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November 29, 2015
Texas gasoline prices drifted lower for a second week in a row this week.
The weekly Triple-A Texas gas price survey found the retail price of regular unleaded self-serve averaging two dollars 25 cents per gallon statewide. That's down two cents.
Dallas has the highest average price at the pump, averaging two dollars 27 cents per gallon. That's down three cents. The lowest prices are in Corpus Christi, which saw the biggest slide in the average price of six cents to two dollars nine cents.
Regular self-serve unleaded averaged two dollars 33 cents per gallon nationwide, down nearly three cents.
Auto club spokeswoman Rose Rougeau says unseasonably warm winter weather in the United States is helping keep crude oil prices below 65 dollars a barrel. That's helping keep retail gasoline prices lower. But she says it's still unclear how long those price declines
will continue in the face of global concerns over Iran's nuclear plans.
Click Here to access the online Public Inspection File
Viewers with disabilities can get assistance accessing this station's FCC Public Inspection File by contacting the station with the information listed below. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, 888-835-5322 (TTY), or firstname.lastname@example.com.


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Green Festival Speakers
Yoga to the People
Yoga to the People is a unique donation-based yoga studio with the goal of recapturing what we consider to be the essence of yoga… simply put, yoga made available to everyone. In a time where yoga as a business is getting a lot of attention, the fact that it is being priced out of many people's reach is in direct conflict with what we consider to be the spirit of yoga itself.
We've heard from people all over the country that they simply can't afford to do yoga on a regular basis. We want to make it possible for everyone to do yoga regardless of economic limitations.
The beauty of this yoga is that it is challenging enough for all, yet not too extreme and therefore accessible to everyone.

subset: commoncrawl


text:
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Rangers exercise option on pitcher Yoshinori Tateyama
From the Rangers:
The Texas Rangers announced this evening that the team has exercised the club option on right-handed pitcher Yoshinori Tateyama for the 2012 season. The club option for next season was part of the contract he signed with Texas prior to the 2011 campaign.
"Yoshi stepped up in the bullpen at a time the club really needed it," commented Rangers General Manager Jon Daniels. "He's a veteran strike thrower with outstanding makeup and we're happy to have him back."
Tateyama, 35, made 39 appearances in his major league debut with Texas in 2011, going 2-0 with a 4.50 ERA (22 ER/44.0 IP). He recorded 43 strikeouts against just 11 walks for a 3.91 strikeout-to-walk ratio, the 8th-best figure among American League relievers. He did not issue a walk to his first 57 batters faced in the major leagues.


text:
Automating the world one-liner at a time…
On Saturday I arrived in Aarhus Denmark for the JAOO conference. JAOO stands for Java And Object Oriented but it is definitely NOT a Java conference - it is a language conference with lots of .NET, Ruby, Ajax content and then just a lot of really smart people talking about software in general.
I'm honored to be invited to talk about Windows PowerShell at a language conference because it allows me to start the process of setting the record straight regarding PowerShell as a language.
People parse the world according to their past experience. What that means is that a lot of people have put PowerShell into the Bash bucket - it is an interactive shell and a tiny bit of a glue language. That is most certainly true - you can successfully use PowerShell for years and years and never go any deeper than that.
What is ALSO true is that PowerShell is a rich SCALABLE language. By "scalable" I mean that it seamlessly scales from a simple ad hoc Bash-style language to a sophisticated (near) Ruby-style programming language. I say "near" because in V2, we still don't provide a easy "native" way to create your own classes and to subclass existing classes (you can do it easily with embedded C# or VB but there is no native mechanism).
Did you realize that people are writing WinForms, WPF, and Web applications using PowerShell? Check out: the PowerShell Player (A podcast player written in PowerShell using the awesome Admin Script Editor which provides a form-builder for PowerShell.
The motivations for allowing the language to scale from simple to sophisticated include:
I want to restate that we are TOTALLY COMMITTED to the simple PowerShell experience. People will always be able to run interactive PowerShell and just type cmdlets and be blissfully ignorant of they power 2 inches away. (It's like swimming in the ocean - if you're staying on the surface - it doesn't really matter whether the water is 20 feet deep or 2,000 feet deep.)
You walk away for the day is this: IF and WHEN I want to, I can use PowerShell as a rich general purpose language.
Jeffrey Snover [MSFT]Windows Management Partner ArchitectVisit the Windows PowerShell Team blog at: http://blogs.msdn.com/PowerShellVisit the Windows PowerShell ScriptCenter at: http://www.microsoft.com/technet/scriptcenter/hubs/msh.mspx
I love the design of the language, the composability and the easy drop-down to .net, but there is also another form of "scalability" where PowerShell unfortunately don't look as good.
When the data sets grows, I have frequently found PowerShell grind to a halt. That have to be addressed.
A simple task (parsing a log file and turning the lines to objects) just didn't cut it when writing it in PowerShell.
It was 25 times slower that the Cmdlet that did just the same thing.
You have to make it possible to write scripts that can handle larger data sets.
Right now, it is limited to those that have small data sets, or those who know how to write cmdlets.
Don't get me wrong. I love the work you have done. It is truly impressive. But you can't keep putting of perf work.
PingBack from http://www.simplynetdev.com/powershell-and-jaoo/
Performance improvements have already started sneaking into the v2 CTPs, so I believe Microsoft is really listening to the community's feedback on performance in v1.
Several months ago, I had exchanged emails with an upcoming book on problem solving (now out, but I won't mention it). The subject of PowerShell came up, to which the author replied something like "the problems are meant to be solved by real programming languages, so PowerShell doesn't really apply".
Out to prove him wrong, I did buy the book, but haven't been able to find the time outside of my other projects to make a point.
For me at least, until Powershell runs on more than one platform (via Mono for eg), it's hard to justify putting much effort into it.
I would like to see powershell material grow beyond system administrators.
As a database analyst with many years invested in vbscript I had really hoped powershell would be something I could dig in and begin using. The problem I am having is that all of the introductory material is aimed at admins, WMI, ADSI, etc.
Until I can figure out how to get data from SQL Server to Excel I am stuck with vbscript no matter how much fun I have playing with posh.
Tell us what scripts you need! SQL Server 2005 or 2008?
Give me an example data structure you'd like to copy to Excel.
If you can use the "AdventureWorks" database to provide an example that would be even easier...
Eric, here is a script to help you get started:
Richard Siddaway, MVP, has recently started authoring a book, and it looks promising:
Looks like it will cover the application specific examples like what SQL admins may want to see.
Hey, guys. Thanks for the responses.
The beginning of the month is hectic for me, but I will post more information as soon as I can (after I check the link above). Thanks again!
I am a developer and I love Powershell - the automation work it has allowed me to do is amazing. However I do work with a lot of infrastructure folks and their take on PowerShell suprises me. Not one of them is actively using it. Couple of reasons they state - slow, requires .NET whereas VB Script is natively enabled on Windows platform, last but not the least is "I don't want to learn programming". The last thing resonated with me - why should a system's administrator care about things like Closures, .NET Framework's rich API and other esoteric progamming language topics. I am just wondering that by adding all the greatest and coolest capabilities in the language, are you missing the exact audience you should be reaching out to?
> I am just wondering that by adding all the greatest and coolest capabilities in the language, are you missing the exact audience you should be reaching out to?
Potentially. But the thinking is that what Admins REALLY need is CMDLETs - high level, task-oriented abstractions. One of the reasons we have added these more sophisticated scripting facilities is to allow a wider range of people to develop cmdlets more easily.
In Volleyball, there is the "setup" and the "spike". We are providing the "setup" and the community has to provide the "spike" (develop and share the cmdlets that admins need). I'm convinced that that will occur and the over time, more and more admins will find that PS provides them the value that they want/need with minimal onboarding costs. Once they get onboard, they'll discover that they can incrementally invest for great reward.
Jeffrey Snover [MSFT]
Windows Management Partner Architect
Visit the Windows PowerShell Team blog at: http://blogs.msdn.com/PowerShell
Visit the Windows PowerShell ScriptCenter at: http://www.microsoft.com/technet/scriptcenter/hubs/msh.mspx


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Chris Trenchard
The Whitest Kids U'Know Invade SF Sketchfest
I'm mid-interview with Sam Brown and Zach Cregger from the sketch comedy troupe The Whitest Kids U'Know, searching for the words that might explain what makes them hilarious, as if they needed one more testimonial. They don't, of course — their IFC show and millions of YouTube video fans are proof that something they're doing is working. But what is it, exactly, that runs through all of their sketches?
For one, they know when to not say "When." They'll often take ideas and extend them and milk them until no surplus jokes remain, and then they'll milk it a bit more.
Five Live Music Shows to Buzz About This Week
Milk Carton Kids at Cafe Du Nord, Tuesday
This minimalist duo has won praise from folks at NPR and Spinner while perfecting a specific blend of Americana, 1950s classic folk and compelling narrative. They've been compared to Ryan Adams and Iron & Wine, and it fits — their soft hush affects on multiple levels, a mind/body/soul trifecta.
John Oliver Smuggles Sage Advice into Cobb's Comedy Club
As a head writer and correspondent for The Daily Show, Jo
Seven Shows to Suit Your Revelatory Needs This Week
We hope some noise canceling earplugs were in your Christmas stocking, because the sounds of the Bay are gonna amp up a notch or two this week with New Year's concerts cropping up everywhere. Here's our our top 7 picks for ringing in the New Year with a ring in your eardrums:
'Twas the Week Before Christmas on the SF Concert Scene...
Scanning the local concert calendars on this particular pre-Christmas week is usually a good way to find some of the hardest working musicians in the game. There's a certain amount of dedication required to brave the winter road, away from home and family. It's also a great time to find local acts squeezing in gigs while home for the holidays. Here we are again, at the end of December in 2011, with dependable examples of both, five of which make us especially grateful for this calendarian coup de tat.
Five Can't-Miss Live Shows
This is usually the time of year when music fans hibernate until NoisePop rears its eclectic, beautiful head. Not this year. Here we are, in the middle of December, and venues are still spelling out recognized and beloved names on their marquees. Here's this week's roster:
Weekend Comedy Roundup: Bobby Slayton and Ben Bailey
If you've ever watched the Discovery Channel trivia game show "Cash Cab," and found yourself thinking "hey, this host is kind of funny," well, that's because he is. Ben Bailey, he of the mighty testosteroned voice, shaved head and 6'6" frame, got his start in showbiz by standing up on a stage telling jokes to strangers — before he made a living driving a casino-lit NYC cab around asking strangers questions.
SF Sound Architect Tycho Building Buzz, Plays Independent Saturday
Odds are, you don't know Tycho, which is fine. But perhaps you know Scott Hansen, the San Francisco-based sound/visual artist behind the crypticism. He resides happily below the radar, where his sonic permutations can grow and change however his muse dictates.
My Morning Jacket at Bill Graham Civic
Not many rock bands seem wholly comfortable in their mid-career britches, when the street cred can begin to fade and the artistic edge becomes susceptible to dulling. But count My Morning Jacket — which played a sprawling 23-song set Friday night at the Bill Graham Civic Center — among the impervious rock bands aging gracefully and suitably (see also: Wilco, Radiohead, and, incidentally, another band who played Bill Graham over the weekend, The National).
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Drink Up: SF's "Cocktail Movement" Bars
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The Best Wine Shops, Neighborhood by Neighborhood
The 7 Best San Francisco Albums of 2010
Refreshingly Unhip: The Best Glazed Dougnuts in SF
Tea: Our 7 Favorite Spots to Drink & Buy
Fireside Buzz: 7 Bars That'll Warm You Up
Beer Tasting Road Trip Itinerary of Sonoma & Mendocino Counties
Six Great Boots for Fall in San Francisco
Get A Room: Bars That Rent Private Spaces
The Best Phone Apps for the Food-Obsessed


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Suspended Sites
- February 29, 2012
- This entry was posted in Airbana, Bug Fixes, Playing Sites, Retail Sites. Bookmark the permalink.
In previous versions of the Airsoft Map if a site was no longer running it was removed from the 'live' database pool. In other words it wouldn't appear if you searched for it or if you visited one of the Map pages.
If however you navigated to a direct link for the site it would still display all the information. There used to be a rationale for this but I believe that to provide a better service to Skirmishers that if a Site no longer exists there is no reason to display it at all.
From now on any site that has been suspended from the database will return a HTTP 404, which in short means "It's not here anymore".
Site details are retained indefinetely so it is possible to resurect a site if it's closure was only temporary etc. If however it is a totally new site and new management then it should be created from scratch so it doesn't retain any old reviews etc.


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History of the Index
Range of the Archive
Subscribing to the Database
Publications & Programs
Staff & Their Interests
Location & Access
Studies in Iconography
Books in the Index
Digital Books
Additional Resources
Follow us on social media!
Enter the Database
Country: FranceSite: Favières, Church, St.-Sulpice-de-FavièresSequence: SH-1Subject: Apostle, Andrew: Scene, kneeling before CrossDate: early 16c.
BLOCK Elaine, Corpus of medieval misericords in France, (Edited by Christel Theunissen, Jos Koldeweij & Frédéric Billiet), Turnhout, 2003, pp. 47-48.RIVIERE Simone, L'église de Saint-Sulpice-de-Favières, Paris, 1991, pp. 38-41.SJOBERG Yves, Saint-Sulpice-de-Favières, Sceaux, 1951.
Provenance: UnknownOne of two cycles in France devoted entirely to Christological, Marian, and saintly scenes (see cycle at Auxerre Cathedral)
[Return to Previous Page]


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Personal Holiness Must Underlie a Bishop's Authority, Says Pope
Receives Prelates From Provinces of Baltimore and Washington, D.C.
| 886 hits
VATICAN CITY, APRIL 30, 2004 (Zenit.org).- John Paul II told visiting bishops from the United States that "the exercise of episcopal authority must be built upon the testimony of personal holiness."
In his address to the prelates from the provinces of Baltimore and Washington, D.C., who were on their five-yearly visits to Rome, the Pope referred to the mission of sanctification of all bishops, whose source "is the indefectible holiness of the Church."
"Because 'Christ loved the Church and gave himself up for her, that he might sanctify her,' she has been endowed with unfailing holiness and has become herself 'in Christ and through Christ, the source and origin of all holiness,'" the Holy Father said Thursday.
This is "a fundamental truth of the faith" that "needs to be more clearly understood and appreciated by all the members of Christ's Body," the Pope said.
Although "the holiness of the Church on earth remains real yet imperfect," it is "both gift and call, a constitutive grace and a summons to constant fidelity to that grace," he said. In fact, the Second Vatican Council reaffirmed "God's universal call to holiness," the Holy Father noted.
"The challenge set before us and before the whole Church" is that "the life of every Christian and all the structures of the Church must be clearly ordered to the pursuit of holiness," an activity that must be "central to the life and identity of every bishop," he said.
"I am deeply convinced that, in a Church constantly called to interior renewal and prophetic witness, the exercise of episcopal authority must be built upon the testimony of personal holiness," John Paul II stressed.
He pointed out that a bishop must "recognize his own need to be sanctified as he engages in the sanctification of others."
In addition, John Paul II said that a bishop "is first and foremost a Christian ... called to the obedience of the faith," who in virtue of his ordination "stands in the place of Christ himself and acts in his person," and thus "is called to progress along a specific path of holiness. The soul of his apostolate must be that pastoral charity which conforms his heart to the heart of Christ in a sacrificial love for the Church and all her members."
Thus, a bishop must be an "attentive hearer of the word of God through daily prayer and the contemplative reading of Holy Scripture," the Pope said.
"Indeed, for the renewal of the Church in holiness, it is essential that the bishop must not only be one who contemplates; he must also be a teacher of the way of contemplation" without forgetting that his prayer "should be nourished above all by the Eucharist," in addition to "regular recourse to the sacrament of penance and ... the celebration of the Liturgy of the Hours."
In regard to "the adoption of a lifestyle which imitates the poverty of Christ," the Pope invited the bishops to undertake "a discernment with regard to the practical exercise of the episcopal ministry in your country, in order to ensure that it will be seen ever more clearly as a form of sacrificial service in the midst of Christ's flock."
"The great challenge of the new evangelization to which the Church is called in our time requires a credibility born of personal fidelity to the Gospel and to the demands of Christian discipleship," John Paul II concluded.
The bishops' five-yearly "ad limina" visit to Rome has three parts. The first is a personal meeting between the bishops and the Pope. In the second part, the bishops pray together at the tombs of Sts. Peter and Paul in Rome. The third part offers the bishops the chance to meet with Roman Curia officials.


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By Andrew Tellijohn
Remember the days when people said "please" and "thank you"? That kind of civility seems to be a thing of the past in government, including at city council meetings. But many Minnesota cities and the League are working to bring it back. ______________________________________________________
A half-dozen years ago, the City of Maplewood was in the newspapers constantly. Distrust and debate over the use and potential sale of some parkland had the community concerned. The 2005 election brought in a new mayor and two city councilmembers, who hired a long-time political ally as city manager without conducting a search.
The drama that unfolded over the next couple years led to heavy turnover on city staff, as about 70 percent of the management team was fired or left voluntarily, which led the alternative weekly paper, City Pages, to call Maplewood the Twin Cities' most dysfunctional suburb.
Ultimately, the issues didn't just make for uncomfortable work days and long, unproductive council meetings. The dissension led to a bevy of lawsuits that jeopardized Maplewood's standing with the League of Minnesota Cities Insurance Trust (LMCIT), and it ground city work to a halt, says Chuck Ahl, who now holds the title of city manager.
Ahl was public works director for the city of 38,000 when the election that brought on the controversy took place. He served as temporary city manager and then assistant city manager through much of the upheaval and the subsequent healing period. He was appointed to his current role in June 2013.
"It didn't matter what side you were on," he says. "The way everybody addressed each other certainly didn't show any respect, and there was no compromise and no attempt to understand the other person's position."
Principles of good government
The next election cycle, the tide began turning. The Council was still divided, but the new Council began working with staff to re-establish civility and stability within the city. Even though the economic downturn created tight budgets, Maplewood established a no-layoff policy to help rebuild trust with labor unions and staff.
And the city instituted what it called the principles of good government, which required those debating the issues to do so in a civilized, respectful manner.
"We clearly established rules for how people address the Council, and that bringing up personal agendas was not allowed," Ahl says. "Those personal issues have no place in a public setting."
Ahl acknowledges that it may take awhile for the labels from the past to completely disappear, but he believes the issues that once plagued Maplewood's politics are no longer a problem.
Incivility spreading rapidly
While the situation in Maplewood was highly publicized and perhaps a bit extreme, observers say it's emblematic of a problem that is popping up in cities all around the state. Dan Vogt, who retired recently after two decades as city administrator in Brainerd and now works as a consultant for Little Falls and Cross Lake, says public employees at all levels used to have more respect from the general public than they do now.
Vogt recalls watching a town hall meeting President Obama conducted in which Obama was practically heckled by an attendee who had not been called on to speak.
Chuck Ahl in Gladstone Savanna Neighborhood Preserve, the parkland
that sparked controversy and dissension in the City of Maplewood.
Photo by Paul Lundquist ______________________________________________________________
"Is that the type of thing that would have been tolerated 20 or 30 years ago?" Vogt asks. "I doubt it. That's just incredible to me. That's a shining example of how uncivil we've become."
He's seen the same kinds of breakdowns regularly in communication between the public and city officials as well as between councilmembers and staff. Some of it is media driven. Some is the trickledown effect of watching hardline negotiations between highly visible Republican and Democrat officials on the state and national levels.
"They're taking what they see in the news or the talking heads on television and how they refer to people and how they interact with people," he says. "That's another part of the problem. I've seen a general deterioration of that discourse."
Incivility in government has become a prominent enough problem that the League of Minnesota Cities (LMC) conducted a panel discussion on the topic at its 2013 Annual Conference and convened a task force to look at the issue, says Kevin Frazell, LMC member services director.
The LMC Civility Task Force is looking into patterns that cause incivility issues to arise and how the League can work to help prevent them from damaging cities. When deliberations go beyond an honest difference of opinion and devolve into personal attacks, it can paralyze the government process and, in some cases, Frazell says, cause staff members to leave.
"Government can't move forward and deal with issues very well when there is acrimony," he says.
A proactive approach
A few years ago budget cuts drove the City of Brooklyn Park to reconsider how it provides services to its 76,000 residents. In addition to the financial issues, the city was dealing with two high-profile incidents of youth violence and a significant home foreclosure issue during the recent recession. So city officials launched the Community Engagement Initiative and began some proactive community outreach efforts that have turned the situation around.
City Manager Jamie Verbrugge says city staff reached out to residents to establish a core planning team that laid out the vision, mission, and strategic objectives for the community. One of the principles that resulted was that city officials would not make decisions without consulting those who are affected by them.
For bigger issues, the city invites residents to "community cafe" discussions, where citizens can talk over their positions with city staff in a forum that is more casual than a Council meeting. The city then aggregates the information it receives and uses it to make more informed decisions.
These discussions are "focused on having people sit around a table with other members of the community," Verbrugge says. "It becomes a more thoughtful and, I think, a more constructive way to receive feedback." _____________________________________________ Robin Martinson announces an upcoming event
at a recent meeting of Brooklyn Park's Community
Engagement Initiative teams.
Photo by Paul Lundquist _____________________________________________
The city has also conducted "call to action" discussions with advocacy groups, nonprofits, and other organizations on issues such as domestic and youth violence, Verbrugge says. These help develop "a more community-based approach rather than a city-centric approach."
Brooklyn Park's Community Engagement Initiative has received national attention, and survey results indicate that it appears to have dramatically improved the community's outlook on the city and those working for its betterment. "We're definitely seeing results," Verbrugge says.
Communication helps
Communicating directly with the community can be a vital step toward maintaining the public's trust and diffusing issues that could later create opportunities for uncivilized behavior. And cities are getting better at telling their story and communicating with citizens. That's a major point in improving civility, says Bob Thistle, who was in city management in Minnesota for 25 years.
"Fifteen to 20 years ago, the basic communication tool was the newspaper or maybe a newsletter that went home once a quarter," Thistle says. "Today cities have websites with all sorts of information. Cities have become much more adept at communicating a story more effectively than we did in the past—because we didn't have the tools."
Communication is also important in educating the public about their rights and responsibilities as far as what is expected of their behavior when attending meetings, adds Doug Anderson, former mayor of Dayton who is currently senior partner with Anderson & Orduno, a startup consulting firm that is working with the League and several cities around the state on civility issues.
Anderson suspects that one of the solutions for improving civil discourse at meetings will be better training for mayors and councils on how to communicate those expectations.
"The big jumping-off point where most people have to start is the communication piece and learning how to listen and how to talk to one another," he says.
Paralyzing effects
It's critical that cities not allow incivility to continue, Anderson adds. When the problems start to fester and grow, incivility ultimately can create tense government bodies that are unable to govern.
"You become ineffective as a council if you have members that are not agreeing with one another in a constructive way," he says. "It leads to a breakdown of trust from councilmember to councilmember, from council to staff, from council to the public. And it really erodes the ability to work effectively."
In some extreme cases, LMCIT had to get involved when councilmembers were doing some unsavory things such as violating the Open Meeting Law or making threats. "Those things can become costly in terms of lawsuits, and insurance premiums can be greatly increased. LMCIT has dropped coverage in the past of cities that can't seem to get their act together," Anderson says.
"That's been a wakeup call to the cities and their residents that this isn't a spectator sport or a 'Jerry Springer' episode. This is pretty serious stuff."
One thing is certain, Thistle says. Public discourse must be conducted in a professional manner. He compared the job of chairing a public meeting with refereeing a sporting event. Rules and boundaries must be set in advance and, if people start getting abusive, they must be confronted.
"There is always a tendency not to want to create a confrontation," he says. "Sometimes people come in [to a council meeting] and they get away with saying things and doing things and they are not called on it."
Thistle says clear rules must be established upfront and, when someone starts getting abusive, the person should be warned or, in extreme cases, removed from the council chambers.
"The trick is calling people on it," he says. "It's like anything else. If you let somebody get away with something, they'll keep doing it. So there needs to be really clear boundaries established."
Maplewood's Ahl agrees. He says it's important to have rules in place for running meetings, and to adhere to them. Communication is key. Dealing with controversial issues is inevitable in government, but it doesn't have to lead to discord or lack of trust.
"It's that issue of making sure you are honest and open," he says. "Establishing those principles and staying true to those principles, making sure meetings are run respectfully—I can't say that enough. It's OK to disagree, but disagreeing disrespectfully is unacceptable."
Andrew Tellijohn is a freelance writer based in Richfield, Minn.
Note: See related article "What's Happened to Civility?"
Read the November-December 2013 issue of Minnesota Cities magazine
* By posting you are agreeing to the LMC Comment Policy.


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Accumulation of misfolded neurotoxic Cu, Zn-superoxide dismutase-1 (SOD1) protein found in both familial and sporadic amyotrophic lateral sclerosis (ALS) is recognized as an important contributing factor of neuronal cell death. However, little is known about the mechanisms controlling the accumulation and turnover of SOD1 protein. Puromycin-sensitive aminopeptidase (PSA/NPEPPS) was recently identified as a major peptidase acting on neurotoxic TAU protein and protecting against TAU-induced neurodegeneration. In addition, recent report implicated PSA/NPEPPS in the direct removal of neurotoxic polyglutamine repeats. These combined data suggest that PSA/NPEPPS might represent a novel degradation pathway targeting pathologically aggregating neurotoxic protein substrates including SOD1. Here, we report that PSA/NPEPPS directly regulates SOD1 protein abundance and clearance via proteolysis. In addition, PSA/NPEPPS expression is significantly decreased in motor neurons of both SODG93A transgenic mice and sporadic ALS patients, suggesting its possible contribution to the disease pathogenesis. These results implicate SOD1 as a new target protein of PSA/NPEPPS and point to the possible neuroprotective role of PSA/NPEPPS in ALS.
Familial amyotrophic lateral sclerosis (FALS) represents about 10% of ALS cases. It is most frequently inherited as an autosomal dominant trait [1]. In about 20% of FALS patients, at least one type of mutation in Cu, Zn-superoxide dismutase-1 (SOD1) can be found [2]. The ubiquitous SOD1 protein converts superoxide radical anions to oxygen and hydrogen peroxide. More than a hundred SOD1 gain-of-function mutations have been identified, which may contribute to increased oxidative stress, altered copper metabolism, protein aggregation, excitotoxicity, or altered axonal transport [3]. Several other genes, including alsin, senataxin, vesicle-associated membrane protein-associated protein B, angiogenin, and TAR DNA binding protein, have also been found to be associated with ALS [4,5]. However, about 90% of ALS cases have no clear genetic cause, and the condition is referred to as sporadic amyotrophic lateral sclerosis (SALS) [4].
One of the hypotheses explaining selective motor neuron degeneration in ALS is the toxicity of intracellular protein aggregates. One of the major protein aggregates commonly found in FALS is the misfolded SOD1 protein [6-8]. Not surprisingly, aggregates of mutated SOD1 protein are found in neurons and astrocytes of SOD1 transgenic animals, including G37R, G85R and G93A models, and the degree of SOD1 accumulation strongly correlates with motor neuron dysfunction [9]. Immunohistochemical studies have also localized these inclusions predominantly to motor neurons, and in some cases, astrocytes [10]. Wild-type misfolded SOD1 is also found in the spinal cord extracts of SALS patients and may play a role in the etiology of SALS [6,11,12].
Accumulation of abnormally folded proteins and peptides is a key feature of many neurodegenerative diseases, including Alzheimer's disease, Huntington's disease and ALS [13-16]. The presence of misfolded SOD1 protein in both familial and sporadic ALS presents a credible explanation of motor neuron specific death in ALS [6,8,11,12,17-19]. Recent work convincingly demonstrated that wild-type SOD1 and mutant SOD1 share a conformational epitope prone to oxidation and therefore exert a strong neurotoxic effect [11,12,20]. These data strongly support the hypothesis that either mutated or wild-type SOD1 misfolding contributes to disease pathogenesis in both familial and sporadic ALS. Recent studies describing RNAi based allele-specific silencing of mutant SOD1 convincingly demonstrated that lowering the levels of mutant SOD1 protein produces a significant therapeutic benefit in SOD1G93A mice [21]. This shows that targeting SOD1 is a viable and important therapeutic strategy for which identification and characterization of mechanisms controlling SOD1 protein degradation would play a central role. Unfortunately, the causes of SOD1 misfolding/accumulation, and more importantly, the mechanisms of the clearance of pathological aggregates remain unclear, which may very well be a valid target of novel therapeutic approaches for ALS.
Recently, we have identified puromycin-sensitive aminopeptidase (PSA, also known as NPEPPS) as a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein [22,23], which was later confirmed by others [24]. Another recent report implicated PSA as the major peptidase digesting polyglutamine sequences in Huntington's disease [25]. In addition, it was recently hypothesized that neuroprotective effect of PSA/NPEPPS may be linked to the autophagy system and several other neurotoxic targets in vitro, including polyQ-expanded huntingtin exon-1, ataxin-3, mutant α-synuclein, and SOD1 [26]. These results suggest that PSA/NPEPPS may represent a universal neuroprotective mechanism acting on pathologically aggregating neurotoxic proteins substrates, including SOD1. However, the questions whether PSA/NPEPPS is capable of removing SOD1 protein directly through its proteolytic activity and whether it contributes to the pathogenesis of familial and sporadic ALS remain unanswered.
Here, we investigated the role of PSA/NPEPPS in SOD1 protein clearance in vitro in cell culture and cell-free systems and evaluated the levels of PSA/NPEPPS in both human postmortem SALS motor neurons and murine ALS model tissues.
We first tested whether PSA/NPEPPS overexpression is able to reduce the abundance of endogenous SOD1 in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were transfected with human PSA/NPEPPS overexpression vectors, pCMV6-XL-hPSA and then the endogenous SOD1 was analyzed with Western blot and immunocytochemistry according to standard protocols and previously published protocols, respectively [27]. The highest transfection peaks for PSA/NPEPPS overexpression was noticed at 48 and 72 hours (data not shown). While the analysis of cells at 24 and 48 hours after transfection did not show any noticeable changes in SOD1 protein expression (data not shown), cells incubated for 72 hours post-transfection demonstrated a significant decrease (nearly 50% reduction; p = 0.0001) of endogenous SOD1 protein (Figure 1A and 1B). We also investigated the effect of knocking down PSA/NPEPPS expression using RNA interference (Stealth-RNAi) on SOD1 levels in SH-SY5Y cells. Reduction of PSA/NPEPPS expression resulted in an accumulation (~2-fold; p = 0.0075) of endogenous SOD1 protein within 72 hours (Figure 1A, B). Our above in vitro experiments in human neuroblastoma cell line support the recent observation that PSA/NPEPPS is a modulator of SOD1 protein abundance in 293A cells [26].
Figure 1. In vitro studies in neuroblastoma cell lines demonstrate co-regulation of PSA/NPEPPS and SOD1. A. Western blot analysis shows decrease of endogenous SOD1 in response to PSA/NPEPPS overexpression (PSA↑) and accumulation of SOD1 in response to PSA/NPEPPS inhibition (PSA↓) with Stealth-RNAi in human SH-SY5Y neuroblastoma cell line. B. Representative immunocytochemistry demonstrates a notable decrease (top) and a rapid accumulation (bottom) of SOD1 protein (green) in response to PSA/NPEPPS overexpression (PSA↑; top; red) and PSA/NPEPPS inhibition (PSA↓; bottom), respectively, in SH-SY5Y cells. The middle image represents normal control. PSA/NPEPPS is red, SOD1 is green, and the nucleus is blue as stained with DAPI nuclear marker. Scale bar 20 μm. C. PSA/NPEPPS expression demonstrated by Western blot is up-regulated in response to SOD1 overexpression in mouse N1E-115 neuroblastoma cell line. Because mouse SOD1 overexpression construct was used, we utilized mouse neuroblastoma cell line to avoid possible side effects of heterologous expression of a mouse protein in a human cell line. For each comparison, three independent experiments were performed (n = 3) with at least three independent replicates in each experiment. Representative Western blot and immunocytochemistry images are shown. Error bars represent standard deviations.
Moreover, we also studied whether overexpression of SOD1 affects the expression of endogenous PSA/NPEPPS. In mouse neuroblastoma cell line N1E-115 transfected with mouse SOD1 overexpression vectors pCMV6-XL-SOD1, mouse PSA/NPEPPS protein expression was upregulated up to 4-fold (p = 0.0001) (Figure 1C). Thus, it seems that PSA/NPEPPS expression is directly proportional to the levels of SOD1 protein and the elevation of SOD1 leads to significant increase in PSA/NPEPPS protein expression. These observations taken together suggest that PSA/NPEPPS is indeed a direct endogenous regulator of SOD1 protein abundance and its expression is controlled in response to alterations of intracellular SOD1 levels through a positive feed-back mechanism. A similar regulation of PSA expression has been reported in PC12 cells that overexpress hungingtin exon 1 containing polyQ sequences, in which PSA/NPEPPS expression is highly induced [28]. These results suggest that there may be a feed-back self-protective mechanism in cells by which PSA/NPEPPS expression is regulated in response to the abundance of aggregated toxic proteins. This further implies the important physiological neuroprotective role of PSA/NPEPPS.
Using human neuroblastoma SH-SY5Y cells we demonstrated a strong linkage of PSA/NPEPPS to SOD1 accumulation/clearance (Figure 1A and 1B). This effect may be mediated by direct interaction of PSA/NPEPPS with SOD1 resulting in SOD1 protein digestion similar to PSA/NPEPPS interaction with TAU-protein [22,23]. However, it is plausible that PSA/NPEPPS has no direct interaction with SOD1, and acts via cleavage of another intermediary, such as the autophagy system [26] or ptoteosome system [25]. Our recent studies of hPSA transgenic mice overexpressing human PSA/NPEPPS at nearly 3-fold revealed that it has no significant effect on either autophagy or proteosome degradation system [29]. Nevertheless, to test the hypothesis that human PSA/NPEPPS can act directly on human SOD1 two types of experiments were performed in the cell-free system using purified SOD1 and PSA/NPEPPS proteins.
First, we prepared post-microsomal protein extracts (S3) from cultured SH-SY5Y cells transfected with PSA/NPEPPS overexpression vectors, PSA/NPEPPS-specific RNAi, and corresponding controls, as described previously [30]. Co-incubation of post-microsomal fractions with purified human SOD1 was carried out at 37°C for one, two and four hours in the Bicine buffer, pH 7.0 with 0.2 mM DTT. One microgram of SOD1 highly purified from human erythrocytes (Sigma-Aldrich, MO) was co-incubated with 25 μg of S3 protein extracts isolated from nontransfected cells (control), cells transfected with PSA/NPEPPS overexpression vectors (PSA↑), and cells transfected with Stealth-RNAi (Invitrogen, CA) specific for human PSA/NPEPPS (PSA↓). The reactions were terminated by the addition of Laemmli SDS sample buffer and boiling for 5 min. Subsequently SOD1 proteins that remained in the reaction mixtures were analyzed by Western blot with SOD1 antibodies (MBL Intl, MO). While one hour incubation did not produce any noticeable effect on SOD1, two hours incubation resulted in a significantly increased SOD1 degradation rate (2-fold, p = 0.04) with the post-microsomal extracts containing elevated PSA/NPEPPS compared to using the post-microsomal extracts from control cells. Prolonged incubation for up to 4 hours resulted in the degradation of SOD1 in both experimental and control samples due to the presence of other proteases in the post-microsomal protein extracts. On the contrary, with post-microsomal protein extracts from PSA/NPEPPS-RNAi treated cells with knocked down PSA/NPEPPS, the rates of SOD1 degradation were significantly reduced (p < 0.01) at all time points in comparison to using protein extracts with elevated PSA/NPEPPS and controls (Figure 2A). The decrease in SOD1 degradation rate ranged from 1.24-fold (p = 0.04) after 1 hour to 9.7-fold (p < 0.01) after 4 hours of co-incubation. Experimental data presented above using the purified SOD1 and post-microsomal protein fractions that lack the autophagy system activity indicate that without the involvement of autophagy system PSA/NPEPPS is still capable of hydrolyzing SOD1 independently.
Figure 2. Experiments in the cell-free system by Western blot analysis confirm direct interaction of PSA/NPEPPS and SOD1. A. Purified human SOD1 was incubated with post-microsomal protein fractions of SH-SY5Y cells transfected with PSA/NPEPPS overexpressing vector (PSA↑), blank vector (Cntr) or Stealth-RNAi specific for hPSA/NPEPPS (PSA↓); and the exhibited SOD1 levels are reversely proportional to the levels of PSA/NPEPPS protein. Independent experimental triplicates are shown. B. Incubation of purified human SOD1 with purified rat PSA/NPEPPS for 6 hours demonstrates up to 80% proteolysis of human SOD1. Controls contained human SOD1 only. The gel bands in B demonstrate the results from two independent co-incubation experiments. Only representative images are shown. Error bars represent standard deviations.
Although post-microsomal protein fractions are free of autophagosomal vesicles, other cytoplasmic peptidases may contribute to SOD1 degradation process [31]. To further confirm that PSA/NPEPPS indeed acts on SOD1 protein directly and is capable of degrading it, we incubated purified human SOD1 with well-purified PSA/NPEPPS in a cell-free system. PSA/NPEPPS was purified from brains of adult male Sprague-Dawley rats (250-300 g) and its activity was measured with 20 μM Leu βNA (Leu-naphthylamide) as described previously [32]. For PSA-SOD1 incubation experiments, digestion of highly purified human SOD1 (Sigma-Aldrich, MO) was carried out at 37°C for 6 hrs in 50 mM Bicine buffer, pH 7.0, containing 0.2 mM DTT, at a molar ratio of 1:6 (PSA:SOD1). The reaction was terminated by 5% perchloroacetic acid and analyzed by Western blot as described above. After 6 hours of incubation, full-length SOD1 was greatly diminished of its original amount (about 80% decrease, p = 0.004) (Figure 2B). These results further strengthen the hypothesis of PSA/NPEPPS-specific SOD1 degradation through its direct proteolytic activity similar to the effect of PSA/NPEPPS on TAU-protein [22,23]. Moreover, our studies with post-microsomal protein fractions showed that such protein fractions even from cells that lack PSA/NPEPPS expression are also capable of digesting SOD1 protein at a low rate, which suggests that there may be other unknown PSA-independent mechanisms responsible for SOD1 hydrolysis, which remain to be verified in the future. Based on observations made by us and by others [26], PSA/NPEPPS may regulate SOD1 degradation through both direct (i.e. its proteolytic activity) and indirect (such as autophagy system involved) mechanisms. Our findings indicate that SOD1 protein may be removed directly through the increased activity of PSA/NPEPPS, and implicate this enzyme as an important modulator of SOD1-induced motor neuron degeneration in ALS.
Even though it seems that SOD1 overexpression in vitro may trigger PSA/NPEPPS upregulation (Figure 1C), the response of PSA/NPEPPS to the expression of mutated and dysfunctional SOD1 found in FALS is unknown. To investigate the effect of long term constitutive overexpression of mutated SOD1 in vivo, we first studied the expression levels of PSA/NPEPPS in SOD1G93A transgenic mice and control littermates [33]. SOD1G93A mice, strain B6SJL-Tg (SOD1-G93A)1Gur, were obtained from The Jackson Laboratory (Bar Harbor, ME). This strain expresses the transgene under the control of the endogenous human promoter [34]. Female SOD1G93A transgenic and non-transgenic control littermates were sacrificed at the age before the onset of the known disease pathology (2 months) and during the symptomatic stage (4 months). Western blot analysis using antibodies against PSA/NPEPPS was performed with the protein lysates extracted from the spinal cords of each group of animals. All animal protocols were in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Los Angeles Biomedical Research Institute and Nathan S. Kline Institute for Psychiatric Research animal studies committees. These experiments demonstrated significant reduction of PSA/NPEPPS in the tissues of SOD1G93A transgenic mice at both ages tested (p = 0.003 and p = 0.001 respectively) compared to control mice, suggesting that contrary to the short-term effect in vitro prolonged accumulation of mutated SOD1 negatively regulates PSA/NPEPPS expression in vivo (Figure 3A and 3B).
Figure 3. PSA/NPEPPS is significantly decreased in both SOD1G93A transgenic mice and motor neurons of postmortem SALS patients. A, B. PSA/NPEPPS protein expression analyzed with Western blot is significantly decreased in the spinal cord of 2 months old (2 m) adult presymptomatic (n = 4) and 4 months old (4 m) symptomatic (n = 4) SOD1G93A transgenic mice compared to the corresponding littermate 2 (n = 4) and 4 (n = 4) months old wild-type mice. C, D. A high-throughput immunohistochemical analysis using SALS tissue microarray reveals a significant decrease of PSA/NPEPPS-positive anterior horn motor neurons in SALS patients (n = 19) compared to healthy controls (n = 6). C. Representative spinal cord anterior horn tissue cores from SALS and control subjects show that PSA/NPEPPS protein expression is reduced in SALS motor neurons. Scale bar 20 μm. D. Bar graphs summarizing the findings from SALS tissue microarray show significant decrease of PSA/NPEPPS in SALS motor neurons. On average, each SALS (n = 19) and control (n = 6) subject was represented by ten spinal cord anterior horn tissue cores [38]. Error bars represent standard deviations.
Although the presence of misfolded SOD1 in the motor neurons of sporadic ALS patients is still a debated topic evidenced by several contradicting reports [6,8,11,12,17-19,35,36], recently published data points to the importance of SOD1 in the pathogenesis of the sporadic disease [11]. It was demonstrated that oxidized wild-type SOD1 shares similar structural and neurotoxic features with mutated SOD1. It appears that SOD1 oxidation process leads to specific conformational changes in SOD1 creating an epitope identical to mutated and neurotoxic SOD1 [11]. In over 50% of SALS patients such aberrant wild-type SOD1 are detected, and SOD1 extracted from tissue samples of SALS patients, but not SOD1 from healthy controls, inhibited axonal transport, pointing to its strong neurodegenerative potential [11]. These results suggest that abnormal conformations of oxidized wild-type SOD1 could indeed mediate motor neuron toxicity in SALS similar to the role of mutated SOD1 in FALS [37].
We then studied whether PSA/NPEPPS expression was altered in SALS patients. Post-mortem paraffin-embedded clinically relevant brain and spinal cord tissue blocks from SALS patients (n = 19) and normal controls (n = 6) were provided by the UCLA Department of Pathology and the National Neurological AIDS BANK (NNAB), and used for tissue microarray (TMA) construction at the UCLA Tissue Array core facility (http://www.genetics.ucla.edu/tissuearray webcite) as described previously [38]. Estimation of PSA/NPEPPS expression was performed in spinal cord anterior horn motor neurons of SALS and control subjects. Briefly, for the estimation of relative PSA/NPEPPS expression, the total number of PSA/NPEPPS positive motor neurons was divided by the total number of NeuN positive motor neurons to derive the PSA expression index (PEI) for a given tissue core. Then, the average PEI for each tissue type and individual was calculated and used to derive the mean PEI for SALS and control subjects. The significance was estimated based on a Student's t-test (P < 0.01). The following primary antibodies were used: mouse monoclonal anti-neuronal nuclei (NeuN; 1:100; Chemicon) and goat polyclonal anti-PSA (1:1000, Millipore). This high-throughput immunohistochemical analysis of TMA showed a significant decrease of PSA/NPEPPS protein expression in the SALS motor neurons (p = 0.0013, Figure 3C and 3D). For the first time, we demonstrated that decreased expression of PSA/NPEPPS may be a novel contributory factor to the pathogenesis of ALS, which leads to the impaired clearance of accumulated SOD1.
Our in vitro results with murine neuroblastoma cell line overexpressing SOD1 demonstrated an increase in PSA/NPEPPS protein expression (Figure 1C). However, the evidence in vivo show that the levels of PSA/NPEPPS protein are dramatically decreased in the transgenic mice overexpressing mutated (G93A) form of human SOD1 and in postmortem spinal cord tissues, more specifically motor neurons, of SALS patients (Figure 3). Two possible mechanisms may explain these conflicting observations in vitro and in vivo: 1. the rapid upregulation of PSA/NPEPPS is just the early-response to elevated intracellular SOD1; however, the prolonged and constitutive elevation of SOD1 eventually leads to the decreased expression of PSA/NPEPPS; 2. In SALS disease, the physiological feed-back regulatory mechanism of PSA/NPEPPS expression in response to SOD1 levels is impaired. The latter may represent a novel angle of view of ALS pathogenesis. Future studies of the interaction of PSA/NPEPPS with SOD1 would be prerequisite to understand its biological mechanisms. In particular, the cross between recently developed hPSA transgenic mice [29] and SOD1G93A mice [33] with subsequent analysis of double transgenic progeny in respect to SOD1G93A protein accumulation would be valuable. Further cell free co-incubation experiments using mutated forms of SOD1 would provide additional information on the specificity of interaction with PSA/NPEPPS. These and other experiments would shed new light on the role of PSA/NPEPPS in the pathogenesis of ALS and may provide novel therapeutic and diagnostic approaches for ALS.
In summary, we present the first evidence that PSA/NPEPPS is a major protease to directly digest SOD1, which may be analogous to its role in TAU-induced neurodegeneration [22-24]. More importantly, its expression is attenuated in both murine ALS model and SALS patients, which suggests its potential contribution to ALS pathogenesis. However, additional functional and etiological studies are needed to fully evaluate the role of PSA/NPEPPS in ALS and its possible use as a therapeutic target facilitating SOD1 protein clearance.
ALS: amyotrophic lateral sclerosis; FALS: familial amyotrophic lateral sclerosis; PSA/NPEPPS: puromycin-sensitive aminopeptidase; SALS: sporadic amyotrophic lateral sclerosis; SOD1: Cu, Zn-superoxide dismutase-1
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
GR, LP, MH carried out all the experiments. ZM maintained the transgenic mice colony, interpreted the data and drafted the manuscript. LCK, KSH, SLK designed the study, performed statistical analysis and drafted the manuscript.
All authors have read and approved the final manuscript.
Acknowledgements and Funding
The work was supported by the RGK Foundation (S.L.K.).
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DOCSIS 3.1 gives multi-gigabit speeds. Phil McKinney, Cablelabs
Ted Rappaport is predicting wireless 5G at 5 gigabits or more by around 2018. G.fast DSL is talking 1 gigabit, probably delivering half. Everyone in New York and LA has been promised 400 megabits this year from Time Warner Cable.. Further out, an Ericsson wireless demo reached 5 gigabits and Alcatel claimed 10 gigabit DSL on two pair.
Some of this is shipping. 300 meg (shared) LTE Cat 6 is starting to ship in Huawei phones. I am told the 400 meg TW Cable gear is installed and being tested. Deutsche Telekom has millions of lines of up to 100 megabit vectored DSL installed and ready to be turned on. John Cioffi has some ingenious plans to use gigabit WiFi to bond 100 meg DSLs from you and your neighbors, delivering several hundred megabits most of the time and gigabits sometimes.
Now to get the politicians and companies to make it so.
Berlin, Paris, Palo Alto, Brooklyn Gigabits everywhere http://bit.ly/Manygigs
Palo Alto 6 February �Wireless capacity will go up 50 times in the next 5-10 years,� Stanford Professor Andrea Goldsmith predicted at a Marconi webinar. Her Stanford colleague A.J. Paulraj and the brilliant Henry Samueli of Broadcom thought 50X reasonable. Both have won the Marconi Prize, the "Nobel Prize" of communications.
Berlin. 8 April 2014 G.fast came out for the first time at the Informa Fixed Access Summit. Deutsche Telekom, British Telecom and France Telecom all described active programs and an intent to deploy. European and American telcos want the hundreds of megabits from G.fast to match cable speeds going to a gig. I have been skeptical: the cost is nearly as high as fiber all the way home, it will take until 2016 or 2017 to get the kinks out and the coverage is more like 100 meters than 500.
Brooklyn, 30 April Ted Rappaports NYU 5G Summit had an amazing group of speakers. AT&T #2, John Stankey, keynoted and is damned serious about moving to 5G before the end of the decade. CTO Seizo Onoe of giant NTT Docomo was also there and soon after the event announced plans for 5G in 2018 with Ericsson, Samsung, Alcatel & Huawei. (3 of which sent CTO level speakers to Brooklyn, flying from around the world.) The enormous support for Ted and his NYU Brooklyn Institute has made him �The Prince of the 5G World.�Rappaport is concentrating on 28 GHz, a top down build which needs access points on nearly every crowded urban block. Others raised the possibility of WiFi �bottoms-up� to deliver similar capacity. The debate is raging, with FON, Free in France and probably the U.S. cablecos on the �bottom-ups� side.
Paris May 20-22 2014 A dozen of the absolute top engineers developing G.fast came together at the outstanding Upperside G.fast Summit. Les Brown provided an in-depth overview of the 300! page standard. CTOs and their peers from Sckipio, Broadcom, Ikanos, Lantiq and more spent three days trying to resolve the details. Top folks from BT, FT, Alcatel & Adtran joined in. Sckipio promises full standard chips in 2014. Broadcom�s customers are being told they will have something in 2014, probably far less than the standard. Some folks thought deployments were possible in 2016. Others thought later. (Deutsche Telecom�s CTO has said trials in 2014. He misspoke.)
Paris May 21 At that same G.fast event, John Cioffi introduced his remarkable plan to get to a gigabit using 100 meg vectored DSLs and gigabit WiFi. It sounds impossible but it definitely could work. In my apartment I see 20-25 WiFis. There is no technical reason preventing sharing bandwidth; WiFi is already at 1.3 gigabits and going higher. Even if 25 homes were watching 2 HD TV and surfing, there isover a gigabit unused that could be shared. Check http://bit.ly/GIGADSL
Belgium, July 9th Alcatel announced 5 gigabit DSL going 30 meters in the lab using 500 MHz of clean spectrum, They combined two lines to put 10 gigabits on the press release and got worldwide pickup. Since no one is delivering even 100 MHz yet, this is a long way off. Huawei is highly likely to do a similar demonstration before October's BBWF.
*** Bob Lucky led teams that won two Nobel Prizes at Bell Labs. Join the free Marconi Webinar with Bob Lucky tomorrow http://marconisociety/webex.com.(psa)
Forbes: India Has More Net Users Than The United States http://bit.ly/IndiabeatsUS
New Minister Ravi Shankar Prasad is promising to meet the revised schedule. He may be the right man to overcome the inertia and corruption that has plagued so many Indian projects. Prasad prosecuted a corrupt Governor of Bihar state and put him in jail.
Facebook claims 100M Indian users, 84M of them wireless. With fewer than 40M landlines, India's broadband future will be wireless. The most intense competition in the world has brought cell phone prices low enough to sell a billion SIMs; probably half the 1.2 billion Indians have a mobile. But most Indian phones are still running on 2G. India is auctioning spectrum for 3G networks and actively building them while the developed world is already starting to refarm 3G for LTE. LTE with MIMO already offers 3-5 times the bits per hertz and the gap is growing.
With few landlines, India needs the absolute maximum performance from wireless. http://bit.ly/IndiabeatsUS
*** What is a Software-Defined Access Network. ASSIA's George Ginis answers that question http://bit.ly/SDACCESS . ASSIA is a leader in bringing SDN home. (ad)
Triductor, The New Chinese VDSL & G.Hn Chipmaker http://bit.ly/IndiabeatsUS
Tan received his UCLA degree directly from Henry Samueli. He has enormous respect for Broadcom. But he's not afraid to take on Broadcom's chips. China is deeply committed to replacing imported chips with Chinese designs. Tan said,"The technology of this chip used to be monopolized by America, so our country had to spend tens of millions of dollars importing from overseas. What my team and I want to do is realize the localization of this chip in the new developing wave of semi-conductor industry, to equip Chinese people with their own high-speed video networks."
Triductor, like HiSilicon, has also announced a G.hn chip. While G.fast is getting the publicity, thanks to an effective campaign by the ITU, it's two years or more away. G.hn, a much simpler system, is already being used to extend "fiber to the basement" to apartments at hundreds of megabits. China Telecom & Unicom, the monopoly landline providers, are fiercely resisting government demands they upgrade something like 100 million apartments from DSL to fiber. Fiber to the basement + G.hn might be an attractive alternative.
700M Broadline Lines Charted http://bit.ly/Broadbandgrowth http://bit.ly/700million
The chart would look differently if wireless smartphones were included. The countries with few wires - India, Indonesia and most of Africa - are seeing fantastic growth in mobile broadband. By around 2017, there will be more Africans than Americans on the net, I've calculated from Cisco data.. http://bit.ly/Broadbandgrowth http://bit.ly/700million
*** Chris DiBona leads Google's Open Source projects. Join the free Marconi Webinar with Bob Lucky tomorrow http://marconisociety/webex.com.(psa)
German regulator Matthias Kurth told me five years ago that DT had no choice but to upgrade where they face cable, but they've been delaying in hopes of persuading the government to cripple their competition. Deutsche Telekom loses 89K subscribers because they delayed VDSL upgrades. Cable offers twice the speed for the same price as DT and covers 2/3rds of Germany. They finally blocked most unbundling in 2013 and began the build of fiber/DSL hybrids. CEO Tim Hottges,"The fiber is the answer on what we are doing," but of course he means fiber/DSL.
German regulator Jochen Homann and EU Commissioner Nellie Kroes are doing what politicians do, claiming their policy of raising prices created the build when everyone in the industry knew DT would do it anyway.
"An apparently disastrous shortage of components for the Sony Xperia Z2 means we may not see the thing landing in the flesh for another seven months" http://bit.ly/1m8wyDq Ray LeMaistre of Light Reading, one of Europe's best reporters, hears from Nokia "a shortage of 'certain components' hurt sales during the first three months of this year. The company expects the problem to persist." Alcatel "has identified the same problem."
TV host Johnny Carson once made a joke about a (nonexistent) shortage of toilet paper. Many rush out and bought a supply the next day the shortage was real. The (highend) chip shortage isn't contrived, however. Apple is looking to sell an extraordinary number of iPhones and bought out the foundry.
Bitter experience is that serious slumps often follow shortages like this. When people believe the factories are catching up, they slow orders and "work off inventory."
April 3
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"We've never had a spectrum shortage." Cell phone inventor Marty Cooper
Stanford Professor Andrea Goldsmith believes wireless capacity can increase 50 times in the next 5 to 10 years. We�ll soon have gigabits rather than the tens of megabits now typical. The cost of delivering each bit - or gigabyte - is dropping at a ferocious rate. Prices are staying high in most countries.
Inability to sell the capacity coming online at the prices they want is far more of a problem for telcos than the wildly exaggerated spectrum "crisis." The result is a desperate effort to eliminate competitors around the world. It�s easy to see price-fixing is the goal behind Sprint/T-Mobile, Bouygues/SFR, Telefonica/E-Plus, Softbank/eAccess, AT&T/Leap and the massive CEO support for ETNO�s campaign to shrink the industry.
Cell phone inventor Marty Cooper points out "we've never had a spectrum shortage." By and large, the �spectrum crisis� has been invented by politicians and lobbyists who pull politicians� strings. In all but limited situations, there�s plenty of bandwidth and spectrum.
Randall Stephenson and St�phane Richard lose sleep about competitors taking too many customers, �commoditizing� the mobile market. Smart public policy advocates dream about the same result - competition bringing prices in line with costs.
To learn more about what's coming, join me and some of the world�s best engineers in two weeks at Ted Rappaport�s 5G event NYU Wireless center. In person http://bit.ly/QTwOe5 or at the (overly expensive) live-stream http://bit.ly/1e39Ewh In two years, Ted has built one of the world's best research centers at NYU.
Plan ahead for the Marconi webinars: Sir David Payne on fiber�s future on April 29th and John Cioffi on �Gigabits to the billions� May 8.
*** G.fast Focus Day at Informa Berlin Tuesday April 8
Gigabit and Faster Wireless Surprisingly Close http://bit.ly/1ejvYMB
*** ASSIA is Vectoring.
Vectoring Goes Live After 10 Years http://bit.ly/OnK6NS
*** Fixed Access Summit Tuesday April 8-10
$200 For Fiber To The Basement In East Europe http://bit.ly/1mQ7u2R
~$1,000/Home Fiber At CenturyQwest http://bit.ly/1fSAkhC
*** ASSIA Active Care dramatically reduces DSL call center costs.
Perlman's PCell Loaded With Hype http://bit.ly/1fgTuNA
What Steve really showed is a lot of hot air and what appears to be a prototype MU-MIMO system. If he has that production ready, that would be an important advance similar to work going on at all the major wireless vendors. Stanford researchers and many others have been working on for years. Literally in the last century, Stanford Professor AJ Paulraj described such systems. more http://bit.ly/1fgTuNA
No One Buys Cable Caps At Time Warner http://bit.ly/1mT8aay
OFCOM: Vectoring And Unbundling Can Work Together http://bit.ly/1e3MtSn
*** Building the Optimal NGA Service Portfolio; A crucial new report from Beno�t Felten on surviving and thriving with next-generation networks. How to build a portfolio that balances attractiveness (to maximise take-up) and profitability (to optimise payback). http://bit.ly/YT74ui
G.Fast DSL Has Momentum But G.Hn Networking Wants Some Action http://bit.ly/1hvxX0c
Telco CTOs must have a plan for higher speeds. although I don't know any where the CFO has signed off on actual deployments. Cable is going to 400 megabits (shared) in New York and Los Angeles this year. Berlin, Brussels, Zurich and Amsterdam are likely to soon follow. There's very little difference in cost today between "up to 400 megabit" cable service and the older 10 meg. 1,000 megabit cable is almost production-ready. Deutsche Telekom, Telia-Sonera, Belgacom and France Telecom are jumping on the bandwagon. Another giant telco, facing unexpected fiber competition, is preparing a G.fast trial. They want to see whether they can get the competitive performance they need with copper in the last 100 meters.more http://bit.ly/1hvxX0c
G.Fast & FTTdp Get New Model From Lantiq http://bit.ly/1hvxb3w
Rainer Strobel of Lantiq, Reinhard Stolle of Hochschule Augsburg and Wolfgang Utschick of Technische Universit�t M�nchen have built a new model that better fits the data. They write me "The industry is using a a cable model back from 1998, originally designed to describe cable properties for single line ADSL transmission. These models, adopted by ETSI and NIPP-NAI, served their purpose reasonably well for VDSL2 frequencies (<30MHz). More http://bit.ly/1hvxb3w
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Jan 1
"The cost dynamics of deploying fiber have radically changed. The interfaces. the home wiring requirements, how you get a drop to a pole and splice it, it's just totally changed." ATT CEO Randall Stephenson at Goldman Sachs.
René Obermann on New Year's Day abandoned the CEO job at Deutsche Telekom, previously a job no one would quit. Carriers around the world face revenue that is likely to decline as network costs come down faster than demand grows. Even on wireless data, signs of overcapacity are everywhere. Cell phone inventor Marty Cooper tells me there's no spectrum shortage in site; don't miss his January 15th Marconi webinar. (Below)
Marty Cooper, who invented the cellphone, is doing a webinar "Solving Spectrum Shortages" for the Marconi Society Jan 15 at 1 p.m. EST. Marty says we've never had a spectrum crisis and shouldn't have one in the future either. But JC at AT&T has a $100M influence budget and it's only now people are realizing it was total spin. I'm moderating, and also will do a Marconi webinar with Arogyaswami Paulraj, the inventor of MIMO, in March. The fellows of the Marconi Society are the finest communication engineers in the world and I'm working with them to promote their ideas.
First Look: Germany Puts Off Vectoring Another Six Months http://bit.ly/1hZ5TsB
DT is having more problems than I knew.
*** Solving Spectrum Shortages January 15 http://bit.ly/1k83InV
AT&T CEO: Fiber Costs Have Plummetedhttp://bit.ly/1bb5DTS
*** ASSIA INTRODUCES THE WORLD'S FIRST COMPREHENSIVE HOME WI-FI MANAGEMENT SERVICE Expresse Wi-Fi Designed to Improve Consumer Wi-Fi Performance by 100 Percent, Helps Users Enjoy the Wireless Experience They Desirehttp://bit.ly/T3sMxr (ad)
*** Building the Optimal NGA Service Portfolio; A crucial new report from Benoît Felten on surviving and thriving with next-generation networks. How to build a portfolio that balances attractiveness (to maximise take-up) and profitability (to optimise payback). http://bit.ly/YT74ui
Broadcast Worried About G.Fast Interferencehttp://bit.ly/1dpmaCH
*** ASSIA Smart Vectoring deals with the remaining network-trashing noises that vectoring exposes but cannot cancel or address. http://bit.ly/13ZuRiv (ad)
$21 For 2 Meg From Time Warner Cablehttp://bit.ly/1hfPIpR
Good News: Alcatel LTE In China Telecomhttp://bit.ly/1hC3bE9
Lantiq: Strong Progress On Vector Interoperabilityhttp://bit.ly/1awr5y4
France's $13 Unlimited Voice, SMS Confirms Mobile Glut http://bit.ly/16Wt2HE
Rogers Cable Big Fiber Home RFPhttp://bit.ly/13UW2f3
ASSIA Wins DSL Patent Case Against British Telecomhttp://bit.ly/1aopE48
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Sept 2
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"[FTTN/DSL offers] a pretty high return on invested capital." Tim Horan, Oppenheimer
Lowell McAdam of Verizon just borrowed $60B to bethe can keep U.S. wireless prices high. As capacity is outstripping mobile demand, that's a tough bet to win. For the next decade, telco profits will plummet anywhere competition is strong. Before the deal went down, I wrote:
Steve Jobs taught us to "think different." I'll be hung as a heretic by some for saying the "spectrum crisis" was bogus, created for political purposes. Even without more spectrum, demand can easily be met in the U.S. and most markets with current capex rates.
Glen Campbell of Merrill Lynch concluded in 2009 "the crucial telco issue would be data pricing." Demand could be limited if carriers price high, as they have. Unequivocal data from AT&T, CTIA and Cisco show a major drop in mobile data growth over the last three years. The initial smartphone boom is playing out. The 100% per year mobile growth of 2011 is down to 50% in 2013 (AT&T's Ralph de la Vega http://bit.ly/1e27eaR). Cisco's respected VNI forecast demand growth dropping 60%.
960-1200 Megabit Cable Modems Ready To Go http://bit.ly/16YUeBU
*** ASSIA Smart Vectoring deals with the remaining network-trashing noises that vectoring exposes but cannot cancel or address. http://bit.ly/13ZuRiv (ad)
China's Plan: 270M In 2015 http://bit.ly/15U2yyP
The first is a full speed stage, ending in 2013, that deploys basic broadband and 3G widely.. The second stage, 2014-2015, is dedicated to a further takeup and wider deployment. That will include 400,000+ LTE cell sites. I believe the government sees this as promoting their national goal of raising closer to the developed standard rural areas, the West and minorities including Uyghur and Tibetans. They have set a goal of 270M fixed connections in 2015, about 80M more than today. At the current growth rate of 4-6M per quarter, that's achievable.
*** �Point Topic is a leading independent resource for fixed global broadband statistics and analysis. We offer comprehensive reliable information at operator and country level covering all the major access technologies - copper, cable, fibre, wireless and satellite. Visit our website at www.point-topic.com to find out more.� (ad) They are everyone's favorite source for broadband data. db
AT&T's Plan: 25-75 Meg U-Verse To 85% Of Network (After Shutting 25%) http://bit.ly/15g75fW
*** 26 September Columbia University New York CITI State of Telecom 2013
While Germany has begun upgrading 12-24M lines to 50-100 megabit vectoring, AT&T has held off on the capital spending. Vectoring could double those speeds again, bringing 50-200 megabit service. AT&T has been a leader in research on vectoring but for now does not intend to deploy it widely. It would require many new boxes in the field, within 300-500 meters. In Q2 2013, T added 641,000 new U-Verse data lines. While most of those were customers pushed to upgrade from older DSL, T is holding its own against cable in U-Verse territory. While their losses in non-U-Verse areas are extreme, T claimed they actually gained share in U-Verse areas in Q1. If cable brings in 100 meg at a good price or finds a market for 400 meg, AT&T is making sure they are ready with vectoring and possibly G.fast to stay in the game.
AT&T�s plan is to shut down landlines to perhaps 25% of their homes to reduce competition for their wireless. http://bit.ly/15g75fW This is the most dramatic cutback in 140 years of telephony, almost ignored by the press. http://bit.ly/15tr6yL
*** ASSIA INTRODUCES THE WORLD�S FIRST COMPREHENSIVE HOME WI-FI MANAGEMENT SERVICE Expresse Wi-Fi Designed to Improve Consumer Wi-Fi Performance by 100 Percent, Helps Users Enjoy the Wireless Experience They Desire http://bit.ly/T3sMxr (ad)
G.fast Will Not Bring You a Gigabit http://bit.ly/18fksz6
Adtran Claims Win In $B Contract At Deutsche Telekom http://bit.ly/17wWBi6
*** Building the Optimal NGA Service Portfolio; A crucial new report from Beno�t Felten on surviving and thriving with next-generation networks. How to build a portfolio that balances attractiveness (to maximise take-up) and profitability (to optimise payback). http://bit.ly/YT74ui
�Some Problems Are Better Identified From The Modem� http://bit.ly/1eaIP62
*** ASSIA's George Ginis blogs on "The Vectoring Tsunami: More and More Service Providers are riding the next wave of broadband. DSL remains strong. http://bit.ly/XkR2hM (ad)
Ladar Levinson's Tough Choice: Spy or Lose Your Business
Spectrum Shortage Solved, Part 1: WiFi is Incredible
Spectrum Shortage Solved, Part 2: LTE Advanced is 10-30X Better
Spectrum Shortage Solved, Part 3: There�s Massive Unused Spectrum
Spectrum Shortage Solved, Part 4: Wireless Growth is Plummeting
Cisco Data: No Spectrum Crunch In 2016 And Unlikely In Following Years http://bit.ly/ArHpNa
Highest broadband penetration? Liechtenstein is 60% - Norway is 43% - Estonia a surprising 42% - U.S. 29% - China 13%. Adjusted for family size, the U.S. doesn�t look so far behind. China has another decade of growth ahead.
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June 26
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"Internet peering was created by a conversation between Bob Kahn and myself. We had two networks we wanted to connect and no way to pay to do it. We established this connection with no equal traffic in both directions." Dave Farber, just elected to the Internet Hall of Fame
Verizon CEO Lowell McAdam still hasn't corrected his whopping error in an NY Times oped, claiming high speed in Europe 97% lower than the actual figure. There's a war on to about whether the government should take action to improve broadband. Like all wars the first victim is truth. Another Times oped was off by a factor of four on carrier profits and about a factor of about two on U.S. prices. The pro-action side needs to correct some errors as well; upgraded telcos (U-Verse, FiOS, etc.) are actually beating cable in about 60% of the U.S., not dying in the face of a cable monopoly.
Debates in Europe and China are no more accurate. A Financial Times report of a carrier claim rules changes would result in "�115bn in annual investments by 2020" was fortunately a misunderstanding; it was an 8 year figure, although still wildly unlikely. Regulation changes rarely have a major impact on investment; technology and consumer demand is far more important. Nothing drives investment more than fear of a strong competitor; ETNO's suggestion of dramatically cutting competition is likely to reduce investment, not increase it. Advocates can easily find economists who for the right price will make almost any claim, experts at burying the truth with unsupportable assumptions and lots of jargon. Reporters and politicians too lazy to actually find the facts are also part of the problem.
I shouldn't complain; my job is taking me to Paris for an ASSIA event Friday and then to Geneva to meet with the ITU.
Say hello to the round fellow with a beard and the irrepressible Jennie Bourne in Paris (Saturday/Sunday) or Geneva (Monday-Wednesday.)
*** Point Topic is a leading independent resource for fixed global broadband statistics and analysis. We offer comprehensive reliable information at operator and country level covering all the major access technologies - copper, cable, fibre, wireless and satellite. Visit our website at www.point-topic.com to find out more. (ad)
Russia Passing U.S. In Fiber. What? http://bit.ly/1249lFy
*** ASSIA Smart Vectoring deals with the remaining network-trashing noises that vectoring exposes but cannot cancel or address. http://bit.ly/13ZuRiv (ad)
400 Megabit Cable Boxes Shipping http://bit.ly/192zLO3
*** ASSIA enables retention and increase of service provider�s current investment through the performance improvement of all DSLs (newly vectored, as well as existing DSLs) as vectoring is introduced incrementally or en masse, http://bit.ly/13ZuRiv (ad)
Huawei In 15 Vectoring Trials http://bit.ly/12kSxND
Worth a look
It's Alcatel, not Calix, providing the box for the remarkable gigabit network at Vermont Tel. Calix just provided the home NID. The Alcatel 7700 routers are doing exceptionally well and emerged as the premier Alcatel product after the reorg. Their creator, Basil Alwan, is probably the #2 guy in the entire company today.
wall street
Lowell McAdam's Error In The NY Times http://bit.ly/1aDfbV4
For the record. In response to a Verizon blog posting attempting to justify shutting down landlines, I commented �Deutsche Telekom has committed that transition to new networks would not leave customers worse off. I urge Verizon to make a similar commitment. Until then, I'm personally opposed to allowing Verizon to shut down wireline service.
In this case, that would mean offering data at less than prohibitive rates. Verizon Wireless charges so much more for data than Verizon DSL the difference is significant.� I was being polite. Verizon�s actual charges on wireless shut down almost everyone who wants to watch more than 20 minutes of video daily. Stop the Cap, DSL Reports, and Harold Feld have done honorable work on this; WaPo, NYT, and WSJ have been negligent.
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May 29
Michel Guité of Vermontel asked me, "Is there any network anywhere in the world doing something better we should learn from? Maybe in Hong Kong or Singapore?" 1,000 homes now can connect at a true gigabit - up and down, with 15,000 more homes soon to follow. That's as good as it gets, especially as broadband stimulus funding has brought the price down to $35/month. I should move to Vermont.
June 20th, please join me at Columbia's CITI for a full day's seminar on "The Future of the Internet." http://bit.ly/13YsiNu Hamadoun Touré of the ITU will keynote and is always worth listening to.
"Look Out Google Fiber, $35-A-Month Gigabit Internet Comes To Vermont" http://bit.ly/10Jewct
The cost to build the network in a mostly rural territory is $3,000 to $5,000 per home. The promise by VTel to pass most of the subsidy to consumers in low prices was surely one reason they were awarded the funds.
"I'm moving to Vermont," was a comment on one of the news stories.
*** 20 June New York Columbia CITI THE FUTURE OF INTERNET GOVERNANCE AFTER DUBAI:
60 Down, 18 Up As VDSL Comes To France http://bit.ly/19YOYgw
*** ASSIA Smart Vectoring Software allows prequalification of the speed gain and profitability of any copper line's conversion to vectoringhttp://bit.ly/13ZuRiv (ad)
*** ASSIA enables retention and increase of service provider's current investment through the performance improvement of all DSLs (newly vectored, as well as existing DSLs) as vectoring is introduced incrementally or en masse,http://bit.ly/13ZuRiv (ad)
*** ASSIA software normalizes high vectoring performance gains regardless of which DSLAM/equipment is selected by a service provider http://bit.ly/13ZuRiv (ad)
Lantiq Sampling 3x3 MIMO For Faster VDSL Gateways http://bit.ly/16HYf0c
Ikanos: Our 192 Port Vector VDSL Chips Are In Customer Tests http://bit.ly/12qPIZ8
*** ASSIA Smart Vectoring deals with the remaining network-trashing noises that vectoring exposes but cannot cancel or address. http://bit.ly/13ZuRiv (ad)


text:
We accept only beef from the very top tier of Choice and Prime grades. Our standards are based on quality, not breed, so all Sterling Silver Premium Beef is highly marbled for rich flavor and aged to perfection.
Flavor Your Family will Love… and Your Guests won't forget
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Sitting down and enjoying a meal together is all about flavor — something Sterling Silver® Premium Beef provides in abundance. That's why we hold our premium meat to the highest levels of quality and consistency, ensuring you serve premium beef that delivers unparalleled flavor every time.


text:
Barbara J. Muller-Borer, Ph.D.; Lead Investigator
|The focus of my research is the study of functional gap junction mediated cell-to-cell communication in cardiac tissue under normal and pathophysiologic conditions. One area of particular interest is the elucidation of the role of cell-to-cell communication on donor cell engraftment, trans-differentiation and function as applied to cell transplantation therapies.
This research includes both an in situ model of a heterogeneous cardiac myocyte/stem cell co-culture and in-vivo small animal heart model. Confocal fluorescence microscopy, a multisite fiber optic imaging system and micro-electrode array data acquisition system are used to image and provide high temporal and spatial measurements of intracellular ionic and transmembrane voltage changes and electrical signal propagation in cardiac tissue.
Barbara J. Muller-Borer, Ph.D.
View a list of Dr. Muller-Borer's publications on the Dept of Cardiovascular Sciences web site.
Co-Program Director of Interdisciplinary Doctoral Program in Biological Sciences (IDPBS)


text:
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Christopher Walken plays a celebrated cellist in "A Late Quartet."
- Filed Under
C-sharp minor: The mere words conjure up a sense of anxious edge, which is the feeling that drives "A Late Quartet." Starring Christopher Walken, Philip Seymour Hoffman, Catherine Keener and Mark Ivanir, this is a chamber piece about chamber musicians, and it's set to Beethoven's emotional Opus 131 string quartet -- in C-sharp minor.
Though the movie is shaped by the piece -- Opus 131 is a complex, demanding work -- "A Late Quartet" is not really about the music. Director Yaron Zilberman is using the intimate collaboration required of a string quartet to examine the ways in which lives become ...


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