text:
Documentation |
On this page… |
Specify options by creating an options structure using the saoptimset function as follows:
options = saoptimset('Param1',value1,'Param2',value2, ...);
See Set Options for simulannealbnd at the Command Line for examples.
Each option in this section is listed by its field name in the options structure. For example, InitialTemperature refers to the corresponding field of the options structure.
Plot options enable you to plot data from the simulated annealing solver while it is running.
PlotInterval specifies the number of iterations between consecutive calls to the plot function.
To display a plot when calling simulannealbnd from the command line, set the PlotFcns field of options to be a function handle to the plot function. You can specify any of the following plots:
@saplotbestf plots the best objective function value.
@saplotbestx plots the current best point.
@saplotf plots the current function value.
@saplotx plots the current point.
@saplotstopping plots stopping criteria levels.
@saplottemperature plots the temperature at each iteration.
@myfun plots a custom plot function, where myfun is the name of your function. See Structure of the Plot Functions for a description of the syntax.
For example, to display the best objective plot, set options as follows
options = saoptimset('PlotFcns',@saplotbestf);
To display multiple plots, use the cell array syntax
options = saoptimset('PlotFcns',{@plotfun1,@plotfun2, ...});
where @plotfun1, @plotfun2, and so on are function handles to the plot functions.
If you specify more than one plot function, all plots appear as subplots in the same window. Right-click any subplot to obtain a larger version in a separate figure window.
The first line of a plot function has the form
function stop = plotfun(options,optimvalues,flag)
The input arguments to the function are
options — Options structure created using saoptimset.
optimvalues — Structure containing information about the current state of the solver. The structure contains the following fields:
x — Current point
fval — Objective function value at x
bestx — Best point found so far
bestfval — Objective function value at best point
temperature — Current temperature
iteration — Current iteration
funccount — Number of function evaluations
t0 — Start time for algorithm
k — Annealing parameter
flag — Current state in which the plot function is called. The possible values for flag are
'init' — Initialization state
'iter' — Iteration state
'done' — Final state
The output argument stop provides a way to stop the algorithm at the current iteration. stop can have the following values:
false — The algorithm continues to the next iteration.
true — The algorithm terminates at the current iteration.
Temperature options specify how the temperature will be lowered at each iteration over the course of the algorithm.
InitialTemperature — Initial temperature at the start of the algorithm. The default is 100. The initial temperature can be a vector with the same length as x, the vector of unknowns. simulannealbnd expands a scalar initial temperature into a vector.
TemperatureFcn — Function used to update the temperature schedule. Let k denote the annealing parameter. (The annealing parameter is the same as the iteration number until reannealing.) The options are:
@temperatureexp — The temperature is equal to InitialTemperature * 0.95^k. This is the default.
@temperaturefast — The temperature is equal to InitialTemperature / k.
@temperatureboltz — The temperature is equal to InitialTemperature / ln(k).
@myfun — Uses a custom function, myfun, to update temperature. The syntax is:
temperature = myfun(optimValues,options)
where optimValues is a structure described in Structure of the Plot Functions. options is either the structure created with saoptimset, or the structure of default options, if you did not create an options structure. Both the annealing parameter optimValues.k and the temperature optimValues.temperature are vectors with length equal to the number of elements of the current point x. For example, the function temperaturefast is:
temperature = options.InitialTemperature./optimValues.k;
Algorithm settings define algorithmic specific parameters used in generating new points at each iteration.
Parameters that can be specified for simulannealbnd are:
DataType — Type of data to use in the objective function. Choices:
'double' (default) — A vector of type double.
'custom' — Any other data type. You must provide a 'custom' annealing function. You cannot use a hybrid function.
AnnealingFcn — Function used to generate new points for the next iteration. The choices are:
@annealingfast — The step has length temperature, with direction uniformly at random. This is the default.
@annealingboltz — The step has length square root of temperature, with direction uniformly at random.
@myfun — Uses a custom annealing algorithm, myfun. The syntax is:
newx = myfun(optimValues,problem)
where optimValues is a structure described in Structure of the Output Function, and problem is a structure containing the following information:
objective: function handle to the objective function
x0: the start point
nvar: number of decision variables
lb: lower bound on decision variables
ub: upper bound on decision variables
For example, the current position is optimValues.x, and the current objective function value is problem.objective(optimValues.x).
ReannealInterval — Number of points accepted before reannealing. The default value is 100.
AcceptanceFcn — Function used to determine whether a new point is accepted or not. The choices are:
@acceptancesa — Simulated annealing acceptance function, the default. If the new objective function value is less than the old, the new point is always accepted. Otherwise, the new point is accepted at random with a probability depending on the difference in objective function values and on the current temperature. The acceptance probability is
where Δ = new objective – old objective, and T is the current temperature. Since both Δ and T are positive, the probability of acceptance is between 0 and 1/2. Smaller temperature leads to smaller acceptance probability. Also, larger Δ leads to smaller acceptance probability.
@myfun — A custom acceptance function, myfun. The syntax is:
acceptpoint = myfun(optimValues,newx,newfval);
where optimValues is a structure described in Structure of the Output Function, newx is the point being evaluated for acceptance, and newfval is the objective function at newx. acceptpoint is a Boolean, with value true to accept newx, and false to reject newx.
A hybrid function is another minimization function that runs during or at the end of iterations of the solver. HybridInterval specifies the interval (if not never or end) at which the hybrid function is called. You can specify a hybrid function using the HybridFcn option. The choices are:
[] — No hybrid function.
@fminsearch — Uses the MATLAB® function fminsearch to perform unconstrained minimization.
@patternsearch — Uses patternsearch to perform constrained or unconstrained minimization.
@fminunc — Uses the Optimization Toolbox™ function fminunc to perform unconstrained minimization.
@fmincon — Uses the Optimization Toolbox function fmincon to perform constrained minimization.
You can set separate options for the hybrid function. Use optimset for fminsearch, psoptimset for patternsearch, or optimoptions for fmincon or fminunc. For example:
hybridopts = optimoptions('fminunc','Display','iter','Algorithm','quasi-newton');
Include the hybrid options in the simulannealbnd options structure as follows:
options = saoptimset(options,'HybridFcn',{@fminunc,hybridopts});
hybridopts must exist before you set options.
See Include a Hybrid Function for an example.
Stopping criteria determine what causes the algorithm to terminate. You can specify the following options:
TolFun — The algorithm runs until the average change in value of the objective function in StallIterLim iterations is less than TolFun. The default value is 1e-6.
MaxIter — The algorithm stops if the number of iterations exceeds this maximum number of iterations. You can specify the maximum number of iterations as a positive integer or Inf. Inf is the default.
MaxFunEval specifies the maximum number of evaluations of the objective function. The algorithm stops if the number of function evaluations exceeds the maximum number of function evaluations. The allowed maximum is 3000*numberofvariables.
TimeLimit specifies the maximum time in seconds the algorithm runs before stopping.
ObjectiveLimit — The algorithm stops if the best objective function value is less than or equal to the value of ObjectiveLimit.
Output functions are functions that the algorithm calls at each iteration. The default value is to have no output function, []. You must first create an output function using the syntax described in Structure of the Output Function.
Using the Optimization app:
Specify Output function as @myfun, where myfun is the name of your function.
To pass extra parameters in the output function, use Anonymous Functions.
For multiple output functions, enter a cell array of output function handles: {@myfun1,@myfun2,...}.
At the command line:
options = saoptimset('OutputFcns',@myfun);
For multiple output functions, enter a cell array:
options = saoptimset('OutputFcns',{@myfun1,@myfun2,...});
To see a template that you can use to write your own output functions, enter
edit saoutputfcntemplate
at the MATLAB command line.
The output function has the following calling syntax.
[stop,options,optchanged] = myfun(options,optimvalues,flag)
The function has the following input arguments:
options — Options structure created using saoptimset.
optimvalues — Structure containing information about the current state of the solver. The structure contains the following fields:
x — Current point
fval — Objective function value at x
bestx — Best point found so far
bestfval — Objective function value at best point
temperature — Current temperature, a vector the same length as x
iteration — Current iteration
funccount — Number of function evaluations
t0 — Start time for algorithm
k — Annealing parameter, a vector the same length as x
flag — Current state in which the output function is called. The possible values for flag are
'init' — Initialization state
'iter' — Iteration state
'done' — Final state
Passing Extra Parameters in the Optimization Toolbox documentation explains how to provide additional parameters to the output function.
The output function returns the following arguments:
stop — Provides a way to stop the algorithm at the current iteration. stop can have the following values:
false — The algorithm continues to the next iteration.
true — The algorithm terminates at the current iteration.
options — Options structure modified by the output function.
optchanged — A boolean flag indicating changes were made to options. This must be set to true if options are changed.
Use the Display option to specify how much information is displayed at the command line while the algorithm is running. The available options are
off — No output is displayed. This is the default value for an options structure created using saoptimset.
iter — Information is displayed at each iteration.
diagnose — Information is displayed at each iteration. In addition, the diagnostic lists some problem information and the options that have been changed from the defaults.
final — The reason for stopping is displayed. This is the default.
Both iter and diagnose display the following information:
Iteration — Iteration number
f-count — Cumulative number of objective function evaluations
Best f(x) — Best objective function value
Current f(x) — Current objective function value
Mean Temperature — Mean temperature function value


text:
The General Principles of Food Law (Articles 5 to 10) entered into force on 21 February 2002 and must be followed when measures are taken. Existing food law principles and procedures must be adapted by 1 January 2007 in order to comply with the general framework established by Regulation EC/178/2002 .
General Objectives
The food law aims at ensuring a high level of protection of human life and health, taking into account the protection of animal health and welfare, plant health and the environment. This integrated "farm to fork" approach is now considered a general principle for EU food safety policy.
Food law, both at national and EU level, establishes the rights of consumers to safe food and to accurate and honest information. The EU food law aims to harmonise existing national requirements in order to ensure the free movement of food and feed in the EU.
The food law recognises the EU's commitment to its international obligations and will be developed and adapted taking international standards into consideration, except where this might undermine the high level of consumer protection pursued by the EU.
Risk Analysis
The Regulation establishes the principles of risk analysis in relation to food and establishes the structures and mechanisms for the scientific and technical evaluations which are undertaken by the European Food Safety Authority (EFSA).
Depending on the nature of the measure, food law, and in particular measures relating to food safety must be underpinned by strong science. The EU has been at the forefront of the development of the risk analysis principles and their subsequent international acceptance. Regulation EC 178/2002 establishes in EU law that the three inter-related components of risk analysis (risk assessment, risk management and risk communication) provide the basis for food law as appropriate to the measure under consideration. Clearly not all food law has a scientific basis, e.g. food law relating to consumer information or the prevention of misleading practices does not need a scientific foundation.
Scientific assessment of risk must be undertaken in an independent, objective and transparent manner based on the best available science.
Risk management is the process of weighing policy alternatives in the light of results of a risk assessment and, if required, selecting the appropriate actions necessary to prevent, reduce or eliminate the risk to ensure the high level of health protection determined as appropriate in the EU.
In the risk management phase, the decision makers need to consider a range of information in addition to the scientific risk assessment. These include, for example, the feasibility of controlling a risk, the most effective risk reduction actions depending on the part of the food supply chain where the problem occurs, the practical arrangements needed, the socio-economic effects and the environmental impact. Regulation EC/178/2002 establishes the principle that risk management actions are not just based on a scientific assessment of risk but also take into consideration a wide range of other factors legitimate to the matter under consideration.
Food safety and the protection of consumer interests are of increasing concern to the general public, non-governmental organisations, professional associations, international trading partners and trade organisations. Therefore, the Regulation establishes a framework for the greater involvement of stakeholders at all stages in the development of food law and establishes the mechanisms necessary to increase consumer confidence in food law.
This consumer confidence is an essential outcome of a successful food policy and is therefore a primary goal of EU action related to food. Transparency of legislation and effective public consultation are essential elements of building this greater confidence. Better communication about food safety and the evaluation and explanation of potential risks, including full transparency of scientific opinions, are of key importance.

subset: commoncrawl


text: A couple of years ago a man in my area was driving his 9 year old daughter home from school when a man in a pickup pulled behind them and began honking and making rude gestures. He then began bumping the first car, ultimately pushing it off the road and into a ditch. It seems the guy in the pickup disagreed with a political bumper sticker the first guy had. Fortunately the man and his daughter weren't injured, but certainly could have been. The second guy was picked up and charged...I don't remember the outcome. I've wondered what I would do in such a situation and am not sure. Opinions?


text:
Developing Portable Mobile Web Applications
Ubuntu 9.10 and the gedit editor.
Safari browser on Windows XP on VirtualBox.
Apache httpd Web server.
GIMP for icon graphics.
jQTouch and jQuery libraries.
iPhone, iTouch, iPad and Android devices.
Installation of the tools is well documented elsewhere. The Resources section for this article gives pointers to the download URLs. To install jQTouch, just put the JavaScript and CSS files in the directory tree of your Web application, and point to them from your HTML  element. jQTouch comes with minimized versions of the files and a minimized jQuery library.
As an example, let's look at a simple notes application that I'll call Webnotes. With it, a user could write notes, and view, edit or delete notes later. A note will consist of a title and an arbitrary-length string. The notes will be stored locally on the smartphone, using HTML5 client-side database APIs, and we'll test it running on a variety of Apple and Android devices. When we're done, we'll compare this to a similar Android sample application that ships with the Android SDK. Because we're using client-side database features that are part of HTML5, we'd expect it to work fine on the iPhone, the Droid and the iPad, and not to work on the HTC G1 (it does not support local storage).
Our app has three screens:
The opening screen will display a list of existing notes, listed by title, in order by the date they were last edited. Touching a title will select that note for edit. Touching a + button will add a new note (Figure 1).
An edit screen will allow viewing, editing or deletion of a note. (Figure 2).
An add screen will create a new note and store it in the database (Figure 3).
Listing 1 is the HTML file, index.html, primarily concerned with layout. Listing 2 is a JavaScript file, webnotes.js, that has the logic we need. Let's go through the HTML first.
Listing 1. index.html
<!DOCTYPE HTML PUBLIC>  <title>WebNotes</title> <link type="text/css" rel="stylesheet" media="screen" href="jqtouch/jqtouch.min.css"> <link type="text/css" rel="stylesheet" media="screen" href="themes/jqt/theme.min.css">

Web Notes
 +

 Title

Add Note
 Cancel
 <form method="post">

<input type="text" class="title" />

<textarea class="note" ></textarea>

 <input type="submit" class="submit" name="action" value="Save Note" />

 </form>

Edit Note
 Cancel Delete
 <form method="post">

<input type="text" class="title" />

<textarea class="note" ></textarea>

 <input type="submit" class="submit" name="action" value="Save Note" />

 </form>

Rick Rogers has been a professional embedded developer for more than 30 years. Now specializing in mobile application software, when Rick isn't writing software for a living, he's writing books and magazine articles like this one.
Android compatibility.
I'm getting my feet wet with mobile development and am trying to get this working. I'm developing on an HTC Droid Eris with Android 2.1. All I'm getting is a black screen. Any one have any ideas if it should work? Or where I should be looking?
"well documented elsewhere"
"Installation of the tools is well documented elsewhere. The Resources section for this article gives pointers to the download URLs."
The resources indeed gives the pointers to the download URLs.
Is there also a link available for "well documented elsewhere"?
Is there also a pointer to the installation of the tools?
M. Moon
As Linux continues to play an ever increasing role in corporate data centers and institutions, ensuring the integrity and protection of these systems must be a priority. With 60% of the world's websites and an increasing share of organization's mission-critical workloads running on Linux, failing to stop malware and other advanced threats on Linux can increasingly impact an organization's reputation and bottom line.
Sponsored by Bit9
Most companies incorporate backup procedures for critical data, which can be restored quickly if a loss occurs. However, fewer companies are prepared for catastrophic system failures, in which they lose all data, the entire operating system, applications, settings, patches and more, reducing their system(s) to "bare metal." After all, before data can be restored to a system, there must be a system to restore it to.
In this one hour webinar, learn how to enhance your existing backup strategies for better disaster recovery preparedness using Storix System Backup Administrator (SBAdmin), a highly flexible bare-metal recovery solution for UNIX and Linux systems.
Sponsored by Storix
Free DevOps eBooks, Videos, and more!
Regardless of where you are in your DevOps process, Linux Journal can help!
We offer here the DEFINITIVE DevOps for Dummies, a mobile Application Development Primer, and advice & help from the expert sources like:
- Forrester
- Gartner
- Linux Journal
Web Development News
Trending Topics
Nmap—Not Just for Evil! | Mar 05, 2015 |
Resurrecting the Armadillo | Mar 04, 2015 |
March 2015 Issue of Linux Journal: System Administration | Mar 02, 2015 |
March 2015 Video Preview | Mar 02, 2015 |
High-Availability Storage with HA-LVM | Feb 26, 2015 |
DNSMasq, the Pint-Sized Super Dæmon! | Feb 24, 2015 |
- Nmap—Not Just for Evil!
- Resurrecting the Armadillo
- High-Availability Storage with HA-LVM
- March 2015 Issue of Linux Journal: System Administration
- Real-Time Rogue Wireless Access Point Detection with the Raspberry Pi
- DNSMasq, the Pint-Sized Super Dæmon!
- Localhost DNS Cache
- Days Between Dates: the Counting
- The Usability of GNOME
- Linux for Astronomers


text:
Va. girl fighting cancer gets memorable sweet 16 surprise birthday
Teen charged with shooting 2 friends, then self, after argument in Clinton, Md.
Watch Florida teen rescue a police officer while he's being booked
17-year-old girl shot in the jaw during boathouse party
Fairfax County man charged with holding 17-year-old girl hostage for sex trafficking
Caught on video: Did Montgomery County Police officer go too far in arrest of 16-year-old Keelan Senior?
Sean Logan, Reston teen, dies after being struck by a car
A Reston teenager who was involved in a crash involving two cars on May 8 has died, according to police.
Jonathon Adams, 17, stabbed to death in SE D.C.
Jonathon Adams, 17, was stabbed to death in Southeast Washington Thursday evening. A reward is offered for information that leads to an arrest and conviction.
DC teen attacked after getting of bus
A local high school student was assaulted and robbed after leaving school in northwest Washington. Two men attacked the 17-year old girl Wednesday around 5:30 p.m. on Ninth Street.
Courtney Manning Jr.: Search continues for shooter
It has been seven years since 16-year-old Courtney Manning Jr. was murdered as he drove his friends home from a birthday party at what was once the Neon teenage nightclub in Clinton.
Bullyvention: Va. teen takes down bullies with high-tech approach
A Fairfax County teenager is taking on one of the biggest problems facing his generation. Viraj Puri has a high-tech approach to get the lowdown on bullies.
Paul Walker crash: Jameson Witty arrested in theft
Detectives arrested a teenager Thursday accused of stealing some wreckage from the Porsche that "Fast & Furious" star Paul Walker was in when he died in a crash, and a second suspect was planning to turn himself in, authorities said.
Teen stabbed at L'Enfant Plaza Metro station
The stabbing happened inside the busy Washington station at about 7:30 p.m., Metro Transit Police say.
Elijah Nathaniel Rivera struck and killed by Amtrak train in Culpeper
A teenager was struck and killed by an Amtrak train in Culpeper. Police say the 19-year old ignored the train's horn and continued to sit on the tracks.
Oxon Hill robbery attempt and shooting
CommentPolice say a 17-year old is recovering after being shot during an overnight robbery attempt in Oxon Hill.
Teen shot in D.C. early Friday morning
CommentA teenager was shot in Northeast D.C. early Friday morning. It happened shortly after midnight near Langston Terrace. Police are searching for one suspect.
Teen sexually assaulted: 11th and Clifton Streets, NW
CommentMPD detectives are searching for the person who sexually assaulted a 14-year-old girl Monday near the U Street corridor.
Brian Lee Wonsom pleads guilty in rape, murder case
CommentBrian Lee Wonsom, 15, pleaded guilty to killing Cheltenham Youth Facility teacher Hannah Wheeling of Bel Air.
RecommendedRecent Facebook Activity
Only On 7
ABC7 News at 4 Now Weekdays!
ABC7 is giving you MORE news in your afternoons with an extra hour, an hour earlier! Join ABC7's Leon Harris and Alison Starling for what's trending in your community and world. Every weekday afternoon at 4pm right after "The Queen Latifah Show" at 3pm on ABC7.


text:
Things you can actually buy in Korea
This site uses Facebook comments to make it easier for you to contribute. If you see a comment you would like to flag for spam or abuse, click the "x" in the upper right of it. By posting, you agree to our Terms of Use.


text:
Austin, TX (Texas Tribune) — More than a dozen gun bills came up for debate in the Texas House Saturday. Of those, ten advanced one step closer to final passage, including two high profile bills that address guns in schools.
Members of the Texas House largely breezed through a slew of gun bills Saturday that could change the conceal handgun licensing process, where CHL holders can carry, and how school kids are protected.
"When are children are being attacked, then and only then will these individuals have the authority to act as law enforcement," said State Representative Jason Villalba, R-Dallas.
Villalba said the deadly shooting of 20 first graders last December in Connecticut led him to file House Bill 1009.
It would create a new law enforcement classification, the school marshal.
Modeled after the federal air marshal program, it would allow schools to designate and train at least one employee to conceal carry on campus.
"Unfortunately in this world of limited resources, we have to find a way to protect those schools that don't otherwise have school resource officers," said Villalba
Villalba's tentatively passed with no real debate.
House Bill 972 by Representative Allen Fletcher, R-Cypress, would allow CHL holders to conceal carry and store their weapons on college and university campuses.
"It's very inclusive about the fact that the universities can opt out or opt in. So they can make these rules on their own," said Fletcher.
Like Villalba's bill, Fletcher's is not a mandate.
Both measures leave it up to the local school district or higher ed institution to enact the changes.
They're pieces of legislation that still have to get final passage in the House, then pass in the Senate.
Lawmakers have filed a total of 100 gun bills this session.
The Texas Tribune has created an easy interactive to help you keep track of the different weapons legislation.
http://www.texastribune.org/library/data/track-83rd-gun-bills/ [1]


text:
Arranged Sham Marriages to Obtain Citizenship for Workers and Relatives
VAREE BRADFORD, 44, of Sammamish, Washington, was sentenced today in U.S. District Court in Seattle to six months in prison and two years of supervised release for Conspiracy to Commit Immigration Fraud, and three counts of Fraud Relating to Immigration Documents. BRADFORD is an owner of the "Thai Ginger" chain of restaurants in the Greater Seattle area. She pleaded guilty October 23, 2009. U.S. District Court Judge Ricardo S. Martinez told her, "You used your money and position to circumvent the law. This mocks the efforts of immigrants who work hard and wait years to obtain citizenship."
BRADFORD admits that she recruited U.S. citizens to engage in sham marriages with Thai nationals, so that the citizens of Thailand could obtain legal status to stay in the U.S. The U.S. citizens were paid $20,000 for entering into the sham marriages. In 2002, BRADFORD had a Thai Ginger employee enter into a sham marriage with one of her relatives so that the relative had legal status in the U.S. In 2005, BRADFORD had a Thai Ginger employee enter into a sham marriage with another Thai Ginger employee. BRADFORD paid the U.S. citizen $20,000 for the fraudulent marriage, telling the citizen the marriage only had to last two years. During that same year, BRADFORD set up a second sham marriage for one of her relatives with a U.S. citizen, again paying the citizen $20,000. In 2006, BRADFORD set up another sham marriage, this one for her nephew, a Thai citizen.
In late 2007, BRADFORD told a U.S. citizen who was in fact an undercover ICE agent, that she would pay him $20,000 for entering into a sham marriage. The "wife" in the sham marriage was changed mid-way through the scheme, when the original citizen had to return to Thailand. Nevertheless, BRADFORD introduced the undercover officer to a second Thai national who he was supposed to marry, and counseled him about how to prepare for the immigration interview. BRADFORD agreed to pay $20,000 to the undercover agent for participating in the sham marriage for two years.
In sentencing documents, prosecutors revealed that the U.S. Department of Labor investigated BRADFORD for violations of overtime laws. BRADFORD required her employees to work beyond their shifts without additional compensation. BRADFORD agreed to pay almost $80,000 in back wages to settle the matter. Despite that run-in with federal authorities, BRADFORD "continued to flagrantly ignore the laws, by engaging in the marriage fraud scheme.... She benefitted from the scheme. As a result of some of the fraudulent marriages, Thai Ginger employees were allowed to remain in the United States, saving Defendant the cost of recruiting, hiring, and training new employees," prosecutors wrote in their sentencing memo.
Referencing the Department of Labor investigation, Judge Martinez noted that as part of the settlement, BRADFORD and her husband agreed to future compliance with all laws. "American citizens have rights and responsibilities," the Judge said. "While that response was fresh in her mind, she engaged in the criminal activity that brought her here today."
"Those who falsely believe our nation's immigration laws don't apply to them should take note," said Leigh Winchell, special agent in charge for ICE's Office of Investigation in Seattle. "Marriage fraud is nothing more than an illegal shortcut to U.S. citizenship and ICE will aggressively investigate those who engage in this activity."
The case was investigated by U.S. Immigration and Customs Enforcement (ICE). The case was prosecuted by Assistant United States Attorneys Jill Otake and Ye-Ting Woo.
For additional information please contact Emily Langlie, Public Affairs Officer for the United States Attorney's Office, at (206) 553-4110 or firstname.lastname@example.com.


text:
- About this Journal ·
- Abstracting and Indexing ·
- Advance Access ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Journal of Biomedicine and Biotechnology
Volume 2012 (2012), Article ID 845618, 10 pages
Classic and New Animal Models of Parkinson's Disease
1Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
2Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA
3Department of Neurology, Columbia University, New York, NY 10032, USA
Received 9 January 2012; Accepted 23 January 2012
Academic Editor: Monica Fedele
Copyright © 2012 Javier Blesa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Neurological disorders can be modeled in animals so as to recreate specific pathogenic events and behavioral outcomes. Parkinson's Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations.
1. Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 1% of the population over 55 years of age [1]. This disease is characterized by the loss of ~50–70% of the dopaminergic neurons in the substantia nigra pars compacta (SNc), a profound loss of dopamine (DA) in the striatum, and the presence of intracytoplasmic inclusions called Lewy bodies (LB), which are composed mainly of α-synuclein and ubiquitin. Although mutations in the α-synuclein gene have thus far been associated only with rare familial cases of PD, α-synuclein is found in all LBs [2]. Therefore, this protein may play an important role in the pathogenesis of this disease. The main features of PD are tremor, rigidity, bradykinesia, and postural instability; however, these motor manifestations can be accompanied by nonmotor symptoms such as olfactory deficits, sleep impairments, and neuropsychiatric disorders [3–5]. Although the complete PD disease process is not yet understood, we have gained a better understanding of its etiology, pathology, and molecular mechanisms, thanks to various animal models [6]. For example, reserpine administration in animals was found to produce a profound depletion of monoamines, including DA, in the brains of injected animals resulting in reserpine syndrome. The symptoms of this syndrome consisted of slowness of movement and rigidity [7] now commonly associated with PD. Interestingly, it was found that L-DOPA was able to reverse many of the symptoms associated with reserpine administration [8], furthering the hypothesis that DA depletion was at the root of PD symptomatology.
For the past several decades, animal models of PD have come in a variety of forms. Typically, they can be divided into those using environmental or synthetic neurotoxins or those utilizing the in vivo expression of PD-related mutations (genetic).
Of the neurotoxic models, compounds that produce both reversible (reserpine) and irreversible (MPTP, 6-OHDA, paraquat, rotenone) effects have been used effectively; however recent studies have focused more on irreversible toxins to produce PD-related pathology and symptomatology. Therefore, the neurotoxins covered in this paper will focus on those that produce an irreversible effect. Neurotoxin-based models produced by 6-hydroxydopamine (6-OHDA) and 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) administration are the most widely used toxic models, while paraquat and rotenone are more recent additions to the stable of toxic agents used to model PD [6, 9]. A common feature of all toxin-induced models is their ability to produce an oxidative stress and to cause cell death in DA neuronal populations that reflect what is seen in PD. Oxidative stress results from increased production of extremely reactive free radicals, including reactive oxidative species (ROS) and peroxynitrite. ROS may be formed during a number of cellular processes, including mitochondrial oxidative respiration and metabolism. There are some drawbacks to the use of these models such as the time factor in these models versus the time factor in the human condition, but these do not negate the value of neurotoxin-based animal models in the study of PD.
Recently, the identification of different genetic mutations (α-synuclein, parkin, LRKK2, PINK1, DJ-1) has led to the development of genetic models of PD [10]. It is important to remember that, at best, only ~10% of PD cases are due to genetic mutations [6], while the vast majority of PD cases arise as sporadic, that is, from unknown origins. Although the above-mentioned genes are mutated in PD and are not overexpressed or knocked out, nonetheless, these animal models are important in that they may reveal specific molecular events that lead to the death of the DA neurons and potential therapeutic targets. In this paper, we try to describe the advantages and disadvantages of all of these animal models and their potential roles in revealing the mechanisms for PD pathogenesis and in testing experimental therapeutics (Table 1).
2. Neurotoxic Models
2.1. 6-Hydroxydopamine
6-OHDA is the classic and oft utilized toxin-based animal model of PD [11–13]. A lot of information on the behavioral, biochemical, and physiological effects of dopamine in the CNS has been derived from this model. 6-OHDA was first isolated in the 1950s [14]. Ungersted [15] first used this neurotoxin to lesion the nigro-striatal dopaminergic pathway in the rat nearly 50 years ago, and the use of 6-OHDA remains widespread today for both in vitro and in vivo investigations. Mice, cats, dogs, and monkeys are all sensitive to 6-OHDA; however it is used much more frequently in rats [16–19]. Even though 6-OHDA exhibits a high affinity for several catecholaminergic transporters such as the dopamine transporter (DAT) and norepinephrine transporter (NET) [20], it is often used in conjunction with a selective noradrenaline reuptake inhibitor such as desipramine in order to spare the noradrenergic neurons from damage in animal models of PD [21].
Although the structure of 6-OHDA is similar to that of dopamine, the presence of an additional hydroxyl group makes it toxic to dopaminergic neurons. This compound does not cross the blood-brain barrier, which necessitates its direct injection into the SNpc, medial forebrain bundle (MFB), or the striatum [22, 23]. It is well known that 6-OHDA destroys catecholaminergic neurons by a combined effect of ROS and quinones [24], and it can induce inflammation in the brain which tends to wane over time. The most common use of 6-OHDA is via unilateral injection into the rat medial forebrain bundle. Injection of 6-OHDA into the SNpc kills approximately 60% of the tyrosine hydroxylase- (TH-) containing neurons in this area of the rodent brain with subsequent loss of TH-positive terminals in the striatum [25] (Figure 1). Several studies have injected this compound directly into the striatum in order to test the hypothesis of retrograde degeneration, explicitly, that TH-positive terminals in the striatum die prior to TH-positive neurons in the SNpc, seemingly a replicate of PD in humans [23, 26, 27]. The magnitude of the lesion depends on the amount of 6-OHDA injected, the site of injection, and the animal species used. This model does not mimic all of the clinical features of PD. Dopamine depletion, nigral dopamine cell loss, and neurobehavioral deficits have been successfully achieved using this model, but it does not seem to affect other brain regions, such as olfactory structures, lower brain stem areas, or locus coeruleus. Although 6-OHDA does not produce or induce proteinaceous aggregates or Lewy-like inclusions like those seen in PD, it has been reported that 6-OHDA does interact with α-synuclein [25]. 6-OHDA is frequently used as a unilateral model because the bilateral injection of this compound into the striatum produces severe adipsia, aphagia, and also death [28, 29] due to the animal's inability to care for itself. One of the most attractive features of the unilateral 6-OHDA model is the fact that each animal can serve as its own control as there is a lesioned and an unlesioned hemisphere. This is particularly useful in behavioral analyses [15] as turning behavior to amphetamine or apomorphine following the unilateral application of 6-OHDA gauges the extent of the induced SNpc or striatal lesion and the efficacy of potential PD therapeutic agents and gene therapies [11, 30].
6-OHDA is an attractive candidate as a possible endogenous toxin for the initiation of the PD neurodegenerative process as it is a product of dopamine metabolism [31], and it is the result of hydroxyl radical attack with the presence of excess dopamine; as a neurotoxin, it does produce lesions in the nigrostriatal DA pathway. However, although it has been measured in the brains of levodopa-treated rats subjected to MPTP treatment, 6-OHDA has yet to be recovered from the PD brain. Despite its limitations, this model has contributed enormously to our understanding of PD pathology. 6-OHDA will continue to afford PD researchers a useful animal model for PD research for long time.
In 1982, MPTP was accidentally discovered in a synthesis process gone awry, and, although it may have caused some mayhem in certain circles, today it represents the most important and most frequently used parkinsonian toxin applied in animal models. Young drug addicts developed an idiopathic parkinsonian syndrome after intravenous injection of this compound. After investigating the etiology of their condition, it was found that MPTP was the neurotoxic contaminant responsible for the parkinsonian effect [32]. Oxidative stress, ROS, energy failure, and inflammation have consistently been pointed to as hallmarks of PD. It has been repeatedly demonstrated that MPTP is indeed the gold standard for toxin-based animal models of PD among PD researchers for replicating almost all of these hallmarks [32]. Unfortunately, lacking in this list is the definitive characteristic of PD, LB formation [33, 34]. Interestingly, some studies have demonstrated the production of Lewy body-like inclusions after MPTP administration [35, 36] although these studies have been difficult to replicate. These studies suggest that, under the right circumstances, we may be able to reproduce the majority of hallmarks found in PD.
MPTP is highly lipophilic and after systemic administration rapidly crosses the blood-brain barrier. Once in the brain, MPTP enters astrocytes and is metabolized into MPP+, its active metabolite, by monoamine oxidase-B (MAO-B). Recent findings show that once released from the astrocytes into the extracellular space via the OCT-3 transporter [37], MPP+ is taken up into the neuron by the dopamine transporter (DAT) and can be stored in vesicles via uptake by the vesicular monoamine transporter (VMAT2) [38]. Consequently, mice lacking the DAT are protected from MPTP toxicity [39]. Once inside the neuron, MPP+ is able to inhibit complex 1 of the mitochondrial electron transport chain, resulting in the release of ROS as well as reduced ATP production. Storing into vesicles can decrease MPP+ toxicity [40–42]. Additionally, MPP+ stored in vesicles is thought to expel DA out into the intercellular space where it can be metabolized into a number of compounds, including toxic metabolites, such as DOPAL and where it is can be subjected to superoxide radical (5-cysteinyl-DA) and hydroxyl radical (6-OHDA) attack [43, 44].
MPTP is used mainly in nonhuman primates and mice but has also been used in many other species such as dogs and cats [45]. For unknown reasons, rats are resistant to MPTP and mouse strains vary widely in their sensitivity to the toxin [46]. MPTP can be administered by a variety of regimens, but the most common and reproducible form is still systemic injection (subcutaneous, intravenous) [47]. When MPTP is administered to nonhuman primates, they exhibit behavioral and neuroanatomical similarities to the human condition showing a bilateral parkinsonian syndrome [48] (Figure 2). Another commonly used route is the unilateral intracarotid injection. This causes mostly a unilateral parkinsonism, whose benefits as an animal model were described earlier, but is technically more complicated to perform [49].
Usually monkeys are treated with high doses of MPTP for a short time (acute model). Recently, however, new schedules have introduced lower doses of the neurotoxin for longer periods of time (subacute to chronic) to replicate more closely the human pathology [50]. There are recent studies attempting to develop a more progressive model of PD. In addition, models are being developed to study compensatory mechanisms or recovery. These models use low to intermittent doses administered once or twice per week [51–54]. It is well known that monkeys exhibit variability in MPTP susceptibility and that older primates are often more susceptible to MPTP [55]. MPTP-treated monkeys respond well to antiparkinsonian treatments like L-DOPA or apomorphine and, like human pathology, after the treatment develop dyskinesias. Recently, some studies have been taken in order to study and evaluate the nonmotor symptoms of the disease using this model [56–61]. This model has also been used for electrophysiological studies, leading to important findings, including the emergence of deep brain stimulation, which is currently the best surgical method to ameliorate symptoms in PD patients [62, 63].
Currently, the MPTP model is used more in mice than in monkeys. Aside from the obvious financial benefits, the mouse model is employed to test theories about cell death in PD, to work out events in the neuronal death process, and to study other pathological effects of PD. It is also extremely useful as an initial screening tool to test potential treatments for PD. On the other hand, the MPTP monkey model is mainly used to discern behavioral and symptomatic components of PD, as mice do not develop a level of impairment equal to the human condition. Monkeys also represent the last level of PD treatment research prior to any treatment being administered to humans [64]. However, the data generated by mouse models has led to a better understanding of molecular mechanisms involved in PD, and its utility has proven invaluable. One of the most important aspects of the MPTP mouse model is the possibility to work with genetically modified mice [65, 66]. This model can be useful for testing neuroprotective therapies. Currently, MPTP is the standard bearer for toxin-based PD animal models.
3. Pesticide/Herbicide Models
3.1. Paraquat
Paraquat (N,N′-dimethyl-4-4-4′-bypiridinium) (PQ) is a herbicide widely used in agriculture that exhibits a structural resemblance to MPP+, and, because of this structural similarity, it was reasoned that PQ should behave like MPP+. Epidemiological reports suggest that pesticide use increases the risk of developing PD, but, in the case of PQ, there have been only 95 cases of PD linked to its toxicity in humans [67]. PQ exerts its deleterious effects through oxidative stress mediated by redox cycling, which generates ROS. In particular, the superoxide radical, hydrogen peroxide, and hydroxyl radicals lead to the damage of lipids, proteins, DNA and RNA [68, 69]. Recent evidence on the effects of PQ in the nigrostriatal DA system is somewhat ambiguous as some researchers report that, following the systemic application of this herbicide to mice, animals exhibit reduced motor activity and a dose-dependent loss of striatal TH-positive striatal fibers and midbrain SNpc neurons [70, 71]. Other researchers claim that no PQ-induced changes occur in the nigrostriatal DA system [72, 73]. However, in a newer recent study, Rappold et al. [74] demonstrate that PQ, in high doses, employs the organic cationic transporter-3 (OCT-3) and the dopamine transporter (DAT) and is toxic to the DA neurons in the SN. Furthermore, they suggest that the damage done by PQ is caused by radicalized PQ and facilitated by the glial cells. This means that PQ behaves like MPP+ in exerting its toxic effects. Although this study increases our understanding of how PQ may work, it does not end the controversy about PQ and PD.
PQ's importance to PD researchers is its ability to induce increases in α-synuclein in individual DA neurons in the SNpc and its ability to induce LB-like structures in DA neurons of the SNpc [75]. The relation of dopaminergic neuron loss with α-synuclein upregulation and aggregation suggests that this model could be valuable for capturing a PD-like pathology. However, the molecular link between oxidative stress and cell death in this model is still unknown. Thus, the significance of PQ in PD research is often limited to the study of the process of LB formation in DA neurons as well as the role of α-synuclein in PD. PQ is only one of the many agricultural chemicals known to cause damage to the dopaminergic system. Maneb (manganese ethylenebisdithiocarbamate) has been shown to decrease locomotor activity and potentiate both the MPTP and the PQ effects [73, 76, 77]. Moreover, the combination of PQ and maneb produced greater effects on the dopaminergic system than either of these chemicals alone. These compounds give credence to the theory that environmental pesticides can cause PD [67, 78–80]. In fact, recent studies have demonstrated that those exposed to PQ or fungicides like maneb or ziram experience a greater risk of developing PD [81, 82]. Further investigations using these models are needed to determine the involvement of environmental exposures in the etiology of PD.
3.2. Rotenone
Unlike PQ, which is a pure herbicide rotenone, is both a herbicide and an insecticide [83]. It is the most potent member of the rotenoid family of neurotoxins found naturally in tropical plants. The half-life of rotenone is 3–5 days depending on its exposure to sunlight, and it is rapidly broken down in soil and in water [83]. For these reasons, rotenone is not considered to be a groundwater pollutant. Rotenone is highly lipophilic and readily crosses the blood-brain barrier. Chronic exposure to low doses of rotenone results in inhibition of the mitochondrial electron transport chain in the rat brain. In animals, rotenone has been administered by different routes. Oral administration appears to cause little neurotoxicity [84, 85]. Chronic systemic administration using osmotic pumps has been the most common delivery regimen, especially in the Lewis rat, which may be more sensitive to rotenone than other strains of rats [86]. Intraperitoneal injections have been reported to elicit behavioral and neurochemical deficits, although mortality is very high [87]. Intravenous administration is able to cause damage to nigrostriatal DA neurons that is accompanied by α-synuclein aggregation, Lewy-like body formation, oxidative stress, and gastrointestinal problems [88]. The apparent beauty of this model is that, like paraquat, it seems to replicate almost all of the hallmarks of PD including causing α-synuclein aggregation and Lewy-like body formation [89, 90]. Interestingly, a subsequent study has found that rotenone is not specific to the DA system and has deleterious effects on other neuronal populations. Likewise, in PD in which neurodegeneration extends beyond the dopaminergic system, rotenone is associated with 35% reduction in serotonin, 26% in noradrenergic, and 29% in cholinergic neurons [89]. However, when rotenone was administered chronically at lower doses to achieve complex I inhibition similar to that observed in patients, it seems to produce a highly selective nigrostriatal degeneration [86] although only about 50% of the treated rats exhibit nigrostriatal lesions. The controversy about the use of rotenone as a model of PD is that although it does augment DA oxidation, evidence is slim on depletion of DA in the nigrostriatal system [91]. Attempts to lesion other animal species such as mice or monkeys have not been successful at all [72, 92]. However, recent studies by two groups have demonstrated that oral administration of rotenone to mice causes nigral degeneration, a decrease of striatal dopamine levels, and motor dysfunction [85, 93, 94]. They also demonstrated α-synuclein aggregation in different areas of the brain [95]. Furthermore, there are no documented cases of rotenone-induced PD in humans. Thus, it is not clear that this model offers any advantage over other toxic models, such as that of 6-OHDA or MPTP.
4. Genetic Models
The underlying principle for studying genetic mutations of a disease is the belief that the clinical similarities between the inherited and sporadic forms of the disease share a common mechanism that can lead to the identification of molecular and biochemical pathways involved in the disease pathogenesis. Genetic mutations in PD are rare and represent only about 10% of all PD cases [6]. And animal models of these mutations (α-synuclein and LRRK2, autosomal dominant PD) and (PINK1/Parkin and DJ-1, autosomal recessive PD) are important as they represent potential therapeutic targets. However, we must first understand the workings of these animal models because it is becoming clearer that there are many facets to PD disease.
Mutations to the α-synuclein gene, which is normally thought to play a role in the synaptic vesicle recycling, were the earliest evidence for genetic link to PD. Two mutations in the α-synuclein gene (A53T, A30P) cause a dominantly inherited form of PD [96] and have been used to create transgenic mice in an effort to recapitulate the pathophysiology of PD. Studies done using α-synuclein transgenic mice have yielded considerable progress, showing that A53T mutations in mice can result in a severe motor phenotype which can eventually lead to paralysis and death [97]. Additionally, mutations to the α-synuclein gene in mice produce inclusions that resemble LBs [98]. However this phenotype is generally restricted to the A53T mutation and not found in A30P transgenic mice. Indeed, it has been shown that knocking out α-synuclein does not affect DA neuron development or maintenance [99, 100] suggesting that the loss of α-synuclein probably plays no role in the degeneration of DA neurons that is seen in PD. Interestingly, studies done in Drosophila expressing mutant α-synuclein show dopaminergic cell loss, reduced TH expression in the SN, filamentous intraneuronal inclusions, and motor deficits [101]. Some of the α-synuclein transgenic mice have olfactory impairments and colonic dysfunction, and it seems that there are other nonmotor abnormalities [102]. Understanding these nonmotor symptoms could offer new model for testing therapies focused on the nonmotor symptoms. However, since the function of α-synuclein has yet to be figured out, the actual role of α-synuclein in PD still remains elusive.
Mutations to the LRRK2 gene have been shown to cause a dominant form of PD [103]. Unlike α-synuclein which is ubiquitous, LRRK2 (leucine rich repeat kinase 2) is localized to membranes. However, similar to α-synuclein transgenic mice, it has been determined that knocking out LRRK2 has no effect on DA neuron development and maintenance [102]. Moreover, Drosophila models are limited in their translation to the human condition, and the LRRK2 mouse model is not particularly a strong model as it shows only minimal levels of neurodegeneration [104].
Mutations to parkin (which accounts for about 50% of the familial cases of PD and 20% of the young onset PD cases), DJ1 (a redox sensitive molecular chaperone and regulator of antioxidant gene expression), and PINK1 (phosphatase and tensin homolog—PTEN-induced novel kinase 1, which is localized to the mitochondrial intermembrane space) cause autosomal recessive forms of PD. Knock-out rodent models of these genes do not demonstrate any nigrostriatal degeneration, present with intranucelar inclusions, or displays any form of DA neuron loss that resembles idiopathic or inherited PD and fail to develope any type of behavioral or pathological phenotype (only PINK1 knock-out mice display reduced DA release in the striatum) [105]. However, recently it has been shown that knocking out parkin in mice at adult age causes neurodegeneration in the SNc [106].
Overall, this genetic mouse models are able to recapitulate specific aspects of PD, although none produce the neuronal degeneration associated with PD; therefore these themselves may be defective and may require additional modulations or modifications, like for example the human environment [107].
5. Conclusions
Animal model systems are the closest to humans that we are able to study. A number of animal models of PD have been developed to understand the pathogenesis and test potential therapeutics of this disease. In this paper we have summarized the most prominent aspects characterizing the most popular toxic and genetic models of PD. Each model has advantages and disadvantages as we have discussed in this paper. Toxic models offer some of the hallmarks of PD while genetic models offer others. Meanwhile the toxic models are useful to screen drugs for symptomatic treatment of the disease; transgenic or knockout models are useful for evaluating the role of genetics in PD. The drawback of the toxin models is that most of them resemble PD at late stages, whereas genetic animal models use either overexpression or knock-out technology to model disease from early on. The choice of the model to be used depends on the questions being asked. With toxin models, we are working toward developing a progressive model by tempering the toxic doses used. With genetic models, we are trying to come up with the right balance of contributing components through knock-in or conditional technology. However, there is much progress to be made, because it seems unlikely that a single model, be it toxic or genetic, can fully recapitulate the complexity of human PD. Future models should involve a combination of neurotoxin-induced and genetically induced models ideally taking into account factors of aging and environmental insults.
The authors are supported by grants from the National Institutes of Health (NS042269, NS064191, NS38370, NS070276, and NS072182), the US Department of Defense (W81XWH-08-1-0522, W81XWH-08-1-0465, and W81XWH-09-1-0245), the Parkinson Disease Foundation, the Thomas Hartman Foundation For Parkinson's Research, Project A.L.S, the Muscular Dystrophy Association/Wings over Wall Street. J. Blesa is supported by a fellowship from the Spanish Ministry of Education.
- A. J. Lees, J. Hardy, and T. Revesz, "Parkinson's disease," The Lancet, vol. 373, no. 9680, pp. 2055–2066, 2009. View at Publisher · View at Google Scholar · View at Scopus
- M. G. Spillantini, M. L. Schmidt, V. M. Y. Lee, J. Q. Trojanowski, R. Jakes, and M. Goedert, "α-synuclein in Lewy bodies [8]," Nature, vol. 388, no. 6645, pp. 839–840, 1997. View at Publisher · View at Google Scholar · View at Scopus
- L. S. Forno, "Neuropathology of Parkinson's disease," Journal of Neuropathology and Experimental Neurology, vol. 55, no. 3, pp. 259–272, 1996. View at Scopus
- H. Braak, E. Ghebremedhin, U. Rüb, H. Bratzke, and K. Del Tredici, "Stages in the development of Parkinson's disease-related pathology," Cell and Tissue Research, vol. 318, no. 1, pp. 121–134, 2004. View at Publisher · View at Google Scholar · View at Scopus
- K. R. Chaudhuri, D. G. Healy, and A. H. V. Schapira, "Non-motor symptoms of Parkinson's disease: diagnosis and management," Lancet Neurology, vol. 5, no. 3, pp. 235–245, 2006. View at Publisher · View at Google Scholar · View at Scopus
- W. Dauer and S. Przedborski, "Parkinson's disease: mechanisms and models," Neuron, vol. 39, no. 6, pp. 889–909, 2003. View at Publisher · View at Google Scholar · View at Scopus
- A. Carlsson, M. Lindqvist, and T. Magnusson, "3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists," Nature, vol. 180, no. 4596, p. 1200, 1957. View at Publisher · View at Google Scholar · View at Scopus
- A. Carlsson, "The occurrence, distribution and physiological role of catecholamines in the nervous system," Pharmacological reviews, vol. 11, no. 2, pp. 490–493, 1959. View at Scopus
- R. Betarbet, T. B. Sherer, and J. Timothy Greenamyre, "Animal models of Parkinson's disease," BioEssays, vol. 24, no. 4, pp. 308–318, 2002. View at Publisher · View at Google Scholar · View at Scopus
- T. M. Dawson, H. S. Ko, and V. L. Dawson, "Genetic Animal Models of Parkinson's Disease," Neuron, vol. 66, no. 5, pp. 646–661, 2010. View at Publisher · View at Google Scholar · View at Scopus
- R. K. W. Schwarting and J. P. Huston, "Unilateral 6-hydroxydopamine lesions of meso-striatal dopamine neurons and their physiological sequelae," Progress in Neurobiology, vol. 49, no. 3, pp. 215–266, 1996. View at Publisher · View at Google Scholar · View at Scopus
- R. K. W. Schwarting and J. P. Huston, "The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments," Progress in Neurobiology, vol. 50, no. 2-3, pp. 275–331, 1996. View at Publisher · View at Google Scholar · View at Scopus
- R. K. W. Schwarting and J. P. Huston, "Behavioral and neurochemical dynamics of neurotoxic meso-striatal dopamine lesions," NeuroToxicology, vol. 18, no. 3, pp. 689–708, 1997. View at Scopus
- S. Senoh and B. Witkop, "Non-enzymatic conversions of dopamine to norepinephrine and trihydroxyphenethylamines," Journal of the American Chemical Society, vol. 81, no. 23, pp. 6222–6231, 1959. View at Scopus
- U. Ungerstedt, "6-hydroxy-dopamine induced degeneration of central monoamine neurons," European Journal of Pharmacology, vol. 5, no. 1, pp. 107–110, 1968. View at Scopus
- T. A. P. Roeling, G. J. Docter, P. Voorn, B. P. C. Melchers, E. C. Wolters, and H. J. Groenewegen, "Effects of unilateral 6-hydroxydopamine lesions on neuropeptide immunoreactivity in the basal ganglia of the common marmoset, Callithrix jacchus, a quantitative immunohistochemical analysis," Journal of Chemical Neuroanatomy, vol. 9, no. 3, pp. 155–164, 1995. View at Publisher · View at Google Scholar · View at Scopus
- H. Valette, P. Deleuze, A. Syrota et al., "Canine myocardial beta-adrenergic, muscarinic receptor densities after denervation: a PET study," Journal of Nuclear Medicine, vol. 36, no. 1, pp. 140–146, 1995. View at Scopus
- L. E. Annett, E. M. Torres, D. J. Clarke et al., "Survival of nigral grafts within the striatum of marmosets with 6-OHDA lesions depends critically on donor embryo age," Cell Transplantation, vol. 6, no. 6, pp. 557–569, 1997. View at Publisher · View at Google Scholar · View at Scopus
- R. Ruffy and M. Leonard, "Chemical cardiac sympathetic denervation hampers defibrillation in the dog," Journal of Cardiovascular Electrophysiology, vol. 8, no. 1, pp. 62–67, 1997. View at Scopus
- C. Sachs and G. Jonsson, "Mechanisms of action of 6-hydroxydopamine," Biochemical Pharmacology, vol. 24, no. 1, pp. 1–8, 1975. View at Scopus
- G. E. Martin, R. D. Myers, and D. C. Newberg, "Catecholamine release by intracerebral perfusion of 6 hydroxydopamine and desipramine," European Journal of Pharmacology, vol. 36, no. 2, pp. 299–311, 1976. View at Scopus
- D. A. Perese, J. Ulman, J. Viola, S. E. Ewing, and K. S. Bankiewicz, "A 6-hydroxydopamine-induced selective parkinsonian rat model," Brain Research, vol. 494, no. 2, pp. 285–293, 1989. View at Scopus
- S. Przedborski, M. Levivier, H. Jiang et al., "Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine," Neuroscience, vol. 67, no. 3, pp. 631–647, 1995. View at Publisher · View at Google Scholar · View at Scopus
- G. Cohen, "Oxy-radical toxicity in catecholamine neurons," NeuroToxicology, vol. 5, no. 1, pp. 77–82, 1984. View at Scopus
- F. Blandini, M. T. Armentero, and E. Martignoni, "The 6-hydroxydopamine model: news from the past," Parkinsonism and Related Disorders, vol. 14, no. 2, pp. S124–S129, 2008. View at Publisher · View at Google Scholar · View at Scopus
- H. Sauer and W. H. Oertel, "Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat," Neuroscience, vol. 59, no. 2, pp. 401–415, 1994. View at Publisher · View at Google Scholar · View at Scopus
- C. S. Lee, H. Sauer, and A. Björklund, "Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat," Neuroscience, vol. 72, no. 3, pp. 641–653, 1996. View at Publisher · View at Google Scholar · View at Scopus
- U. Ungerstedt, "Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system," Acta Physiologica Scandinavica, Supplement, vol. 367, pp. 95–122, 1971.
- W. M. Bourn, L. Chin, and A. L. Picchioni, "Enhancement of audiogenic seizure by 6-hydroxydopamine," Journal of Pharmacy and Pharmacology, vol. 24, no. 11, pp. 913–914, 1972. View at Scopus
- J. Knoll, "The pharmacology of (-)deprenyl," Journal of Neural Transmission. Supplementum, vol. 22, pp. 75–89, 1986. View at Scopus
- J. D. Graham, M. J. Lewis, and J. Williams, "Proceedings: The effect of delta-1-tetrahydrocannabinol on the noradrenaline and dopamine content of the brain and heart of the rat," British Journal of Pharmacology, vol. 52, no. 3, p. 446, 1974. View at Scopus
- J. W. Langston, P. Ballard, J. W. Tetrud, and I. Irwin, "Chronic parkinsonism in humans due to a product of meperidine-analog synthesis," Science, vol. 219, no. 4587, pp. 979–980, 1983. View at Scopus
- L. S. Forno, L. E. DeLanney, I. Irwin, and J. W. Langston, "Similarities and differences between MPTP-induced parkinsonsim and Parkinson's disease. Neuropathologic considerations," Advances in neurology, vol. 60, pp. 600–608, 1993. View at Scopus
- G. Halliday, M. T. Herrero, K. Murphy et al., "No Lewy pathology in monkeys with over 10 years of severe MPTP parkinsonism," Movement Disorders, vol. 24, no. 10, pp. 1519–1523, 2009. View at Publisher · View at Google Scholar · View at Scopus
- N. W. Kowall, P. Hantraye, E. Brouillet, M. F. Beal, A. C. McKee, and R. J. Ferrante, "MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons," NeuroReport, vol. 11, no. 1, pp. 211–213, 2000. View at Scopus
- F. Fornai, O. M. Schlüter, P. Lenzi et al., "Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and α-synuclein," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 9, pp. 3413–3418, 2005. View at Publisher · View at Google Scholar
- M. Cui, R. Aras, W. V. Christian et al., "The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway," Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 19, pp. 8043–8048, 2009. View at Publisher · View at Google Scholar · View at Scopus
- J. A. Javitch, R. J. D'Amato, S. M. Strittmatter, and S. H. Snyder, "Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: Uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity," Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 7, pp. 2173–2177, 1985. View at Scopus
- E. Bezard, C. E. Gross, M. C. Fournier, S. Dovero, B. Bloch, and M. Jaber, "Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter," Experimental Neurology, vol. 155, no. 2, pp. 268–273, 1999. View at Publisher · View at Google Scholar · View at Scopus
- R. R. Gainetdinov, F. Fumagalli, Y. M. Wang et al., "Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice," Journal of Neurochemistry, vol. 70, no. 5, pp. 1973–1978, 1998. View at Scopus
- T. S. Guillot, K. R. Shepherd, J. R. Richardson et al., "Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis," Journal of Neurochemistry, vol. 106, no. 5, pp. 2205–2217, 2008. View at Publisher · View at Google Scholar · View at Scopus
- T. S. Guillot and G. W. Miller, "Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons," Molecular Neurobiology, vol. 39, no. 2, pp. 149–170, 2009. View at Publisher · View at Google Scholar · View at Scopus
- W. J. Burke, V. B. Kumar, N. Pandey et al., "Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine," Acta Neuropathologica, vol. 115, no. 2, pp. 193–203, 2008. View at Publisher · View at Google Scholar · View at Scopus
- W. M. Panneton, V. B. Kumar, Q. Gan, W. J. Burke, and J. E. Galvin, "The neurotoxicity of DOPAL: behavioral and stereological evidence for its role in Parkinson disease pathogenesis," PLoS One, vol. 5, no. 12, Article ID e15251, 2010. View at Publisher · View at Google Scholar · View at Scopus
- M. J. Zigmond, T. W. Berger, A. A. Grace, and E. M. Stricker, "Compensatory responses to nigrostriatal bundle injury. Studies with 6-hydroxydopamine in an animal model of parkinsonism," Molecular and Chemical Neuropathology, vol. 10, no. 3, pp. 185–200, 1989. View at Scopus
- C. C. Chiueh, S. P. Markey, and R. S. Burns, "Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat," European Journal of Pharmacology, vol. 100, no. 2, pp. 189–194, 1984.
- S. Przedborski, V. Jackson-Lewis, A. B. Naini et al., "The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety," Journal of Neurochemistry, vol. 76, no. 5, pp. 1265–1274, 2001. View at Publisher · View at Google Scholar · View at Scopus
- J. W. Langston, E. B. Langston, and I. Irwin, "MPTP-induced parkinsonism in human and non-human primates—clinical and experimental aspects," Acta Neurologica Scandinavica, vol. 70, supplement 100, pp. 49–54, 1984.
- K. S. Bankiewicz, E. H. Oldfield, and C. C. Chiueh, "Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)," Life Sciences, vol. 39, no. 1, pp. 7–16, 1986.
- M. M. Iravani, E. Syed, M. J. Jackson, L. C. Johnston, L. A. Smith, and P. Jenner, "A modified MPTP treatment regime produces reproducible partial nigrostriatal lesions in common marmosets," European Journal of Neuroscience, vol. 21, no. 4, pp. 841–854, 2005. View at Publisher · View at Google Scholar · View at Scopus
- P. Hantraye, M. Varastet, M. Peschanski et al., "Stable parkinsonian syndrome and uneven loss of striatal dopamine fibres following chronic MPTP administration in baboons," Neuroscience, vol. 53, no. 1, pp. 169–178, 1993. View at Publisher · View at Google Scholar · View at Scopus
- E. Bezard, C. Imbert, X. Deloire, B. Bioulac, and C. E. Gross, "A chronic MPTP model reproducing the slow evolution of Parkinson's disease: evolution of motor symptoms in the monkey," Brain Research, vol. 766, no. 1-2, pp. 107–112, 1997. View at Publisher · View at Google Scholar · View at Scopus
- S. Mounayar, S. Boulet, D. Tandé et al., "A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery," Brain, vol. 130, no. 11, pp. 2898–2914, 2007. View at Publisher · View at Google Scholar
- J. Blesa, C. Juri, M. Collantes et al., "Progression of dopaminergic depletion in a model of MPTP-induced Parkinsonism in non-human primates. An 18F-DOPA and 11C-DTBZ PET study," Neurobiology of Disease, vol. 38, no. 3, pp. 456–463, 2010. View at Publisher · View at Google Scholar
- A. Ovadia, Z. Zhang, and D. M. Gash, "Increased susceptibility to MPTP toxicity in middle-aged rhesus monkeys," Neurobiology of Aging, vol. 16, no. 6, pp. 931–937, 1995. View at Publisher · View at Google Scholar · View at Scopus
- M. Pessiglione, D. Guehl, E. C. Hirsch, J. Féger, and L. Tremblay, "Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism. I. Effects of task complexity," European Journal of Neuroscience, vol. 19, no. 2, pp. 426–436, 2004. View at Publisher · View at Google Scholar · View at Scopus
- JS Schneider, Modeling Cognitive Deficits Associated with Parkinsonism in the Chronic-Low-Dose MPTP-Treated Monkey, CRC Press, Boca Raton, Fla, USA, 2006.
- G. Anderson, A. R. Noorian, G. Taylor et al., "Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease," Experimental Neurology, vol. 207, no. 1, pp. 4–12, 2007. View at Publisher · View at Google Scholar · View at Scopus
- S. H. Fox, R. Chuang, and J. M. Brotchie, "Serotonin and Parkinson's disease: on movement, mood, and madness," Movement Disorders, vol. 24, no. 9, pp. 1255–1266, 2009. View at Publisher · View at Google Scholar · View at Scopus
- Q. Barraud, I. Obeid, I. Aubert et al., "Neuroanatomical study of the A11 diencephalospinal pathway in the non-human primate," PLoS One, vol. 5, no. 10, Article ID e13306, 2010. View at Publisher · View at Google Scholar · View at Scopus
- J. Vezoli, K. Fifel, V. Leviel et al., "Early presymptomatic and long-term changes of rest activity cycles and cognitive behavior in a MPTP-monkey model of Parkinson's disease," PLoS One, vol. 6, no. 8, Article ID e23952, 2011. View at Publisher · View at Google Scholar
- H. Bergman, T. Wichmann, and M. R. DeLong, "Reversal of experimental Parkinsonism by lesions of the subthalamic nucleus," Science, vol. 249, no. 4975, pp. 1436–1438, 1990. View at Scopus
- J. Guridi, M. T. Herrero, M. R. Luquin et al., "Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis," Brain, vol. 119, no. 5, pp. 1717–1727, 1996. View at Publisher · View at Google Scholar · View at Scopus
- E. Bezard and S. Przedborski, "A tale on animal models of Parkinson's Disease," Movement Disorders, vol. 26, no. 6, pp. 993–1002, 2011. View at Publisher · View at Google Scholar
- M. Vila, V. Jackson-Lewis, S. Vukosavic et al., "Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 5, pp. 2837–2842, 2001. View at Publisher · View at Google Scholar · View at Scopus
- W. Dauer, N. Kholodilov, M. Vila et al., "Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP," Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 22, pp. 14524–14529, 2002. View at Publisher · View at Google Scholar · View at Scopus
- C. Berry, C. La Vecchia, and P. Nicotera, "Paraquat and parkinson's disease," Cell Death and Differentiation, vol. 17, no. 7, pp. 1115–1125, 2010. View at Publisher · View at Google Scholar · View at Scopus
- B. J. Day, M. Patel, L. Calavetta, L. Y. Chang, and J. S. Stamler, "A mechanism of paraquat toxicity involving nitric oxide synthase," Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 22, pp. 12760–12765, 1999. View at Publisher · View at Google Scholar · View at Scopus
- S. Przedborski and H. Ischiropoulos, "Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson's disease," Antioxidants and Redox Signaling, vol. 7, no. 5-6, pp. 685–693, 2005. View at Publisher · View at Google Scholar · View at Scopus
- A. I. Brooks, C. A. Chadwick, H. A. Gelbard, D. A. Cory-Slechta, and H. J. Federoff, "Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss," Brain Research, vol. 823, no. 1-2, pp. 1–10, 1999. View at Publisher · View at Google Scholar · View at Scopus
- A. L. McCormack, M. Thiruchelvam, A. B. Manning-Bog et al., "Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat," Neurobiology of Disease, vol. 10, no. 2, pp. 119–127, 2002. View at Publisher · View at Google Scholar · View at Scopus
- C. Thiffault, J. W. Langston, and D. A. Di Monte, "Increased striatal dopamine turnover following acute administration of rotenone to mice," Brain Research, vol. 885, no. 2, pp. 283–288, 2000. View at Publisher · View at Google Scholar · View at Scopus
- M. Thiruchelvam, B. J. Brockel, E. K. Richfield, R. B. Baggs, and D. A. Cory-Slechta, "Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson's disease?" Brain Research, vol. 873, no. 2, pp. 225–234, 2000. View at Publisher · View at Google Scholar · View at Scopus
- P. M. Rappold, M. Cui, A. S. Chesser et al., "Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3," Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 51, pp. 20766–20771, 2011. View at Publisher · View at Google Scholar
- A. B. Manning-Bog, A. L. McCormack, J. Li, V. N. Uversky, A. L. Fink, and D. A. Di Monte, "The herbicide paraquat causes up-regulation and aggregation of α-synuclein in mice: paraquat and α-synuclein," Journal of Biological Chemistry, vol. 277, no. 3, pp. 1641–1644, 2002. View at Publisher · View at Google Scholar · View at Scopus
- R. N. Takahashi, R. Rogerio, and M. Zanin, "Maneb enhances MPTP neurotoxicity in mice," Research Communications in Chemical Pathology and Pharmacology, vol. 66, no. 1, pp. 167–170, 1989.
- A. Kachroo, M. C. Irizarry, and M. A. Schwarzschild, "Caffeine protects against combined paraquat and maneb-induced dopaminergic neuron degeneration," Experimental Neurology, vol. 223, no. 2, pp. 657–661, 2010. View at Publisher · View at Google Scholar · View at Scopus
- P. G. Butterfield, B. G. Valanis, P. S. Spencer, C. A. Lindeman, and J. G. Nutt, "Environmental antecedents of young-onset Parkinson's disease," Neurology, vol. 43, no. 6, pp. 1150–1158, 1993. View at Scopus
- J. M. Gorell, C. C. Johnson, B. A. Rybicki, E. L. Peterson, and R. J. Richardson, "The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living," Neurology, vol. 50, no. 5, pp. 1346–1350, 1998. View at Scopus
- B. K. Barlow, E. K. Richfield, D. A. Cory-Slechta, and M. Thiruchelvam, "A fetal risk factor for Parkinson's disease," Developmental Neuroscience, vol. 26, no. 1, pp. 11–23, 2004. View at Publisher · View at Google Scholar · View at Scopus
- C. C. Tang, K. L. Poston, V. Dhawan, and D. Eidelberg, "Abnormalities in metabolic network activity precede the onset of motor symptoms in Parkinson's disease," Journal of Neuroscience, vol. 30, no. 3, pp. 1049–1056, 2010. View at Publisher · View at Google Scholar · View at Scopus
- C. M. Tanner, F. Kame, G. W. Ross et al., "Rotenone, paraquat, and Parkinson's disease," Environmental Health Perspectives, vol. 119, no. 6, pp. 866–872, 2011. View at Publisher · View at Google Scholar
- J. Hisata, Lake and stream rehabilitation: rotenone use and health risks. Final supplemental environmental impact statement, Washington Satet Deparment of Fish and Wildlife, 2002.
- M. Inden, Y. Kitamura, H. Takeuchi et al., "Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone," Journal of Neurochemistry, vol. 101, no. 6, pp. 1491–1504, 2007. View at Publisher · View at Google Scholar · View at Scopus
- M. Inden, Y. Kitamura, M. Abe, A. Tamaki, K. Takata, and T. Taniguchi, "Parkinsonian rotenone mouse model: reevaluation of long-term administration of rotenone in C57BL/6 mice," Biological and Pharmaceutical Bulletin, vol. 34, no. 1, pp. 92–96, 2011. View at Publisher · View at Google Scholar
- R. Betarbet, T. B. Sherer, G. MacKenzie, M. Garcia-Osuna, A. V. Panov, and J. T. Greenamyre, "Chronic systemic pesticide exposure reproduces features of Parkinson's disease," Nature Neuroscience, vol. 3, no. 12, pp. 1301–1306, 2000. View at Publisher · View at Google Scholar · View at Scopus
- M. Alam, A. Mayerhofer, and W. J. Schmidt, "The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA," Behavioural Brain Research, vol. 151, no. 1-2, pp. 117–124, 2004. View at Publisher · View at Google Scholar · View at Scopus
- J. R. Cannon, V. Tapias, H. M. Na, A. S. Honick, R. E. Drolet, and J. T. Greenamyre, "A highly reproducible rotenone model of Parkinson's disease," Neurobiology of Disease, vol. 34, no. 2, pp. 279–290, 2009. View at Publisher · View at Google Scholar · View at Scopus
- G. U. Höglinger, J. Féger, A. Prigent et al., "Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats," Journal of Neurochemistry, vol. 84, no. 3, pp. 491–502, 2003. View at Publisher · View at Google Scholar
- T. B. Sherer, J. H. Kim, R. Betarbet, and J. T. Greenamyre, "Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation," Experimental Neurology, vol. 179, no. 1, pp. 9–16, 2003. View at Publisher · View at Google Scholar · View at Scopus
- Y.-N. Wu and S. W. Johnson, "Dopamine oxidation facilitates rotenone-dependent potentiation of N-methyl-d-aspartate currents in rat substantia nigra dopamine neurons," Neuroscience, vol. 195, pp. 138–144, 2011. View at Publisher · View at Google Scholar
- R. J. Ferrante, J. B. Schulz, N. W. Kowall, and M. F. Beal, "Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra," Brain Research, vol. 753, no. 1, pp. 157–162, 1997. View at Publisher · View at Google Scholar · View at Scopus
- H. Takeuchi, T. Yanagida, M. Inden et al., "Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson's disease models," Journal of Neuroscience Research, vol. 87, no. 2, pp. 576–585, 2009. View at Publisher · View at Google Scholar · View at Scopus
- F. Pan-Montojo, O. Anichtchik, Y. Dening et al., "Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice," PLoS One, vol. 5, no. 1, Article ID e8762, 2010. View at Publisher · View at Google Scholar · View at Scopus
- F. J. Pan-Montojo and R. H. W. Funk, "Oral administration of rotenone using a gavage and image analysis of alpha-synuclein inclusions in the enteric nervous system," Journal of Visualized Experiments, no. 44, Article ID e2123, 2010. View at Publisher · View at Google Scholar
- R. Krüger, W. Kuhn, T. Müller et al., "Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease," Nature Genetics, vol. 18, no. 2, pp. 106–108, 1998.
- B. I. Giasson, J. E. Duda, S. M. Quinn, B. Zhang, J. Q. Trojanowski, and V. M. Y. Lee, "Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein," Neuron, vol. 34, no. 4, pp. 521–533, 2002. View at Publisher · View at Google Scholar · View at Scopus
- E. Masliah, E. Rockenstein, I. Veinbergs et al., "Dopaminergic loss and inclusion body formation in α-synuclein mice: Implications for neurodegenerative disorders," Science, vol. 287, no. 5456, pp. 1265–1269, 2000. View at Publisher · View at Google Scholar · View at Scopus
- A. Abeliovich, Y. Schmitz, I. Fariñas et al., "Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system," Neuron, vol. 25, no. 1, pp. 239–252, 2000. View at Scopus
- B. Thomas, A. S. Mandir, N. West et al., "Resistance to MPTP-Neurotoxicity in α-synuclein knockout mice is complemented by human α-synuclein and associated with increased β-synuclein and Akt activation," PLoS One, vol. 6, no. 1, Article ID e16706, 2011. View at Publisher · View at Google Scholar
- M. B. Feany and W. W. Bender, "A Drosophila model of Parkinson's disease," Nature, vol. 404, no. 6776, pp. 394–398, 2000. View at Publisher · View at Google Scholar · View at Scopus
- D. Wang, B. Tang, G. Zhao et al., "Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons," Molecular Neurodegeneration, vol. 3, no. 1, article no. 3, 2008. View at Publisher · View at Google Scholar · View at Scopus
- A. Zimprich, S. Biskup, P. Leitner et al., "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology," Neuron, vol. 44, no. 4, pp. 601–607, 2004. View at Publisher · View at Google Scholar · View at Scopus
- Y. Li, W. Liu, T. F. Oo et al., "Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease," Nature Neuroscience, vol. 12, no. 7, pp. 826–828, 2009. View at Publisher · View at Google Scholar · View at Scopus
- D. J. Moore and T. M. Dawson, "Value of genetic models in understanding the cause and mechanisms of Parkinson's disease," Current Neurology and Neuroscience Reports, vol. 8, no. 4, pp. 288–296, 2008. View at Publisher · View at Google Scholar · View at Scopus
- J.-H. Shin, H. S. Ko, H. Kang et al., "PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in parkinson's disease," Cell, vol. 144, no. 5, pp. 689–702, 2011. View at Publisher · View at Google Scholar
- J. Peng, M. L. Oo, and J. K. Andersen, "Synergistic effects of environmental risk factors and gene mutations in Parkinson's disease accelerate age-related neurodegeneration," Journal of Neurochemistry, vol. 115, no. 6, pp. 1363–1373, 2010. View at Publisher · View at Google Scholar · View at Scopus


text:
Folks, facts, orgs ... (February 2014)
Apache, Baker Hughes, Bechtel, Cross Country Pipeline, CVA Group, Devon, EnerVest, EOC, Flotek, GDF Suez, GE, Harris Corp., IDC Energy Insights, ITC Global, MTN Communications, New Century Software, dGB Earth Sciences, NOV, Aggreko, Paradigm, Noble, Exprodat, Seitel, EarthCube. ....(Snip!)...
This article contains approximately 381 words. Click here to request a free copy.
Offer Limited to one article per month for non-subscribers
If your browser does not work with the MailTo button, send mail to firstname.lastname@example.com with OilIT_1402_13 as the subject. Copyright © 2014 The Data Room - all rights reserved.


text:
This where the flash should stand...
26/07/2013Breguet supports the 10th edition of the Great Mountains International Music Festival & School, one of the most expected summer events in Korea. Through this association, the Manufacture pays tribute to the famous composers and musicians who have featured in the Breguet story.
The GMMFS welcomes every year hundreds of festival-goers seduced by its eclecticism. They appreciate the performances of internationally acclaimed musicians, but also enjoy discovering rising stars, going to concerts hosted by young musical talents or conversing with artists from across the globe.
Breguet and the GMMFS will officially celebrate their partnership on Saturday, July 27, 2013. Throughout this special event including a cocktail reception hosted by Breguet, artists such as Daekun Jang, Clara-Jumi Kang and Roberto Diaz will perform with the GMMFS Orchestra and the National Chorus of Korea.
The 10th edition of the Great Mountains International Music Festival & School takes place in the Gangwon Province until Tuesday, August 6, 2013.
© Montres Breguet SA - CH - 1344 L'Abbaye - Suisse Tél. +41 (0)21 841 90 90 - Fax +41 (0)21 841 90 84 |
Press room | Jobs | Sitemap |


text:
Poem: 'Mother Stone'
Selima Hill
You are not logged in
- If you have already registered please login here
- If you are using the site for the first time please register here
- If you would like access to all 12,000 articles subscribe here
- Institutions or university library users please login here
- Learn more about our institutional subscriptions here
Vol. 9 No. 20 · 12 November 1987 » Selima Hill » Poem: 'Mother Stone'
page 16 | 224 words


text:
Deperate Housewife Eva Longoria and Eduardo Cruz have called time on their on-off romance.
A representative for the Spanish musician, who is Penelope Cruz"s brother, confirmed the sad news.
The couple were rumoured to have split in March, just a month after their first anniversary.
But they were soon spotted back in each other"s arms, canoodling on a string of dates.
Just last month, the actress said: "I"m in love. I"m a hopeless romantic."
Thirty-seven-year-old Eva began dating Eduardo, 27, just months after her divorce to basketball player Tony Parker was finalized.
She recently told Spanish Vanity Fair: "I was very lucky to find Edu".
Before Tony, Eva was married once before, to General Hospital actor Tyler Christopher. Their two year marriage ended in 2004.
Related posts:
- Eva says "adios" to her Spanish hunk Eduardo
- "This time I"m going to stay single": Peter makes "emotional" return to "I"m a Celeb…"
- Eva keeps it short and sweet on date night with her sexy Spanish señor
- Eva so in love: Desperate Housewife still with her young Spanish hunk
- Eva Longoria and Eduardo Cruz Split


text:
an Outreach service of Penn State
Posted in {title},
What do you think? Be the first to comment!
Post Comment
We welcome your comments. WPSU reserves the right to edit, not post, or delete comments. Comments may not appear immediately upon submission.
More Options
Electric Bill Spikes--Was it Really Just That Cold?
Take Note: Meet the 5th Congressional District's Democratic Candidates: Kerith Strano Taylor and Thomas Tarantella
The Artemas Poems by Jerry Wemple
Take Note: Penn State Alum Dr. David Teplica on Gender-Appropriate Plastic Surgery
I Believe in Gratitude Johanna Wagner State College


text:
Cannibalism at Jamestown: Listening to the Bones
She was thrown out, or at least her head was, with the remains of other animals — dogs, horses, squirrels — and other debris that the colonists discarded during the winter of 1609–10.
She was thrown out, or at least her head was, with the remains of other animals — dogs, horses, squirrels — and other debris that the colonists discarded during the winter of 1609–10.
A breakthrough in helping the body to produce more insulin could make tedious injections of the hormone history.
Mapping out how an Alzheimer's gene works could lead to new treatments
Researchers have more questions than answers about the latest bird flu circulating in China, including whether birds are the only reservoir for the virus.
Promising trials hinted that circumcision could lower rates of HIV infection, but until now, researchers didn't fully understand why
Researchers report a breakthrough in generating powerful antibodies that can neutralize HIV.
The rates of U.S. children affected by attention-deficit/hyperactivity disorder (ADHD) are skyrocketing, according to a recent report, but experts caution that the latest numbers require a bit of decoding.
That information …
Less than half of U.S. adolescents are living heart-healthy lives, and lack of exercise and poor diets could be creating a new generation of heart-disease patients.
According to the latest research, it may be on your breath.
SARS raised the worldwide alarm for how vulnerable we are to disease epidemics. Did we learn our lesson?
Needles may not seem like the best tool for treating stress, but acupuncture could be tapping into basic biological systems that keep stress under control.
Pope Francis is a pioneering pontiff in many ways — he's the first to take the name of Francis, the first pope from South America, and the first to don the papal robes with an unusual medical condition.
Researcher and former skater Jessica Green wanted to test how microbes are spread by contact. What better way to do so than via a sport with plenty of contact?


text:
"Specializing in you"
Boyd Thomas Clothing for men and women is a locally-owned clothing store in downtown Maryville, Tennessee.
Our goal at Boyd Thomas Clothing is to offer quality apparel at reasonable prices with great personal service.
Owners Bill and Marti Womac have a combined 40 years of experience in the clothing and fashion merchandising industry.


text:
In each issue of Children's Ministry Magazine we offer exclusive extra content, ideas, and downloadables found only at childrensministry.com as a benefit to our readers. Use these Web Exclusives to help you as you minister to children and their families.
| For more great articles like this, subscribe to Children's Ministry Magazine.
- Page 23. Train Template.
- Page 35. Recyclable Wreaths. Bible Verses.
- Page 40. Prayer Pail label.
- Page 54. Safety training for the kids in your ministry.


text:
Wednesday, 19 March 2014
Monochromatic Mothers Day
9 comments:
- Alycia said...
I love the monochromatic look! Thanks for joining us at Sister Act. :) -Alycia
- 20 March 2014 at 04:23
- DIANA L. said...
Gorgeous, I love the papers
Thank you for joining my DL.ART Thankful Thursday Anything Goes March Linky Party. Have a great day
- 20 March 2014 at 11:11
- Molecraft said...
A fantastic monochrome creation...thanks for joining us at A Gem Of A Challenge!
Helen x - 20 March 2014 at 15:31
- Mynn xx said...
This is SO gorgeous! LOVE the elegant pattern and the fabulous monochrome colors! Stunning! HUGS and have a great weekend! :) Mynn xx
PS: I'd love it if you'd visit my blog (On a Stampage)--I have blog candy! :) - 22 March 2014 at 01:44
- Billie A said...
Very pretty monochromatic card and the stamp is awesome. Thanks for joining us at Aud Sentiments for our ATG challenge.
- 22 March 2014 at 10:22
- Hazel said...
Thank you so much for joining my Craftyhazelnut's Patterned Paper Challenge for March with your lovely creation - hope to see you again soon. x
- 23 March 2014 at 02:47
- rudlis said...
Beautiful card! Thanks for joining us at SweetStamps challenge.
- 24 March 2014 at 21:01
- sara said...
Beautiful card thanks so much for joining us at Bunnyzoes this month
Hugs Sara x x - 27 March 2014 at 03:05
- sara said...
beautiful card thanks so much for joining us at Bunnyzoes this month
hugs sara x x - 16 April 2014 at 17:42


text:
We want to ensure that making a return is as easy and hassle-free as possible! If for any reason you decide that your purchase just isn't for you, simply return the item within 30 days of receipt and we'll cover the return shipping when you choose our FREE Pre-Paid Return Shipping Label. Learn more about our return policy.
Shop now and get Free Value Shipping on most orders over $29.95 to contiguous 48 states, DC and to all U.S. Military APO/FPO/DPO addresses.
Hunting for the best Ram Mounts Fishing Gear through your computer is easily accomplished when you visit OpticsPlanet! These excellent Fishing Gear by Ram Mounts were designed to provide you with the best opportunity for success. OpticsPlanet's hope is to offer you a ton of of Ram Mounts Fishing Gear. In our never-ending mission to be your one-stop shop for Ram Mounts Fishing Gear and our other great product types, we've expanded OpticsPlanet to include hundreds of thousands of products. We're also certain you'll appreciate our inventory of high performance and dependable hunting gear, fashionable eyewear and highly advanced scientific tools. OpticsPlanet.com also has a large in-house service team located in the USA and full teams of expert specialists who are happy to answer all your questions.


text:
HALO's manual deminers provide the backbone of most clearance programs.
People can work in almost any ground conditions and reach places where it would be impossible to take machines. This makes manual demining the most versatile component of HALO's operations.
Manual deminers are equipped with electronic detectors which alarm on even the smallest metal components in landmines. Each piece of metal must be carefully excavated to determine if it is a landmine or not. This is painstaking work, and each individual deminer may only clear 10-50 square meters a day. Manual deminers work in small teams but many HALO clearance areas have dozens of teams and hundreds of deminers – while it is not unknown for over a thousand deminers to be working in one place (such as along the old Taliban/Northern Alliance front lines south of Bagram airbase in Afghanistan).
In some areas metal detectors cannot be used efficiently due to the high amount of metal in the ground, in these cases all of the surface soil must be removed to the required depth using hand tools. HALO has also pioneered the use of ground-penetrating radar in humanitarian mineclearance which enables deminers to differentiate between metal rubbish and actual landmines. The range of equipment and procedures used by HALO deminers across the world reflects the variety of threats they face (anti-personnel mines, anti-tank mines, cluster munitions) and the different types of terrain in which they have to work (fields, mountains, river beds, deserts, beaches, jungle, savannah and more).