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Finite Element Models of Elasto-Plastic Deformation in Volcanic Areas
Istituto Nazionale di Geofisica e Vulcanologia Sezione di Catania, Catania, Italy
In volcanic areas, the presence of heterogeneous materials and high temperatures affect the rheological behaviour of the Earth's crust that calls for considering the anelastic properties of the medium surrounding the magmatic sources. A thermo-mechanical numerical model is performed for evaluating the temperature dependency of the elasto-plastic solution. Both temperature distributions and ground ...
Modeling Pit Lake Flooding After Mine Closure
S. Jordana[1], A. Nardi[1]
[1]Amphos 21, Barcelona, Spain
Most of mining works, either on the surface or in the underground, demand continuous groundwater pumping in order to operate under dry conditions. When the mining activity stops, dewatering also stops and mining facilities begin to flood, quite quickly at the beginning but becoming slower as the water level in the pit lake rises. The rise of the surface of the lake decelerates due to the bigger ...
Using COMSOL for Optimal Design of Engineering Barriers of Nuclear Waste Repositories
L.M. de Vries[1], A. Nardi[1], A.E. Idiart[1], P. Trinchero[1], J. Molinero[1], F. Vahlund[2], H. von Schenck[2]
[1]Amphos 21, Barcelona, Spain
[2]Swedish Nuclear Fuel and Waste Management, Stockholm, Sweden
The Swedish Nuclear Fuel and Waste Management Co (SKB) is responsible for final disposal of spent fuel and radioactive waste. SKB operates SFR, an underground waste repository in crystalline rock. The evolution of groundwater flow within the repository needs to be estimated considering different options for the design of the engineered barriers. The goal is to predict the effects of flow and ...
An Extension of Lauwerier's Solution for Heat Flow in Saturated Porous Media
S. Saeid[1] and F.B.J. Barends[2]
[1]Technical University of Delft, Delft, The Netherlands
[2]Deltares and TU-Delft, Delft, The Netherlands
One of the crucial topics in this century is sustainable energy. In this respect, the exploitation of geothermal energy from deep hot aquifers becomes opportune. Hence, insight is required in the heat balance of potential aquifer systems. Essential issues are convection, conduction and dispersion. This article focuses on Lauwerier's problem. As an extension, it is suggested that beside ...
A Finite Element Test of the 2002-2003 Etna Eruption
F. Pulvirenti[1][2], M. Aloisi[1], G. De Guidi[2], M. Mattia[1], and C. Monaco[2]
[1]Istituto Nazionale di Geofisica e Vulcanologia, Sezione di Catania, Catania, Italy
[2]Dipartimento di Scienze Geologiche, Università di Catania, Catania, Italy
Structural, morphological and ground deformation studies suggest that the eastern flank of Mt. Etna (eastern Sicily) is spreading seaward. Three contrasting models have been proposed: deep-seated spreading, shallow sliding and tectonic block movements. In order to better understand the kinematics of instability processes on eastern flank of Mt. Etna, a numerical simulation has been applied to a ...
The Effect of the Disintegration of Chemical Stratification on the Time-dependent Behavior of the Earth's Mantle
A. Galsa, and M. Herein
Eötvös University
Budapest, Hungary
Based on recent results from seismology, geochemistry etc. the distinct chemical character of the D'' layer (lowest part of the mantle around the Earth's core) has appeared unequivocally. Numerical calculations have been carried out to investigate the effect of the disintegration, mixing and homogenization of the dense D'' on the time-dependent behavior of mantle convection. A ...
BHE Field Design by Superposition of Effects in Space and Time
S. Lazzari[1], E. Zanchini[1]
[1]DIENCA - University of Bologna, Bologna, Italy
A design method for BHE fields in the absence of groundwater flow is presented, based on the superposition of effects. The effects of any periodic heat load with a period of one year can be obtained by a weighted sum of the effects of a monthly unit step heat load, properly displaced in time. The interference among BHEs is evaluated by the superposition of effects in space. The result of the ...
Intraplate Stress Analysis by COMSOL Multiphysics
G. Swetha, G. Pavankumar, and A. Manglik
National Geophysical Research Institute
Andhra Pradesh, India
Mathematical modeling tools are extensively used in Geosciences to delineate the earth structure at various spatial scales as well as to simulate coupled earth processes involving multiphysics concepts. COMSOL, a Multiphysics finite element method based numerical modeling package, can be used to analyze complex systems like earth where various physical parameters are involved and ...
Upscaling of Heterogeneous Rock Properties via a Multiscale Image to Simulation Approach
S. Zhang[1], M. Pal[2], P. Barthelemy[1], M. Lei[1]
[1]Visualization Sciences Group, Burlington, MA, USA
[2]Shell International Exploration and Production, Rijswijk, The Netherlands
The mass and recoverability of oil and gas in unconventional reservoirs strongly depend on the understanding the petrophysical properties of the rocks at a large range of scales. Three-dimensional imaging is capable of unveiling the detailed microstructures within the rocks down to the nanometer scale. Using a multiscale imaging protocol, a Devonian shale rock sample with heterogeneities is ...
Reactive Transport Processes in Compacted Bentonite
A.E. Idiart[1], M. Pekala[1], A. Nardi[1], D. Arcos[1]
[1]Amphos 21, Barcelona, Spain
The Swedish Organization for Radioactive Waste (SKB) is considering disposal High Level Wastes in a deep underground repository. Bentonite clay is planned to be used in the near-field of the waste packages as buffer material. The buffer is expected to provide a favorable environment with limited radionuclide migration due to slow diffusion and retardation by sorption and cation-exchange effects. ...


text:
|Project Name
|Price (USD)
|Project Name
|Price (USD)
|Access to SQL Server transfer
|...a local Access database that is password protected. User want to upgrade from Access to SQL Server and...and want the data previously stored in Access transferred to the SQL Server system. This utility... 1. Textbox containing the location of Access database. There should be a button next to the textbox
|PHP, Visual Basic, Windows Desktop, Engineering, SQL, Software Architecture, Microsoft Access, Software Testing, Microsoft, MySQL
|May 1, 2005
|May 1, 2005Ended
|Transfer / upgrade access database to SQL server 08
|...relational database with about 10 tables in ms Access . I would like to upgrade this data and table structure...structure to SQL server so Access will be the Front End, SQL server the back end
|PHP, Software Architecture
|Dec 16, 2014
|Dec 16, 2014Ended
|access DataBase Sql injct
|...poster. TASK: sql injctn our Databse server Apache2. The following data is required from the...CSi Scg is not PCI compliant. Then please transfer the data into excel format. I really need the project...project done ASAP. 1-2 days MAX for Access database & encrypt data and imprt in excl sht. please let
|PHP, Linux, CSS, Software Architecture, Apache
|Jul 14, 2012
|Jul 14, 2012Ended
|SQL, MySQL, Database Administration
|Nov 17, 2011
|Nov 17, 2011Ended
|Access to SQL
|Objective: Try to use the existing Access application as the front end, and use sql server as the back end. ...to upsize the data current Access data to SQL. The client likes the features of the Access application...over a network due to the fact that Access pulls the full database over the network when using it at a
|PHP, Engineering, SQL, Software Architecture, Microsoft Access, Software Testing, MySQL
|Jul 2, 2004
|Jul 2, 2004Ended
|Transfer data from SQL Server to Access and back
|Simple code in VB6 ONLY to transfer data from MS Access table to SQL table and vice-versa. MUST not use...two connection subs (one for the access Db and the other for the SQL (e.g. Public function ConnectToAccess(byval...Byval sPass as string)As Boolean and similar for the SQL connection) and two further functions to do transfers:
|PHP, Visual Basic, Engineering, SQL, Software Architecture, Microsoft Access, Software Testing, MySQL
|Apr 24, 2006
|Apr 24, 2006Ended
|Microsoft SQL Server Database Transfer
|...Microsoft SQL Server 2000 database which sits on a server which I can remote into and access via Enterprise...need to transfer this database (structure and all data) to a Microsoft SQL Server 2008 Database hosted...give us access to this via an online manager (myLittleAdmin) or an IP Host name. The database is relatively
|SQL, MySQL, Database Administration
|Jul 14, 2010
|Jul 14, 2010Ended
|...offices an Access database that has several tables, forms and queries. ? We need to have this database structure...structure and current data migrated to a more stable Microsoft SQL Server 2005. We need to be able to...to use Access to contact the database via ODBC, but ? the data will enjoy the benefit of centralized
|PHP, Project Management, Engineering, SQL, Software Architecture, Microsoft Access, Software Testing, MySQL
|Jul 6, 2009
|Jul 6, 2009Ended
|SQL database transfer database
|Request database to database transfer. In cases where we need to transfer databases between different...Reliable -We want to transfer data one sql database to another database in same sql server.
|May 15, 2013
|May 15, 2013Ended
|SQL, Microsoft Access
|May 24, 2011
|May 24, 2011Ended
|Access to SQL data transfer system
|Access97 to MSDE2000 data collection system ## Deliverables Rent A Coder requirements notice: As originally
|PHP, Engineering, SQL, Software Architecture, Microsoft Access, Software Testing, MySQL
|Nov 12, 2007
|Nov 12, 2007Ended
|19994 transfer .sql file into access
|...to my server recently. The database that was sent over was a .sql database but I cant get it to work with...first put this .sql file into a database thats readable by the script, (either access, or SQL) and then get...SQL2005 here but if you get the database into Access, I can put it into SQL very easily.
|PHP, Perl, Script Install, Website Design, Translation, Anything Goes
|May 27, 2006
|May 27, 2006Ended
|SQL Database Transfer
|...involves copying the data in one SQL 2000 database to another server running sql 2005 express. Both databases
|PHP, Project Management, Engineering, SQL, Software Architecture, Software Testing, MySQL
|Apr 9, 2008
|Apr 9, 2008Ended
|Mass Transfer of Data to Access Database
|...basically a mass data entry project, we need to move 10 excel files into an access database. Very easy project...delivered with the final database with all entires entered. a sample excel file and database is in the zip file...just added the zip file ## Platform excel, access
|PHP, Engineering, Software Architecture, Microsoft Access, Software Testing, MySQL
|Apr 5, 2006
|Apr 5, 2006Ended
|SQL Database transfer
|...I need you to add the SQL database to this new domain. I will provide the sql file. 2) There are...the login and password information for, with all data stored remaining intact. Paying $30 for this
|PHP, Javascript, MySQL, HTML
|May 16, 2012
|May 16, 2012Ended
|Data DownloaD AND TRANSFER TO SQL DATABASE
|Need to download data from website and transfer to my database
|MySQL, Database Administration
|Mar 1, 2015
|Mar 1, 2015Ended
|Imports Access Database into SQL
|I have an Access database that strongly relational that I need imported into SQL. The SQL schema is generated...contained in the database, I cannot include the Access database, but it loosely contains similar data to the image
|SQL, Microsoft Access, MySQL
|Sep 17, 2011
|Sep 17, 2011Ended
|Access / SQL Database Migration
|...for whom we've built a new website and CMS using SQL 2008 R2 / ASP.Net / VB.Net. The CMS now needs extending...comprises two Access 2007 plus one SQL 2000 database that need to be migrated to the new SQL 2008 R2 database...database. Data needs to be moved and forms / reports with same functionality created in ASP.Net / VB.Net
|ASP, .NET, SQL, Microsoft Access
|Jun 21, 2013
|Jun 21, 2013Ended
|Data transfer by email attachment, Access XP
|Enable transfer of data from one network to the other. An Access 2003/XP application is used to enter...enter data to a SQL Server database. There is a master database on Network1. Networks 2, 3, etc have their...connected and must use the Access application to perform logic to send the data. We cannot move to a web
|Windows Desktop, Project Management, Engineering, SQL, Software Architecture, Microsoft Access, Software Testing, Microsoft, MySQL, Visual Basic for Apps
|Nov 10, 2010
|Nov 10, 2010Ended
|Access to SQL Server Migration
|...running Access. We need a utility that will reliable transfer any data in the Access database to the SQL...SQL Server version. The Requirements document that details these steps would not fit in this text box...Please read completely and based on your knowledge of SQL server feel free to suggest alternatives/additions
|PHP, Visual Basic, Engineering, SQL, Software Architecture, Microsoft Access, Software Testing, MySQL
|May 7, 2003
|May 7, 2003Ended

subset: commoncrawl


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After literally years of procrastination, I finally put together some of my designs in a format suitable for sale. Now on RedBubble, I have several tshirts, prints and stickers available for purchase.
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If a buyer is paying cash it is one thing, no appraisal. It they are financing, you are correct the appriasal may come in lower then the accepted offer. At that point the buyer and the seller can continue their negotiating and maybe meet in the middle but that still means the Buyer will have to bring money too the table or they can walk away. But I would think it they really like the house they will find the extra money.
Good luck to your friends :)
Roger Roe
616-299-2771 cell
616-796-9784 office
Good Luck,
Karen Paytas, GRI, CMS
Real Living Kee Realty
The LISTING price, whether it is a HUD home or not, is a number to get things started:
It may be a HIGH number, to convey the Seller's WORTH of the home. Or, it may be a very low price, to foment multiple offers. It is never set in stone.
Many Buyers have not been in this MARKET before; and do not understand that this one of the "normal" markets we see over the long term.
It is not an aberration; this is the usual way to bid and buy a house. If you cannot handle it, if you want things to unfold before you like a red carpet; you should have been looking a year ago.
As all the experts before me have revealed, the reality of todays market requires a buyer to wake up and smell the coffee. What many buyers don't realize is there currently exist 4 purchasing levels for homes. If a buyer is dependant on Trulia or Zillow, or for that matter even wasting time on these entertianment sites, they are yet to detect the aroma of the roasted Arabica been.
In the past week, two homes were systemicly sold, one in (-1) days on market, the other sold the very first day. For the home seller it was EZ. Every inquirer was advised to know what 'Fair Market Value' was. An educated buyer is the very best buyer.These buyers do their research (with the professional they hired) to get the facts and won't be caught on real estate aggregate websites. Their time is too valuable. In the mentioned cases, the buyer understood the issue was "HOW FAR ABOVE LIST" they were willing to go. With the assist of a little caffine, the buyer(s) easily recongnized the VALUE and reponded accordingly. Those who needed to think about it had their decision made for them.
A buyer would be well advised to understand, when a home is ready for sale. the first folks notiifed is those within the listing agents data base.
The second group will be those agents in the listing agents office.
The third will be all the agents who have done business (successfully and without drama) with that agent.
The fourth will be the activie agents in the area.
Fifth the home is placed on the MLS
Then eventually, the data is changed and appears on real estate aggregate websites.
If you want to succeed in purchasing a home, you need to get the 'real' information, respond according to what 'market value' dictates, and if you find yourself asking 'WHY?" you need to understand the plan you have in play needs to be modified. The suggestion that 'Fair Market Value" as determined by willing seller and willing and able buyer (not the bank) equates to overpaying may suggest a bit of a disconnect with the current market.
That is the role your multi-dimensional real estate professional fulfills.
Very often, a commitment to the agent representing the buyer, can get a serious buyer in the loop for level one to four. These resources will not be spent on tire kickers and those 'looking for a deal' or under the delusion HUD homes in 'move-in' condition are at such a great value to merit the frustration.
There are many ways to make sure your offer prevails. However, these suggestions are of great value and should not be deminished by offering them freely here.
It is however, easy to recognize, that real estate professionals have many resources they can bring to bear in acquiring a 'move in Ready' home. For a buyer to maintain a pedantic fixation of bank owned property suggests an unwillingness to adapt to what the current real estate market requires.
Consult with your real estate professional. Thats what they are being paid for. The buyer and seller, however, MUST folllow the guidance provided by those they have hired. That is how you get the results you want, not by second guessing those who you hire to guide you.
Best of success to you,
Annette Lawrence, Broker/Associate
Remax Realtec Group
Palm Harbor, FL
The first is with bidding on a HUD home it is the net outcome which is the most important.
If there are 2 bids one for $49,000 and one for $50,000 but the $50,000 asked for 3% in closing costs then the $49,000 bid would win.
The second is the price listed is the HUD appraised price.
HUD homes are appraised against similar foreclosed homes that have recently sold in the general area, including other HUD homes. The condition of the home is taken into account with the cost of any needed repairs in mind and with the understanding that they're being sold "as-is." HUD does not want to hold onto inventory, so list prices are set at levels to secure buyers.
Given this criteria when I work with Buyers buying a HUD home we also do comps on all homes in the area. The HUD appraisal is important but when financing appraisal is completed they will use all the relevant comps and not just the foreclosures which can, but may not raise the price. The type of financing can be relevant also FHA vs RD vs Conventional.
The third is the earlier you bid the better. If 2 identical bids come in but one comes in on day 1 and the other at 5pm on the final day of the listing, the first bid wins. It is a true first come, first served. I have had clients in my office at 6am on opening day. Thank goodness I live on a farm!!! Keep in mind not all initial winning bids go through. I advise my clients they can keep their options open by becoming back-up bids.
The fourth is my company has a couple of agents who specialize in HUD's; listing several hundred in the last few years. When I started with HUD offers I sought their advice. They felt that within the first 90 days bids within 5-7% of the list price (including concessions) were the most successful. After 90 days there is more room for movement.
Overbidding the appraised price on a HUD home does not necessarily denote overpaying for the property. My advice make sure their agent is running the comps for them and they are getting their bids on in as soon as possible.


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text: Bessie Lenora Wilt Moss SOUTHERN PINES, N.C. - Bessie Lenora Wilt Moss passed away on Saturday, November 30, 2013. She was born on June 27, 1928, in Newport News, Virginia, the only daughter of the late Raymond and Gertrude Todd Wilt. She was preceded in death by her beloved husband of 65 years, Arthur Curtis "A.C" Moss Jr., who passed away on January 28, 2013. She was also preceded in death by two of her brothers, Ray Wilt and Arthur Wilt. She devoted her adult life to family and church. She was active in Girls Auxiliary and served as G.A. Director for many years. In addition, she was involved in leadership roles with the Girl Scouts. She encouraged her children's talents through the arts; piano, dance, and art lessons. Church and community involvement was a priority. She loved to travel with her husband and was exceptionally talented in many areas, sewing, stained glass, quilting, and organizing. She was known by family as "Sis" and friends called her "Bessie". Bessie is survived by her two daughters, Linda Moss Leonard and husband, Mike, of Cleveland, Tennessee, and Laura Moss Phillips of Sanford, North Carolina. She is also survived by four grandchildren, Jennifer Phillips Williams and husband, Tony, of Belmont, North Carolina, Laura Drumm Edrington and husband, Doug, of Harrison, Tennessee, Arthur Scott Drumm of Cleveland, Tennessee, and Blair Phillips Nail and husband, Jordan, of Cary, North Carolina; two brothers, Lawrence Wilt and wife, Sissy, of Seaford, Virginia, and James Wilt and wife, Joanie, of Williamsburg, Virginia. She also leaves behind many nieces and nephews. A graveside memorial service at Peninsula Memorial Park in Newport News, Virginia, will be scheduled for some time in March 2014, where she will be laid to rest along with her beloved husband. Online condolences can be made at www.smithfuneralhomebroadway.com. Arrangements are by the Smith Funeral Home of Broadway.


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Seed Capital, the Danish venture capital firm, said it has had a DKK 500m ($75.2m) first closing of its third fund, with pledges from such investors as ATP, Dansk Vækstkapital, The Danish Growth Fund and Augustinus Fonden.
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Thank you, Voluntarist.<quoted text>
You dont speak for me tinker bell, I like hugh.
Messianic Jews say they are persecuted in Israel
There are 71939 comments on the Newsday story from Jun 21, 2008, titled Messianic Jews say they are persecuted in Israel. In it, Newsday reports that:Safety pins and screws are still lodged in 15-year-old Ami Ortiz's body three months after he opened a booby-trapped gift basket sent to his family.
Join the discussion below, or Read more at Newsday.
Kingston, Jamaica
#59488 Oct 3, 2013
"Legumes of the World Unite "
Since: Sep 11
Location hidden
#59489 Oct 3, 2013
Kingston, Jamaica
#59491 Oct 3, 2013
Volintarist---You are a vile disgusting human being, who happens to be Jewish, that makes you a filthy jew.
HughBe--- In other words, being "a vile disgusting human being" is not a characteristic that is limited to some people of ALL other RACES.
Put it this way, in EVERY race there are " vile disgusting human being(s)". You are CORRECT.
Kingston, Jamaica
#59492 Oct 3, 2013
Joel--Hugh is sexually attracted to a certain gay American poster on this forum who has rejected his online advances but still Hugh persists in a sort of subconscious way.
Hugh--- Funny,very.
Joel---Of course, Hugh's not intentionally rude and unlike many others he holds no grudges, forgives easily and wishes people well.
Hugh--- The onset of wisdom, on display.
Kingston, Jamaica
#59493 Oct 3, 2013
Frijoles---Glad to see Hugh is perpetually in your thoughts
Joel--Please calm down.
Kingston, Jamaica
#59494 Oct 3, 2013
Did he finally confess?
Kingston, Jamaica
#59495 Oct 3, 2013
So,in your simple and dishonest mind, a man that is regarded as "the generations GREATEST authority on religious law" has no influence outside of Israel.
Listen to this, a man called Billy Graham had great influence in the US and elsewhere in the world and he was not regarded as the GREATEST SAGE of his generation.
In essence you talk too much CS. Let me change that to HS where H=HOG.
Kingston, Jamaica
#59496 Oct 3, 2013
Your 99.9% claim underscores your lack of HONESTY.
Give me a link to the source of such information. I have no interest in the REAR link and I suspect that is where you dug it out of.
"Legumes of the World Unite "
Since: Sep 11
Location hidden
#59497 Oct 3, 2013
Your only source for that assertion is an article in an Israeli Newspaper. Find another source or more to back you up, one based here in US and we can talk. Until then, you are FOS. As usual
Kingston, Jamaica
#59498 Oct 3, 2013
Given that he is not KNOWN in the US, I expect that his death shall not be covered.
"No Allah: know peace"
Since: Jun 07
A sacred grove in Tujunga, CA
#59499 Oct 3, 2013
Is his following as big as that of Rev. Sun Young Moon? Is it any more relevant?
Kingston, Jamaica
#59500 Oct 3, 2013
1. Was Moon regarded as the GREATEST sage of his generation in Christianity?
2. Did Moon CHANGE the religious and political life in Korea?
3. The relevance of size is to determine span of influence in country as well as in his religion i.e. Yosef and Judaism. Now of the over 2 BILLION Christian what % followed Moon?
4.Of the RELIGIOUS Jews of Judaism what % was affiliated to Yosef's Judaism?
United States
#59501 Oct 3, 2013
Right but the educated MD was 100% wrong about the gall stone.
Does your husband still have his gall bladder?
United States
#59502 Oct 3, 2013
Over reactionary government, those idiots couldn't trap a skunk.
Kingston, Jamaica
#59503 Oct 3, 2013
Read and understand.
"He(Yosef) is considered by his followers directly, ultra-Orthodox Sephardic public, and indirectly, the WIDER religious society as a MASTER sage, or Maran, and the generations GREATEST authority on religious law. Hence, his HEALTH is no laughing matter."
Tell me about the death of Moon. What impact did it have on the 2.1 Billion Christians?
When Yosef dies, will it be known outside of Israel?
Will it have National IMPACT on Israel?
Let us see the reaction to that event.
"No Allah: know peace"
Since: Jun 07
A sacred grove in Tujunga, CA
#59504 Oct 3, 2013
Well, he and his followers certainly thought so.
He wanted to change the whole world.
In case this went over your head, the point is that both are irrelevant little pissants with no significance anywhere. You just want an excuse to practice your antisemitism.
United States
#59505 Oct 3, 2013
I cant resist, ask Frijoles, he is an expert on sphincters.
United States
#59506 Oct 3, 2013
Stones originate in the liver.
Kingston, Jamaica
#59507 Oct 3, 2013
HughBe---Again,Yosef is considered by his followers and the wider religious society as a MASTER sage, or Maran, and the generations GREATEST authority on religious law. Hence, his health is no laughing matter.
Frijoles---What wider society?
HughBe--- Answer from extract, "wider religious society "
Frijoles--- Israeli, sephardic, and religious. Pretty small, considering.
HughBe--- Pretty small in relation to what?
Quantify the "WIDER RELIGIOUS SOCIETY"
Are you really calling the "WIDER RELIGIOUS SOCIETY" plus Yosef's group "pretty small"? Tell me about the LARGE group.
Get off the cocaine.
United States
#59508 Oct 3, 2013
I had 3 businesses running at the same time, small retail operations that allowed me to make a decent living.
The only problem with that was the 80 hour work weeks, heavy overhead and lots of responsibilities.
I was entirely self financed, instead of opening the second and third operations I bought out 2 existing establishments for cheap because they were distressed. I invested lots on remodeling and increased revenues by 100% give or take.
What happened was that the market reached maximum penetration in 2000 and started a slow decline from 2001, each year declining 8 to 10% per year. It was easy to predict the viability of the business by 2010 would be poor.
Leases ran on the two buildings and developers bought the properties and told us we had to leave.
I was left with one business which lasted until 2012 until I finally shut it down because the market wasn't there anymore.
It wasn't anything that I did wrong, everyone shut down. Cant give too many details because that will divulge my identity.
But now I have 2 service type businesses running and profitable with a third I plan on opening shortly which I have been carefully watching and planning since 1996.
The best thing about it is that I will be completely diversified and I dont have to work more than 20-30 hours per week.
Glad that I am out of retail.
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The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies which suggest that higher plasma concentrations of a number of pro-inflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug (NSAID) regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early onset familial PD, Parkin-deficient (parkin-/-) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin -/- mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin-/- mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin-/- mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in pre-clinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.
Parkinson's disease (PD) is primarily characterized by degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) that project to the striatum, the output of which governs locomotor behavior. While 90-95 % of PD cases have no known genetic basis, approximately 5-10 % arise from inherited mutations (reviewed in Farrer, 2006). Roughly half of early-onset PD is caused by loss-of-function mutations in the parkin gene (Lucking et al., 2000), which encodes an E3 ubiquitin ligase. The age-of-onset of parkinsonism in humans bearing parkin mutations can vary significantly, even within families carrying identical mutant alleles (Lucking et al., 2000). Although parkin-/- mice have dopaminergic system dysfunction, unlike humans bearing parkin mutations, they do not display nigrostriatal pathway degeneration (Goldberg et al., 2003; Itier et al., 2003; Von Coelln et al., 2004; Zhu et al., 2007).
A wealth of evidence in the last decade indicates that dysregulated neuron-glia interactions result in neuronal loss (Wersinger and Sidhu, 2002; McGeer et al., 2003; Mrak and Griffin, 2005; Zhang et al., 2006; Tansey et al., 2007). Post-mortem examination of brains from PD patients confirms the presence of neuroinflammation, raising the possibility that inflammatory mediators contribute to the progression of PD (McGeer et al., 1988; Banati et al., 1998; Hunot et al., 1999; Cassarino et al., 2000; Pavese et al., 2006; Whitton, 2007). While end-stage analysis does not prove a causal link, in vivo imaging of microglial activation with the peripheral benzodiazepine receptor binding ligand [11C]-(R) PK11195 in positron emission tomography scans confirms that irrespective of the number of years with the disease, patients with idiopathic PD have markedly elevated neuroinflammation in the pons, basal ganglia, striatum, and frontal and temporal cortical regions compared to age-matched healthy controls (Gerhard et al., 2006). Therefore, microglia may become and remain activated early in the disease process, possibly contributing to disease progression (for review see Tansey et al., 2007; Whitton, 2007). Evidence that inflammatory processes modulate PD risk in humans comes from prospective studies which suggest that higher plasma concentrations of the pro-inflammatory cytokine interleukin-6 increased the risk of developing PD (Chen et al., 2008) and chronic nonsteroidal anti-inflammatory drug (NSAID) regimens reduced the incidence of PD by 46 % (Chen et al., 2003; Chen et al., 2005). However, since other studies do not find significant protection by NSAIDs (Ton et al., 2006), additional studies are needed to establish a causal role for inflammation in the interplay between genetics and environment as underlying factors in the pathogenesis of PD.
The purpose of this study was to test the hypothesis that Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. To this end, we exposed parkin-/- and wild-type mice to repeated intraperitoneal injections of low-dose lipopolysaccaride (LPS) and evaluated locomotor behavior, nigral DA neuron loss, and markers of neuroinflammation and oxidative stress.
All mice were housed in a pathogen-free, climate controlled facility in the Animal Resources Center at The University of Texas Southwestern Medical Center at Dallas and given food and water ad libitum. All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee at The University of Texas Southwestern Medical Center at Dallas in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
The regimen of LPS injections for our studies was chosen based on published protocols which have been shown to trigger a neuroinflammatory response and hasten appearance and progression of amyloid-associated burden in a transgenic mouse model of Alzheimer's disease (Kitazawa et al., 2005). Young adult (6-13 week old) parkin-/- mice on a C57BL/6 background (backcrossed for over ten generations) and wild-type littermate mice were given either 7.5 × 105 EU/kg lipopolysaccharide (LPS) from Escherichia coli O111:B4 (Sigma-Aldrich, Saint Louis, MO, USA) or 0.9 % sodium chloride (vehicle control, Braun Medical, Inc, Irvine, CA, USA) injections intraperitoneally (i.p.) twice a week for 2 months (n = 3 mice per group), 3 months (n = 11-12 mice per group), or 6 months (n = 11-12 mice per group) (Figure 1 and Supplementary Figure S1). An additional group was given systemic LPS or vehicle for 3 months followed by a 3-month wait period during which no additional i.p. injections were administered (n = 8 mice per group). Following the last i.p. injection, the animals were divided into two sets and processed for either immunohistochemistry or QPCR (Figure 1).
For all behavioral tests, mice (n = 8 per group) were evaluated at baseline (before i.p. injections began) and depending on the regimen again at 3 and 6 months after LPS or saline administration (Figure 1).
Open-field behavior in a glass container (diameter, 24.5 cm) was recorded for 5 min for evaluation of time spent moving and number of rearing events by an investigator blinded to genotype and treatment history.
A narrow beam (1.1 cm diameter, 80.6 cm testing length) with a home cage at one end was used. Initial training prior to treatment consisted of 3 sessions of 3 trials per session for 4 consecutive days. Mice received additional training sessions at 3 months and 6 months after the start of treatment regimen consisting of 3 sessions of 3 trials per session on one day. Testing was conducted the day after training and consisted of one session of 3 trials. Average time to traverse the full length of the beam was determined and used for data analysis.
A base speed of 20 rpm with an acceleration of 0.2 rpm/second was used on the rotarod (Economex 0207-005 M, Columbus Instruments, Columbus, OH). Mice were trained prior to treatment in 3 sessions of 4 trials each for 4 consecutive days. Mice received additional training sessions at 3 months and 6 months after start of treatment consisting of 3 sessions of 4 trials per session on one day. Testing consisted of one session of 3 trials the day after training was completed. Latency to fall (seconds) was calculated and used for data analysis.
Following the last i.p. injection, mice in the 2-month cohort (n = 3 mice per treatment group) were deeply anesthetized with halothane, decapitated, and the brain rapidly removed and microdissected into 4 regions on an ice-cold glass Petri dish: olfactory bulb (OB), cerebellum (CB), ventral midbrain (MB) and cortex (CX) then snap-frozen in liquid nitrogen and stored at -80°C until processed for RNA extraction. For quantitative real time polymerase chain reaction (QPCR), mice in the 3-month, 3-month/3-month wait, and 6-month treatment cohort (n = 4 mice per treatment group) were deeply anesthetized with euthasol then intracardially perfused with 0.1 M phosphate buffered saline (PBS) pH 7.4 supplemented with 0.1 % glucose and 1 U/mL heparin prior to rapid whole brain removal. Microdissected tissue was snap-frozen or put in RNAlater (Ambion, Austin, TX, USA) and stored at - 80 ° until processed for QPCR. For immunohistochemistry, mice in the 3-month, 3-month/3-month wait, and 6-month treatment cohort (n = 7 - 8 mice per group) were perfused with 0.1M PBS followed by 4 % paraformaldehyde in PBS (pH 7.4). Brains (in the skull) were post-fixed overnight in 4 % PFA. Brains were dissected out then cryoprotected for 24 hr in 20 % sucrose in 0.1 M PBS pH 7.4, embedded in Neg 50 (Richard Allen Scientific, Kalamazoo, MI), and frozen in dry ice-cooled isopentane.
Total RNA was isolated from tissue samples using Tri Reagent® (Molecular Research Center, Cincinnati, OH, USA), treated with DNAse I (Invitrogen, Carlsbad, CA), and reverse transcribed to obtain cDNA. QPCR was performed using SYBR Green Master Mix (ABI) on an Applied Biosystems Prism 7900HT sequence detection system as described (Kurrasch et al., 2004). Primers for each gene (available upon request) were designed using Primer Express Software (PerkinElmer Life Sciences, Wellesley, MA, USA) and validated by analysis of template titration and dissociation curves. Results for QPCR were normalized to the housekeeping gene cyclophilin B and evaluated by comparative CT method (user bulletin No. 2, PerkinElmer Life Sciences). RNA levels are expressed relative to the wild-type saline-injected (vehicle) mice.
Coronal serial sections (30 μm thickness) were cut on a Leica CM 1850 cryostat and placed on Superfrost/Plus microscope slides (Fisher Scientific). Sections on slides were stored at -80° C until processed for immunohistochemistry.
Sections were stained for tyrosine hydroxylase (TH) using published protocols (Abbott and Jacobowitz, 1995; Frank et al., 2003). Sections were permeabilized in 0.3 % TritonX-100 in PBS pH 7.4. Endogenous peroxidases were quenched with 1 % H2O2 and non-specific binding was blocked with 5 % normal serum (goat or horse, Equitech-Bio, Inc., Kerrville, TX). Sections were incubated with primary antibodies against TH (rabbit polyclonal diluted 1:2000, Chemicon International, Temecula, CA, USA), or neuronal nuclear antigen (NeuN) (mouse monoclonal diluted 1:1000, Chemicon) overnight at room temperature followed by biotinylated secondary antibody (goat anti-rabbit or horse anti-mouse rat absorbed, or goat anti-rat IgG diluted 1:400, Vector Laboratories, Burlingame, CA, USA) and NeutrAvidin-HRP (diluted 1:5000, Pierce Biotechnology, Inc., Rockford, IL, USA). The tissue bound peroxidase activity was developed with a 0.024 % diaminobenzadine (DAB, Sigma), 0.006 % H2O2 in 0.05 M Tris-HCl buffer pH 7.6 for 20 min with or without nickel intensification. Tissue sections were dehydrated in a graded series of ethanols, immersed in xylene, and coverslipped with Permount (Fisher Scientific).
Brain sections were stained for microglial markers using a standard immunofluorescence protocol (McCoy et al., 2006). Auto-fluorescence was quenched in 0.2 M glycine in PBS pH 7.4, for 1 hr at room temperature. Sections were then permeabilized in 0.3 % Triton X-100 with 1 % normal goat serum in 20 mM Tris-buffered saline (TBS) pH 7.4. Non-specific binding was blocked with species-appropriate 1% normal serum in TBS. Sections were incubated overnight at 4° C with rat monoclonal antibody made against mouse CD68 (diluted 1:150, Serotec, Raleigh, NC) and rabbit polyclonal anti-TH (diluted 1:250, Chemicon) followed by Alexa-488 goat anti-rabbit (Invitrogen) secondary antibody (Fab) or Alexa-594 goat anti-rat secondary antibody (each at 1:1000 dilution, Invitrogen) for 4 hr at room temperature. Antibodies were diluted in blocking buffer with 0.1 % Triton X-100. Washes were done in TBS with 0.2 % Triton X-100 (TBST). Following secondary antibody incubations, slides were rinsed briefly with dH2O, then counterstained with Hoescht 33258 (at 1:20,000, Invitrogen) for 15 min, and coverslipped with aqueous mounting media with anti-fade (Biomeda Corp, Foster City, CA, USA).
The optical fractionator probe of Stereoinvestigator software (MicroBrightField, Inc., Williston, VT, USA) was used to obtain an unbiased estimate of TH-positive and NeuN-positive neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) as per the atlas of Paxinos (Paxinos, 2001). Stereologic parameters were as follows: counting frame, 50 μm × 50 μm; optical dissector: 20 μm; grid size, 120 μm × 160 μm. For the population size estimate (number of sections per animal), a target coefficient of error (Gundersen's m = 1) of less than 0.10 was considered acceptable.
Coronal serial sections (30 μm thickness) were cut between Bregma -1.22 to 1.70 on a Leica CM 1850 cryostat and placed on Superfrost/Plus microscope slides (Fisher Scientific). Tissue sections were immunostained for TH and developed using DAB as described above. Images of striatum (caudate putamen) from 12 tissue sections per animal were taken with a Color digital camera (Model CX9000) mounted on a Nikon Eclipse 80i microscope. Exposure times were kept constant for all images. TH-positive fiber density was determined using background corrected integrated optical density (IOD) measurements for each section using an Alpha Innotech FluorChem FC2 imaging workstation and software. All sections for each animal were averaged and group means were used to compare between treatment groups.
Levels of striatal DA and its metabolites (DOPAC, HVA and 3-MT) were quantified by HPLC with electrochemical detection. Mice were euthanized by carbon dioxide asphyxiation and the striatum was immediately dissected on an ice-cold glass Petri dish, weighed and stored at -80 until analysis. Frozen brain tissue was sonicated in 49 volume/weight (mg of tissue) of 0.1 M perchloric acid containing 0.2 mM sodium metabisulfite and centrifuged at 20,000 rpm 20 minutes 4°C in a benchtop centrifuge to clear debris. 20 μL of cleared supernatant was injected onto a C18 HPLC column and separated by isocratic elution at a flow rate of 0.6 ml/min with MD-TM mobile phase (ESA Inc, Chelmsford, MA). Neurotransmitter monoamines and metabolites were detected using a BAS electrochemical cell set to a potential of +800 mV and compared to external standards.
Multiple-way analysis of variance (ANOVA) with significance level α = 0.05 were used as indicated for each set of experimental data. Significant differences between groups were further evaluated using Tukey's HSD post hoc test. Kruskal-Wallis analysis was the nonparametric statistical test used for testing equality of population medians of integrated optical density measurements of striatal TH fiber density.
First, we sought to establish proof-of-concept that our prolonged, serial regimen of low-dose intraperitoneal (i.p.) LPS injections could trigger a neuroinflammatory response in the central nervous system (CNS). Therefore, we evaluated the expression of inflammation-related genes in various brain regions of young adult wild-type and parkin-/- mice. All mice in the proof-of-concept cohort were sacrificed after 2 months of twice-weekly i.p. LPS or saline (vehicle) injections (Supplementary Figure 1A). Wild-type and parkin-/- mice responded to repeated systemic low-dose LPS with similar (approximately 2-fold) increases in Cox-1 mRNA in olfactory bulb and increases in CD45 mRNA, a membrane-associated tyrosine phosphatase upregulated in activated microglia, in midbrain; but neither Cox-1 nor CD45 were upregulated in the cortex. (Supplementary Figure 1B; 3-way ANOVA, Tukey's HSD posthoc at α = 0.05; TNF: F15, 47 = 2.11, p = 0.037; CD45: F15, 46 = 4.48, p = 0.0002; Cox-1: F15, 47 = 2.19, p = 0.031). No significant increase in expression of mRNA tissue content for the pan-microglial marker CD68 was detected (p = 0.26). Taken together, these data provide proof-of-concept that our prolonged, serial low-dose systemic LPS injection regimen successfully triggered a neuroinflammatory response in anatomical regions that show early involvement in PD (olfactory bulb and midbrain) and not in areas that are unaffected in the early stages of the disease (cortex) in both wild-type and parkin-/- mice.
We performed behavioral testing on all treatment groups (Figure 1) to investigate the extent to which the prolonged, serial low-dose systemic LPS regimens could cause locomotor alterations. A number of behavioral tasks were measured at the time-points indicated until the various cohorts were sacrificed for gene expression or immunohistological analysis of microdissected brain tissue. To assess gross locomotion, we measured open-field and rotarod performance. No differences were noted on rotarod performance (Figure 2A; p = 0.19) or open-field testing (data not shown). Thus, in the present study, prolonged, serial i.p. injections of LPS or saline did not cause gross motor abnormalities. To assess fine-motor performance, mice were subjected to the narrow beam-walk test. Our results indicate that parkin-/- mice chronically injected with LPS displayed a significantly slower average time-to-cross compared to saline-treated parkin-/- mice or either group of wild-type mice (Figure 2B, 3-way ANOVA Tukey's HSD post-hoc at α = 0.05; beam: F15,248 = 8.55, p < 0.0001).
To test the hypothesis that Parkin deficiency increases vulnerability to inflammation-related nigral degeneration, we exposed wild-type and parkin-/- mice to various systemic LPS regimens (Figure 1). We measured endpoint immunohistological outcomes for unbiased stereological analyses of DA neuron number and total neuron number by staining midbrain sections with the DA neuron marker TH and the pan-neuronal marker NeuN (Figure 3C). Compared to similarly dosed wild-type mice, parkin-/- mice that received 3 months of repeated low-dose systemic LPS did not exhibit significant reductions in TH positive or NeuN positive neurons in the SNpc. In contrast, parkin-/- mice but not wild-type mice that received 3 months of repeated low-dose systemic LPS followed by a 3-month lag period displayed a significant reduction in the number of both TH positive and NeuN positive SNpc neurons (Figure 3A, C, 3 way ANOVA. Tukey's HSD posthoc at α = 0.05; SNpc TH: F11,75 = 4.78, p < 0.0001; SNpc NeuN: F11,75 = 3.54, p = 0.0007). Wild-type mice which were injected with low-dose LPS for 6 months displayed a reduction in the number of TH positive neurons but not of NeuN positive SNpc neurons (Figure 3A). By contrast, parkin-/- mice which received low-dose LPS for 6 months showed significant loss of SNpc TH positive and NeuN positive neurons compared to saline-treated parkin-/- mice and to wild-type mice treated with either saline or LPS. To investigate the extent to which the loss of DA neurons was selective to nigra, we performed stereological counts of TH and NeuN positive cells in ventral tegmental area (VTA). VTA TH positive and NeuN positive cell counts did not differ between the two genotypes in any of the different LPS regimens with the exception of a slight but significant reduction in the number of TH positive (but not NeuN positive) neurons in the parkin-/- mice treated for 6 months with low-dose systemic LPS (Figure 3B, 3 way ANOVA. Tukey's HSD posthoc at α = 0.05, VTA TH: F11,75 = 1.92, p = 0.05; VTA NeuN: not significant, p = 0.16). Taken together, these data suggest that Parkin deficiency selectively increased the vulnerability of nigral DA neurons to the degenerating effects of neuroinflammation triggered by repeated low-dose i.p. LPS injections.
To investigate whether the loss of nigral DA neurons was accompanied by loss of dopaminergic terminals at the striatum, we stained striatal sections for TH. Although slight decreases in striatal TH fiber immunoreactivity was detectable in brain sections from parkin-/- mice treated with low-dose systemic LPS for 6 months (Figure 4B), densitometric analysis of multiple sections indicated the decrease did not reach significance (Figure 4A). To extend and confirm these findings, we measured the tissue levels of DA and its metabolites in microdissected striatum by HPLC and electrochemical detection. In agreement with the immunohistological results, repeated low-dose i.p. LPS injections did not cause striatal DA depletion or changes in DA turnover in either genotype (Figure 4C).
To investigate the possibility that the LPS-induced nigral DA neuron loss in parkin-/- mice may have resulted from an enhanced neuroinflammatory response, we labeled midbrain sections from mice in the 3-month treatment groups with antibodies against TH and the pan-microglial marker CD68. Our analysis revealed comparable microgliosis between LPS-injected mice of both genotypes (Figure 5A); similar results were obtained with an antibody against the activation marker CD45 (data not shown). To extend these observations and quantitatively assess markers of neuroinflammation at the point where nigral cell loss was evident, we used QPCR to measure the relative mRNA expression of Cox-1, TNF, CD45, and CD68 in midbrain and cortex in the mice from the 6-month treatment groups. We found that both parkin-/- and wild-type mice displayed comparable increases in midbrain CD45 and TNF mRNA in response to prolonged, serial low-dose i.p. LPS (Figure 5B; 3-way ANOVA, Tukey's HSD posthoc at ± = 0.05; TNF: F7,31 = 3.93, p = 0.007; CD45: F7,31 = 5.1, p = 0.001; CD68: not significant, p = 0.17; Cox-1: not significant, p = 0.19). To quantify the extent of astrocytosis, we measured mRNA levels of the pan-astrocyte marker connexin-43 by QPCR and found no difference between treatment groups or genotypes (data not shown). Additionally, we stained brain sections from mice in the 6-month treatment groups with hematoxylin-eosin and found no evidence of lymphocyte and/or neutrophil infiltration into the SNpc (data not shown). Taken together with results obtained after a 2-month systemic LPS exposure (Supplementary Figure 1B), these data suggest that even the longest systemic low-dose LPS regimen examined did not trigger exaggerated midbrain neuroinflammatory responses in parkin-/- mice relative to that displayed by wild-type mice.
We next hypothesized that the nigral cell loss in parkin-/- mice following prolonged, serial systemic LPS administration might have resulted from an inability to respond normally to neuroinflammation-induced oxidative stress. To test this hypothesis, we used QPCR to measure the level of expression of key antioxidant genes implicated in protection of DA neurons in the midbrain of parkin-/- mice that received 3- or 6-month low-dose systemic LPS administration. Based on the current literature, we elected to analyze the transcription factor NF-E2 related factor (Nrf2), which binds to the antioxidant response element (ARE) to induce expression of antioxidant and phase 2 detoxification enzymes, NAD(P)H:quinone oxidoreductase (NQO1), heme-oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), superoxide dismutase-1(SOD1), and superoxide dismutase -2 (SOD2). In the 3-month exposure cohorts, we found no differences between genotypes or treatment groups. In the 6-month exposure cohorts, we detected slight but significant differences in baseline levels of iNOS mRNA expression between saline-injected wild-type and parkin-/- mice, suggesting an age-dependent increase in this marker of oxidative stress in parkin-/- mice. While SOD2 mRNA was significantly increased in parkin-/- LPS compared to wild-type saline, the LPS-induced increases in iNOS, Nrf-2, and HO-1 mRNA were similar for both genotypes. NQO1, and SOD1 mRNA did not differ between any of the groups (Figure 6; 3-way ANOVA, Tukey's HSD posthoc at α = 0.05; Nrf2: F7, 31 = 4.9, p = 0.002; HO-1: F7, 30 = 2.94, p = 0.02; NQO1: not significant, p = 0.44; iNOS: F7, 30 = 5.26, p = 0.001; SOD1: not significant, p = 0.19; SOD2: F7, 31 = 3.0, p = 0.02). Thus, saline-treated parkin-/- midbrain displayed signs of increased oxidative stress relative to wild-type midbrain but the midbrain anti-oxidant response of parkin-/- mice to repeated and prolonged systemic LPS administration was similar to that displayed by wild-type mice.
We report here the development of a mouse model of nigral DA neuron loss that supports the hypothesis that genetic susceptibility and environmental factors synergize to enhance the vulnerability of nigral DA neurons. Specifically, by varying the length of serial systemic low-dose LPS exposure, we uncovered an increased vulnerability of SNpc DA neurons in parkin-/- mice relative to wild-type mice, implicating a specific role for Parkin in neuroprotection against inflammation-related degeneration. We detected no loss of TH positive or NeuN positive SNpc neurons in mice of either genotype exposed to low-dose systemic LPS for 3 months alone. However, after an additional 3-month wait only the parkin-/- mice displayed a reduction in TH positive (26 % loss) and NeuN positive (31 % loss) neuron number. Moreover, when the injections of low-dose systemic LPS were administered for 6 months, the parkin-/- mice displayed a larger reduction (44 % loss) of SNpc TH positive neurons and SNpc NeuN positive neurons (43 % loss). It should be noted that after 6 months of repeated low-dose i.p. LPS injections, both wild-type and parkin-/- mice displayed significant reductions in TH-positive neuron number (27 % and 44 % loss, respectively) compared to saline administration, while significant NeuN positive neuron loss was observed for LPS-treated parkin-/- mice (43 % loss) but not for LPS-treated wild-type mice (14 % loss). It is possible that the reduction in TH positive neuron count in wild-type mice may reflect downregulation of TH expression (and not frank neuron loss) and/or that the NeuN positive neuron count in the wild-type group might have progressed to a significant level given additional time. The decrease in NeuN positive neurons for both genotypes exceeds the expected range given the observed losses in TH positive cells, assuming 50-80% of the NeuN positive nigral cells are dopaminergic and TH-positive (McCormack et al., 2006; Kramer et al., 2007). Thus, it is possible that our systemic LPS regimen may have also caused some loss of non-dopaminergic nigral neurons in parkin-/- mice. With the exception of a slight but significant decrease in the TH positive (but not NeuN positive) counts in parkin-/- mice treated for 6 months, we found no significant reduction in the number of TH positive or NeuN positive neurons in VTA, indicating greater vulnerability of SNpc over VTA to repeated low-dose i.p. injections of LPS. Taken together, these results suggest that Parkin deficiency heightens the sensitivity of DA neurons in SNpc to inflammatory stimuli.
Although we observed deficits in beam walk performance in LPS-treated parkin-/- mice, these locomotor abnormalities did not correlate tightly with nigral DA neuron loss or striatal DA depletion. Specifically, parkin-/- mice in the 3-month low-dose systemic LPS treatment group displayed beam walk abnormalities, yet there was no statistically significant nigral DA neuron loss. Moreover, the parkin-/- mice which developed both beam walk deficits and significant nigral DA neuron loss did not display striatal TH terminal damage or DA depletion. Given these observations, we suspect that the locomotor abnormalities in parkin-/- mice are not the direct or sole result of dopaminergic system dysfunction, but may instead reflect inflammation-related dysfunction in other neuronal populations involved in regulation of motor behavior.
A number of non-mutually exclusive possibilities may explain the observed loss of nigral DA neurons without a parallel decrease in striatal TH immunoreactivity or decreases in striatal DA levels. First, our data suggests that the loss of nigral DA neurons occurs over the course of several months, which would allow compensatory upregulation of TH within existing terminals and perhaps sprouting of additional terminals. Another more interesting possibility is that the lack of obvious striatal damage may reflect an intrinsic difference in the inflammatory response/arsenal between the two brain regions. In support of this idea, MPTP intoxication has been reported to elicit induction of iNOS mRNA to a significantly greater extent in nigra compared to striatum and predictably, genetic ablation of iNOS resulted in substantial preservation of nigral DA neurons but did not attenuate striatal dopaminergic fiber damage which may be mediated instead by nNOS (Liberatore et al., 1999). Similarly, orally administered peroxisome proliferator-activated receptor-gamma (PPARγ) agonist pioglitazone attenuated the MPTP-induced glial activation and loss of DA neurons in SNpc but not the striatal glial response or loss of striatal DA and dopaminergic terminals (Breidert et al., 2002). Lastly, our previous studies in which intranigral, but not intrastriatal, infusion of dominant negative TNF inhibitor (DN-TNF) significantly attenuated nigral DA neuron loss induced by a striatal 6-hydroxydopamine lesion (McCoy et al., 2006) suggested that marked differences in regulation of TNF-dependent inflammatory responses may exist between SNpc and striatum. A systematic investigation of these potential differences is needed to further establish their significance.
While our studies are the first to combine prolonged, serial systemic low-dose LPS injections with a genetic mouse model that displays dopaminergic dysfunction, the vulnerability of nigral DA neurons to LPS-induced degeneration is supported by multiple studies. Chronic low-dose LPS delivered intranigrally caused selective, delayed, and progressive degeneration of nigral DA neurons (Gao et al., 2002). Ventral mesencephalon cultures display increased sensitivity to both MPTP and rotenone when the exposure is combined with LPS (Gao et al., 2003a; Gao et al., 2003b). Prenatal exposure to LPS predisposes nigral DA neurons to 6-OHDA or rotenone-induced degeneration in adulthood (Ling et al., 2004a; Ling et al., 2004b). Pre-exposure to low-dose systemic LPS increases susceptibility to intrastriatal 6-OHDA-induced nigral DA neuron loss through a mechanism that is likely to involve pro-inflammatory signaling by IL-1β and TNF (Koprich et al., 2008). Taken together, these studies suggest that neuroinflammation could act in concert with genetic susceptibility loci and/or other environmental factors to accelerate nigral DA neuron loss. In support of this idea, a recent report by Lee and Trojanowski demonstrated that overexpression of wild-type and pathologic forms of human α-synuclein interact with neuroinflammation (intranigral LPS injection) and synergistically contribute to dopaminergic neurodegeneration (Gao et al., 2008).
The exact molecular mechanism by which loss of Parkin increases susceptibility to systemic inflammation-related nigral degeneration is unclear and will require further investigation. Our findings indicate that repeated low-dose LPS triggered a neuroinflammatory response in midbrain that preceded nigral DA neuron loss. Ventral midbrain DA neurons are extremely sensitive to the neurotoxic effects of TNF (McGuire et al., 2001) and the extended systemic LPS regimens used in our study that induced nigral cell loss also increased TNF expression in the midbrain. Our previous work demonstrated that blocking soluble TNF signaling in SNpc rescues approximately 50% of nigral DA neurons from 6-OHDA- or low-dose intranigral LPS-induced degeneration (McCoy et al., 2006), further implicating TNF as a critical mediator of nigral DA neuron death. To date, specific TNF-dependent signaling pathways required to exert neurotoxic effects on DA neurons have not been identified. However, it has been firmly established that activation of TNFR1 elicits two opposing signaling cascades: a pro-apoptotic signaling cascade involving MAPK and executioner caspase activation, and an anti-apoptotic signaling cascade involving activation of the NFκB pathway; whether a cell lives or dies is determined by the relative strength and duration of these signaling cascades (Aggarwal, 2000; Chen and Goeddel, 2002). Given that Parkin has been reported to activate the NFκB pathway by enhancing proteasomal degradation of the IKK complex (Henn et al., 2007), it is possible that loss of Parkin function in DA neurons results in attenuated activation of the NFκB pathway in response to a TNF stimulus, thus biasing the functional outcome of a TNF stimulus in favor of the apoptotic cascade and hastening the death of nigral DA neurons. Future studies will be aimed at investigating this and other mechanisms. Our analyses of oxidative stress markers in the midbrain of parkin-/- mice did not indicate exaggerated responses to prolonged, serial systemic LPS administration relative to that of wild-type mice, making it unlikely to constitute the basis for the increased nigral DA neuron loss in LPS-treated parkin-/- mice. While this finding was somewhat unexpected, it is consistent with reports that Parkin deficiency does not increase susceptibility to oxidative neurotoxins such as MPTP, 6-OHDA and methamphetamine (Perez et al., 2005; Thomas et al., 2007; Zhu et al., 2007). However, if robust increases in oxidative stress markers represent an attempt to restore redox homeostasis, we cannot rule out the possibility that the inability of parkin-/- mice to mount a more robust anti-oxidant response to prolonged, serial systemic LPS administration might have contributed to increased nigral DA neuron loss.
In conclusion, we have developed an animal model of nigral DA neuron loss using prolonged, serial i.p. LPS injections as the environmental trigger to elicit nigral degeneration in parkin-/- mice, suggesting a specific role for Parkin in neuroprotection against inflammation-induced degeneration. We believe the use of this model in preclinical neuroprotective trials may help identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.
We thank M.K. McCoy and F.E. McAlpine for assistance with behavior studies, S. Jiang for assistance with QPCR, K. Crouch for assistance with histology, G. Kramer for assistance with HPLC, and members of the Tansey and Goldberg labs for useful discussions. This work was made possible with funding from The Michael J. Fox Foundation for Parkinson's Research (MGT and MSG) and the National Institutes of Health NINDS 1R01NS049433-02 (MGT).
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Yesterday, Linda Evangelista was in Manhattan Family Court again, fighting for child support for her 4-year-old son, Augusten James. Only recently, it was awkwardly and scandalously revealed that the boy's father is François-Henri Pinault, who you know otherwise as Salma Hayek's husband and father to her 3-year-old daughter, Valentina, as well as the CEO of PPR, which owns Gucci, Yves St. Laurent, and Bottega Veneta, among other labels. The model's lawyer says Pinault has paid nothing in child support to Evangelista, who now asks for $46,000 a month from him — in what "would probably be the largest support order in the history of the Family Court," the judge said.
Model wants pretty penny [NYP]


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iHerb Customer Reviews
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text:
22nd April 2014
US: City council indefinitely postpones consideration of anti-discrimination policy
3:28 PM — A Michigan city council has indefinitely postponed consideration of a proposal to ban discrimination based on sexuality or gender identity.
4th April 2014
Obama spokesman: It would be 'redundant' to ban anti-gay workplace discrimination with executive order 2
9:19 PM — White House press spokesman Jay Carney has claimed it would be 'redundant' for Barack Obama to issue an executive order to ban workplace discrimination.
4th March 2014
Kansas: Gay rights groups call to have sexual orientation added to law banning discrimination 1
7:34 PM — Following the progression of a bill to legalise anti-gay discrimination, gay rights groups are calling for sexual orientation to be added to a Kansas anti-discrimination law.
13th January 2014
Disney World joins coalition of Florida businesses supporting anti-discrimination law 5
8:06 PM — Walt Disney World joined other influential businesses in the US state of Florida to throw weight behind a bill to ban anti-LGBT discrimination in the workplace.
26th September 2013
US: Washington National Cathedral to mark Matthew Shepard's death with 'Honouring LGBT Youth' weekend 1
4:10 PM — Washington National Cathedral has announced that it will mark the fifteenth anniversary of Matthew Shepard's murder with a weekend of events to honour LGBT youth who have suffered bullying, discrimination and violence.
24th September 2013
Video: Italian politicians stage kiss-in protest during debate over LGBT discrimination protection bill 7
6:10 PM — A political party in Italy interrupted a debate over an LGBT discrimination protection bill, to stage a kiss-in protest in solidarity with the LGBT community.
12th August 2013
US radio host: Nondiscrimination laws actually discriminate and 'create a climate of suspicion, spite and revenge' 19
3:24 PM — US Christian radio host Linda Harvey has spoken out on the issue of anti-discrimination laws, to say that they actually make discrimination worse, and that they "create a climate of suspicion, spite and revenge".
31st July 2013
Liverpool FC bans staff from using anti-gay slurs 1
5:30 PM — Liverpool Football Club has issued a new set of rules to its workers banning the use of "unacceptable" words and phrases such as "faggot", "fairy", and "that's gay".
20th June 2013
Malta: Bill introduced to increase protections against sexual orientation discrimination 4
6:28 PM — A private member's bill has been introduced in Malta in order to amend the country's Constitution to increase protections against discrimination based on sexual orientation.
17th June 2013
US: Knox County to add LGBT protections to hiring procedure
2:17 PM — The anti-discrimination act for employment by Knox County in Tennessee, is to be updated in order to protect LGBT people, despite officials say that such discrimination is already not allowed.
13th June 2013
US: Major League Soccer teams up with anti-discrimination campaign 1
2:01 AM — The football league representing the highest level in the US, Major League Soccer (MLS), has announced that it is upping efforts to tackle anti-LGBT discrimination by joining up with the You Can Play Project.
10th May 2013
Albania: Deputy Defence Minister accused of homophobic discrimination 3
6:00 PM — The Albanian Deputy Defence Minister Ekrem Spahia, and a Socialist Party official Artan Lame, have both come under heavy criticism for publicly using discriminatory language against the LGBT community.
9th May 2013
US: Philadelphia Mayor to sign landmark LGBT protection bill into law 2
5:45 PM — The Mayor of the US city of Philadelphia is to sign a city-wide ordinance offering protections, and benefits for LGBT citizens into law, in a ceremony on Thursday.
27th April 2013
US: Bill prohibiting anti-LGBT discrimination to be introduced in South Carolina 12
5:59 PM — The US State of South Carolina is looking to make discrimination against LGBT people in the workplace illegal.
23rd March 2013
US: Kentucky Governor vetoes bill protecting right to act based on religious belief following lobbies by LGBT rights groups 34
10:25 AM — The Governor of Kentucky has vetoed a bill proposing legal protection be given to people acting on religious motivations, which activists warned was "a clear and present danger to the gay and lesbian community".
21st March 2013
Canada: Bill criminalising anti-transgender discrimination passes in House of Commons 3
2:24 PM — A bill protecting transgender people from discrimination narrowly passed in Canada's House of Commons on Wednesday.
16th March 2013
Video: Doctor claims promiscuity is a legitimate reason to discriminate against LGBT people 49
4:12 PM — A committee considering anti-discrimination laws in America have heard evidence that employers should be able to choose straight people over LGBT people because gay men are promiscuous and make "inappropriate models" for children.
15th March 2013
US: Maryland gender identity bill fails to pass Senate committee 3
2:39 PM — A bill which aimed to tackle discrimination in employment, credit, housing and public accommodations, based on gender identity or expression, failed to pass the committee stage of Maryland's Senate.
1st March 2013
Moldova: Second largest city overturns local ban on 'gay propaganda' 2
1:14 PM — A court in the second largest city in Moldova has struck down a local ban on what authorities had referred to as "homosexual propaganda".
15th January 2013
UK: Defeat for anti-gay Christians at European Court of Human Rights 87
11:46 AM — Two Christians, who claim that they were fired because they wouldn't work with gay couples, have lost their anti-discrimination case at the European Court of Human Rights.


text: SAN FRANCISCO (MarketWatch) -- BlackRock Advisors LLC BLK, -0.58% said Wednesday that a shareholder complaint was filed against the investment firm earlier this month in the Supreme Court of the State of New York. The lawsuit, filed Aug. 4, relates to four closed-end funds, and alleges that "BlackRock Parties breached their fiduciary duties to the common shareholders," BlackRock said. The four funds named in the suit are BlackRock MuniYield Insured Fund Inc. MYI, +1.46% BlackRock MuniYield California Insured Fund Inc. MCA, -0.07% BlackRock MuniYield Fund Inc. MYD, +0.29% and BlackRock MuniHoldings Insured Investment Fund MFL, -0.93% BlackRock said that, "The claims asserted in the complaint are without merit."


text:
anonymous asked:
I think you're great, but your view of economics is so twisted, it makes me sick. This experiment with Keynesian economics and central planning has sent the country trillions of dollars into debt. And you think handouts will help this? People respond to incentives, so why would people contribute to society when they can get things for free? And the minimum wage? I hoped you'd be smart enough to realize how horrible it is for low-skilled workers.
It was nice to receive this ask because the rest of tumblr thinks I am such a proletariat-hating capitalist.
But anyway:
1. The question of whether a minimum wage is bad for low-skilled workers is far from settled, and anyone who claims that it is either unambiguously good or bad just hasn't done much reading on the topic.
2. Why would people contribute to society when they can get things for free? Well, people are slightly more complicated than you're giving them credit for, but no matter. Welfare is not a rational alternative to work in the United States or anywhere else in the industrialized world, and instituting a minimum income would not make it a rational alternative to work, because those checks would go to people who have jobs as well as those who don't.
3. Just as a general point, I think there is a habit among a lot of people (myself included) to take one economics class in college and think that we are experts, but generally it's better just to do some research and understand that even economists who do this stuff for a living disagree all the time. Economics is not a science like other sciences: No one is definitively right. (That said, Keynes came out of the Great Recession looking pretty damned good, even according to his detractors.)


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After 10 Years Kit
By Trixie Scraps Designs
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- Type: Combo Pack
- Designer: Trixie Scraps Designs
- Download Size: 172.4 MB (approximate)
Design Elements
- Digital Papers: 15
- Page Elements: 51
- Monograms Characters: 72
Designer Notes
I created my newest digital scrapbooking collection, After 10 Years, in honor of my upcoming 10th wedding anniversary with my husband, Erick. It is my hope that the rich patterns, unique color palette, and variety of elements will help you scrap about your best anniversaries... that this collection will help you tell your significant other how much you love them... and even help you scrap your most treasured wedding, formal and family heritage photos, as well! This full kit contains fifteen 12x12 papers (10 patterns and 5 solids, all 300 dpi, JPG format) plus 50 elements and 1 full alpha (all 300dpi, PNG format). Approved for personal use, Scrap4Hire/Scrap4Others, too.
Make sure to check out the coordinating pieces from the whole collection!