCs and suggesting using these cytokines as markers for different sub-populations of PSCs.
Accumulating evidence indicate that targeting PSCs and/or macrophages needs to be focused on targeting specific sub-populations of these cells. Even though M2 macrophage populations are a good target, further studies are needed to determine markers of the pro-cancer PSCs (Figure 1).
Figure 1. Interactions between macrophages and stellate cells mediating promotion of pancreatic cancer with a short list of possible mediators of these interactions.
Multiple studies have tried targeting pathways rather than targeting the whole cell populations. Therapies against molecules or pathways such as vascular endothelial growth factor (VEGF) (Taeger et al., 2011), sonic hedgehog (Olive et al., 2009), and hyaluronic acid (Provenzano et al., 2012) are now tested. Other studies including our work suggest that the IL-6 and STAT3 pathway is a relevant target due to its constitutive activation in the pancreatic cancer cells, immunosuppressive cells, and in PSC within the stroma (Corcoran et al., 2011; Lesina et al., 2011; Huang et al., 2012).
In summary, we have gained a lot of knowledge about the interactions between cancer cells and cells present in the tumor microenvironment, especially the interactions between cancer cells, macrophages, and PSCs. Ample work is needed to understand how cells in the tumor microenvironment regulate PSCs phenotype. Periostin could be is a good candidate to differentiate between different populations of PSCs.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supported by K01AA019996, P01CA163200 and Department of Veterans Affairs.
Al-Assar, O., Demiciorglu, F., Lunardi, S., Gaspar-Carvalho, M. M. I., McKenna, W. G. I., Muschel, R. M., et al. (2014). Contextual regulation of pancreatic cancer stem cell phenotype and radioresistance by pancreatic stellate cells. Radiother. Oncol. 111, 243–251. doi: 10.1016/j.radonc.2014.03.014
Alvarez, R., Musteanu, M., Garcia-Garcia, E., Lopez-Casas, P. P., Megias, D., Guerra, C., et al. (2013). Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br. J. Cancer 109, 926–933. doi: 10.1038/bjc.2013.415
Apte, M. V., Haber, P. S., Applegate, T. L., Norton, I. D., Korsten, M. A., Pirola, R. C., et al. (1998). Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43, 128–133. doi: 10.1136/gut.43.1.128
Apte, M. V., Park, S., Phillips, P. A., Santucci, N., Goldstein, D., Kumar, R. K., et al. (2004). Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29, 179–187. doi: 10.1097/00006676-200410000-00002
Arumugam, T., Ramachandran, V., Fournier, K. F., Wang, H., Marquis, L., Abbruzzese, J. L., et al. (2009). Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 69, 5820–5828. doi: 10.1158/0008-5472.CAN-08-2819
Bachem, M. G., Schneider, E., Gross, H., Weidenbach, H., Schmid, R. M., Menke, A., et al. (1998). Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115, 421–432. doi: 10.1016/S0016-5085(98)70209-4
Bachem, M. G., Schunemann, M., Ramadani, M., Siech, M., Beger, H., Buck, A., et al. (2005). Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907–921. doi: 10.1053/j.gastro.2004.12.036
Beatty, G. L., Chiorean, E. G., Fishman, M. P., Saboury, B., Teitelbaum, U. R., Sun, W., et al. (2011). CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616. doi: 10.1126/science.1198443
Bennewith, K. L., Huang, X., Ham, C. M., Graves, E. E., Erler, J. T., Kambham, N., et al. (2009). The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res. 69, 775–784. doi: 10.1158/0008-5472.CAN-08-0987
Cabrera, M. C., Tilahun, E., Nakles, R., Diaz-Cruz, E. S., Charabaty, A., Suy, S., et al. (2014). Human pancreatic cancer-associated stellate cells remain activated after in vivo chemoradiation. Front. Oncol. 4:102. doi: 10.3389/fonc.2014.00102
Corcoran, R. B., Contino, G., Deshpande, V., Tzatsos, A., Conrad, C., Benes, C. H., et al. (2011). STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71, 5020–5029. doi: 10.1158/0008-5472.CAN-11-0908
De Lisle, R. C., and Logsdon, C. D. (1990). Pancreatic acinar cells in culture: expression of acinar and ductal antigens in a growth-related manner. Eur. J. Cell Biol. 51, 64–75.
Edderkaoui, M., Hong, P., Vaquero, E. C., Lee, J. K., Fischer, L., Friess, H., et al. (2005). Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G1137–G1147. doi: 10.1152/ajpgi.00197.2005
Erkan, M., Kleeff, J., Gorbachevski, A., Reiser, C., Mitkus, T., Esposito, I., et al. (2007). Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology 132, 1447–1464. doi: 10.1053/j.gastro.2007.01.031
Erkan, M., Michalski, C. W., Rieder, S., Reiser-Erkan, C., Abiatari, I., Kolb, A., et al. (2008). The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 6, 1155–1161. doi: 10.1016/j.cgh.2008.05.006
Erkan, M., Reiser-Erkan, C., Michalski, C. W., Deucker, S., Sauliunaite, D., Streit, S., et al. (2009). Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia 11, 497–508. doi: 10.1593/neo.81618
Gardian, K., Janczewska, S., Olszewski, W. L., and Durlik, M. (2012). Analysis of pancreatic cancer microenvironment: role of macrophage infiltrates and growth factors expression. J. Cancer 3, 285–291. doi: 10.7150/jca.4537
Habbe, N., Shi, G., Meguid, R. A., Fendrich, V., Esni, F., Chen, H., et al. (2008). Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl. Acad. Sci. U.S.A. 105, 18913–18918. doi: 10.1073/pnas.0810097105
Hamada, S., Masamune, A., Takikawa, T., Suzuki, N., Kikuta, K., Hirota, M., et al. (2012). Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 421, 349–354. doi: 10.1016/j.bbrc.2012.04.014
Huang, C., Huang, R., Chang, W., Jiang, T., Huang, K., Cao, J., et al. (2012). The expression and clinical significance of pSTAT3, VEGF and VEGF-C in pancreatic adenocarcinoma. Neoplasma 59, 52–61. doi: 10.4149/neo_2012_007
Hwang, R. F., Moore, T., Arumugam, T., Ramachandran, V., Amos, K. D., Rivera, A., et al. (2008). Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926. doi: 10.1158/0008-5472.CAN-07-5714
Ino, Y., Yamazaki-Itoh, R., Shimada, K., Iwasaki, M., Kosuge, T., Kanai, Y., et al. (2013). Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br. J. Cancer 108, 914–923. doi: 10.1038/bjc.2013.32
Kanno, A., Satoh, K., Masamune, A., Hirota, M., Kimura, K., Umino, J., et al. (2008). Periostin, secreted from stromal cells, has biphasic effect on cell migration and correlates with the epithelial to mesenchymal transition of human pancreatic cancer cells. Int. J. Cancer 122, 2707–2718. doi: 10.1002/ijc.23332
Kikuta, K., Masamune, A., Watanabe, T., Ariga, H., Itoh, H., Hamada, S., et al. (2010). Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 403, 380–384. doi: 10.1016/j.bbrc.2010.11.040
Lesina, M., Kurkowski, M. U., Ludes, K., Rose-John, S., Treiber, M., Klöppel, G., et al. (2011). Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469. doi: 10.1016/j.ccr.2011.03.009
Liou, G. Y., Doppler, H., Necela, B., Edenfield, B., Zhang, L., Dawson, D. W., et al. (2014). Mutant Kras-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov. 5, 52–63. doi: 10.1158/2159-8290.CD-14-0474
Liu, C. Y., Xu, J. Y., Shi, X. Y., Huang, W., Ruan, T. Y., Xie, P., et al. (2013). M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab. Invest. 93, 844–854. doi: 10.1038/labinvest.2013.69
Lonardo, E., Frias-Aldeguer, J., Hermann, P. C., and Heeschen, C. (2012). Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 11, 1282–1290. doi: 10.4161/cc.19679
Mace, T. A., Ameen, Z., Collins, A., Wojcik, S., Mair, M., Young, G. S., et al. (2013). Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 73, 3007–3018. doi: 10.1158/0008-5472.CAN-12-4601
Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715. doi: 10.1016/j.cell.2008.03.027
Mantoni, T. S., Lunardi, S., Al-Assar, O., Masamune, A., and Brunner, T. B. (2011). Pancreatic stellate cells radioprotect pancreatic cancer cells through beta1-integrin signaling. Cancer Res. 71, 3453–3458. doi: 10.1158/0008-5472.CAN-10-1633
Masamune, A., Kikuta, K., Watanabe, T., Satoh, K., Hirota, M., and Shimosegawa, T. (2008). Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G709–G717. doi: 10.1152/ajpgi.90356.2008
Matsuda, Y., Yoshimura, H., Ueda, J., Naito, Z., Korc, M., and Ishiwata, T. (2014). Nestin delineates pancreatic cancer stem cells in metastatic foci of NOD/Shi-scid IL2Rgamma(null) (NOG) mice. Am. J. Pathol. 184, 674–685. doi: 10.1016/j.ajpath.2013.11.014
Means, A. L., Meszoely, I. M., Suzuki, K., Miyamoto, Y., Rustgi, A. K., Coffey, R. J. Jr., et al. (2005). Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132, 3767–3776. doi: 10.1242/dev.01925
Means, A. L., Ray, K. C., Singh, A. B., Washington, M. K., Whitehead, R. H., Harris, R. C. Jr., et al. (2003). Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology 124, 1020–1036. doi: 10.1053/gast.2003.50150
Mizuuchi, Y., Aishima, S., Ohuchida, K., Shindo, K., Fujino, M., Hattori, M., et al. (2014). Anterior gradient 2 downregulation in a subset of pancreatic ductal adenocarcinoma is a prognostic factor indicative of epithelial-mesenchymal transition. Lab. Invest. 95, 193–206. doi: 10.1038/labinvest.2014.138
Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., et al. (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461. doi: 10.1126/science.1171362
Ozdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C. C., Simpson, T. R., et al. (2014). Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734. doi: 10.1016/j.ccr.2014.04.005
Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., and Hingorani, S. R. (2012). Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429. doi: 10.1016/j.ccr.2012.01.007
Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., et al. (2014). Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747. doi: 10.1016/j.ccr.2014.04.021
Sandgren, E. P., Luetteke, N. C., Palmiter, R. D., Brinster, R. L., and Lee, D. C. (1990). Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61, 1121–1135. doi: 10.1016/0092-8674(90)90075-P
Schneeweiss, A., Seitz, J., Smetanay, K., Schuetz, F., Jaeger, D., Bachinger, A., et al. (2014). Efficacy of nab-paclitaxel does not seem to be associated with SPARC expression in metastatic breast cancer. Anticancer Res. 34, 6609–6615.
Shek, F. W., Benyon, R. C., Walker, F. M., McCrudden, P. R., Pender, S. L., Williams, E. J., et al. (2002). Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am. J. Pathol. 160, 1787–1798. doi: 10.1016/S0002-9440(10)61125-X
Shi, C., Washington, M. K., Chaturvedi, R., Drosos, Y., Revetta, F. L., Weaver, C. J., et al. (2014). Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction. Lab. Invest. 94, 409–421. doi: 10.1038/labinvest.2014.10
Siegel, R., Naishadham, D., and Jemal, A. (2012). Cancer statistics. CA Cancer J. Clin. 62, 10–29. doi: 10.3322/caac.20138
Song, S. Y., Gannon, M., Washington, M. K., Scoggins, C. R., Meszoely, I. M., Goldenring, J. R., et al. (1999). Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha. Gastroenterology 117, 1416–1426. doi: 10.1016/S0016-5085(99)70292-1
Taeger, J., Moser, C., Hellerbrand, C., Mycielska, M. E., Glockzin, G., Schlitt, H. J., et al. (2011). Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer. Mol. Cancer Ther. 10, 2157–2167. doi: 10.1158/1535-7163.MCT-11-0312
Takikawa, T., Masamune, A., Hamada, S., Nakano, E., Yoshida, N., and Shimosegawa, T. (2013). miR-210 regulates the interaction between pancreatic cancer cells and stellate cells. Biochem. Biophys. Res. Commun. 437, 433–439. doi: 10.1016/j.bbrc.2013.06.097
Wehr, A. Y., Furth, E. E., Sangar, V., Blair, I. A., and Yu, K. H. (2011). Analysis of the human pancreatic stellate cell secreted proteome. Pancreas 40, 557–566. doi: 10.1097/MPA.0b013e318214efaf
Weizman, N., Krelin, Y., Shabtay-Orbach, A., Amit, M., Binenbaum, Y., Wong, R. J., et al. (2014). Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 33, 3812–3819. doi: 10.1038/onc.2013.357
Yadav, D., and Lowenfels, A. B. (2013). The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144, 1252–1261. doi: 10.1053/j.gastro.2013.01.068
Zaninovic, V., Gukovskaya, A. S., Gukovsky, I., Mouria, M., and Pandol, S. J. (2000). Cerulein upregulates ICAM-1 in pancreatic acinar cells, which mediates neutrophil adhesion to these cells. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G666–G676.
Keywords: stellate cells, macrophages, pancreatic cancer, periostin, TGF-beta
Citation: Pandol SJ and Edderkaoui M (2015) What are the macrophages and stellate cells doing in pancreatic adenocarcinoma? Front. Physiol. 6:125. doi: 10.3389/fphys.2015.00125
Received: 18 February 2015; Accepted: 07 April 2015;
Published: 15 May 2015.
Edited by:Atsushi Masamune, Tohoku University Graduate School of Medicine, Japan
Reviewed by:Kyoko Shimizu, Tokyo Women's Medical University, Japan
Shin Hamada, Tohoku University Graduate School of Medicine, Japan
Mert Erkan, Klinikum rechts der Isar - Technische Universitaet Muenchen, Germany
Copyright © 2015 Pandol and Edderkaoui. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mouad Edderkaoui, Departments of Medicine, Cedars-Sinai Medical Center, Veterans Affairs-Los Angeles and University of California, Los Angeles, 8700 Beverly Boulevard, Davis Building, Suite 3100 Los Angeles, CA 90048, USA, email@example.com


text:
Hell Really Exists
While he lived there about 150 years after Tertullian had died, Saint Augustine was familiar with Carthage. In his Confessions he recalls this city where he was sent to be educated at the age of sixteen, and where he spent most of the decade of his twenties, first as a student, later as a teacher: "I went to Carthage, where I found myself in the midst of a hissing cauldron of lust." As the largest cosmopolitan city in the Roman territory of Africa, Carthage was an epicenter of popular entertainment in the empire, famous for its circus, amphitheater and gladiatorial shows - a fourth-century Las Vegas. As a libidinous teenager, Augustine's particular weakness was for the theater, he tells us, "because the plays reflected my own unhappy plight and were tinder to my fire." He was a fan of romantic tragedies, and the more the actors moved him to pity, the more delight he derived. The uniting and then distressing separation of lovers was an exquisite pleasure to witness, he admits, although he had "no wish to endure the sufferings which I only saw on the stage."24 But the sweet tears these imaginary fictions brought to his eyes absorbed him and strangely ramped up from friendly feelings toward the victims of love, he confides, into full-force torrents of lust.
While not much of a fan of gladiators himself, Augustine describes at length the experience of his close friend, Alypius, who was "caught in the whirl of easy morals at Carthage, with its continual round of futile entertainments, and had lost his heart and his head to the games in the amphitheater." For a time Alypius was able to overcome his craving for the games, but then on a trip to Rome he set out to prove his mastery of his former obsession by accompanying friends to the arena for a gladiatorial show, determined to keep his eyes clamped shut and thus serve as a model of virtue to his companions. In a gripping passage, Augustine describes the scene:
An incident in the fight drew a great roar from the crowd, and this thrilled him so deeply that he could not contain his curiosity. ... So he opened his eyes____When he saw the blood, it was as though he had drunk a deep draught of savage passion. Instead of turning away, he fixed his eyes upon the scene and drank in all its frenzy, unaware of what he was doing. He reveled in the wickedness of the fighting and was drunk with the fascination of bloodshed. He was no longer the man who had come to the arena, but simply one of the crowd which he had joined [W]hen he left the arena, he carried with him a diseased mind which would leave him no peace until he came back again.25
From these accounts, we get a sense for the perverse appeal Augustine finds in the popular forms of entertainment of his day. It is an appeal he knows first-hand; when one succumbs, the will is overcome with a craving that cannot be controlled. Although Augustine's reservations about the spectacles did have something to do with their pagan elements and with the work of demons for whom they offered cover, criticisms he shared with Tertullian, they had even more to do with their irresistible attractiveness to human cupidity - to our proclivity to surrender our will to unrestrained cravings for objects that are less than God.
It is worth noting that much had changed in the Roman Empire in the years that separated Augustine from Tertullian. After Emperor Constantine's conversion to Christianity in 312 ce, pagan society had begun feeling pressure from edicts granting greater tolerance for the Church and less tolerance for pagan religion. During Augustine's life, laws were issued by Emperor Theodosius I directing local officials to remove idols and altars from pagan temples and to destroy them, to confiscate property on which pagan rites were performed, to prohibit visits to pagan temples, and to exclude pagans from imperial employment. Because the Roman senate and army remained largely pagan, these laws were resisted by local officials, but intense and violent pressure from bands of Christian vigilantes such as the Circumcellions in Egypt was very effective in curbing the open practice of pagan religion. Still, the games held on; they had a firm grasp on the popular imagination - for both pagans and Christians.
Given the ebb and flow of pagan devotion in the late fourth century, the time was ripe for someone to discern what this meant. Augustine stepped up to the challenge. In his Confessions, On Christian Doctrine, and his monumental City of God, he marked the passing of pagan culture by distinguishing between pagan poetry, temple cult, and philosophy. For the most part, he favored its philosophy but wrote abusively about its poetry, myth, and cult. The philosophers, and particularly the Platonists, he wrote in On Christian Doctrine, "have said things which are indeed true and are well accommodated to our faith."26 In the City of God, he lays down a sweeping criticism of the work of the poets and their stories of the gods - stories frequently performed at the theater - insisting that these stories are "foolish things" that cannot be rendered into real wisdom with any amount of interpretation.
But as is often the case with Augustine, these declarations do not tell the whole story. On the opening page of the City of God he transcribes a stanza from the pagan poet Virgil - the author of the epic poems about the ancient gods that became primary source material for the dramas upon which Augustine heaped so much scorn - to summarize the basic dialectic of his own argument in two brief lines:
Show pity to the humbled soul,
In these two lines of poetry Augustine draws on the authority of the pagan Virgil to introduce his Christian argument about the city of God (the humbled soul) and the earthly city (the sons of pride). In fact, the City of God contains frequent transcriptions of Virgil, accompanied by such endorsements as "the most famous poet speaks truly ... "27 In the Confessions he suggests that while the fables of the poets are not "true," they nevertheless "provide real food for thought."28 Following a long examination of the myriad corruptions of nature and miseries that have been introduced as a result of original sin and the curse, he pauses to consider the "blessings of God" which have persisted in spite of it all. Among these blessings he lists such "astonishing arts" as weaving, navigation, architecture, painting, sculpture, the theater, song and musical instruments, each of which owes its existence to God's providence - God who has filled the human mind with exuberant inventiveness, vigor and a marvelous nimbleness, and not removed these as punishment for our sin. "The little spark of reason," Augustine assures us, "which was the image of God in him, has not been quite quenched." Even the theater receives a guarded endorsement here. "What wonderful spectacles," he writes, "are exhibited in the theaters, which those who have not seen them cannot credit!"29 While Augustine, like Tertullian, was a pagan who had been recast into a Christian, unlike Tertullian he retained a real affection for the world he had turned his back on - a world that was now itself threatened both internally by the growing Christian influence, and externally by the incursions of barbarians from northern Europe - and took the view that aspects of pagan culture ought to be preserved and put into the service of the church.
In effect, Augustine softened the boundary between the church and the surrounding culture that had been erected by Tertullian and other church fathers. In Augustine's terms, while the earthly and heavenly cities had two different ultimate destinies, for the present, they "are mingled together from the beginning down to the end."30 The two cities, he wrote, "are entangled together in this world, and intermixed until the last judgment effects their separation."31 Citizens of both cities inhabit overlapping spaces for the duration of history, and spend their lives passing through the same buildings, participating in the same institutions, witnessing the same works of art, and engaging in many of the same social practices that constitute the earthly city. The difference between them is not in the external accoutrements of their lives, but in the quality of their love and attachment to these things. We are citizens of the earthly city to the extent that we love the earthly city as an end in itself; we are citizens of the heavenly city to the extent that we make use of the earthly city - including its astonishing arts and cultural attainments - as a way of loving God.
With respect to cultural phenomena that functioned in the ancient world as popular culture - such as the games, the theater, pagan philosophy, myth and ritual - Tertullian readily associated the bulk of it with false gods and idolatry. As such, he insisted that participating in them at any level would draw Satan and his demons into the world to do their work. Augustine, on the other hand, suggests that while idolatry is bad and to be avoided in every case, idols and their stories can be examined for what they can tell us about various attributes and actions of God. The various mysterious powers attributed to the gods, by which particular things are caused to be, by which seeds germinate, diseases are healed, eloquent speech is uttered, wars are fought and won, the waters are governed, the light of the sun is sustained, and human minds acquire knowledge of the arts that are necessary for life - the very powers that had been distributed among the gods in the pagan imagination - "these are the things the one true God makes and does."32 Examining the powers of the gods can be viewed as a primitive form of metaphysics that accurately analyzes the forces that operate in the universe, even if it fails to determine their true source.
And so, Augustine urges, the pantheon of pagan gods should not be spurned out of hand given what they might teach us about how the world works and, moreover, about the attributes of the true God. "We ought rather to seek to know what gods these are, and for what purpose they may appear to have been selected." Augustine then lists, among others, the gods whose specialized powers are well known: Jupiter, Saturn, Mercury, Mars, Neptune, and Venus. It is important to note, first, he suggests, that despite their rivalries, these gods work for the most part in concert. The pantheon is at least a distorted recognition that the cosmos is unified and coherent. Furthermore, the ancients who "invented the images, badges, and adornments of the gods" did so, he speculates, out of a humane desire to provide people with vessels they could see with their own eyes, vessels that contain real mysteries. And while this took away some of their fear of cosmic mysteries, a worthy achievement in Augustine's view, it also added error.33 But for Augustine this is worth sorting through; there is much to be gained from an investigation of the invented symbols and fabulous deities of the pagans regarding knowledge of an array of powers that are in reality the work of the one true and supreme God who is the great mystery deep below the surface. Given that humans are made to long for God, and given the inescapable fact that even proper worship requires the use of signs, it is to be expected, Augustine argues, that humans will discover in earthly and celestial forces a rich supply of "symbols of mystery ... which increase our mystical knowledge." Thus, even in the scriptures God is called lamb, calf, lion and rock, which are all sanctioned ways to signify God, provided God is treated as that to which these things point.34
Behind this view of a true religion which adores the world as a means to worship God is Augustine's fundamental principle of the human condition, namely that the heart is restless until it finds peace in God. It is with this recognition that Augustine framed his Confessions, his autobiographical examination of his own restless life. Looking back he understood that his life had been a succession of grasping for some enduring consolation - ideas, bodily gratifications, social esteem, friendships, metaphysical schemes - to which he became attached, eventually grew weary, then moved on. Driving this restlessness, he concluded, was an unslakable desire for the true God, a desire that kept pressing him to fix onto some aspect of reality larger than himself. God alone can satisfy this longing; the world can function only as a set of signs through which God is encountered.
One can find in Augustine two norms that guide his judgments regarding which elements of pagan culture deserve to be preserved. First, he claims that "Wherever we may find truth, it is the Lord's."35 With this norm in mind, he makes such observations as:
We should not think that we ought not to learn literature because Mercury is said to be its inventor, nor that because the pagans dedicated temples to Justice and Virtue and adored in stones what should be performed in the heart, we should therefore avoid justice and virtue.36
He goes on, "If the philosophers have said things that are indeed true and are well accommodated to our faith, they should not be feared; rather, what they have said should be taken from them as from unjust possessors and converted to our use." Just as the people of Israel took vases, ornaments, garments, gold and silver from the Egyptians when they fled, "as if to put them to a better use," Christians should plunder the philosophers.37
The second norm is charity. Augustine writes: "Knowledge which is used to promote love is useful."38 In his handling of pagan religious symbols and forms of devotional practice, Augustine adamantly rejects those that have arisen from collusion with demons. But this does not exhaust all pagan symbols and practices; there are many that the Romans had borrowed from nature and history, which are for Augustine legitimate sources for symbolizing the divine, and only become problematic when observed in an idolatrous manner. This misuse, however, does not invalidate them as potentially useful religious signs that can be used in understanding or worshipping the one true God. To test their usefulness as genuine religious symbols, Augustine proposes that they be interpreted in the chamber of the conscience. If in a particular interpretation of an appropriated pagan symbol the interpreter is aware of himself becoming more proficient at loving God and neighbor, then there is something worthy of retrieval in the symbol. By proficiency in love, Augustine has in mind "the motion of the soul toward the enjoyment of God for God's own sake."39
This understanding of love as the "enjoyment" of God is a technical definition in Augustine. He frequently distinguishes between the terms "enjoyment" (frui - as in the word fruition) and "use" (uti - as in the word utilize). To enjoy something is to love it for its own sake. To use something is to employ it in moving closer to that which is loved. But both enjoyment and use are ways of loving. The first is appropriate to human love for God and the second is appropriate to human love for other creatures. In this distinction, Augustine prescribes the proper attitude one is to take regarding religious symbols. "In this mortal life," he writes, "wandering from God, if we wish to return to our native country where we can be blessed we should use this world and not enjoy it ... so that by means of corporal and temporal things we may comprehend the eternal and spiritual."40 Or, expressed differently: "Love those things by which we are carried along for the sake of that toward which we are carried."41 Thus, any sign, whether it is a symbol or a custom, may be appropriated by a Christian provided one's application of it propels the soul in this movement toward God which Augustine calls charity.
This is precisely the shortcoming of the pagans in their poetic and theatrical portrayals of the gods. The pagan gods are presented as moral criminals. Augustine is fond of citing the example of Jupiter, who is "painted, cast, beaten, carved, written, read, acted, sung, and danced"
in the act of committing adultery.42 This sort of behavior attributed to the gods can only inspire similar immorality in humans, who know instinctively that they are to imitate the divine. Consequently, these religious symbols and performances make people unfit for society and depraved, and thereby fall short of the criteria of charity. In any legitimate representation of the divine, it is incumbent, according to the very idea of divinity, "to publish in plain terms the laws of a good life."43 The theater, then, is not intrinsically evil; all depends upon the love of God and neighbor that it inspires.
Even the artistry and ornamentation that is incorporated into the most mundane objects can be an occasion for gratitude to God. In Confessions, Augustine writes,
By every kind of art and the skill of their hands men make innumerable things - clothes, shoes, pottery, and other useful objects, besides pictures and various works which are the fruit of the imagination. They make them on a far more lavish scale than is required to satisfy their own modest needs or to express their devotion, and all these things are additional temptations to the eye, made by men who love the worldly things they make themselves but forget their own Maker and destroy what he made in them. But, O my God, my Glory, for these things too I offer you a hymn of thanksgiving. I make a sacrifice of praise to him who sanctifies me, for the beauty which flows through men's minds into their skilful hands comes from that Beauty which is above their souls and for which my soul sighs all day and night.44
Thus, Augustine offers a strategy for the appropriation of pagan religious symbols and all varieties of popular art. They may be appropriated if they can be pressed into the service of charity, into the journey of the soul to God, as a means of devotion rather than as objects of devotion, if they can be "used" rather than "enjoyed." Pagan customs, figures, metaphors, fables, precepts, poetry, theater, paintings, sculptures, clothing, shoes, and pottery may be plundered if they can be put to use in such a way as to enable one to enjoy God and imitate divine goodness.
Furthermore, Augustine encourages this appropriation. First, by pointing out that it is the fitting thing to indulge the human need for tangible signs, and, second, by claiming that truth artfully adorned is more persuasive, comprehensible, and conducive to stirring human beings to charity. Augustine, for these reasons, is receptive to a Christian use of elements of popular culture from outside of the church. The treasures of the pagans and even conventional ornaments may be plundered and converted to a better use in the worship of the one true God.
Was this article helpful?


text:
Regular price
These smart black ankle boots from Camper are practical yet chic. They have a contrast blue pull at the front and back to add a splash of colour, and are perfect to take your child through Autumn/ Winter. Brand new and unworn.
Brand: Camper
Size: 27
Condition: Brand New


text:
Jegerlehner, James L., 1995, John Deere Dubuque Works, Workers' Participation Helps Reduce Cumulative Trauma Disorder Injuries, Advances in Industrial Ergonomics and Safety VII.
John Deere Dubuque Works manufactures industrial equipment. Some of the products include diesel engines, backhoe loader tractors, and crawlers. The company employs over 2600 workers. The company employs an older workforce with an average age of over forty-eight years old. In performing different tasks workers had to manually lift, push, and hold heavy parts, turn the hand feed wheel of a radial drill, bending and extended reaching to grasp the parts, and spend an extended period of time on their knees to attach the shifter linkages inside the operator cab.
A review of OSHA 200 log did not reveal a high incidents of CTDs in this particular area. Further information is not available.
Heavy components, up to 30 lbs., had to be manually lifted and pushed by operators.
Bending and extended reach were required to perform tasks.
There were some repetitive tasks. Moreover, performing one task required spending an extended period of time on operator's knees.
Successful Pro-active Ergonomics program was an ongoing effort being conducted by employees out on the shop floor and the critical component of it was an active wage employee ergonomics team.


text:
40 East Main Street
Directions Tilton, NH 03276
When you want to command the streets of New Hampshire with unrelenting power, turn to AutoServ Ford of Tilton. Our Ford dealership near Concord, NH, has an array of 2019 Ford Super Duty trucks for sale that will give new life to your time on the road. You'll conquer worksites and heavy-duty tasks without breaking a sweat thanks to the efficient 2019 Ford Super Duty diesel engine, impressive Ford F-350 towing capacity and available 2019 Ford Super Duty accessories. Learn more about the 2019 Super Duty truck and visit our Tilton Ford truck dealer to test-drive the Ford Super Duty model you've been dreaming of.
If you're ready to tackle the roads of New Hampshire from the driver's seat of a high-performance pickup, it's time to meet the 2019 Ford F-250, 2019 Ford F-350 and 2019 Ford F-450 Super Duty trucks. You have your choice between best-in-class torque and best-in-class horsepower, depending on which Ford Super Duty powertrain you prefer. The 2019 Ford Super Duty diesel engine is the class leader with its output of 450 horsepower and 935 pound-feet of torque. Meanwhile, the Flex-Fuel V8 powertrain boasts a class-leading 430 pound-feet of torque. The Ford TorqShift® Heavy-Duty SelectShift™-G automatic transmission will provide smooth shifting around every turn when you finance a 2019 Ford F-250 gas engine model. The 2019 Ford Super Duty specs and other performance features may include:
An array of performance-focused features makes the 2019 Ford Super Duty a true leader in its class. The available 8-inch LCD Productivity Screen provides you with essential information on the go including a connection checklist for hitching up a trailer and transmission tow/haul settings. When you consider the impressive 2019 Ford F-350 towing capacity and its best-in-class maximum payload of 7,640 pounds, it's easy to see why this Ford Super Duty is popular with workers and weekend warriors alike. And with the best-in-class 21,000-pound 2019 Ford F-450 towing capacity, you can haul anything your heart desires through all of New England. Do you need to bring gear and tools along? Opt for the 2019 Ford F-250 XLT to take advantage of class-exclusive BoxLink™ where you can store all your 2019 Ford Super Duty accessories and other belongings. More Ford Super Duty towing and handling features may include:
Once you climb into a 2019 Ford Super Duty truck, you'll discover the difference a Ford makes. Every truck in the 2019 Super Duty model lineup has a high-strength, military-grade aluminum-alloy body that adds to this pickup's incredible fuel efficiency and durability. Its rear seat storage and flat load floor interior features allow you to secure everything you need for your journeys around the highways and byways of Tilton and Concord. You'll love your new Super Duty truck's connected interior, from the available SYNC® infotainment system to the optional class-exclusive Blind Spot Information System (BLIS®) with Cross-traffic Alert and Trailer Tow. Interested in the convenience of FordPass™ Connect? Opt for the 2019 Ford F-250 Lariat trim to access a 4G LTE Wi-Fi® hotspot from the driver's seat. More 2019 Ford Super Duty interior features may include:


text:
Client: Northern Ireland Environment Agency & SportNI (Strategic Partners)
The Challenge
To develop of a quantitative baseline for outdoor recreation in Northern Ireland
The Role
To deliver the following components:
Objectives & Scope
- Clarify the objectives of the research (based on how the results will be used, by whom and for what purpose)
- Scope out priority topics/questions to include
- Consider other factors eg. frequency of sampling, costs etc
Best practice
- Review and compare surveys in England, Scotland and Wales
Situation in Northern Ireland
- Identify and review existing continuous population surveys with questions relating to the outdoors/recreation/participation such as the CHS and Health Survey
- Review other previous surveys in Northern Ireland
- Consider how the research will coexist/complement other Northern Ireland level research data
- Consult with key stakeholders
- Consult with other organisations with an interest or expertise including Queens University, NISRA, private research agencies
- Examine the appropriate data collection methods to carry out the research eg. continuous surveys, omnibus
- Research considerations eg sample design and sample size, recruitment questions
- Consider question type
- Draft up research questions
- Put forward options for methodology and approach
- Put forward options for tendering
- Assess these in terms of cost, how well they meet the research objectives etc
- Recommend approach and associated costs


text:
Order hand-made round Shemurah (Chaburah) Matzah baked primarily in the Pupa/Tzailem Matzah bakery in New York.
These thin and delicious Matzos are baked fresh shortly before Pesach for the Cleveland community by our very own HaRav Yehudah Blum Shlita of Khal Yereim Shul in Cleveland Hts and are available to us at a greatly discounted price.
Place your order today by calling Shloimy Modes 24 hours @ 216.397.9495 or for text messages only 216.401.7507. (Orders that haven't been confirmed haven't been received. We apologize up front for this rare occurrence and ask that you try again.)
Please place your order by Parashas Zachor, Feb 24th, to ensure quantities. (This time frame includes those ordering Matzos baked prior to the Rav's baking.)
In case it's closer to chodesh Nissan and you haven't yet ordered, or you need to add to your previous order, feel free to call as late as Chol Hamoed, as extra Matzah is baked and occasionally extra Matzah becomes available even after we are officially sold out.
In case you are interested in ordering Shitas HaRosh Chaburah Matzah, please be aware that almost no extra is baked. So please don't put off ordering. Please order NOW.
The Matzah is sold at Khal Yereim Shul 1771 S. Taylor Rd. on March 21 & 22. Please mark your calendars and check back at Local Jewish News after Purim for more details.
The prices for the Matzos are determined after shipping and handling, a day or two before the selling. Signs with the prices will be be posted in the Shul on the days of the selling.
The Matzah is sold by the pound.
A number of varieties are available:
1. Regular (white flour Matzah)
2. Semi Whole Wheat (mix of white & ww flour)
3. 100% whole wheat (usually $2 more per lb)
4. Spelt
5. Oat
6. Matzah Meal (also shemurah)
7. Special Shitas HaRosh Chaburah Matzah with or without Arizona or similar flour. (Usually about $10 more per pound.) May also be available as Satmar Matzos.
Thanks to the thin nature of these Matzos, most years the main varietes have 8 to 9 Matzos per pound. As much as we try to prevent breakage, thinner Matzos can break easier. Most years most pounds that we sell are mostly Halachicaly Shleimim. We cannot however be responsible for breakage under any condition. All sales are final.
No one, not even those involved with the selling of the Matzos, including Rav Blum himself, picks & chooses through their Matzos.
We are a not for profit community service which Rav Blum's father started over half a century ago for his Kehillah & the community at large. Rav Blum has carried on the tradition.


text:
A.T.A.P. Companies
A.T.A.P. Insurance Clearinghouse
555 S. Highland Street, Mt. Dora, FL
Who Needs Insurance
What Kind of Insurance?
Buying Life Insurance
Trusted Insurance Provider
Free Life, Health, and Annuity Quotes
Highland Place
Jesus said "ALL THINGS ARE POSSIBLE" to him who believes. Mark 9:23
One of the illusions is that the present hour is not the critical decisive hour. Write it in your heart that every day is the BEST day of the year.
-Ralph Waldo Emerson
Are you in earnest? SEIZE this very minute. What you can do, or dream you can do, begin it. Begin it and the work will be completed.
- Johann Wolfgang von Goethe
He can inspire a group only if he himself is filled with CONFIDENCE and hope of success.
- Floyd V. Filson
You can easily judge the CHARACTER of others by how they treat those who can do nothing for them or to them.
- Malcolm Forbes
COURAGE and perserverance have a magical talisman, before which difficulties disappear and obstacles vanish into air.
- John Quincy Adams
NOTHING can stop the man with the right mental attitude from achieving his goal; nothing on earth can help the man with the wrong mental attitude.
- W.W. Ziege


text:
The God That Failed
Search this Site
Recent Posts
- SoundMoneyShow.Com: CODE RED, protect your savings – John Mauldin Interview
- Concentrating on Euro Vigilante
- GoldMoney podcast: Gordon Kerr: 'I was on the grassy knoll'
- GoldMoney podcast: Mish Shedlock's case for deflation
- GoldMoney podcast: Doug Casey: 'We are living in the middle of the biggest bubble in history'
- Austrian Economics
- Austrian Economics: The Essential Guide
- Blogging
- Divide and Rule
- Dollar Vigilante
- Euro Vigilante
- Faber
- Goldbugs
- GoldMoney
- Inflation
- Keiser
- King World News
- Mogambo Guru
- Paleo
- Podcasting
- Podcasts
- Politics
- Privacy
- Property and Freedom Society 2012
- Radio Free Market World Report
- Rothbardian Novels
- SoundMoney
- Turk
Tag Archives: Gold Money
GoldMoney podcast: Godfrey Bloom MEP on Germany's "golden opportunity"
My latest podcast, this time with Godfrey Bloom MEP, who sits on the European Parliament's Economic and Monetary Policy Committee: GoldMoney's Andy Duncan talks to Godfrey Bloom, who represents Yorkshire and North Lincolnshire in the European Parliament, and who is … Continue reading
Posted in GoldMoney, Podcasts Tagged Deutschland, Godfrey Bloom, Gold, Gold Deutschmark, Gold Money, GoldMoney
Deteriorating bonds and China: Bernanke will be forced into more quantitative easing
There's an interesting analysis by John Hathaway, on King World News, about the corner Ben Bernanke has painted himself into recently, with his statement that he may not engage in any more quantitative easing. Hathaway's basic position is that as … Continue reading
Posted in King World News Tagged Bernanke, Bonds, China, Gold, Gold Money Leave a comment
Jim Rickards: The first major currency to go towards gold backing will be the only currency that anyone wants
Although this blog will eventually get to other subjects other than the rather narrow topic of gold money, this is another video in the recent Turk series, this time with Jim Rickards, in which Mr Rickards is brave enough to … Continue reading
Posted in Goldbugs Tagged Gold Money, James Turk, Jim Rickards 2 Comments
Dominic Frisby: Why Gold is the Currency of the Free
I have just discovered an astonishingly good 22-minute speech by Dominic Frisby, delivered in the UK earlier this year, at the Cheviot Sound Money Conference, in London's splendid Guildhall, by one of the UK's leading voice-over artists. [Does this make … Continue reading
Posted in Goldbugs Tagged Cheviot Sound Money Conference, Dominic Frisby, Gold, Gold Money, Hayek, Mises, Road to Serdom, Rothbard 1 Comment


text:
During the process of booking a flight, we ensure that catering services meet the expectations of every client, by providing excellent and unique meals of the highest quality.
Goal of Life Line Aviation is to make the experience of catering during flight equal to that of most luxurious restaurant.
The flavors offered satisfy every taste. The constantly renewable menu is adapted to the needs and requirements of each customer.


text:
Snoop Dogg Shutters Clothing Line
Snoop Dogg Shutters Clothing Line
- Genre : Hip Hop
- Type: News
- Author : Super Admin
- Date : Tue, 20 Jul 2010
Nothing, not even a rapper's lifestyle clothing company, is safe from the recession. WoooHaHa reports that Snoop Dogg's Rich & Infamous clothing line has reportedly been shut down after two years at retail carriers. Snoop himself had talked about the economic crisis having an effect on his apparel brand last year and he spoke of keeping prices down. The line initially launched in the summer of 2008, but Snoop and company have officially suspended all online sales of the clothing company and shut down the Rich & Infamous online store and website. No official plans have been set to relaunch the line or if Snoop plans to permanently shut it down. Snoop even stopped wearing Rich & Infamous gear in public, which set off alarm bells that something was amiss or afoot with his line.
Did you wear any threads from Rich & Infamous? And when will this damn economy bounce the hell back?
—Amy Sciarretto
Did you wear any threads from Rich & Infamous? And when will this damn economy bounce the hell back?
—Amy Sciarretto


text:
Steven M. Salberg describes some techniques he uses for 2 diabolo toss-ins:
I can do all of these and have used them all on various occasions as I've become more adept at 2 diabolos. Number (1) looks less obvious than (4) to the untrained eye, so I usually use (1) but teach (4).
Is it easier to drive with the right hand or lift with the left or a combination of both ? I notice Guy (Heathcote) seems to push them under (with 2 & 3) whereas others pull them over (if you know what i mean).
You're going to encounter people who believe both ways (isn't that always the way). One thing is absolutely certain: if you don't drive the diabolos across the bottom, they will lose speed. The diabolo gets "powered" by the stroke across the bottom. If you are successfully pumping the diabolo across the bottom, you only have to subtly aim the diabolo with the other handstick to make it fly across the top.
Here're some pointers.
In the beginning, when you've just thrown the second diabolo onto the (we'll use a right handed example) right side of the string, you probably will have to use the left handstick to toss the diabolo across a couple of times until you get your rhythm and diabolo speed up. Then pump the right handstick up in a semi-circle as if you are tracing the left side of a circle from bottom to top. The up-ward motion strokes the string across the spindle of the diab (imposing spin) and the left-ward arc shoots the diabolo across to the left (actually both motions push the diabolo to the left, but let the MIT professors describe it). The hard part is getting the timing of when to pump. As the diabolo lands on the right side of the string and starts to roll down it, PUMP! Just at that moment the other diabolo should be taking off from the left string and flying across towards the right.
You can use the left hand to push the diabolo across to change the timing of the trick. If you lift the diabolo forcibly higher with the left handstick, you can create a larger center hole so you can stick your leg or arm into the pattern so the diabolos will jump over your chosen appendage... and yes, some people need a bigger... erm, uh... oh forget it!
How do I correct a straying diabolo, since normal methods mean the other one falls through the space...?
The faster the diabolo is spinning, the more stable it will be. But I don't understand your description. What do you consider normal methods? If the diabolos ARE NOT CROSSING and are just falling down into the center of the pattern, then the cure is my description of pumping with the right hand to make sure the diabolo is crossing the bottom. That gives it enough speed and angle coming off the left string to cross over the top.
To correct precession and forward/backward tilting you have to use the right handstick to touch various parts of the diabolo. No time to go into that now (it's late and the non-diaboloers are getting bored).


text:
The American Law Register, Volume 1; Volume 10
D.B. Canfield & Company, 1862 - Law
What people are saying - Write a review
We haven't found any reviews in the usual places.
Selected pages
Other editions - View all
Common terms and phrases
action agent Akyab alleged appear applied arrest assignment attorney authority Bank bill bonds Chancery charitable choses in action cited claim common law concerning charities Constitution contract conveyance corporation Court of Chancery court of equity creditor damages debt decided decision declared decree deed defendant doctrine domicil dower effect enforced entitled equity estopped estoppel eurice evidence executed executors exemption existence fact favor fee simple feoffees feoffment given grant ground heirs held holder homestead husband indorser interest intestacy issue judge judgment jurisdiction jury justice land lease legislature liable lien Lord maker marriage ment mortgage notice officer opinion owner parties payment plaintiff plaintiff in error possession principle promissory note purchaser question Railway reason regard rent Reports residence rule seisin statute Supreme Court tenant testator tion transfer trial trust valid void voyage warrant wife
Popular passages
Page 531 - The court of general sessions of the peace in and for the city and county of New York.
Page 715 - The principle asserted is, that one legislature is competent to repeal any act which a former legislature was competent to pass; and that one legislature cannot abridge the powers of a succeeding legislature. The correctness of this principle, so far as respects general legislation, can never be controverted. But, if an act be done under a law, a succeeding legislature cannot undo it. The past cannot be recalled by the most absolute power.
Page 532 - Federal courts, no person shall be compelled in a criminal case to be a witness against himself, nor deprived of his liberty, without due process of law.
Page 591 - ... must be considered in the same situation as to responsibility as if the facts with respect to which the delusion exists were real.
Page 91 - The sovereignty of a state extends to everything which exists by its own authority, or is introduced by its permission; but does it extend to those means which are employed by congress to carry into execution powers conferred on that body by the people of the United States?
Page 719 - That the taxing power is of vital importance, that it is essential to the existence of government, are truths which it cannot be necessary to reaffirm.
Page 717 - The only security against the abuse of this power, is found in the structure of the government itself. In imposing a tax, the legislature acts upon its constituents. This is, in general, a sufficient security against erroneous and oppressive taxation. The people of a state,- therefore, give to their government a right of taxing themselves and their property, and as the exigencies of government...
Page 298 - ... for seeing somebody must be a loser by this deceit, it is more reason that he that employs and puts a trust and confidence in the deceiver should be a loser, than a stranger.
Page 717 - All subjects over which the sovereign power of a State extends are objects of taxation; but those over which it does not extend are, upon the soundest principles, exempt from taxation.
Page 276 - An act to provide for the better security of the lives of passengers on board of vessels propelled in whole or in part by steam...


text:
Dignity Privacy and Respect at Work Training Course
This Dignity Privacy and Respect at Work Online Course presents the theory course in a format that is both easy to digest and apply to the work environment.
As a result, it will also benefit all employees who work within a Healthcare as well as the Social Care environment.
It also benefits those who require this knowledge as part of their induction, or in addition as part of their company mandatory training programme.
As a result after the successful completion of the training, learners will have obtained the under-pinning knowledge of dignity, privacy and respect.
This will enable learners to understand the above learning outcomes and also be able to implement those outcomes within their working environment.
Learning Outcomes
- Understanding the definitions of Dignity, Privacy and Respect
- Legislation policy/procedure of organisation
- Poor practice
- Discrimination
- Best practice
- Specific care needs
- Implementing change
- Person centered care using dignity, privacy and respect at work
- 60 Minutes
Why the Dignity, Privacy and Respect at Work Training course?
Atom Training e-learning makes the most complex of subjects easier to digest through media and content-rich exercises that motivate and engage. What makes us different is that our e-learning courses uses:
- Interactive exercises/gaming
- Media-rich content
- Interactive scenarios
- Content provided by market leading experts
- Relevant photography and illustrations
- Multi-generational content and style
- And much more?
Other Features
This course and assessment is based online.
After completing your assessment, the results will displayed immediately along with the option to print or request a print out of your certificate (further charges may apply).
We understand that you may not be happy with your results, no worries! You can resit the test for free within 12 months (since the date of purchase).
We understand that everyone may not have aces to a PC at all times, hence, you can study while on the go using a smart phone, tablet or laptop. Only you can decide how long you want to study for each sessions.
Does the online course expire?
Although our online courses have no expiry date. After the online course has been provided to the candidate they will have 12 months to complete the course. After that they will receive their certificate.


text:
Dr. Stephen Hoffman has done what many considered to be the impossible.
As the founder and CEO of the biotech company Sanaria, Hoffman created a vaccine that offers 100 percent immunity from malaria. While vaccines for viruses like polio and bacteria like tetanus have been around for decades, his vaccine is the first that completely protects you from the malaria parasite, the leading cause of death in many developing countries. After ten long years of work on the vaccine, Hoffman published his findings this past August, and the vaccine is currently under trial. But while his historical discovery may seem like the end of a long journey, it's really just the beginning. The vaccine isn't yet ready for market, and Hoffman must now figure out how to make enough of the stuff to truly put a dent in the world's malaria problem.
According to the Centers for Disease Control, there are 3.4 billion people around the world who are currently at risk of contracting malaria. In 2012 alone, says the World Health Organization, 207 million people contracted the disease, and 627,000 died from it. Hoffman's vaccine certainly has the potential to reduce these numbers, but there's a catch. The vaccine is made up of tiny malaria parasites that have been treated with radiation while living in the salivary glands of mosquitoes, and today, extracting these parasites involves a powerful microscope and a highly trained human hand to dissect the mosquito. It's an almost artisanal process, one that Hoffman knows could prevent the vaccine from reaching a truly large number of people.
That's why he and his company are building the SporoBot. Developed in partnership with the Harvard Biorobotics Laboratory, the SporoBot is a robot that can do all the delicate work that goes into making the vaccine, with one crucial difference: It can do it 20 to 30 times faster. That could be the secret to finally bringing Hoffman's vaccine to the people who need it most.
Hoffman is currently raising $250,000 on the crowdfunding site Indiegogo to develop a working prototype. That's an unorthodox move from a company that has spent some $120 million developing the vaccine and has received millions of dollars in grant funding from the likes of the Gates Foundation and the National Institute for Health. But grant funding can be slow. Hoffman hopes the crowd is quicker. "Between 1,000 and 3,000 children will die today of malaria," he says. "We have to leave no stone unturned in getting this done and getting it done as fast as possible."
Three Decades in the Making
Hoffman has been working on the malaria problem for nearly three decades, starting as a Naval doctor in Jakarta, Indonesia, specializing in tropical diseases. For years, he treated patients and watched "many, many, many young Indonesians die" in his care from malaria. Passionate as he was about treating patients, though, he eventually realized that he could have a much bigger impact if he could develop a vaccine to eradicate the disease altogether.
Hoffman has resorted to extreme measures in the name of this mission. Once, he subjected himself to the bite of 3,000 mosquitoes, after discovering an unusual method of vaccination that first arose in the 1970s. At the time, researchers found that after volunteers were bitten by 1,000 malaria-infected mosquitoes that had been treated with radiation, they developed immunity to malaria. When Hoffman tested the theory with 3,000 mosquitoes, not only did it make him immune to malaria, but it became the basis for Sanaria's current vaccine.
Rather than forcing people to endure thousands of mosquito bites, Hoffman figured there must be a way to grow these parasites and inject them into the body. In 2002, he founded Sanaria from his kitchen table to figure out how to do just that. It wasn't easy. First, the team had to figure out how to make sterile mosquitoes, how to make them live long enough, how to make them feed, and how to extract the parasites, purify, and preserve them. At the same time, Hoffman had to find a way to raise money for this research at the height of the global recession and in the face of a barrage of criticism from the scientific community.
'A Gift From Heaven'
By 2010, Sanaria launched its first clinical trial of the vaccine and found–to Hoffman's utter disappointment–that it didn't offer subjects the level of protection he was looking for. "We come to work every single day with the idea that we're working on something that, when we succeed, will save millions of lives," he says. "It's an incredible way to live your life, but at the same time, when it doesn't work, it can be really problematic."
The vaccine failed primarily because it was being injected into the skin. Hoffman guessed that if it were given intravenously, it would be more potent. He was right. In 2012, Sanaria launched its another trial, during which the vaccine was given intravenously, and by the end of it, the trial subjects were still 100 percent immune. "It was a gift from heaven," he says, remembering that day. "It was a treasure."
The vaccine is still undergoing clinical trials and will be tested on some 500 volunteers in seven sites around the world this year. If successful, Sanaria will still have to wrestle with substantial logistical problems. For instance, the vaccine must be preserved in liquid nitrogen, which could pose a delivery challenge. The intravenous method of delivery could also make mass vaccination campaigns a challenge, says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "It would be important to determine if the vaccine can be administered in a different and less difficult form, such as intramuscularly, with similar good results," he says.
Sanaria, he says, must also prove that its vaccine is as effective in the field as it is in highly controlled experiments. "If the high degree of efficacy of the Sanaria vaccine holds up under ongoing field trials, then this would be very important and encouraging," Dr. Fauci says.
But the biggest hurdle, in Hoffman's opinion, will be scale.
Enter the Robot
That's why, about two years ago, he began working with Harvard Biorobotics Lab to begin developing a robot that could produce mass quantities of the vaccine. That too, says Yaroslav Tenzer, who helped design the SporoBot, was a major technological undertaking. "Mosquitoes are very small and fragile," he says. "Dissecting them and extracting the saliva glands in a sterile environment is a big manipulation challenge."
But over the course of two years, Tenzer and his team managed to design working prototypes for each step of the process. First, the machines must restrain the mosquito. Then they pick it up, dissect it, extract the saliva gland, and collect it. Each step requires sophisticated image processing technology to ensure the right parts are being dissected and extracted. Now, Sanaria is trying to raise the money to put all the pieces together to build the SporoBot, a machine that wouldn't be much larger than a microwave.
Once a basic prototype is built, Tenzer expects other roboticists will join in and help optimize the SporoBot. "But first, basic research needs to be done," he says, "and that's what we're doing."
As of Monday, Sanaria had raised just over $35,000 of its $250,000 with just four days left, a testament to just how difficult it is to crowdfund a product that you can't give away as a perk for donating. Still, Hoffman says even if Sanaria can't meet its crowdfunding goal, he won't stop until he finds the funding somewhere. It is, he says, quite literally a matter of life or death. "I'm envisioning total success," he says. "I won't be in a situation where we can't produce enough of this vaccine in the most rapid period of time because we don't have robots doing this one part of the process."


text:
Tag: trafficking
GPDOTS Enforcement Consultant Rob Mulloy discusses the opioid epidemic on the Sheldon McLeod Show News 957
Tamara Ballard from GPDOTS discusses the recent trafficking case of Dr Sarah Jones – Global News N.S.
Tamara Ballard from GPDOTS comments on the recent RX drug bust in Chester NS – CTV News
Leah Bordage pleads guilty to trafficking in the death of Ryan Good – CBC News
Do not let RX drug drop off day mislead you
Prescription Drug Drop Off Day is fast approaching. In the past GPDOTS has supported different take back day initiatives. When this became a national initiative and Partnership for Drug Free Canada started funding the Rx drug take back day the messaging seemed to change in a direction myself and other group members feel is misleading. Examples… Continue reading Do not let RX drug drop off day mislead you


text:
Ahmadiyya marriage ceremony impaired by mullas
Jhuddo Naukot, District Mirpur Khas; March 14, 2019: Mr. Altaf Ahmad an Ahmadi's daughter's wedding was scheduled on March 14, 2019. The marriage party had come from Green Town, Karachi. The reception was arranged at a marriage hall named "Hareem Hall" in Jhuddo. When the wedding feast was at the end, mullas came in numbers and told the hall owner to get the hall vacated of those Ahmadis forthwith. Under pressure from the mullas the owner expressed his helplessness and asked for the evacuation of the hall. Ahmadis had to comply and the wedding party had to shift to the bride's residence where farewell formalities took place.


text:
Opening to positive reviews from around the country, Pincushion, an independent film by Deborah HayWood, features the songs 'Mirrors' and 'The Boulevard Song' by Wardlaw artist Sally Oldfield.
After moving to a new town, lonely teenager, Iona and her mother, Lyn, who suffers from learning disabilities, begin the process of inventing their lives within this town; much to the despise of their new neighbours and the social hierarchy of Iona's school.
Pincushion is a tale that focuses on mental abuse and bullying, whilst highlighting the problems caused by these actions.
Released on the 13th of July, Pincushion will be shown across the United Kingdom and U.S.A in various cinemas.