Environmental consciousness and sustainable practices are today extremely important for companies. Public organisations such as Bruxelles Environnement strive to recognise those companies that commit to sustainable and environmentally friendly practices by awarding them the 'Enterprise éco-dynamique' label.
To communicate companies' environmental efforts externally there must be improved internal communication among staff. Yet, how can companies' environmental approaches be communicated to staff and stakeholders and how can they build an image that reflects their environmental and sustainable efforts?
Managing Director of Arctik, Cédric Hananel, has contributed to Bruxelles Environnement's Guide de Communication/Communication Guide report, 'Comment Communiquer sur votre démarche environnementale?'/'How to Communicate your environmental approach?'. By exploring how companies can communicate their sustainable image to staff and stakeholders and present their environmental achievements, the extensive methodology of the report gives insight into objectives and means of structuring environmental communication strategies for companies which appreciate sustainable practices.
The full report is available for free here.


Broga® is the brainchild of Matt Miller, a larger than life former American football star and yoga lover.
Broga® is a real challenge and suited to those that want to build strength, stamina and flexibility and is for both males and females of any age. We run monthly courses with one session a week on a Wednesday evening at 6:30pm. Each month we target a different body part to improve flexibility whilst giving a whole body workout.
A unique benefit of this session is that we test the range of movement of that body part e.g. hamstrings at the beginning of the course and then again at the end of the course to see how much you have improved your flexibility.
Broga® is a trademark signature yoga practice designed for those who want to improve their flexibility but at the same time build their strength. It is a strong, intense and physically challenging workout with accessible postures that challenge the body in new ways, increase performance and capability in sport and reduces the possibility of injury or painful impingement.
To find out more about Broga® and Matt Miller visit http://www.broga.uk.com.


Online users do not visit or purchase from websites that claim to sell "Forskolin," a so-called dietary supplements created by so-called Anna and Samantha Williams from Shark Tank or Dragons' Den. This is because the websites are scams created by online scammers and the so-called Anna and Samantha Williams featured on the fake websites are actually Shelly Hyde and Kara Haught, who have nothing to with the product. Shark Tank or Dragons' Den is a reality television format program featuring entrepreneurs pitching their business ideas in order to secure investment finance from a panel of venture capitalists.
Weight Loss Product That Naturally Burns Fat Gets Biggest Deal In Reality TV Show History. It was the most watched episode in the show's history when sisters Anna and Samantha Williams won over the Investors panel.
The Facebook comments on the websites are fakes. The fake comments have been placed on the website to convince potential victims into purchasing the fake dietary supplement. And, do not be fooled by the claims that the product was seen by The New York Times, TODAY, StyleWatch and Redbook, this is not true. It is just another trick to convince potential victims into falling for the scam. The scammers may also claim the product is loved by celebrities, but again, this is a lie used to convince potential victims into purchasing the fake product.
I responded to their add for 1 bottle of Forskolin Extract (which is supposed to be a weight loss supplement) at a total cost of $4.87.
Only had the product for 1 week and they charged my account another $92.27!
I would say it isn't worth anything since it has not done anything for me!
That is totally deceptive advertising!
DO NOT BUY ANTHING FROM THIS COMPANY!
I was scammed by this product! I thought I was ordering one item for on the the shipping cost of 1.99 but ended up purchasing 4 different products totaling about 40.00. Then, a month later I ended up with another two charges on my debit card totaling 150.00!! I called my credit union and changed cards, and also the company to dispute the charges. They have refunded 30.00 so far and promised to refund the rest when I mail back the bottles.
We will see. It was a tough lesson! I hope Facebook becomes more diligent in removing scams like this!! It takes away from the legitimate companies trying to do honest business online.


materials. Please note: The documents below are archived documents. New versions may be available. For additional help call: 1-800-828-HEAT INSTALLATION & SERVICE MANUALS Programmable Thermostat Wiring Diagrams - Installing a programmable thermostat is not unlike installing any other thermostat for your HVAC system. The key is to get the right thermostat for your HVAC system. And to make sure it is wired properly. Unit Heaters. Extensive research and development has resulted in a technically advanced range of unit heaters that delivers the highest possible standards of energy efficency and performance.
gas-fired unit heaters are power vented in order to eliminate heat losses up the flue pipe. Power vented models have a higher initial cost than similar "gravity" vented models, but will save money on fuel costs. Please provide as much information as possible to help us assist you better. Please select the Topic and Subtopic of your inquiry first, before filling out the rest of the form. These Summaries contain information specifically tailored to engineers and contractors with water, gas, electrical, dimensional, service clearance and venting information in an easy-to-read format.


text:
BIN = node_modules/.bin
MOCHA = $(BIN)/_mocha
ISTANBUL = $(BIN)/istanbul
JSHINT = $(BIN)/jshint
JSCS = $(BIN)/jscs

TESTS = $(shell find test -name "*.test.js")

install: node_modules

node_modules: package.json
	@npm install

jshint:
	$(JSHINT) --exclude-path .gitignore .

jscs:
	$(JSCS) .

make cover:
	NODE_ENV="test" $(ISTANBUL) cover $(MOCHA) $(TESTS)
	$(ISTANBUL) report cobertura

make lint: jshint jscs

test: jshint jscs cover

server:
	@supervisor index

.PHONY: server install cover test jshint jscs lint production

redpajama_set_name: RedPajamaGithub


Morning Light is a collaboration between Justin Timberlake and Alicia Keys on Timberlake's album Man of the Woods. It's released on February 2, 2018.In the song, Justin Timberlake and Alicia Keys described their love for their partner and how they dream about each other every night.
We additionally have an amazing Morning Light - Justin Timberlake, Alicia Keys ringtone which would empower you get ringtones out of your favorite songs. Download and install it on a call and let you enjoy it with every new incoming call.
So I say to myself, "I don't even wanna try"


text:
What is Emerge?
Since 2002, Emerge has offered a premier, 70 hour in-depth training program that provides aspiring women leaders with cutting-edge tools and training to run and win elected office. We recruit, train and provide a powerful network for our Emerge women with staff, alumnae, and volunteers on the ground 365 days each year.
What is the Mission of Emerge?
Our mission is to increase the number of Democratic women in office who are reflective of the incredible diversity of the Democratic party by recruiting, training and providing a powerful network.
How does Emerge differ from other women's political training programs?
Many political training programs are non-partisan. Emerge exclusively grooms self-identified Democratic women to run for office and connects program members to networks of local Democratic politicians, leaders, and activists. Emerge provides a powerful sisterhood and network for our participants.
Which organizations do you partner with?
Emerge maximizes its impact through strong and strategic relationships with other political groups, including the Democratic Party political committees, EMILY's List and state women's training organizations, Planned Parenthood, America Votes, NARAL, national labor unions, Higher Heights for America, Victory Fund, Run for Something, Latino Victory, Moms in Office, Onward Together and many others.
Why focus on women exclusively?
The US ranks 75th in the world for representation of women in elected office in their national legislatures. At the state level, only 29.3% of legislators are women and only 7.4% are women of color.
Too often women don't believe they are qualified to run for political office – whether for school board president or Congress. Moreover, women are less likely to be asked to run for office. Emerge believes that the answer to persistently low levels of women in office lies in early stage recruitment, comprehensive cohort-based training, and ongoing support.
How do you recruit members for an Emerge training?
Emerge recruits program members through political contacts, board members, alumnae, and relationships with other political organizations, labor unions and community organizations. We also hold information sessions during the recruitment season for women who are interested in applying.
How do I join an Emerge Training?
Information on Emerge training programs in our states can be found here on our website. You can find program dates, descriptions of classes and a link to your state to complete an application.
What makes the Emerge model unique?
Emerge takes a fresh approach to women's underrepresentation: We are creating a larger pool of qualified women candidates by training them early on in their political careers.
We only train Democratic women
We have a proven commitment to equity and justice and are committed to training the New American Majority
In our Signature Training program, we provide 70 hours of in-depth candidate training over a 6-month period to ensure our participants are fully ready to run upon graduation.
In our Boot Camp Training program, we provide intensive training over a weekend for active candidates.
We are locally-based and provide our program members with strong ties to the local community and political leadership.
We make a long term investment in the women we train, directing them to promising electoral contests, providing them with strategic advice, and connecting to the political community.
Does Emerge train on any issues?
Emerge does not train on any issues, but we do require all program participants to be registered members of the Democratic Party and read and sign the Democratic Party platform, which covers many important issues. Emerge relies on our strong network of partners to provide support to alums on particular issues. Alums are able to go to these partner organizations who are experts in a wide range of issues for additional guidance and information.
How are you funded?
Emerge is funded by donations from individual donors, labor unions, and Political Action Committees. Our supporters share our vision of building a more reflective and inclusive democracy through inspiring, training, and supporting the next generation of Democratic women candidates.
Are you a 501(c)(3) organization/are donations to Emerge tax-deductible?
Emerge is a 527 political organization and donations are not tax deductible. Emerge is not a PAC and does not endorse candidates and does not make contributions to, or coordinate its spending with, any candidates or political parties.
Do you have a targeted group?
Emerge's trainings are for self-identified women, 18 years old and older, who are Democrats, engaged in their communities and interested in running for office.
Is there an Emerge in my state?
You can find our list of affiliates here.
Can I bring an Emerge training to my state?
In 2021, Emerge will be hosting no-in person training and most of our state affiliates are following suite. Emerge is building back from the impact of COVID-19 and we will not be physically launching new affiliates. We will be providing virtual Boot Camp training for active candidates in 2021, in regions across the country. Please sign up to receive more information on virtual opportunities to get trained near you.
How do I learn more about your upcoming trainings?
Please visit our Candidate Training page on our website. Here you can learn about our State Affiliates Signature Training program as well as upcoming National Emerge Candidate Boot Camps and Step Forward Trainings. Additionally, here you can reach out to Emerge about bringing an Emerge training to your state or working on joint training opportunities with like-minded groups on the ground.
Can I get involved?
There are numerous ways for you to learn more about Emerge, attend one of our training or be involved.
Join us for a training. Please visit our training page here to learn about upcoming opportunities.
Donate and support us. The vast majority of our funding comes from individual donors across the country. You may donate online here. Checks can be mailed to: Emerge America, 351 California St, Ste. 930, San Francisco, CA 94104. Please email jeanette@emergeamerica.org if you have questions or would like to make a contribution via wire transfer or a donation of stock.
Follow Emerge on social media.
Facebook: Facebook.com/EmergeAmerica
Twitter: @EmergeAmerica
Instagram: @EmergeAmerica
YouTube: Emerge America

redpajama_set_name: RedPajamaCommonCrawl


The European Commission's Energy Union proposal to establish post-2020 legislation for renewables is a clear signal to investors that Europe is open for business on zero-carbon energy, says the chief executive officer of the European Wind Energy Association.
The Vice President for Energy Union Maros Sefcovic plans to put forward a Renewable Energy Package as soon as next year to guarantee that the 2030 climate and energy targets are met cost-effectively.
With the Energy Union in mind, EWEA is calling for the disorderly patchwork on energy policies in the 28 Member States to be addressed. This is currently sending a confusing message to those in financial circles and would-be investors.
Actions taken at national level should serve to complement the EU's long-term climate and energy objectives by avoiding arbitrary and retroactive changes to domestic policies while also ensuring that the binding targets for 2020 are achieved.
The Commission's paper also states that the development of new infrastructure, especially interconnections, needs to lower the cost of integrating renewable electricity into the internal energy market.
Wind energy can already meet 10.2% of the EU's electricity consumption but for Europe to become the world number one in renewables, existing grid infrastructure is in desperate need of an upgrade.
"Wind power deployment is well-placed to be the backbone of the EU's energy security strategy whilst significantly reducing the region's import bill," he said.
Read the full communication from the European Commission.


Faux Marble Table Top (Marbleizing with Envirotex Lite and Acrylic Paints) | Epoxy Resin Coatings, Casting, Mold Making & More - Environmental Technology, Inc.
Protect work area with a plastic drop sheet or newspaper. Elevate project surface from work area.
Paint project surface with a dark color such as black or brown, allow paint to dry.
Important, mix double the amount of EnviroTex Lite product required to flood coat your project. Refer to Envirotex Lite product coverage chart.
Divide mixture equally into four containers. Add one color of paint to each of the containers. Add just enough paint to color and no more, blend well!
Pour each color in random patterns across project surface.
Use a disposable bristle brush to lightly blend colors (do not use a foam brush).
Raise project piece and tip to allow colors to run and blend. Hold for one to two minutes, then rotate piece in another direction. Repeat this process until the colors begin spread open.
Continue to rotate and tip your project, this is necessary to allow the colors to open and spread.
Once you've achieved a marbled like pattern, place your project back on your work surface. If at first your not satisfied with your result, you can repeat this process while the coating is still liquid.
Remove bubbles as per the EnviroTex Lite Instructions. Allow coating to cure for 12 hours, then flood coat with a clear coat of EnviroTex Lite for added hardness and durability.


text:
*Leave No Trace* is an algorithm for safe reinforcement learning. The key idea is that an agent should only do things that it can undo. For example, a robot should not break a glass, because it will be unable to put it back together; a robot should not walk off a cliff because it cannot un-fall off the cliff.

Leave No Trace was proposed in [Leave no Trace: Learning to Reset for Safe and Autonomous Reinforcement Learning](https://arxiv.org/pdf/1711.06782.pdf). Videos of the algorithm are shown on the [project website](https://sites.google.com/site/mlleavenotrace/). If you use this code, please consider including the citation at the bottom of this page.

##### How does Leave no Trace work?
*Leave No Trace* works by learning two policies. The *forward policy* attempts to complete the main task, such as navigating a maze or running forwards. The *reset policy* attempts to undo the actions of the forward policy. If the forward policy is navigating a maze, the reset policy learns how to navigate back to the start. If the forward policy is running forwards, the reset policy learns how to run back to the start.

##### Limitations

1. Users must manually define a reward function for the reset policy.
2. Users must manually define a function indicating whether the reset policy has successfully reset.
3. Leave no Trace only works in environments where it is possible to go backwards from the goal state to the start state. While this encompasses a wide range of tasks, it excludes tasks such as cooking (a robot cannot un-slice a carrot, un-crack and egg, and un-bake a cake).

If you're interested in working on any of these open problems, feel free to reach out to <eysenbach@google.com>.

### How to use Leave No Trace

We have implemented Leave No Trace as a *safety wrapper*. We wrap the environment in this projective layer to prevent an outside learning algorithm from taking dangerous actions. Under the hood, the safety wrapper learns the reset agent, and uses the reset agent to avoid taking dangerous actions. Leave no Trace abstracts away the safety problem, allowing users to learn safely without any modifications to their learning algorithm:
```
# 1. Create a reset agent that will reset the environment
reset_agent = Agent(env, name='reset_agent', **agent_params)

# 2. Create a wrapper around the environment to protect it
safe_env = SafetyWrapper(env=env, reset_agent=reset_agent, **lnt_params)

# 3. Safely learn to solve the task.
Agent(env=safe_env, name='forward_agent', **agent_params).improve()
```

##### Installation

1. Clone this repository

```
git clone https://github.com/brain-research/LeaveNoTrace.git
```

2. Install coach. In the dialogue that appears, only install the coach dependencies

  ```
  cd coach
  git submodule init
  git submodule update
  ./install.sh
  ```

3. Install the other dependencies.

  ```
  pip3 install gym==0.9.3
  pip3 install mujoco-py==0.5.7
  ```

If you run into any problems with installation, please create an issue or
directly create a pull request for updating the documentation. Doing so will
greatly help future users avoid the same problems.

##### Usage

Basic usage - activate the virtual environment and run the demo script.
  ```
  source coach/coach_env/bin/activate
  python3 demo.py
  ```
After training, you should see a plot that looks like the one below. The green dots show the average per-step reward throughout training. As expected, the agent's reward increases throughout training. The solid blue line shows the cumulative number of hard resets throughout training. Notice that fewer and fewer new hard resets are performed later in training, as the reset agent learns to automatically reset the agent.
![example plot](plot.png)

This implementation of Leave No Trace currently only supports environments with discrete actions. Additionally, this implementation does not support learning an ensemble of value functions. Support for environments with continuous actions and ensembles of value functions is coming in early May 2018!

### Miscellany

##### Citation
If you use this code, please consider including the following citation:
```
@inproceedings{
  eysenbach2018leave,
  title={Leave no Trace: Learning to Reset for Safe and Autonomous Reinforcement Learning},
  author={Benjamin Eysenbach and Shixiang Gu and Julian Ibarz and Sergey Levine},
  booktitle={International Conference on Learning Representations},
  year={2018},
  url={https://openreview.net/forum?id=S1vuO-bCW},
}
```

##### Funding
Work done while Ben Eysenbach was a member of the Google Brain Residency Program <g.co/brainresidency>.

##### Legal
This is not an officially supported Google product.

##### Contact
Please send pull requests and file issues with @ben-eysenbach. For other correspondence, email <eysenbach@google.com>.


Taylor Swift drops new album alongside Eminem; Sings about past relationships?
The popstar, Taylor Swift is reportedly dropping a surprise new album which contains stories about past romance.
Taylor Swift reportedly has a new album, and it is on the way. Considering all the challenging things that have happened to the pop star for the past three years, Swift has a lot of inspiration in writing new songs and creating a new album.
According to recent reports, Taylor Swift is finally working on her new album, and she reportedly includes some songs she wrote about her past relationships. Apparently, fans are excited to know more about her respective split with Calvin Harris and Tom Hiddleston, especially because of the controversy they went through after their sudden break-up with the "We Are Never Ever Getting Back Together" hitmaker.
Will the fans hear a new song from Taylor Swift this year?
All things aside, the singer-songwriter has been having a good run with her albums, topping major charts ever since. There have been minor hints about her comeback but was later overshadowed by her trial against David Mueller. Mueller allegedly groped her lower back during an event at Pepsi Center. The jury sided with her which ended the case. The situation even sparked Swift's interest in helping others who had experienced sexual assault in any form.
Although the 27-year-old performer has yet to give full details about a new album, it seems like she has been prepping for the release aside from the subtle hints on social media, she finally gave her yes on putting back her songs on Spotify. It was a huge news back then when Swift was trying to raise the issue of some musicians being unfairly compensated while streaming companies earn from their music.
Swift to release new album along with Eminem's new record?
The "Blank Space" singer is expected to release a single before the year ends.
Another musician who is making history is also on his way to drop more about Marshall Mathers. Eminem is also planning to drop a new album and continue performing live next year.
Various acts from the music scene have collected their own shares of success this year. Big names such as Drake, Bruno Mars, The Weeknd, Kendrick Lamar, DJ Khaled, Ed Sheeran and more. The 2018 music award shows should bring so many stars together at once, and the excitement is already building even though we are still months away from December.
If Taylor Swift's new album comes into play somewhere between October to December of this year, what do you think the songs will be about? Could the album contain several songs about her past romances?


text:
San Fernando's traditions to take centerstage in fiesta
PAMPANGA. City of San Fernando Mayor Edwin Santiago, Councilors Harvey Quiwa, BJ Lagman, Reden Halili, Nelson Lingat, Ruping Dumlao, Barangay Chairmen Ariel Carreon, Tina Lagman and Atty. Rolly Macalino flash the Fernandino First sign during Monday's (May 6) unveiling of the 2019 Pyestang Fernandino calendar of events at the City hall. Joining them are the Fiesta Committee and department heads. (Chris Navarro)
PRINCESS CLEA ARCELLAZ
THE rich culture and heritage of the City of San Fernando will take centerstage in this year's month-long celebration of "Pyestang Fernandino" in honor its patron St. Ferdinand this May.
Anchored on the theme "Pamagpasalamat, Pamibuklud, Mitmung Tula uli ning bie masaplala," this year's celebration highlights the city's thanksgiving for all its remarkable accomplishments through further strengthening and reviving its culture and tradition.
"Our celebration this year is aimed at showcasing the cultures and values of Fernandinos and at the same time a thanksgiving for the many blessings that we have received, we are receiving and those that we will be receiving," said Pyesteng Fernandino Executive Committee chairman Alex Magsino during Monday's (May 6) press conference.
Magsino, an active socio-civic leader, added that the month-long festivity will also celebrate the strong partnership between the private and public sector in the city as manifested in the executive committee.
"Our activities this year, just like in the many events that we held, were formed through the suggestions of the members from the private sector and the city government and so the success of our Pyestang Fernandino is a success for the city's public-private partnership," he said.
City Tourism Officer Ching Pangilinan, meanwhile, disclosed the activities slated in this year's event, which include inter-barangay basketball and volleyball competition, Little Miss Fernandina, Mutya at Lakan Ning San Fernando, Miss Gay Fernandino Fiesta Queen, El Circulo Fernandino, Ultimate Fernandino Frisbee Open, and variety shows and battle of the bands.
The Pyestang Fernandino is also coinciding with the celebration of the National Heritage Month wherein the City Government slated several activities such as the Heritage Open House Tours and Kalesa Tours, National Flag Day, Seminar on Flag and Heraldic Code and the unveiling of the bust monument of local hero Sotero Baluyut.
Agricultural programs such as Symposium on the Philippine Rice Tarrification during Farmers' Week and Refill Revolution, as well as seminar for responsible pet ownership with free grooming and trade fairs and mall sales are also set this month, Pangilinan said.
And aside from preserving the city's culture and heritage, the City Government is also inclined in developing the potentials of Fernandino youth e-sports competition, which is starting to gain ground in the international arena.
Pangilinan said the 1st Pyestang Fernandino Esports Tournament dubbed the "The Road to E-Sports World Cup" in DOTA 2 and Mobile Legends tournaments will be held on May 21 and 25, respectively.
"We organized an e-sports tournament to provide a training ground for our potential and even professional games since we saw how e-sports is now being recognized internationally and is even included in this coming SEA Games," Pangilinan said.
City of San Fernando


text:
Home > June 2006 - Volume 26 - Issue 2 > Immunohistochemical Evidence of Inducible Nitric Oxide Synth...
Article as PDF (1019 KB)
Immunohistochemical Evidence of Inducible Nitric Oxide Synthase and Nitrotyrosine in a Case of Clinically Isolated Optic Neuritis
Tsoi, Veda L; Hill, Kenneth E BS; Carlson, Noel G PhD; Warner, Judith E. A MD; Rose, John W MD
Journal of Neuro-Ophthalmology: June 2006 - Volume 26 - Issue 2 - p 87-94
doi: 10.1097/01.wno.0000223266.48447.1b
Original Contribution
Background: Optic neuritis (ON) is a demyelinating inflammation of the optic nerve that may occur as an isolated disease or related to multiple sclerosis (MS). There is little evidence of whether the immunohistochemistry of ON resembles that of typical cerebral MS lesions.
Methods: Pathologic optic nerves were obtained from a patient who died of causes unrelated to ON after clinical recovery from clinically isolated ON. Normal control optic nerves were obtained from an eye bank. Normal and pathologic tissues were probed with antibodies to pathologic proteins including myelin basic protein (MBP) fragment, the inducible form of nitric oxide synthase (iNOS), macrophage markers CD14 and CD64, nitrotyrosine, and cyclooxygenase (COX-2). We also examined MBP, the oligodendrocyte marker cyclic nucleotide phosphodiesterase (CNPase), and glial fibrillary acidic protein.
Results: In the affected pathologic nerve, iNOS-positive macrophages/microglia, iNOS-positive astrocytes, COX-2, and nitrotyrosine were observed. iNOS and COX-2 were occasionally observed in the unaffected nerve.
Decreased expression of MBP and CNPase was seen in the pathologic optic nerves, along with evidence of gliosis and ongoing myelin degradation indicated by the presence of MBP fragment.
Conclusions: The immunohistochemistry of clinically isolated optic neuritis, as judged by this single case, resembles that of cerebral lesions of MS in showing abnormally high levels of iNOS and nitrotyrosine as well as other mediators of immune damage.
Neurovirology Research Laboratory (VLT, KEH, NGC, JWR), Geriatric Research Education and Clinical Center (GRECC) (NGC), and Neuro-ophthalmology (JW), Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah; Neurobiology and Anatomy (NGC), Neurology (KEH, NGC, JWR), Brain Institute (NGC, JWR), and Neuro-Ophthalmology (JW), Moran Eye Center, University of Utah, Salt Lake City, Utah.
Address correspondence to John W. Rose, MD, Neurovirology Research Laboratory (151B), VASLCHCS, 500 Foothill Drive, Salt Lake City, UT 84148; E-mail: jrose@genetics.utah.edu
Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah (JEAW).
Patient History
Immunofluorescent Assay
Immunohistochemistry of Normal Optic Nerves
Expression of Myelin Basic Protein, Cyclic Nucleotide Phosp...
Expression of Myelin Oligodendrocyte Glycoprotein
Active Demyelination
Inducible Nitric Oxide Synthase Expression in Reactive Astr...
Expression of Nitrotyrosine and COX-2
Optic neuritis (ON) is characterized by inflammation and demyelination of the optic nerve. Clinical symptoms include a loss of visual acuity, scotomas, periocular pain, and Uhthoff phenomenon. ON is often the first clinical manifestation of multiple sclerosis (MS) in 15%-20% of individuals ultimately diagnosed with clinically definite MS (CDMS). ON eventually occurs in 50%-75% of patients with MS (1,2).
Previous studies of ON have focused on predicting the likelihood of development of CDMS after a first demyelinating event such as ON. These studies demonstrate that the risk of development of CDMS after ON increases if the patient has an abnormal MRI scan showing at least one T2 lesion that also enhances on T1 imaging after gadolinium administration (3,4). Additional studies have shown that an increase in anti-myelin antibodies to myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG) in the cerebrospinal fluid of patients with clinically isolated syndromes (CIS) may also be used to predict the likelihood of development of MS (5-7). Prior pathologic investigations on ON have described the inflammation and demyelination in the optic nerves, but few studies have detailed the immunohistochemistry of ON.
The mechanisms leading to the death and damage of oligodendrocytes and the loss of myelin from immune and inflammatory-mediated responses is not yet fully understood. However, several factors have been implicated in this process. One possible mediator is nitric oxide (NO), which is synthesized by the inducible form of the enzyme nitric oxide synthase (iNOS) (8-10). iNOS has been found in multiple cell types, including reactive astrocytes and inflammatory monocytes/macrophages (11-13). NO can combine with superoxide to generate peroxynitrite (ONOO-), a molecule capable of damaging cells, membranes, and DNA (14). Peroxynitrite-mediated damage is indicated by the presence of nitrotyrosine (15,16). COX-2 has also been implicated in the pathogenesis of MS and has been found closely associated with iNOS activity in MS lesions (17). Myelin degradation products, MBP fragments, and lipids have also shown a close association with iNOS (12). To study how the pathology of ON may parallel that seen in MS lesions, we have used immunofluorescent confocal analysis to examine whether similar pathologic markers are present in the optic nerves of a patient with CIS recovering from an episode of ON.
For this study, normal optic nerves were obtained from the Utah Lion's Eye Bank at the Moran Eye Center, University of Utah. ON-affected optic nerves were obtained from a patient with CIS treated at the University of Utah who died of causes not related to the disease (see patient history). Research using these tissues was performed in compliance with Department of Health and Human Services federal regulation 45CFR46. Pathologic tissues were formalin-fixed and paraffin-embedded. Normal optic nerves were paraformaldehyde-fixed and paraffin-embedded. Normal optic nerves were dissected in both longitudinal and cross sections. ON nerve tissue was fixed only in cross section. Tissues were sliced in 20 μm thick sections and mounted on glass slides. Tissue obtained from the patient with CIS included the clinically affected left and clinically unaffected right optic nerves.
The patient presented with left periocular pain and loss of vision in February 1997. Visual acuity was 20/15 in the right eye and 20/400 in the left eye. He had a l.2 log unit left relative afferent pupillary defect (APD) with impaired color vision (0/13 Ishihara plates). There was no uveitis. Mild optic nerve swelling was observed in the left eye. Humphrey visual fields showed a large central scotoma in the left eye and was normal in the right eye. MRI performed at another facility revealed a high T2 signal in the anterior portion of the left optic nerve. Contrast enhancement of the left optic nerve on T1 images was suspected, but interpretation was limited by technical factors. No imaging abnormality was detected in the right optic nerve. In addition, the T2-weighted MRI revealed five high signal cerebral lesions, including one periventricular ovoid lesion. The patient was initially treated with intravenous methylprednisolone, with recovery of visual acuity from 20/400 to 20/20 within one month. The central scotoma and APD resolved completely, but left optic disc pallor remained. The patient was then placed on treatment with interferon beta-1a. In subsequent MRI scans, the optic nerves did not enhance and were normal in appearance on T2-weighted and T1-weighted scans. The patient died of accidental causes ten months later, and the optic nerves were obtained at autopsy.
Immunofluorescent assays were performed to identify the presence of various inflammatory signals and demyelination in both normal and MS optic nerves (Table 1). Primary antibodies used included goat anti-COX 2 (Alpha Diagnostic International, San Antonio, TX), rabbit anti-myelin basic protein (Accurate Chemical and Scientific Corporation, Westbury, NY), goat anti-myelin oligodendrocyte glycoprotein (Santa Cruz Biotechnology Inc., Santa Cruz, CA), mouse antibody to human cyclic nucleotide phosphodiesterase (CNPase) (Sigma-Aldrich Corp., St. Louis, MO), mouse anti-MBP fragment, mouse anti-CD64, mouse anti-CD14 (Research Diagnostics Inc., Benecia, CA), rabbit anti-nitrotyrosine, rabbit anti-inducible nitric oxide synthase, and rat anti-glial fibrillary acidic protein (GFAP) (Calbiochem, San Diego, CA). Primary antibodies were diluted in ranges from 1:40 to 1:1000, according to manufacturer specifications. Secondary fluorochrome antibodies were Cy5-conjugated anti-mouse, anti-rat, and anti-goat, FITC-conjugated anti-rabbit and anti-mouse (Jackson Immunoresearch Laboratories, West Grove, PA). Secondary antibodies were used in concentrations ranging from 1:800 to 1:2000. The fluorochrome antibodies were cross-adsorbed to immunoglobulins from other species to ensure specificity. Phosphate buffered saline (PBS) with 0.02% Tween-20 was used in all dilutions. Tissues were permeabilized with PBS with 0.2% Triton X-100 and blocked with Image-iT Fx signal enhancer solution (Molecular Probes, Eugene, OR). The combined primary antibodies were added to each section and incubated overnight in a humidified chamber at 4°C. After washing in PBS, conjugated secondary antibodies were then applied for one hour at room temperature. Propidium iodide (PI) (15 μM) was added for an additional hour. Sections were mounted with ProLong anti-fade mounting medium (Molecular Probes, Eugene, OR.)
Personal Confocal Microscopy PCM-2000 (Nikon, Melville, NY) with Argon, green and red HeNe lasers was used to acquire the image. The fluorochromes were resolved into three different image channels. The FITC label was detected with the Argon laser at 488 nm, Cy5 with the red HeNe laser at 633 nm, and PI with the green HeNe laser at 605/32 nm. Tissues were individually scanned for each respective fluorochrome. Simple Personal Confocal Image Program (PCI, Compix, Cranberry Township, PA), a multifocus (z-focus) program, was used to create a stereopsis image. The three separate images were then merged to create the final triple-colored image. The PI was converted to blue during the merging process, allowing for comprehensive visualization of labeling throughout the tissue. Images were stored as digital files, and final figures were created with the use of Adobe Photoshop 7.0.
Antibodies that recognize normal myelin and cellular antigens including anti-CNPase specific for oligodendrocytes, anti-MBP specific for myelin basic protein, and anti-GFAP specific for astrocytes were used to demonstrate the structure of the nerves. Fluorescent labeling of the normal optic nerves with anti-MBP showed complete myelination extending throughout the nerve (Fig. 1A). CNPase expression was similarly abundant, showing no apparent signs of damage or death of oligodendrocytes. In the normal optic nerve, iNOS and nitrotyrosine were infrequently seen and usually not observed (Fig. 1, B and C, respectively). Subsequent probing for MBP fragments, CD64+ and CD14+ macrophages/microglia, and COX-2 revealed no detectable labeling of the tissue (data not shown). The results from labeling normal and pathologic optic nerves are summarized in Table 2.
Expression of Myelin Basic Protein, Cyclic Nucleotide Phosphodiesterase, and Glial Fibrillary Acidic Protein in the Pathologic Optic Nerves
Compared with the normal optic nerves, there was a sharp contrast in patterns of MBP, GFAP, and CNPase expression in the pathologic optic nerves. The clinically unaffected optic nerve showed only one small area of demyelination (Fig. 2A). However, there was a marked reduction in both CNPase and MBP expression in the affected nerve. In both normal and pathologic tissues, the pattern of CNPase distribution mirrored that of MBP (Fig. 2, C and D). In the clinically affected optic nerve, the majority of myelin and oligodendrocytes was concentrated in the center of the nerve, whereas demyelinating activity occurred mostly on the periphery of the nerve. GFAP was inversely expressed in the affected pathologic optic nerve; intense labeling of reactive astrocytes was present in demyelinated areas compared with more uniform and diminished expression in the myelinated areas (Fig. 2E).
After establishing that the pathologic optic nerve showed a decrease in myelin expression, we searched for other characteristics associated with inflammation and demyelination in ON. The anti-MOG antibody used in this investigation binds to a region near the carboxy terminus of MOG. This antigen is generally detected only when damaged myelin is present. The MOG c-terminal antigen was seen only in the affected optic nerve and was restricted to isolated cells located toward the interior of nerve fascicles (Fig. 2B).
We then searched for evidence of recent demyelination by assessing whether MBP fragments were present in the pathologic optic nerves. Detection of MBP fragments would be indicative of an ongoing demyelinating process. MBP fragments detected by a monoclonal antibody specific for an epitope found on recently digested MBP were present in both the unaffected (Fig. 3A, see *) and affected optic nerves (Fig. 3B, see arrow); however, MBP fragments were more prominent on the affected optic nerve. MBP fragments were predominantly found in areas exhibiting extensive demyelination, generally near the periphery of areas still rich in myelin.
Inducible Nitric Oxide Synthase Expression in Reactive Astrocytes and Macrophages/Microglia
We assessed whether iNOS, a major inflammatory enzyme associated with demyelinating lesions, was expressed in ON (11-13). Cellular expression was observed predominantly in the affected nerve, although small amounts were seen in the unaffected nerve. The majority of iNOS was associated with inflammatory infiltrates in the nerve septa toward the periphery of the nerve as well as in the adventitia of the central retinal arteries. Most of the iNOS was expressed in or near macrophage and microglia subtypes co-labeled with either anti-CD14 (Fig. 4A), a specific marker for a type of macrophages/microglia that phagocytose apoptotic cells, or anti-CD64, a specific marker for the high-affinity Fcγ receptor (18,19). CD64+ macrophages/microglia localized to cell clusters in the septa in iNOS positive regions (Fig. 4B, see arrow). In these areas, CD64+ macrophages/microglia sometimes expressed iNOS.
CD14+ macrophages/microglia were found adjacent to iNOS-positive cells (Fig. 4A, see arrow). CD14+ cells were most numerous in the septa on the perimeter of the myelinated area of the affected optic nerve. They were also observed in the tissue surrounding the central retinal artery. Little or no expression of CD14+ cells was seen toward the interior of the nerve in the myelinated regions. In regions of overlap, iNOS and CD14 were generally co-expressed within the same cells. Neither CD14+ nor CD64+ cells were detected in the unaffected nerve (not shown).
In addition to expression of iNOS in inflammatory infiltrates, occasional isolated reactive astrocytes in the affected optic nerve also showed considerable expression iNOS (Fig. 4C, see arrow). Nearby non-GFAP-positive cells also expressed iNOS (Fig. 4C, see *). These iNOS-positive reactive astrocytes were found near the outer edge of the myelinated areas in both the septa and in parenchymal tissue. Additionally, a few iNOS-positive astrocytes and other cells were also detected toward the interior of the nerve in the myelinated area.
After establishing the presence of iNOS in the diseased nerves, we determined whether nitrotyrosine and COX-2 were present and associated with iNOS, as seen in MS plaques. The degree of peroxynitrite-mediated damage was assessed by determining the formation of nitrotyrosine. Nitrotyrosine was present among inflammatory infiltrates in the adventitia of the central retinal vessels and in the septa between fascicles (Fig. 4D). Nitrotyrosine was largely not detected in GFAP-positive cells (Fig. 4D, see *), nor was it found in the unaffected nerve.
COX-2 was rarely detected in either the unaffected (Fig. 4E) or affected (Fig. 4F) pathologic optic nerves. However, when present, COX-2 was located in large inflammatory cells either on the periphery of the nerves, where most of the myelin damage occurred, or in the nerve septa.
In this study, we have demonstrated antigen detection by MBP, GFAP, and CNPase antibodies specific for normal cellular and myelin components in the control optic nerves. Positive labeling of these three antibodies provided a structural image of the nerve consistent with normal optic nerve histology. Additional probing for pathologic markers associated with MS lesions (anti-iNOS, anti-COX-2, anti-nitrotyrosine, and anti-MBP fragment) was negative, demonstrating that normal nerves lack these indicators.
Histological analysis of the affected optic nerve from a patient with CIS recovering from ON showed a pathology similar to that of chronic active MS plaques, including localized loss of myelin proteins, evidence of myelin breakdown, and presence of iNOS and nitrotyrosine (12). The formalin- and paraformaldehyde-fixed tissues used in this study allowed for better preservation of tissue structure and reduced non-specific staining of artifacts and lipids common to frozen tissues. Our ability to detect antigens in these tissues illustrates the potential to analyze archival tissues for future investigations of ON pathology.
iNOS was detected in the affected and unaffected optic nerves of the patient with CIS but not in the normal control nerves. iNOS has been found in astrocytes as well as activated macrophages/microglia in both acute and chronic active MS lesions (11-13). Although iNOS immunoreactivity in the optic nerves was not as intense as had been previously observed in MS lesions, it was prominent in or adjacent to CD14+ and CD64+ macrophages/microglia. These inflammatory infiltrates were most frequently observed on the edges of the nerve exhibiting active demyelination, implicating iNOS in the inflammation and demyelination in ON.
Our patient was in clinical remission after methylprednisolone treatment and had undergone interferon therapy for ten months at the time of his accidental death. Treatment with interferon beta-1a after a first episode of ON has been shown to significantly decrease the risk of development of CDMS and has led to slower disease progression among patients who have CDMS (20-24). Clinical remission as well as ongoing therapy may have contributed to less intense iNOS staining in the ON compared with the chronic active plaques from MS patients that we previously studied (12).
Additionally, some isolated reactive astrocytes in damaged areas expressed iNOS. This observation parallels our previous studies on MS plaques (12). However, a few scattered iNOS-positive astrocytes were also detected in areas showing no apparent active or past demyelination. It has been suggested that NO derived from these distal astrocytes, which are observed in mice with experimental allergic encephalomyelitis (EAE) and in MS brain sections, may actually serve a protective role in hindering the spread of inflammation (13,25). This idea is supported by the results obtained in some experiments with EAE animals, in which NO inhibition actually aggravated the symptoms of the disease (26-29). Our results suggest that iNOS expressed by astrocytes may have opposing effects in ON, although the net effect of iNOS is probably deleterious.
Significantly less COX-2 was observed in the optic nerves than had been previously seen in chronic active MS lesions (17). In addition to the goat anti-COX-2 used to obtain the final results, the tissues were tested with multiple antibodies to COX-2, including mouse and rabbit anti-COX-2, which demonstrated limited COX-2 presence, possibly suggesting that distinct pathologic features of ON may not induce increased COX-2 expression. Alternatively, in MS brain tissue, COX-2 was mostly found in CD64-positive macrophages/microglia on the active edges of MS plaques (17). Although CD64-positive cells were observed in ON, they were not detected as frequently as in MS lesions. Since activation of CD64, the high-affinity Fcγ1 receptor, is linked to COX-2 expression in monocytic cells, a reduced number of activated CD64-positive cells may also contribute to the rarity of COX-2 detection (30).
Additionally, interferon therapy could have suppressed COX-2 expression in our patient. However, when detected, COX-2 was found in inflammatory infiltrates in areas commonly expressing iNOS. Like iNOS and MBP fragments, COX-2 was occasionally detected in the unaffected nerve. However, it was entirely undetected in the normal control nerves, indicating a low level of pathology in the unaffected eye.
Peroxynitrite has been strongly implicated as a mediator of myelin and tissue damage very early in the progression of demyelinating disease (31). This role is supported by evidence that uric acid and other inhibitors of peroxynitrite formation have led to improvements in clinical symptoms in experimental models of MS (32,33). We identified peroxynitrite-mediated damage by the presence of nitrotyrosine, a stable marker. Nitrotyrosine was commonly found among inflammatory infiltrates in iNOS-positive regions only in the affected optic nerve, which is consistent with previous observations of co-localization of nitrotyrosine and iNOS (11-13). Although nitrotyrosine was one of the more prevalent markers detected, immunoreactivity for nitrotyrosine in the affected optic nerve was not as intense as has been observed in acute or chronic active MS lesions. However, because the patient was in a period of recovery and treatment, our findings parallel previous observations indicating that nitrotyrosine is less frequently detected in the remitting disease phase in the mouse model of EAE, even when inflammation and some clinical symptoms are still present (31).
Although the patient was undergoing treatment of ON and showed clinical recovery, evidence of ongoing demyelinating and inflammatory activity continued in the affected eye. MBP fragments, which are only present for approximately seven days after phagocytosis of myelin, were frequently observed in the affected nerve and occasionally in the unaffected nerve, signifying active demyelination (34). MBP fragments were also observed in chronic active MS lesions (12). The detection of MOG in the affected nerve, as well as the reduced expression of MBP and oligodendrocytes in both pathologic optic nerves, demonstrates extensive myelin and oligodendrocyte damage. The optic nerves from patients with neuromyelitis optica have shown similar signs of demyelination but without evidence of active demyelination and with some signs of partial remyelination (35). In these examples, there was intense labeling of GFAP in astrocytes in demyelinated areas, consistent with reactive astrogliosis in response to central nervous system and optic nerve injury (36-38). Astrogliosis in these areas may lead to astrocytic scar formation, preventing remyelination of axons (36,39).
We have demonstrated that the affected optic nerve from a patient with CIS has a pathology similar to MS lesions. The unaffected and affected nerves showed a decrease in oligodendrocytes, mild to extensive demyelination, astrogliosis, and ongoing demyelination. Pathologic indicators were less prevalent in the unaffected nerve, although it did show some signs of disease, including occasional expression of iNOS and COX-2. Nitrotyrosine and the macrophage markers CD14 and CD64, as well as iNOS and COX-2, were also detected in the affected optic nerve. Overall, these findings indicate the need for better imaging techniques to detect disease progression after a first demyelinating event and suggest possible treatments for ON. Diffusion tensor imaging, magnetization transfer imaging, and proton MR spectroscopy may be more sensitive than conventional MRI and may allow pathologic events seen in the postmortem optic nerve including myelin and axonal loss, gliosis, and inflammatory activity to be noted, opening possibilities for novel therapy.
We greatly appreciate the donation of normal optic nerve samples from the Utah Lions Eye Bank. MS samples were provided by the Rocky Mountain Multiple Sclerosis Center and the UCLA Brain Bank. This work was supported by grants from the National Multiple Sclerosis Society (to JWR and NGC), VA Merit Review (JWR and NGC), and the Cumming Foundation.
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Expression of Myelin Basic Protein, Cyclic Nucleo...
Inducible Nitric Oxide Synthase Expression in Rea...
Journal of Neuro-Ophthalmology26(2):87-94, June 2006.
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Simulating Radiation-Induced Shifts in MOSFET Threshold Voltage
Irradiation by energetic particles can degrade semiconductor device performance. The particles involved can be electrons, positrons, neutrons, protons, alpha particles, heavy ions, or high-energy photons. As they pass through a device, these particles interact with the lattice. Energy deposited through these interactions may damage the lattice directly by displacing its atoms, or may result in the creation of electron/hole pairs. A sudden excess of electron/hole pairs may trigger a latchup, possibly damaging the device through overcurrent. Holes generated within an insulator may become trapped there, leading to a gradual accumulation of charge that worsens performance and eventually causes the device to fail. Consideration and modeling of these effects is important when designing semiconductor devices that will be exposed to high-energy radiation.
The device simulator Victory Device has models to account for the following radiation effects:
Local electron/hole pair generation along particle tracks caused by individual particle strikes — single event upsets.
Generation and recombination of electron/hole pairs caused by the ongoing radiation of a device.
Insulator charging caused by the trapping of radiation-generated electrons and holes within insulator materials.
Lattice dislocation defects caused by the accumulated flux of radiation through a device.
In this article, we illustrate some effects that radiation may have on the electrical characteristics of a device. We shall consider an n-MOSFET that is exposed to x-rays, consequently experiencing radiation-induced generation and recombination that leads to charging of the oxide region below the gate.
Insulator Charging
In insulator materials, because very few carriers are present, trap states usually do not become charged, although quantum mechanical tunneling may cause some charging near interfaces. Irradiation by energetic particles, however, can generate electron/hole pairs within the body of an insulator. Under the influence of an electric field, the electrons and holes from these pairs can separate and become trapped, leading to a gradual accumulation of charge both within the insulator and on its surface. The processes involved are illustrated in Figure 1. An energetic particle such as an x-ray photon first enters the body of an insulator. There it may be scattered by the crystal lattice and, in the process, generate an electron/hole pair. Once an electron/hole pair has been created, it becomes subject to two opposing forces. The first force arises from the Coulomb attraction between the electron and hole, which tends to cause the pair to recombine. The second is the electric field that arises from the applied biases, which tends to separate the carriers. This simple description is sufficient provided that that distinct pairs of electrons and holes are far enough apart that the separate pairs do not interact. A sparse distribution like this is denoted by the adjective geminate.
Figure 1. Physical processes leading to insulator charging.
In accounting for the generation of electron/hole pairs, the generation rate due to high energy radiation can be expressed as the product of the irradiation dose-rate and a generation factor that is specific to the irradiated material. This generation factor is basically just the material density divided by the energy it takes to create an electron/hole pair in that substance. Departures from this basic rate can be accounted for by applying a numerical enhancement factor. Taking the density of SiO2 as 2.2 g/cm3 and the formation energy of an electron/hole pair as 18 eV, we calculate a basic generation factor for SiO2 of 7.6x1012 pairs/cm3•rad. Multiplying this by a dose-rate expressed in rad/s gives us a generation rate in units of pairs/cm3•s. However, not all electron/hole pairs that are generated become active in the device. Some pairs recombine so soon after they are generated that neither carrier has a chance to be transported1. This is called geminate recombination. It is accounted for by multiplying the basic generation rate by a yield function. Based on the work of Dozier, et al.2 and others, the yield function used by Victory Device takes the form
|E| is the magnitude of the electric field,
Y0 is the zero-field yield factor,
E0 is a critical field value, and
A0 moderates the growth rate of the function. (Here A0 is non-negative.)
The parameters of the yield function depend on both the type of the radiation and the material being irradiated. Typical curves for SiO2 are shown in Figure 2.
Figure 2. Geminate yield functions for SiO2.
If an electric field is present, electrons and holes from pairs that survive the geminate recombination process drift apart under the influence of the field. Insulator charging occurs when some of these carriers become trapped by impurities or other crystal defects present within the insulator material. The magnitude of this charging is determined by a balance between carrier capture and emission processes.
The capture process for insulator traps is the same as for traps in ordinary semiconductors, but the emission process appears to be different. According to the model of Kimpton and Kerr3, the primary energy source stimulating the detrapping process is the geminate recombination of electron/hole pairs during irradiation. As illustrated in Figure 1, a geminate recombination event emits a quantum of energy that may prompt the emission of a hole from a donor-like trap, or the emission of an electron from an acceptor-like trap. Meanwhile, the trap energies are assumed to be far from the band edges, so the ordinary thermally-stimulated emission processes are negligible.
According to these assumptions, donor-like insulator traps emit holes at the rate
G0 is the generation factor, with units of generated-pairs/cm3•rad,
δ is the dose rate in rad/s,
Y is the geminate yield,
Vϕ is the emission interaction volume for a trap,
Nt is the density of traps, and
f is the probability that a trap is filled.
The expression for the emission of electrons from acceptor-like traps is similar.
Breaking down the rate equation: G0δ is the rate of electron/hole pair creation per unit volume, (1−Y) is the fraction of pairs that undergo geminate recombination, and Vϕ Nt f is the probability that a phonon created by a geminate recombination event will interact with a filled trap to empty it.
To demonstrate the effects of insulator charging due to exposure to high-energy radiation, we shall use Victory Device to simulate an n-MOSFET that is bombarded by x-rays. The structure and doping of the MOSFET are typical, as shown in Figure 3.
Figure 3. n-MOSFET structure used in simulation of radiation effects.
In Victory Device, the radiation models only apply to semiconductors. Consequently, to model radiation effects in an insulator, you must tell Victory Device to regard the material as a semiconductor. To do this, set the SEMICONDUCTOR flag on an appropriate MATERIAL statement. You may also need to define a limited number of semiconductor properties for the material. For this simulation, we set the following:
# Semiconductor properties for oxide
MATERIAL MATERIAL=oxide NC300=2e19 NV300=2e19 EG300=9 SEMICONDUCTOR
MATERIAL MATERIAL=oxide MUN=1 MUP=1e-3
MATERIAL MATERIAL=oxide M.VTHP=1
We also specify the following traps in the insulator body and on its interface with the semiconductor. These will become charged as the device is irradiated.
# Conditions for radiation-induced oxide charging
INTOXIDECHARGING R1MATERIAL=oxide R2MATERIAL=silicon JMODEL.P NT.P=3e12 \ SIGMAT.P=1.5e-13 SIGMAN.P=1e-30 SIGMAPH.P=1.5e-13 \
JMODEL.N NT.N=1e4 SIGMAT.N=1e-30 SIGMAP.N=1e-30 SIGMAPH.N=1e-30 MFP.PHONON=0.013
OXIDECHARGING MATERIAL=oxide JMODEL.P NT.P=4e18 SIGMAT.P=1.5e-13 \
SIGMAN.P=1e-30 SIGMAPH.P=1.5e-13 JMODEL.N NT.N=1e10 SIGMAT.N=1e-30 \
SIGMAP.N=1e-30 SIGMAPH.N=1e-30
The source of radiation will be x-rays at a dose-rate of 1 rad/s:
# Radiation environment
RADIATION DOSERATE=1 XRay
The simulation in our example consists of two parts. In the first part, we begin by irradiating the device while it is under a forward gate bias of 5 V, up to an exposure of 1 M-rad. In the second part, we remove the gate bias and continue the irradiation up to a total exposure of 2 M-rad. At the start of the simulation, after the first part, and at the end, we shall sweep the gate bias to determine the threshold voltage.
Irradiation under forward bias induces a shift in the threshold voltage of the IV curve, as seen in Figure 4. This is due to the trapping of holes in the oxide. With a positive bias on the gate electrode, holes generated within the oxide are pushed away from the gate, so most of the trapping takes place near the oxide/silicon interface. When the gate bias is removed, only half of the radiation-generated holes will migrate towards the oxide/silicon interface, while the other half migrate towards the gate. Consequently, irradiation with the bias removed releases some of holes that were trapped near the interface, eventually reducing the threshold shift by about half.
Figure 4. Shift in IDVG threshold voltage due to insulator charging.
In Victory Device, we can set a PROBE near the oxide/silicon interface to investigate how the areal concentration of trapped holes changes during the course of this simulation:
# Probe conditions near the oxide/silicon interface
PROBE MATERIAL=oxide INT.DONOR.TRAPS X=0 Y=-1e-6 NAME="trapped int holes"
The results are shown in Figure 5. With irradiation under a forward gate bias, the concentration of holes trapped at the interface gradually increases. Eventually it should saturate, but the saturation level is not reached during the course of this simulation. After the bias is removed, the rate at which holes impinge on the traps is reduced by roughly half while the hole emission rate remains nearly the same, leading to a reduction in the concentration of trapped holes.
Figure 5 also shows a curve for a reversed gate bias. Under a reversed bias, holes generated in the oxide are pulled away from the oxide/silicon interface and towards the gate. Consequently, little or no trapping takes place at the interface. When the reverse bias is removed, approximately half the holes generated in the oxide start diffusing towards the interface, and some of them are trapped there. With irradiation continuing at zero gate bias, both the upper and the lower curves in Figure 5 appear to be headed towards the same level. Indeed, under conditions of constant irradiation and constant bias, the distribution of trapped holes eventually approaches an equilibrium value that depends only on the final bias3.
Figure 5. Response of trapped interface holes to gate bias and irradiation.
We have shown one way in which the operation and performance of semiconductor devices can be altered or degraded by exposure to high-energy radiation. However, these effects can be mitigated if they are taken into consideration during the design of a semiconductor device. A simulator such as Victory Device, which can model radiation effects, can be a useful tool in the design of radiation-hardened electronics.
R. J. Milanowski, et al., "TCAD-Assisted Analysis of Back-Channel Leakage in Irradiated Mesa SOI nMOSFETs," IEEE Transactions on Nuclear Science, Vol. 45, No. 6 (1998): 2593–2599.
C. M. Dozier, et al., "An Evaluation of Low-Energy X-Ray and Cobalt-60 Irradiations of MOS Transistors," IEEE Transactions on Nuclear Science, Vol. 34, No. 6 (1987): 1535–1539.
D. Kimpton and J. Kerr, "A Simple Trap–Detrap Model for Accurate Prediction of Radiation Induced Threshold Voltage Shifts in Radiation Tolerant Oxides for all Static or Time Variant Oxide Fields," Solid State Electronics, Vol. 37, No. 1 (1994): 153–158.
Simulation Standard - 2014


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What is chiropractic? It's a Western natural healthcare and wellness discipline that focuses on the integrity of your nervous system and your body's innate, self-healing ability to restore and maintain optimal health. In the USA, there are over 50,000 practicing chiropractic physicians with doctorate level qualifications similar to medical doctors.
Common health problems that are resolved through chiropractic care include headaches, back pain, scoliosis, neck pain, numbness, pain in joints, bed wetting, colic, ear infections and much more.
Explore this site to discover how chiropractic can help you and your family. Then call Bangalore Chiropractic to make an appointment to see one of our Western-trained doctors.
The Doctor knew what to do, very fast and effective.
I'm more than satisfied coming over for my neck and back pain. Definitely will recommend to family and friends. My neck in one sitting feels so much better. Thanks!
Good to have been seen by a chiropractor. Feel so much better…. Thank you!


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On the 14th of June we went to Panevegis district in order to participate in the librarians' annual camp with the workers.
We had a small show called "Zuikis puikis" about the importance of books and library. We played a lot of games and competed with other libraries.
There was a party for which we dressed as if we were from the 17th century. We slept in tents, listened to Lithuanian songs, met a lot of people, danced traditional dances and had much fun.


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Never Let Me Go è un singolo del gruppo musicale britannico Florence and the Machine, il terzo estratto dal secondo album in studio Ceremonials e pubblicato il 2 aprile 2012.

Descrizione
I Florence and the Machine presentarono in anteprima Never Let Me Go con altre due canzoni dell'album, Spectrum e Heartlines, al New York's Creators Project il 15 ottobre 2011, due settimane prima della pubblicazione di Ceremonials. Island Records ha pubblicato Never Let Me Go, come quarto singolo estratto dall'album, il 2 aprile 2012 e, con la versione Clams Casino Remix, lo ha immesso nella versione limitata "Limited 12" vinyl single".

Il video
Il video ufficiale del brano è stato girato su una pista di ghiaccio e vede la partecipazione dell'attore Jamie Campbell Bower, che accompagna i movimenti di Florence Welch.

Tracce
Digital download
Never Let Me Go - 4:31

Limited 12" vinyl single
Never Let Me Go – 4:34
Never Let Me Go (Clams Casino Remix) – 4:14

Note

Collegamenti esterni

redpajama_set_name: RedPajamaWikipedia


text:
Home » News » Gears of War 3 on Xbox One leaked by Gears of War's own website
Gears of War 3 on Xbox One leaked by Gears of War's own website
The Gears of War official website today outed the release of Gears of War 3 on the Xbox One.
The site went so far as to include a release date of 25 August.
You can see the full site screengrab below:
We're sure to hear more about Gears of War 3 on Xbox One at Microsoft's press conference in just a short period of time.
TagsEpic Gears of War 3 Microsoft
Xbox Game Pass February 2023 additions and removals
Minecraft Legends release date set as 18 April
Super Smash Bros.: Ryu, Roy confirmed, available today


text:
Kasbah announce exploratory drill campaign
Kasbah Resources has announced a new drilling campaign at its Achmmach tin project to test the continuity of mineralisation and potentially increase the project's resource.
Currently, the Achmmach Resource sits at 14.9 million tonnes of ore, with a tin grade of 0.85%. Although this gives a respectable contained tin content of 127,300 tonnes, Kasbah is aiming to increase this by testing the Sidi Addi Trend, which sits parallel to the strike of the main Meknes Trend. The Meknes Trend currently holds 98% of the ore in the resource, but the 2% in the Sidi Addi Trend is thought be higher grade (1.25%).
The proposed drilling programme is estimated to take two to three months, and will comprise 10 diamond drill holes, producing over 2.000m of drill core. However, should the initial programme prove successful in indicating continuing tin mineralisation along the Sidi Addi Trend, Kasbah plans to define a mineral resource following further drilling.
Our view: Sidi Addi was found to be the highest priority target for Kasbah following an independent review of the company's exploration projects. Soil samples from the Sidi Addi Trend suggest that tin mineralisation in the subsurface is possible, although the company claims that any additional mineralisation will not change the Achmmach development plan.
Tags: Achmmach, Kasbah, Kasbah Resources, Morocco


With its technology firmly embedded in the dashboard of nearly every new vehicle on the market, SiriusXM has an enviable place in the music business.
Amazon.com Inc. is considering a massive expansion of its cashierless AmazonGo stores, aiming to open as many as 3,000 nationwide by 2021, according to a report by Bloomberg News.
"These are not quick and easy systems to install, and they're not cheap," said one expert.


God keeps his promises! Discover how Jesus fulfills a great big promise that God made to David in 2 Samuel in the Monday Easter Week devotional. Stream the Easter Week Devotional series on Jellytelly.
Not a Jellytelly member? Sign up to receive your first week free and get instant access to the full devotional series plus more Christian kids shows and devotionals!
What do you know about the life of King David? God loved David so much, even though David didn't always follow God. God loved David so much that he made him a very special promise. What do you think that teaches us about God and his character?
Jesus fulfilled the Davidic Covenant, which was a promise God made to David that someone from his family would rule over God's people forever. Do you think the Jewish people were expecting someone like Jesus? How do you think Jesus was different from their expectations?
3. Download a coloring page of Jesus here.


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The growing complexity of organizational processes and business competitiveness, transparency and the known stakeholders has introduced a need for corporations to have a governance policy. Consequently, the adoption of good corporate governance practices increases corporate value and helps to improve the continuity of the organization or specific area. In this context, the reliability of systemic information needs to be guaranteed through indicators, thus generating visibility and transparency desired by the organizational stakeholders.
Therefore, it is important to have an automated process that, by means of reports and dashboards, presents indicators concerning to IT collected and consolidated historically and in an evolutionary way.
Eccox Application Quality Management for IT Governance loads the data from other sources in a pre-set standard for the purpose of storing and consolidating these data historically to generate information by means of reports that can also integrate different sources. It acts as a portal that is capable of presenting a variety of information from several information systems in a unified and transparent way, facilitating understanding of the IT indicators.
•	Allows integration for authentication in two different ways: proprietary authentication or via Microsoft Active Directory, and can be used by different teams with different profiles.


text:
Daniel H. Knopp, Jr.
Memorial Contributions
Memorial Contributions may be made to his family when a benefit will be planned in October. This event will be announced at a later date.
Obituary of Daniel H. Knopp, Jr.
Daniel H. Knopp, Jr., 47, of Fulton passed away Thursday, September 8, 2016. He was born in Oswego and recently celebrated his 30th year of employment with Fulton TV and Appliance. Dan served four years as Alderman of Fulton's 2nd Ward and was president of the Common Council instrumental in creating the Lake Neatahwanta Revitalization Project. He was passionate about improving his community, participating and leading various events and organizations. Most notably, Dan volunteered as a coach for Fulton Youth Soccer, bell ringer for the Salvation Army and the Fulton May Day cleanup. He was a former member of the First Congregational Church of Phoenix and Pathfinder Rod & Gun Club. Dan enjoyed many outdoor activities especially hunting, fishing and camping. His joy was spending time with his family and yearly vacations in Maine. He is survived by his wife of 23 years, Juliann (Bracco) Knopp; daughters, Kerriann, Chelsie and Jordan Knopp; a son, Ryan Knopp; his mother and step-father, Ruth and Gary Castano of Fulton; a brother, David Knopp and partner, Rose Stone of Hastings; a sister, Denise (Knopp) Enright and brother-in-law, Bruce; a niece, Madeline and nephew, Cole Enright all of North Syracuse as well as various aunts, uncles, and cousins. Calling hours are 4 to 7 p.m. Wednesday, September 14, 2016 at the Fulton Alliance Church, 1044 State Route 48, Fulton. A private service will be held following the calling hours. In lieu of flowers, contributions may be made to his family when a benefit will be planned in October. This event will be announced at a later date. Michael E. Brown Funeral Services is assisting the Knopp family.


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Jay Rayner: my life in takeaways
Does he like fish and chips, kebabs, or a cheeky Nandos? One of the nation's most revered food critics tells us what he orders in a lockdown.
Words: Alexandra Jones
Jay Rayner is a journalist and broadcaster, as well as one of the country's most well-respected food critics (a job he has done for more than 20 years, "it helps that I'm greedy," he says). He is also the presenter of a podcast that was called Out To Lunch (the premise being that he interviews a celebrity over lunch) but is now called In for Lunch, for obvious reasons. "We've been ordering Deliveroo and eating over video chat," he explains. Given, though, that he eats in the world's most illustrious restaurants (and even some of those get panned – he once called the food at three Michelin starred Le Cinq in Paris "the stuff of therapy"), does he mind slumming it with a takeaway?
What is your earliest takeaway memory?
When I was a child there was a very good fish and chip shop in South Harrow – I grew up in Harrow on the Hill – and there was a place called Louie's. Every now and then – probably about four times a year when my mum didn't want to cook, and it always was my mum because my dad rarely got involved in cooking – my parents would get fish and chips and I'd get spare ribs. These were, in my memory, extremely good. They were a weird shade of orange and their final cooking moment was a journey through the deep fat fryer. But yeah, they were very good, greasy spare ribs and chips — I was very happy.
What about as a student? Where would you find yourself at 2am?
I was a student in Leeds in the mid-80s and there was a great place, and I actually do think it was great, called Theo's Charcoal Grill. It was right opposite the student building and it did amazing kebabs, in the Turkish mould, with good salads and chilli sauce. The less quality option was the kebab van that used to park outside the student's union. Not sure how I didn't get poisoned but they did good samosas. A couple of those when you were steaming after a night in the bar was a very good thing.
What music was playing at the union?
Well, I was listening to jazz a lot then [and now] it's become a very important part of my life. But at the union… Alison Moyet, China Crisis and The Smiths. There was quite a big goth movement in Leeds at the time, but it didn't really do it for me.
Were you any good at cooking at this point?
I was probably better than most but that's not saying much. I mainly learned to cook in my twenties from cookbooks I bought for my girlfriend for her birthday. She's my wife now… she'd ask for cookbooks, but I was the one who ended up cooking from them. I've still got one, in fact.
It's a Reader's Digest Complete Guide to Cookery by a brilliant woman called Anne Willan. It's not really got recipes but it's got method… technique. I still refer to it now.
What's your most used method or technique?
Almost certainly meat roasting. Like, the perfect roasting time for medium rare, that kind of thing.
Where's your go-to local takeaway?
The first thing to say is that my original go-to, the one that I loved, is gone. It was a Portuguese piri piri house on Brixton Hill called The Gallery. Their charcoal grilled chicken and their charcoal grilled ribs were always fantastic. (I've always loved ribs.) I did say, at one point, if you were to judge my favourite restaurant based on the one I ate from most often, it would be The Gallery. Unfortunately it changed hands a few times, then there was a fire and now it's gone. I love a Nando's but it's not as good.
My happy place is the chicken wings from Mamalan in Brixton Village. Those chicken wings with the chilli oil and the pork and vegetable dumplings, grilled.
Namban is also very good, the ramen travels very well. And I've recently become a fan of Bird, which does fried chicken. I like their pickles and their seasonal salads.
What's the worst takeaway you've ever had?
There was a Thai place I tried in Brixton once. It was awful. I once said in a piece that even bad Thai food is still good but then I realised that I was wrong. All I remember about it was that it featured a lot of boiled carrots.
Do you think that your experience as a critic has changed your views on takeaway food?
No, I think I'm just greedy. And that's useful as a critic – certainly one that's going to carry on doing the job for 20 years.
How often do you get takeaways now?
Every Friday, it's a tradition, my boys – I call them "boys" but one's 21 and one's 16 – get to choose. In lockdown I've managed to recast that as an economic responsibility to support the restaurant industry. We have had a couple of two takeaway weeks.
Have they persuaded you to try something you wouldn't normally try?
Well, the younger one does have a Domino's habit.
Don't we all…
It has to be said, the thing I love about Domino's is how spectacularly efficient they are.
Are there any places outside of London that you're keen on?
Yes, let me see… Lussmanns, they're a small group of fish and grill restaurants and they have a lovely menu with classics that they do for delivery. There's also Lunya – they have three restaurants, one in Manchester and two in Liverpool. They're generally Spanish delicatessens and tapas restaurants but they're doing some great ready meals. The chef there, Peter, is currently doing a shepherd's pie that uses his mother's recipe. There's also a place called East Pier Smokehouse in St Monans in Fife. It's one of those absolutely exquisite restaurants, you go there for lobster and chips in a cardboard box. They're now doing takeaway – fish curry, fishcakes, that sort of thing. If I lived takeaway distance, I'd definitely go there.
Season 3 of Out To Lunch with Jay Rayner starts 28th April and is available on all podcast providers
Jay Rayner


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