[jump to video]

Long story (not very) short? One night in 2003--after killing it in front of audience of about 30 lucky people in Oakland--The Long Winters needed a place to crash, and my wife and I were happy to oblige. 

So, they drove their Big Stinky Blue Van over the bridge, slept on our floor, and by breakfast the next morning, it'd become clear to me that I'd provided lodging to a man who was not only very likely a member of my karass--he was also one of the smartest bullshit artists I'd ever met. 

Almost eight years later, although I don't see him nearly as much as I'd like, I still count the guy as one of my best pals ever.

That's John Roderick. And, I think you need to know about him.

John doesn't read this site--he's more of a Twitter person--so I don't risk feeding his astounding excess of dignity by saying he's one of the most gifted writers and bon vivants of our generation. He's just the best. In large part because he's congenitally incapable of suffering bullshit.

This was never more apparent than the Saturday morning in 2007 when we sat in my back yard and talked about a lot of stuff. Playing guitar, advertising on the web, the evil work of promoters, and why everyone is always trying to shortchange everyone on copper pipe. 

That talking became a four-part interview I ran on the late and occasionally lamented The Merlin Show, and, to this day, it's one of my favorite things I've been lucky enough to post to the web.

So, y'know how I'm definitely "not for everyone?" Well, John is really "not for everyone."

He's opinionated and arrogant and undiplomatic and unironically loves Judas Priest--meaning everyone will find at least one thing not to like about him. Despite being hairy and enjoying laying on your bed, John is not exactly a teddy bear. 

But, John's also right a lot. And, he never sands off the edges of his personality or opinions to make you theoretically "like" him. Which, it will come as no surprise to you, is a big reason I love the guy more than a free prime rib dinner. 

So, why the jizzfest about that awful jerk, John Roderick?

Because, as I noted the other day on the Twitter, in our first episode of Back to Work I misattributed a line that should have been credited to John. Which in itself is unimportant, except inasmuch as finding that link to correct the error got me watching our 50-some minutes of chatting again. I also received some at-responses and emails that reminded me how much people enjoyed our chat. 

But, really it made me realize how much that rambling morning in my back yard still resonates so much with stuff I care a lot about. Independence. Agency. Directness. And, never apologizing for wanting to get paid. Also, guitars and talkative hippies.

So, anyway. John. 

I edited all four parts of the video into one big (streamable/downloadable) movie that should make it way easier to watch at a sitting. Should that interest you. Which it may not. Which, as ever, is totally fine, and kind of the point.

But. If you like Dan and my new show (and, seriously—God bless you magnificent bastards who helped briefly make B2W the most popular podcast in the world [gulp]), I think you'll really like this interview a lot too. I hope so, anyway.

Thus, submitted for your disapproval, permit me to present my four-year-old visit with the acerbic, opinionated, and reportedly unlikeable bullshit artist whom I respect and adore more than just about anybody. 

Meet Hotrod.

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Introducing Instapaper 4.0 for iPad and iPhone

The lede here is that my pal, Marco, has just released the stellar new 4.0 version of his Instapaper suite.

This is fantastic news, and–as if you needed one more of Marco’s beta testers to say so–I do sincerely hope you’ll mark the occasion (and support his hard work) by purchasing the Instapaper iOS app(s). I promise you’ll be treating yourself to a massive update to an already excellent product.

Now, it’s fortunate and appropriate that you’ll be hearing this advice at length from a lot of people this week. Because, if it’s not already obvious, Marco’s little app (and its associated services) enjoys a rabid fanbase of sundry paragraph cultists who are as eager as I am to spread the word; and, yes, we do want you to join the Reading Nerd cult.

But, I also want to mark the occasion by adding a few thoughts on exactly what Instapaper has done, and continues to do, for me. (As you may already know, I’m a big Marco fan.)

Thing is, I want to tell you how Marco has made a magical machine for people who have decided to read.

Long-Time Fan

For years, Instapaper has been one of the best made, most used, and most beloved apps in my iOS ecosystem. It’s always lived on my iPhone’s home page, and, as you can surmise, that’s because I use Instapaper a lot. Like, a lot a lot. Specifically, I use Instapaper a lot because it helps me do four things extremely well. Four things that work together to make my life a little better.

In that typically annoying mixed order I can’t seem to stop doing, here goes.

2. Deciding WHEN to read

Second, and most obviously, I use Instapaper maybe five to ten times a day to catch up on my reading. Which is great. This is what Instapaper is actually for, right? You read stuff.

Long articles, smaller features, short books, big piles of documentation, and really just anything that I would like to read…later. More saliently, these are things that I have decided to read. This decision part’s important, but more on that in a couple minutes.

But, how does all this “stuff” I’ve decided to read get in to Instapaper?

1. Deciding WHAT to read

See, this is the really important first part. Because as much as I use Instapaper for all manner of reading, its use as an ephemeral destination for mostly ephemeral content wouldn’t be nearly so useful if I didn’t have so many ways to collect all that stuff. So, that flexibility in collecting material is where I end up using some form of Instapaper dozens of times each day.

Examples?

I have a bookmarklet for adding items to Instapaper in 4 browsers on 7 devices. I have (and use the hell out of) the “Send to Instapaper” services that are built in to everything from Google Reader to Reeder to Flipboard to Instacast to Tweetbot to Zite to you name it. I can automate in or out of Instapaper with If This Then That, I can email items directly to Instapaper–hell, I can even just copy a URL from iOS Safari, and paste it directly into the motherscratching Instapaper app.

Suffice it to say, there are many ways to get “stuff” into Instapaper. E.g.:

But, that banner dump only tells part of the story.

Yes, a big part of this is about ubiquity and ease-of-use. But, the practical result is that all those little entrees to Instapaper are available to me everywhere I might need them, and they each represent a single little click that silently adds an item of “stuff” to my Instapaper pile.

Each button is one more simple opportunity for me to decide to read.

3. Deciding WHERE to read

Now, the third part of this magic is less immediately obvious, not least because the reading experience of the Instapaper iOS apps is, for my own purposes, perfect. But, there’s more.

Because, all that support for getting stuff into Instapaper is mirrored by an endless number of ways to get stuff back out. To, in fact, read. That thing I decided to read is now everywhere.

However I ended up deciding to read something, seconds after that *click*, the real magic starts happening, and–through whatever inscrutable black art and transmogrification is happening inside the fearsome celestial engine Marco has made–that decision to read is expressed in the most elegant of results and in a startlingly broad variety of convenient places.

It’s readable on a website; it’s readable on an iPhone, and 2 iPads; it’s readable on a Kindle 3; it’s readable on the crazy number of apps and services that display Instapaper items. And, it’s even preserved for posterity in my private Pinboard archive.

So, for practical purposes, this stuff that I’ve decided to read can now go whooshing through a network of customized tubes, and gently land practically anywhere that well-formed bits may reside.

4. Just…Deciding to Read

I know most of you know these things. I know you’re familiar with the many “Features and Benefits” of Instapaper. And, I even know that most of you reading this are probably already using Instapaper–perhaps even to read this very article.

So, the point here is not simply that Instapaper is flexible, idiot-proof, and sanity-savingly redundant. Although it is all those things and many more.

The point is that my life always gets better when I decide to read things–and then actually read those things I decided to read. This is not a trivial point.

We’re all busy, and we’re all bombarded with 10,000 potential calls on our attention every day. Some days, we handle that better than others. Some days, we don’t handle it all.

All I know, is that, throughout my life, deciding to read has made that life better.

It made my life better at 7 with Henry Huggins. It made my life better at 16 with Slaughterhouse-Five. It made my life better at 20 with Absalom, Absalom!. And, it made my life way better at 25 with A Confederacy of Dunces (cf.).

And, now, for the past few years–following over a decade during which I read way more href tags than actual prose paragraphs–my life has gotten better, in part, due to Instapaper. I’ve finally gotten my hands around this “too much stuff” issue, at least insofar as it relates to words of theoretical interest. Now, I know where it goes. It goes into Instapaper.

Because, now? Yeah. Twenty-some years after a college career sucking down over 1,000 pages a week, I am finally returning to reading a lot more. Because, I am deciding to read a lot more. Instapaper means there’s no excuse for not reading a lot more. Period.

How about you?

What Are YOU Deciding?

When you’re in line at the ATM or the professional sporting event, what do you do?

If you’re like a lot of people, you hit your mobile device like a pigeon on a goddamned pellet. Then, you decide what happens.

You can decide to throw birds at pigs. You can decide to check in on which strangers are pretending to like you today. You may even decide to see what you would look like if you were really fat.

Thing is, you could also decide to read. Just for a couple minutes. Maybe more. Maybe less. Who knows. It’s your decision.

A Nudge Towards “Better”

But, if you have followed the circuitous skeins of yarn comprising this little sweater you’ve been reading, it comes down to this:

If you’ve decided that you want to read, Marco’s app will really help you. He’s removed any phony barriers you’ve built about “not having time” or “not having it with you” or “not knowing where to put it.” There are no excuses, apart from the superficial animated ones you’ve constructed out of cartoon birds.

As for me? In the last week alone, I decided to read a lot of things in Instapaper. A small sampling:

I decided to read about an American family’s educational experiment in Russia.

I decided to read about what Heidegger means by Being-in-the-World.

I decided to read about why toasters are so bad.

I decided to read about responsive web design.

I decided to read about why Charlie Kaufman wrote Being John Malkovich.

I decided to read about how Open Data could make San Francisco Public Transportation better.

I decided to read about how John Siracusa remembers Steve Jobs.

I decided, and then I read. I read, and I read.

So, thanks, Marco. You’ve made my life better by making it easier to decide to read. Then, you made it way easier to do the actual reading.

And, to you–the kind readers-of-prose-paragraphs who were inexplicably patient enough to decide to read this long article–please consider supporting Marco’s work.

Please get an account at Instapaper and, if you have an iOS dingus, please do buy the Instapaper app.

In addition to having exquisite taste in app icons and a lovely speaking voice, Marco’s just a very good human. And, good humans more than deserve our support.

Buy Instapaper 4.0 by Marco Arment.

The DML News App offers the best in news reporting.

The post VIDEO: AG Barr criticizes Mueller’s handling of Steele dossier appeared first on Dennis Michael Lynch.

The DML News App offers the best in news reporting.

The post REPORT: Recent documents reveal number of Secret Service agents with COVID-19 appeared first on Dennis Michael Lynch.

The DML News App offers the best in news reporting.

The post VIDEO: GOP senator says China made ‘conscious decision’ to allow COVID-19 to spread beyond border appeared first on Dennis Michael Lynch.

The province is investing $1.5 million to support a housing project in Muskoka to help people with no place to call home.

An "appalling prank" in Innisfil sent South Simcoe Police officers on a mission to identify the culprits involved.

While infection rates remain steady across the region, the Simcoe Muskoka District Health Unit is reporting more than half of all 360 cases have now recovered.

The incident happened in the West Point Grey neighbourhood around 3:30 p.m. on Wednesday, police said.

B.C. recorded 29 more cases of COVID-19 and one more death over the last 24 hours, provincial health officials announced Friday.

The following article, Donald Trump Jr. Offers To Walk Bride-to-Be Down The Aisle After Liberal Parents Refuse To Attend Her Wedding Because Fiance Is A Conservative, was first published on 100PercentFedUp.com.

TDS or Trump Derangement Syndrome brings out the worst in a lot of people. One young Texan girl’s story of her intolerant parents who refuse to attend her wedding because she’s marrying a conservative, however, is a new low. Lawyer and conservative civil rights activist, Rogan O’Handley tweeted a Tik Tok video of a Texan […]

Continue reading: Donald Trump Jr. Offers To Walk Bride-to-Be Down The Aisle After Liberal Parents Refuse To Attend Her Wedding Because Fiance Is A Conservative ...

The following article, Univ of Pittsburg Researcher, China Native, Dr. Bing Liu, “On the verge” of COVID19 Breakthrough Is Murdered…Alleged Gunman, Hao Gu, Kills Himself, was first published on 100PercentFedUp.com.

A 37-year-old China native and "outstanding researcher" at the University of Pittsburgh...

Continue reading: Univ of Pittsburg Researcher, China Native, Dr. Bing Liu, “On the verge” of COVID19 Breakthrough Is Murdered…Alleged Gunman, Hao Gu, Kills Himself ...

The following article, BREAKING: CBS News Allegedly Staged Fake COVID19 Testing In MI…Makes Dem Gov Whitmer Look Like She’s Doing More To Help Citizens Than Fed Government [VIDEO], was first published on 100PercentFedUp.com.

Project Veritas founder James O’Keefe has done it again. He’s uncovered yet another deceitful piece of coverage on the Wuhan coronavirus pandemic in America by CBS News. O’Keefe begins his interview with a man whose identity is being hidden, “You’re telling me—you’re 100% certain, that CBS News, CBS News Corporation national—staged a fake event. They […]

Continue reading: BREAKING: CBS News Allegedly Staged Fake COVID19 Testing In MI…Makes Dem Gov Whitmer Look Like She’s Doing More To Help Citizens Than Fed Government [VIDEO] ...

The following article, BREAKING: Sen Marsha Blackburn Introduces Stop COVID Act…Allowing US Citizens To Sue Communist China For Damage They’ve Inflicted On Our Nation, was first published on 100PercentFedUp.com.

Yesterday, Senator Marsha Blackburn (R-TN), along with Senator Martha McSally (R-AZ) introduced the Stop COVID Act, giving Americans the ability to sue Communist China for the damage they’ve inflicted on our nation. Senator Blackburn appeared on Fox News with host Judge Jeanine where she explained the act to Jeanine Pirro. Blackburn told the Fox News […]

Continue reading: BREAKING: Sen Marsha Blackburn Introduces Stop COVID Act…Allowing US Citizens To Sue Communist China For Damage They’ve Inflicted On Our Nation ...

The following article, 77-Yr-Old MI Barber Defies Gov Whitmer’s Shutdown Order: ”I don’t need another mother” Shop Will Stay Open Until “Jesus walks in or until they arrest me” [VIDEO], was first published on 100PercentFedUp.com.

Emergency orders that “non-essential businesses” remain closed during the Covid-19 crisis have devastated small business owners across America. A wave of business owners across the nation are defying executive orders by their governors and opening their businesses anyhow. Yesterday, we reported about a small business owner in the state of Michigan, where Governor Gretchen Whitmer […]

Continue reading: 77-Yr-Old MI Barber Defies Gov Whitmer’s Shutdown Order: ”I don’t need another mother” Shop Will Stay Open Until “Jesus walks in or until they arrest me” [VIDEO] ...

The following article, BREAKING: MI Lawmakers File Lawsuit Challenging Governor’s “Improper” and “Invalid” Emergency Orders: “We’ve attempted to partner with our governor, but she’s rejected”, was first published on 100PercentFedUp.com.

In addition to crushing Michigan's economy, the governor's reckless, one-size-fits-all executive orders are harming an untold number of Michigan citizens.

Continue reading: BREAKING: MI Lawmakers File Lawsuit Challenging Governor’s “Improper” and “Invalid” Emergency Orders: “We’ve attempted to partner with our governor, but she’s rejected” ...

The following article, NY Shame: Workers Who Tested Positive For COVID-19 Were Allowed To Remain On The Job At Nursing Homes, As Death Toll For Nursing Home Patients Exceeds 3,000, was first published on 100PercentFedUp.com.

The coronavirus crisis at New York’s nursing homes is even worse than previously thought. Monday night, the state Department of Health issued new data, adding more than 1,600 people who were presumed to have died of the virus in nursing homes, but did not have a confirmed diagnosis, to the official toll. As of May […]

Continue reading: NY Shame: Workers Who Tested Positive For COVID-19 Were Allowed To Remain On The Job At Nursing Homes, As Death Toll For Nursing Home Patients Exceeds 3,000 ...

The following article, Dem Congresswoman: Biden Allegation ‘Put To Rest’ Because He ‘Went on TV’ And Denied It, was first published on 100PercentFedUp.com.

Democrat Rep. Dina Titus says that the allegations against 2020 Democrat presidential candidate Joe Biden are “put to rest” because he “went on TV” and denied them. Rep. Titus spoke with MSNBC’s Ayman Mohyeldin today about how she believes Biden because he flatly said he didn’t do it and didn’t say he doesn’t remember. It’s […]

Continue reading: Dem Congresswoman: Biden Allegation ‘Put To Rest’ Because He ‘Went on TV’ And Denied It ...

The following article, Chicago Inmate Switches Identities While Wearing Mask…Is Released from Jail, was first published on 100PercentFedUp.com.

A Cook County, Chicago inmate, was able to switch identities with another inmate allowing the wrong inmate to be released. How did they carry that off without anyone catching them? The inmate was wearing a mask when he was released, so it wasn’t as easy to identify him. Last Saturday, Quintin Henderson (pictured below), 28, […]

Continue reading: Chicago Inmate Switches Identities While Wearing Mask…Is Released from Jail ...

The following article, Texas Gov Abbott Frees Salon Owner Shelley Luther: “Criminals shouldn’t be released to prevent COVID-19 just to put business owners in their place”, was first published on 100PercentFedUp.com.

Texas Governor Greg Abbott just changed the coronavirus order to free Salon A La Mode owner Shelley Luther from jail. Abbott tweeted out a comment about the poor treatment of the business owner: Throwing Texans in jail whose biz’s shut down through no fault of their own is wrong. I am eliminating jail for violating […]

Continue reading: Texas Gov Abbott Frees Salon Owner Shelley Luther: “Criminals shouldn’t be released to prevent COVID-19 just to put business owners in their place” ...

The following article, Video Scrubbed of Obama-Biden Ambassador To China Praising Their Response to Coronavirus: “I take my hat off to China”, was first published on 100PercentFedUp.com.

During a recent interview on CNN, Obama-Biden ambassador to China (2014-2017) Max Baucus compared standing up to China on the coronavirus to “Hitler in the ’30s.” Baucus has proven himself to be sympathetic to China in recent interviews, where he puts down America and praises the Chinese. The MSNBC video via The Washington Free Beacon […]

Continue reading: Video Scrubbed of Obama-Biden Ambassador To China Praising Their Response to Coronavirus: “I take my hat off to China” ...

The following article, President Trump’s Navy Valet Tests Positive for Coronavirus, was first published on 100PercentFedUp.com.

One of President Trump’s personal Navy valets has tested positive for coronavirus. The valet, a member of the US Navy who works at the White House, had symptoms of the coronavirus Wednesday morning. He was tested, and his test came back positive for the virus. President Trump was reportedly informed about the situation and fake […]

Continue reading: President Trump’s Navy Valet Tests Positive for Coronavirus ...

The following article, Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days, was first published on 100PercentFedUp.com.

Salon A La Mode owner Shelley Luther was just released from jail today. The Texas Supreme Court and Texas Governor Greg Abbott both called for her release today (see below). When Luther left jail she was greeted by supporters who yelled “Shelley’s Free!” She thanked all of the new friends she’s made during this difficult […]

Continue reading: Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days ...

The following article, Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO], was first published on 100PercentFedUp.com.

While campaigning for her community organizer turned presidential candidate husband, Barack, Michelle Obama told a crowd of his supporters in Milwaukee, Wisconsin that for the first time in her life, she was proud to be an American. Four years later, Michelle Obama was a keynote speaker at the DNC convention, where she told Democrats how […]

Continue reading: Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO] ...

The following article, Woman Shoots Three Teenage McDonald’s Workers For Telling Her She Couldn’t Eat In Dining Room Over COVID19 Restrictions, was first published on 100PercentFedUp.com.

An angry Oklahoma woman shot at a group of teenagers working at a local McDonald’s after they explained to her that the dining room was closed due to coronavirus restrictions. 32-year-old Gloricia Woody was arrested by the Oklahoma City Police and charged with the shooting. From the Oklahoma City Police -Last night, officers were called […]

Continue reading: Woman Shoots Three Teenage McDonald’s Workers For Telling Her She Couldn’t Eat In Dining Room Over COVID19 Restrictions ...

The following article, BREAKING: Ex-Cop Father and Son Arrested and Charged With Murder of Black Man Jogging In Neighborhood…President Trump Responds [VIDEO], was first published on 100PercentFedUp.com.

The Georgia Bureau of Investigations has arrested a father and son duo, 64-year-old ex-cop, Gregory McMichael, and his son, 34-year-old Travis McMichael for the February murder of  24-year-old Ahmaud Arbery, a black man who was jogging through their neighborhood when they jumped in their truck and pursued him. Yashar Ali shared the news of the […]

Continue reading: BREAKING: Ex-Cop Father and Son Arrested and Charged With Murder of Black Man Jogging In Neighborhood…President Trump Responds [VIDEO] ...

The following article, BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations, was first published on 100PercentFedUp.com.

Barack Obama knew. Documents released yesterday that were used to exonerate President Trump’s new NSA General Flynn, prove that President Barack Obama was aware of the details of Michael Flynn’s intercepted phone calls on December 16 with then-Russian Ambassador Sergey Kislyak. On January 5, 2017, then-Deputy Attorney General, Sally Yates attended an Oval Office meeting […]

Continue reading: BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations ...

The following article, BREAKING: President Trump’s Fiery Interview On Fox & Friends…”These are dirty politicians and dirty cops…They put our nation in danger with other nations, including Russia” [VIDEO], was first published on 100PercentFedUp.com.

This morning during a nearly one hour interview with Fox & Friends, President Trump addressed the decision by the DOJ to drop the case against the innocent General Michael Flynn. Trump ripped into the “dirty politicians and dirty cops” who went after General Michael Flynn. President Trump called the players involved in the horrible plot […]

Continue reading: BREAKING: President Trump’s Fiery Interview On Fox & Friends…”These are dirty politicians and dirty cops…They put our nation in danger with other nations, including Russia” [VIDEO] ...

The following article, Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom, was first published on 100PercentFedUp.com.

The normalizing of pedophilia is not a far-right conspiracy theory...

Continue reading: Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom ...

The following article, BREAKING: Vice President Mike Pence’s Press Sec Katie Miller, Wife of President Trump’s Sr. Advisor, Stephen Miller, Tests Positive For COVID-19, was first published on 100PercentFedUp.com.

Only moments ago, White House Press Secretary Kayleigh McEnany confirmed that a member of Vice President Mike Pence’s team tested positive for coronavirus. Watch: White House Press Secretary Kayleigh McEnany confirms a member of Vice President Mike Pence's team tested positive for coronavirus pic.twitter.com/3VaUXbwMq7 — Bloomberg QuickTake (@QuickTake) May 8, 2020 Reuters White House Correspondent […]

Continue reading: BREAKING: Vice President Mike Pence’s Press Sec Katie Miller, Wife of President Trump’s Sr. Advisor, Stephen Miller, Tests Positive For COVID-19 ...

The following article, Busted! Late-Night Hack Comedian, Jimmy Kimmel Is Forced To Apologize For Sharing Highly Edited Video Of VP Pence To Make Him Look Bad, was first published on 100PercentFedUp.com.

Last night, Jimmy Kimmel, host of the low-rated, late-night Jimmy Kimmel Show, shared a deceptively edited video clip of Vice President Pence delivering PPE to a nursing home. Today, liberal activist Matt McDermott tweeted the videotaped segment on VP Pence that was edited to make the vice president look like he was faking a delivery […]

Continue reading: Busted! Late-Night Hack Comedian, Jimmy Kimmel Is Forced To Apologize For Sharing Highly Edited Video Of VP Pence To Make Him Look Bad ...

The following article, Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen”, was first published on 100PercentFedUp.com.

Is Joe Biden going to become the Democrat nominee and run against Trump in the fall?

Continue reading: Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen” ...

The following article, Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut, was first published on 100PercentFedUp.com.

When Dallas, Texas salon owner Shelley Luther opened her salon in defiance of the lockdown order in Texas, she was visited numerous times by the local police and then sentenced to 7 days in jail with a fine of $7,000. After public outrage at her punishment, the Texas Supreme Court stepped in to demand her […]

Continue reading: Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut ...

The following article, Watch: Biden Pulls Awkward Stunt During Town Hall, was first published on 100PercentFedUp.com.

Joe Biden began his virtual town hall on Saturday with the political stunt of wearing a mask in his own home. Biden was attempting to host a live town hall with NowThis News, but glitch after glitch happened throughout the Biden campaign’s attempt to reach supporters. When the video below begins, it looks like he’s […]

Continue reading: Watch: Biden Pulls Awkward Stunt During Town Hall ...

The provincial government has announced it will support child care centres that have been closed since March with their fixed operating costs as the fight against COVID-19 continues.

One more person has died from the coronavirus in the Windsor-Essex region on Saturday and nine new cases have been reported by the health unit.

Mother's Day is Sunday, but with COVID-19, it's forcing many to change their plans.

Health officials with the Manitoba government announced on Friday that a COVID-19 outbreak at the Health Sciences Centre has officially been declared over.

Brandon police officers are searching for a man who was caught on camera attempting to pump gas in his car – without prepaying.

21 April 2020

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid–liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+. We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders.

Interferon-regulated myxovirus resistance protein B (MxB) is an interferon-induced GTPase belonging to the dynamin superfamily. It inhibits infection with a wide range of different viruses, including HIV-1, by impairing viral DNA entry into the nucleus. Unlike the related antiviral GTPase MxA, MxB possesses an N-terminal region that contains a nuclear localization signal and is crucial for inhibiting HIV-1. Because MxB previously has been shown to reside in both the nuclear envelope and the cytoplasm, here we used bioinformatics and biochemical approaches to identify a nuclear export signal (NES) responsible for MxB's cytoplasmic location. Using the online computational tool LocNES (Locating Nuclear Export Signals or NESs), we identified five putative NES candidates in MxB and investigated whether their deletion caused nuclear localization of MxB. Our results revealed that none of the five deletion variants relocates to the nucleus, suggesting that these five predicted NES sequences do not confer NES activity. Interestingly, deletion of one sequence, encompassing amino acids 505–527, abrogated the anti-HIV-1 activity of MxB. Further mutation experiments disclosed that amino acids 515–519, and Pro-515 in particular, regulate MxB oligomerization and its binding to HIV-1 capsid, thereby playing an important role in MxB-mediated restriction of HIV-1 infection. In summary, our results indicate that none of the five predicted NES sequences in MxB appears to be required for its nuclear export. Our findings also reveal several residues in MxB, including Pro-515, critical for its oligomerization and anti-HIV-1 function.

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.

Invitation Only Research Event

Event participants

Ali Farhan Hamid, Governor of Anbar Province
Chair: Dr Renad Mansour, Senior Research Fellow, Middle East and North Africa Programme, Chatham House

6 January 2020

Invitation Only Research Event

Event participants

Chair: Dr Lina Khatib, Director, Middle East and North Africa Programme, Chatham House