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Perhaps you've read somewhere or other that there are over 3,000 traditional Peruvian festivals held throughout the year? It's a popular claim that pops up time and again in guidebooks and on websites, and though we ourselves haven't verified the number, it certainly wouldn't surprise us! Peru is a country that holds onto its traditions while increasingly embracing innovation as well, a perfect storm for festivals and fiestas of all types to flourish and to grow.

If you're planning to visit Peru, you might find yourself intrigued by the prospect of observing, or even participating in, one of these many different Peruvian festivals. If that's the case, you're in luck--we've taken the liberty to compile a list of some of our favorite Peruvian festivals, including one for each month of the year in hopes that you'll find something that corresponds with the dates of your trip. Keep in mind that this is very much just the tip of the iceberg--all of these Peruvian festivals are fantastic, but there are many more that we've had to leave out simply due to the nature of our list. If we haven't included any options that work out with your travel itinerary, don't fret--get to researching and we're sure you'll find the festival for you.

So without further ado, let's get to it! Here is our list of twelve awesome Peruvian festivals, one for each month of the year:

1. January--Trujillo Marinera Festival

Trujillo, a coastal city in northern Peru, is the traditional home of the marinera, an elegant couple's dance making use of handkerchiefs as props. Since 1986 it's been the official national capital of this dance, a status celebrated annually in a month-long marinera festival held throughout the city! The Festival de Marinera, as it's known in Spanish, features dance competitions, parades, and even exhibitions of the Peruvian Paso, a breed of horse also recognized as part of the cultural patrimony of the Trujillo region. One of our favorite Peruvian festivals, this one is a can't miss if you find yourself in the area during January.

2. February--Fiesta de la Candelaria

The Fiesta de la Candelaria is not only the largest and most famous festival in Peru, but also one of the largest in South America as a whole--in fact, throughout the continent, it's only dwarfed by the world-famous Carnival in Rio de Janeiro and the Carnaval de Ouro in Bolivia. The first of many religious Peruvian festivals on our list, the Fiesta de la Candelaria celebrates the Virgin of Candelaria, the patron saint of the town of Puno where the festivities are held. Music and dance are at the core of this festival, all of it performed by elaborately-costumed participants numbering well over 40,000. An incredible two week-long synthesis of indigenous and Catholic traditions, this is one of the most iconic Peruvian festivals.

3. March--Festival Internacional de la Vendimia

Depending upon where Easter falls during a given year, the month of March can either be very busy or very quiet as far as major Peruvian festivals are concerned. That said, we figured we may as well take a break from the religious festivals to focus on something else with a different sort of appeal--wine! The Ica Region of Peru is famous for a number of things, the Nazca Lines and the desert oasis of La Huacachina among them, but those in-the-know also recognize it as the finest wine-producing region in the country. This role has been celebrated annually in March since the 1950s during the Festival Internacional de la Vendimia, or the International Harvest Festival, in which a queen is famously chosen to ceremoniously stomp the first grapes of the season.

 4. April--Festividad del Señor del los Temblores del Cusco

El Señor de los Temblores, or the Lord of the Earthquakes, is the patron saint of Cusco and the celebratory focus of this major Holy Week celebration. The story goes that during an earthquake here in 1650, a canvas image of Jesus Christ was held to the sky as prayers were offered, causing the tremors to subside and saving the town from ruin. Since then, this statue commemorating the original image has become the focal point of an important annual celebration. Each Easter Monday at 7 PM, the statue is removed from Cusco's cathedral and paraded throughout the city. Amazingly, it's said that the statue was not originally black, but rather that its color is due to years of exposure to smoke from incense during religious ceremonies.

5. May--Fiesta de las Cruces

First of all, let's be clear: the Fiesta de las Cruces, or the Festival of the Crosses, is not a uniquely Peruvian celebration. However, the way the Peruvians celebrate it does make it one of the most important Peruvian festivals. You see, the Festival of the Crosses is not held in just one spot in the country. Rather, the festival is celebrated in towns and cities throughout Peru, each putting their own unique spin on things. Though the name may conjure up solemn images, don't worry--festivals throughout the Peruvian highlands include music, dancing, and even events such as bullfighting as part of the celebrations.

6. June--Inti Raymi

Inti Raymi, the ancient Inca Festival of the Sun, is one of the most traditional Peruvian festivals on our list, indigenous in design and untouched by Catholic tradition. Held annually on June 24th, Inti Raymi is meant to celebrate the Winter Solstice--remember that we're in the Southern Hemisphere here! Banned by the Spanish and the Catholic Church after 1535, the modern incarnation of the celebration began in 1944 based on the few historical records of the festivities that managed to survive. Since then it has grown in size and scope, and though sometimes derided as tourist pageantry by detractors, its historical and cultural significance definitely make it worth checking out among the many Peruvian festivals.

7. July--Fiesta de la Virgen del Carmen

Another fine example of traditional Andean culture blended with Catholicism, the Fiesta de la Virgen del Carmen is held annually around the 16th of July in the relatively small town of Paucartambo, some four hours outside of Cusco. This three or four day festival is nominally religious but also one of the biggest and wildest parties in Peru, drawing visitors from all over the country, many of whom pass the nights sleeping under the stars as there's simply not enough space in town! If you know what you're looking for, you'll actually notice some serious Peruvian history depicted in the festival's songs, costumes, and dance--for example, black-masked dancers represent African slaves imported to work the silver mines here during the colonial era.

8. August--Día de Santa Rosa de Lima

Santa Rosa de Lima was the first native-born American saint canonized by the Catholic Church, and her legacy is celebrated throughout the world. However, it should come as no surprise that the grandest festivities take place in her home country of Peru. On August 30th, the anniversary of her death, celebrations and memorials take place throughout the country, the most famous being in Santa Rosa de Quives just outside of the capital city itself.

9. September--Mistura Culinary Festival

As you should know by now, Peruvian cuisine is some of the world's best and Lima in particular features what is probably South America's most impressive culinary scene. And as if the food wasn't enticing enough year round, the prospect of eating your way through Peru becomes even more appealing each September when the Mistura Culinary Festival rolls around. Featuring over 200 restaurants and bars not to mention plenty of outdoor vendors and food carts, well over half a million visitors stop by to enjoy the festival's offerings over the course of some ten days in mid-September. Though certainly not one of the most traditional Peruvian festivals on our list, this is without a doubt the most delicious.

10. October--Procesión del Señor de los Milagros

The story might sound a bit familiar--an 18th Century earthquake destroyed a good part of town leaving only this iconic image of Jesus Christ standing. This was considered a miracle, the image became even more venerated, and with time the celebration of its feast day became the largest religious celebration in Peru featuring one of the longest processions of any religious gathering in the world. If you're just looking to have fun, this one probably isn't for you--however, this considerably more solemn celebration is one of the most important Peruvian festivals and we couldn't leave it off our list.

11. November--Puno Week

Perhaps the name Puno rings a bell? If so, you've got a good memory--this is the same city where our February festival choice of the Fiesta de la Candelaria took place! Puno Week takes place during the beginning of November and centers around November 5th, also known as Puno Day. The purpose of Puno Day, and by extension Puno Week, is to celebrate the legendary birth of one Manco Cápac, said to be the first Inca. This involves a very interesting reenactment of his arrival on the shores of Lake Titicaca bordering the city--and it's also just a great excuse to party the whole week long.

12. December--Santuranticuy

As we wind down our list, a few things should by now be obvious: the first is that Peruvians love their festivals, and the second is that many of these Peruvian festivals feature religious--and here that means Catholic--themes. The final entry on our list is of course no exception--Santuranticuy is held exclusively in the city of Cusco each year on Christmas Eve, December 24th, and is essentially a massive outdoor marketplace set up to celebrate the holiday. The festival's name, which means "sale of saints," is quite appropriate, as the primary draw here are dolls, sculptures, and figurines used to decorate the nacimientos, or Catholic nativity scenes, found in many Peruvian homes during the Christmas season. However, even if you aren't religious, you're sure to find something of interest at this most shopper-friendly of Peruvian festivals.

When someone mentions “Peru,” images of bucolic mountain pastures, ancient Incan ruins, and verdant Amazonian jungle are probably the first thing that pop into your mind. But this beautiful South American nation boasts miles and miles of gorgeous Pacific coastline, and it is also home to some amazing beaches. Let’s take a look at some of best beaches Peru has to offer.

Cabo Blanco: Arguably the most famous beach along Peru’s 2,500 kilometers of coastline, Cabo Blanco is routinely hailed as one the best surf spots in the world. When Peruvian surfer Gordo Barreda was scouting the area for great waves, he randomly paid a visit to the village, where he stumbled upon the now famous Peruvian Pipeline. A hollow, powerful left-hanging wave, it is arguably one of the best places to catch a wave on the continent’s entire Pacific coastline. Even before Barreda’s famous discovery, this fishing hamlet long enchanted visitors with its small-town charm and thriving fishing industry. In the 1950s and 1960s, fishermen routinely made the trek to Cabo Blanco in search of the area’s legendary large marlin. The famous writer Ernest Hemmingway spent several months here during the filming of the movie adaptation of his novel “The Old Man and the Sea.” During his stay, he reportedly caught a 700-pound marlin.

Mancora: Once a quaint fishing village, Mancora has exploded onto Peru’s backpacker scene as a major hub in the last decade or so. Located right in the middle of Peru’s sunniest and warmest region, you can relax on beautiful beaches during the day and then party the night away. Mancora is great for travelers on a budget, and cheap hostels abound.

Vichayito: If you want great beaches without a slew of rowdy partiers, Vichayito is an excellent option. Situated about 7 kilometers to the south of Mancora, this is an ideal spot for families. The water is ideal for swimming and kite surfing, and the beaches are clean and quiet.

Punta Hermosa: Just an hour drive from Peru’s capital, Punta Hermosa is popular with Limeños looking for a summer retreat from the city. While not as spectacular as the beaches of Paracas or Mancora, Punta Hermosa’s proximity to Lima makes it a great option for looking for a quick weekend escape from the city.

Asia: Peru’s most opulent beach, Asia is all about glitz and glamour. The upper echelons of Peruvian society have luxurious summer homes at this beach resort town, making it a hub of wealth. The beaches are great, but what really make Asia stand out are its high-end restaurants, luxury shopping center, and dazzling nightclubs.

Paracas: The Paracas National Reserve boasts some of Peru’s most dramatic desert landscape. Here, enormous sand dunes and dramatic sandstone rock formations meet the azure waters of the Pacific. The reserve, which consists of a total of 335,000 hectares of tropical desert on the Paracas Peninsula, is intended to preserve the area’s rich marine ecosystem as well as protect its unique cultural heritage (the site was of great significance to the Paracas, a pre-Colombian indigenous group that inhabited the area between roughly 800 BC and 1000 BC). There are no formal hotels within the reserve, though there are many sites popular with beach campers.

If you are looking for more luxurious accommodations, they can certainly also be found. Though beach destinations to the north of the country often attract the majority of tourist attention, it is Paracas where you will find the most luxurious beach vacations Peru has to offer. Just a few miles from the park’s entrance, you will find Hotel Paracas, a Luxury Collection Resort complete with 5-star accommodations, three pools, and a luxury spa.

Marcona: For those really looking to get off of Peru’s beaten tourist trail, we recommend a visit to the rugged, windswept beaches of Marcona, located roughly 8 hours south of Lima. The waters here can be quite cold year-round thanks to the Humboldt current, which brings water up from Antarctica along the Pacific coast of Chile and southern Peru. But the cold temperatures mean that waters are teeming with marine life. With any bit of luck, visitors might catch a glimpse of one of the zone’s enormous seal colonies. The beaches are known for their dramatic rock formations and rough surf, but they are a great place for those looking for options totally free of tourists.

So they you have it, our pick of the best Peruvian beaches. Happy adventuring in Peru!

Part of the Going for gold promo for the BBC UK Homepage

Steve Jobs' 2005 Stanford Commencement Address

No one wants to die, even people who want to go to Heaven don't want to die to get there.

And yet, death is the destination we all share. No one has ever escaped it.

And that is as it should be. Because death is very likely the single best invention of life.

It's life's change agent; it clears out the old to make way for the new.

[…]

Your time is limited, so don't waste it living someone else's life. Don't be trapped by dogma, which is living with the results of other people's thinking. Don't let the noise of others' opinions drown out your own inner voice, heart and intuition. They somehow already know what you truly want to become. Everything else is secondary.

None of us should ever have to face death to accept the inflexible and, too-often, novel sense of scarcity that it introduces.

In fact, it'd be great if we could each skip needing outside permission to be awesome by not waiting until the universe starts tapping its watch.

A simple start would involve each of us learning to care just a little more about a handful of things that simply aren't allowed to leave with us--whether today, tomorrow, or whenever. Because, I really believe a lot of nice things would start to happen if we also stopped waiting to care. A whole lot of nice things.

If that sounds like fancy incense for hippies and children, perhaps in a way that seems frankly un-doable for someone as practical and important and immortal as yourself, then go face death.

Go get cancer. Or, go get crushed by a horse Or, go get hit by a van. Or, go get separated from everything you ever loved forever.

Then, wonder no longer whether caring about the modest bit of time you have here is only for fancy people and the terminally-ill.

Because, the sooner you care, the better you'll make. The better you'll do. And the better you'll live.

Please don't wait. The universe won't.

[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.

• Vimeo Page
• Direct Download Link (589 mb, requires login)

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.

An eight-year-old boy with good intentions sparked a missing person search on Tuesday.

The Ontario government gave garden centres and nurseries the green light to open their doors to the public on Friday.

Police officers responding to a call about a man with a machete in Oppenheimer Park Friday afternoon found what they were looking for, and then some.

As British Columbians digest the implications in the steps the premier announced in reopening the province's economy, some residents have come to the conclusion they’re too much too soon.

With the eviction date looming for campers to leave Oppenheimer Park, B.C.'s social development minister says everyone is still expected to be out of the park by Saturday.

Labour laws haven’t changed in our province, but legal experts are already urging B.C. employers to be flexible and reasonable — while warning employees they may not be legally protected if they refuse work during the pandemic.

The following article, MI Barber Shop Owner Defies Gov. Whitmer Shutdown Order…Opens Business…Police Officer Walks In…Says, “I love you!”…Walks Out, was first published on 100PercentFedUp.com.

Last week, we reported about how Shelley Luther, owner of the Salon Á La Mode in North Dallas, Texas, who opened up her business in defiance of lockdown orders in the city. The salon owner said that she was ignoring a citation and a cease and desist order from the city to shut down. This one […]

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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] ...

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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, Breaking: Texas AG Calls for Immediate Release of Salon Owner Jailed for Opening…Texas Lt Gov Offers to Pay Salon Owner’s $7k Fine, was first published on 100PercentFedUp.com.

Salon A La Mode owner Shelley Luther opened her salon in defiance of the lockdown order for salons to stay closed during the coronavirus crisis. She boldly ripped. up the citation she was given by the police and refused to shut her doors. Luther hired a lawyer and went to court where an activist judge […]

Continue reading: Breaking: Texas AG Calls for Immediate Release of Salon Owner Jailed for Opening…Texas Lt Gov Offers to Pay Salon Owner’s $7k Fine ...

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, Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn, was first published on 100PercentFedUp.com.

Yesterday, after 3 1/2 years of having his character and integrity called into question, President Trump's first NSA, General Michael Flynn was finally...

Continue reading: Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn ...

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, Obama Private Call Released: Implores Political Operatives to Help Protect Him…”We gotta make this happen”, was first published on 100PercentFedUp.com.

Michael Isikoff at Yahoo News on Friday night released audio of a call from former President Barack Obama to political operatives and the media to help protect “the rule of law” by protecting him. Obama desperately wants the Deep State and media to protect him by helping elect Joe Biden: “The fact that there is […]

Continue reading: Obama Private Call Released: Implores Political Operatives to Help Protect Him…”We gotta make this happen” ...

At a time when store front vacancies are growing thanks to COVID-19, a new retail cannabis store in Pillette Village is hoping to open soon.

Essex County OPP have released a composite drawing of a suspect reported to be impersonating a police officer in Lakeshore.

Ontario’s provincial parks and conservation areas will reopen this week but campgrounds and beaches will continue to be off-limits for now.

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

A beverage company in the U.S. is inviting moms to let out a ‘quaranscream’ this Mother’s Day on a designated ‘zero-judgement venting hotline’ for a chance to win its wine spritzers.

Environment Canada has issued a special weather statement for the southwestern area of Manitoba.

21 April 2020

7 May 2020

The atypical trichromatic cyanobacterial phytochrome NpTP1 from Nostoc punctiforme ATCC 29133 is a linear tetrapyrrole (bilin)-binding photoreceptor protein that possesses tandem-cysteine residues responsible for shifting its light-sensing maximum to the violet spectral region. Using bioinformatics and phylogenetic analyses, here we established that tandem-cysteine cyanobacterial phytochromes (TCCPs) compose a well-supported monophyletic phytochrome lineage distinct from prototypical red/far-red cyanobacterial phytochromes. To investigate the light-sensing diversity of this family, we compared the spectroscopic properties of NpTP1 (here renamed NpTCCP) with those of three phylogenetically diverged TCCPs identified in the draft genomes of Tolypothrix sp. PCC7910, Scytonema sp. PCC10023, and Gloeocapsa sp. PCC7513. Recombinant photosensory core modules of ToTCCP, ScTCCP, and GlTCCP exhibited violet-blue–absorbing dark-states consistent with dual thioether-linked phycocyanobilin (PCB) chromophores. Photoexcitation generated singly-linked photoproduct mixtures with variable ratios of yellow-orange and red-absorbing species. The photoproduct ratio was strongly influenced by pH and by mutagenesis of TCCP- and phytochrome-specific signature residues. Our experiments support the conclusion that both photoproduct species possess protonated 15E bilin chromophores, but differ in the ionization state of the noncanonical “second” cysteine sulfhydryl group. We found that the ionization state of this and other residues influences subsequent conformational change and downstream signal transmission. We also show that tandem-cysteine phytochromes present in eukaryotes possess similar amino acid substitutions within their chromophore-binding pocket, which tune their spectral properties in an analogous fashion. Taken together, our findings provide a roadmap for tailoring the wavelength specificity of plant phytochromes to optimize plant performance in diverse natural and artificial light environments.

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts.

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1.

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

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.

21 January 2020

Discussions of North African integration have evoked ideas of a shared identity and a common destiny in the region. However, recent attempts to build regional blocs in North Africa have been unsuccessful. This paper examines the benefits of a ‘synergistic’ approach to North African cooperation. 

Invitation Only Research Event

Event participants

Jason Pack, Non-Resident Fellow, Middle East Institute
Tim Eaton, Senior Research Fellow, Middle East and North Africa Programme, Chatham House
Chair: Elham Saudi, Director, Lawyers for Justice Libya

19 February 2020

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection.

Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1.

Type IV filaments (T4F), which are helical assemblies of type IV pilins, constitute a superfamily of filamentous nanomachines virtually ubiquitous in prokaryotes that mediate a wide variety of functions. The competence (Com) pilus is a widespread T4F, mediating DNA uptake (the first step in natural transformation) in bacteria with one membrane (monoderms), an important mechanism of horizontal gene transfer. Here, we report the results of genomic, phylogenetic, and structural analyses of ComGC, the major pilin subunit of Com pili. By performing a global comparative analysis, we show that Com pili genes are virtually ubiquitous in Bacilli, a major monoderm class of Firmicutes. This also revealed that ComGC displays extensive sequence conservation, defining a monophyletic group among type IV pilins. We further report ComGC solution structures from two naturally competent human pathogens, Streptococcus sanguinis (ComGCSS) and Streptococcus pneumoniae (ComGCSP), revealing that this pilin displays extensive structural conservation. Strikingly, ComGCSS and ComGCSP exhibit a novel type IV pilin fold that is purely helical. Results from homology modeling analyses suggest that the unusual structure of ComGC is compatible with helical filament assembly. Because ComGC displays such a widespread distribution, these results have implications for hundreds of monoderm species.

Chatham House and Routledge, Taylor & Francis are launching the Journal of Cyber Policy on 2 July.