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Day 47: The Highs and Lows of Working Retail
High: You know which aisle each item is located in when you go shopping.
Low: Going shopping reminds you of work.
High: You provide a much-needed service for modern living.
Low: Your appreciation for humanity dwindles into a dark chasm.
High: You brighten people's day with a nice smile.
Low: Pretending to be fucking happy for eight hours straight.
High: If you're a cashier, you get to stay in one place.
Low: If you're a cashier, you have to stay in one place all freaking day.
High: You get mandatory breaks.
Low: Your breaks are 14 minutes and 59 seconds, not including peeing, pooping, smoking cigarettes, waiting in line to pay for the 12 Pizza Rolls that take 2 minutes to cook and 1 minute to eat.
High: You don't have to show up early.
Low: You can't punch in early and you can't punch in late, so if you are a punctual person you get to sit in your car for ten to fifteen minutes before work, smoking that last cigarette and contemplating your poor life choices, including the hangover that is pounding in your head.
High: If you are on the floor you get great exercise.
Low: You have to push a row of twenty carts through that sloppy foot of snow mid-March.
High: It is easy to get a job in retail.
Low: You are expendable.
High: You get discounts.
Low: You give your paycheck back to the people that gave you the money.
High: You have the opportunity to work up the corporate ladder.
Low: You have the opportunity to lose all of your dignity and become the very thing you used to hate.
High: You are welcomed with the holiday spirit as soon as you walk through the door.
Low: Listening to the same twenty songs for two straight months; Black Friday; all of December; December 23rd; December 24th; December 26th; and any other holiday.
High: Pricing and stocking shelves can be a zen-like experience.
Low: Facing the shelves can feel like a fine line between Purgatory and Hell.
High: Free old donuts.
Low: Becoming so depressed that you don't care that you are eating stale food.
High: Working a forklift.
Low: Dropping a big screen TV from fifty feet in the air and having to take a piss test after you've been smoking weed for the past five years straight.
High: Making fun of the customers.
Low: Knowing the customers are secretly judging you too.
High: Making close friends.
Low: Personal drama mixing with work drama, and work drama mixing with personal drama.
High: Learning how to properly fold clothes
Low: Folding a million fucking pairs of t-shirts, jeans, and sweaters every day, all day.
Author's Note #1: I have worked at Sam's Club, Best Buy, and Meijers. None of them compare to the great times I had working at Frank's Supermarket. Represent that green vest.
Author's Note #2: If you are moving and need boxes, go to your local grocery store and get egg boxes. They. Are. The. Best.


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This position supports the Life Cycle Contractor Support for the Joint Pacific Multinational Readiness Capability Instrumentation System (JPMRC-IS) program under the Army TADSS Maintenance Program (ATMP) at Schofield Barracks, Hawaii. JPMRC-IS operations support the Army s USARPAC mission: to provide realistic joint and combined arms training focused on developing soldiers, leaders, and units of the United States military for success on the 21st century battlefield. This experience includes capabilities of many of the world's best systems integration and engineering in the technical integration of live, virtual and constructive (LVC) training support.
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subset: commoncrawl


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21 Mar island car rental jamaica
Car Rental Jamaica Lease a car in Jamaica
Right under Cuba, right of Mexico and also left of Haiti sets Jamaica. An archipelago of islands between the UNITED STATES and southAmerica. A great holiday island along withmany sight observing locations and points to find, particularly throughrental car. Please check out our low-priced rental rates for Jamaica by carrying out a quote.
Here some tips to make it memorable.
Touring the Amazing Jamaica along witha Rental Car
Jamaica is actually officially referred to as the Commonwealthof Jamaica and it is actually the fourthmost extensive island car rental jamaica country one of the Greater Antilles nations. It is actually additionally measured as the fifthmost extensive country in the Caribbean. The nation was as soon as under the regulation of the Spanish, however it became a Britishcolony in the year 1655, under today title Jamaica. Jamaica is actually an Island along witha wealthy history, a lot of natural sceneries, communities as well as towns, therefore a lot more for its site visitors.
What are actually the nation' s access demands and also Customs?
If you are actually a U.S or even Canadian consumer, you perform certainly not require a ticket to get in Jamaica. All you need is actually prove that you are actually without a doubt a long-lasting citizen of these countries. Every other visitors, Britishincluded demand valid travel permits witha lowest of 6 months credibility period. There are actually migration memory cards that visitors receive issued withat the airport terminal, as well as you need to maintain it safely and securely, given that you need to surrender it when it involves leaving the country.
Can I rent a car in Jamaica?
There are plenty of cheap car hire companies in Jamaica, thus if you want to rent a car and also trip the Island in fashion, you may effortlessly access the solutions. The bright side is that there are a lot of global car rental companies where you may get services from, and you can easily also work witha car online. These providers do not focus on car rental alone, however you may additionally lease a motorcycle. To be on the risk-free edge, it is vital that you produce a car rental booking in advance, especially in the higher time. Various other transport means in Jamaica include;
What is the formal foreign language of Jamaica?
Jamaica utilizes Englishas its own main language. Nonetheless, a combination of Englishas well as a number of various other African languages, known as Patois is largely utilized. It is actually mainly utilized in country setups, however it is actually rapidly obtaining recognition in city facilities at the same time. A lot of Jamaicans understand as well as communicate Dialect.
What concerning money?
The money utilized in Jamaica is called the Jamaican buck. If you would like to spend for some given services like car rental, food, taxis to name a few things, it is most effectively to possess some Jamaican dollars withyou. Create an attempt to exchange your cashmoney at trusted banking companies and also certified money exchange bureaus.
Is it worthgoing to Jamaica?
Jamaica is actually an island wealthy in traveler locations. If you possess plans to travel the nation, go straight ahead of time, you are going to certainly not receive let down. There are impressive tourists' ' tourist attractions including;
The canopy scenic tour
An adrenaline-charged zipline is a tour where you get to envision trees that are actually forty five feets high. This is actually where you can open withthe heavy cover. If you desire that adventure of riding withcharming covers of a tropical paradise, challenge joining this fantastic excursion. You also appreciate scenic nature walks.
Dunns Waterway Fall/Ocho Rios buying Tours
Ocho Rios has actually emerged a paradise for buyers, and also it takes pride in the world renowned Dunns Stream falls. You acquire the option to travel the many craft markets in this unique community, just before eventually moving on to watchthe panoramic Dunns Waterway Loss that waterfall 600 ft (180m) into the sea.
Ocho Rios Dolphin run into
You obtain a chance to swim in the deep waters for thirty minutes witha dolphin, after a briefing and also intro from experienced resident instructors.
Car rental recommendations for Jamaica
Traffic rules in Jamaica
Traffic proceed the right edge of the road, overtaking gets on the right. Velocity limitations are actually: in towns 50 kilometres per hour; in open roadways 80 km per hour; on highway 110 kilometres per hour. It is actually certainly not enabled to cease on a main road; within 15 meter of a road junction; at or nearer than 12 meter from traffic signal, mundane crossings, fireplug, bus stopover, healthcenter or even institution entryway; on bulge back bridge.
Additional information
Most roadways are actually narrow, and also a ton of streets are in por circumstances without signs. Overseas chauffeurs should be incredibly mindful on streets and also consistently watchout for folks walking when driving or inbound cars and trucks driving in the moderate. Heavy storms may occur at any moment of the year and regularly leave streets imposible to pass. Motorists need to check climate condition from the media. In the course of complainer period, all roads near the ocean are actually filled withproperty complainers intercrossing the streets to come to the sea.
Additional driver
Extra driver/s could be included in the rental arrangement at an added cost. All vehicle drivers must be present back then of pick up plus all have to have authentic driving licenses.
Hotel delivery/collection
Additional cost for having actually the motor vehicle provided and also or collected from a resort address. Hotel distribution handle should be actually recommended when creating the reservation. Shipment is actually free within 1 mile of headquarters in Kingston.
For most locations it is actually feasible to take a rental car away from office hrs. When making a scheduling you may choose the pick up time. If the pick up opportunity desires opening hours, please inspection if there is an out of hours cost relevant. This charge must be actually spent on landing directly to the car rental firm. You can find the relevant information in the thoroughterms.
A rental car can merely be actually driven due to the major chauffeur but there is actually a possibility to add an added vehicle driver whichprimarily possesses an extra charge. You can figure out how muchit is actually by checking the in-depthconditions. The extra chauffeur will certainly need to have to be current at the local rental workplace when picking up the car to present his/her driver certificate. Some limitations may use. Satisfy check the thoroughconditions for this information.
Most car services supply a FAMILY DOCTOR navigation unit to browse your technique to your destination. It has an added cost whichis explained in the terms. Satisfy be urged as FAMILY DOCTOR navigating units are subject to accessibility of the car rental providers.
Rentalcargroup. com works witha lot of large and small car rental agencies, eachcar rental provider possesses their own terms and conditions. We encourage you to constantly read throughand inspect meticulously the thoroughterms prior to you reserve you car rental. Our call center is 7 days on call throughphone or even conversation if you have any sort of uncertainties pertaining to the conditions, we are happy to help you.
Rentalcargroup. com gives car rental in greater than 35000 places, whatsoever major airports as well as areas as well as railway stations. Listed below on this page you observe a chart along withall the car rental companies our experts collaborate within Jamaica.
Facts regarding car rental in Jamaica
I was actually really satisfied and satisfied along withcar rental adventure, customer support was the best ever before, island car rental in kingston jamaica is actually the most effective, they exceed and also past to create your rental an unforgettable one.i are going to be actually making use of island car rental jamaica and also will suggest all of them to everybody. derrick williams coming from canada.
Staff was friendly and also pick up and drowse off was actually all excellent! rncar was actually great nevertheless one tire worn out negative, some frontal point sound too, absolutely nothing serious however, returning the car was actually swift as well as i had placed a little blemishon frontal bumper and also there was one actually certainly there too, he didn't drive it, he let me go, nice guy really was. many thanks pal! i will certainly rent there once again if the cost is as good as it was. good job children!


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Why Kinetic Emails Are Setting Marketing on Fire in 2020
But what are Kinetic Emails?
Basically, kinetic emails are interactive content that boost your email marketing to the next level of engagement. Not to mention fun. Kinetic emails primarily include interactive email design elements, like sliders, search menus, GIFs etc, that create an interactive experience for readers.
If executed correctly, kinetic emails provide a more website like experience for users.
Mirroring a website experience, allows users to take advantage of multiple interaction points and explore a host of product offerings.
Because kinetic design utilizes CSS3 and HTML5 to enhance interactive elements, it is compatible with Gmail, Yahoo, AOL, Outlook 2003, Outlook.com, iPhones, iPads and some Android devices. Many platforms also integrate fallback techniques to ensure that these emails do not render poorly. Especially on email domains that do not support kinetic content and design.
Why Are Kinetic Emails Becoming So Popular?
Well, there are a few reasons. Firstly, consumers want everything at their fingertips, right now. Thanks to the rise of the connected era, consumers have access to literally everything within seconds. Kinetic emails allow consumers to view and interact with your content and products instantly. All without having to commit to visiting your website.
By the same token, modern consumers have adopted a choose your own adventure mindset. Meaning, they want to steer the ship when it comes to their interactions with brands.
Basically, that means they need to be able to peruse your wares at their leisure. Equally important, consumers want to decide when and if they are going to visit your website in their own time. Kinetic emails allow them to do just that. Which intern creates relationship of trust between them and your brand.
As if these weren't enough to get you to dive into adding kinetic emails into your marketing strategy, check out some of the other awesome reasons why kinetic will be taking over the email marketing landscape in 2020.
Rich Visual Experience
Kinetic emails are designed around the concept of offering the users a rich visual experience, directly in their inbox. Additionally, visually rich emails use a coding technique that enables creation and rendering of high-impact, interactive emails.
Website Experience
Kinetic emails use animation and style templates to highlight key content. As a result, kinetic design provides more of a website experience within the actual email itself. Uniquely giving users the opportunity to interact with the email content and explore different product offerings.
Rich User Interaction
Entertaining Email Recipients
According to proven psychological principles, the utilization of interactive content leads to curiosity among email recipients. Of course, curiosity and exploration often foster higher engagement rates which is an important goal for any marketer.
Creating an entertaining way for users to interact with your brand and explore your products creates excitement. Coupled with a commitment free way for consumers to explore your products, this strategy builds trust and ultimately boosts brand loyalty.
Email Personalization
The key ingredient of dynamic emails is the content. It especially plays a vital role in retail campaign management because it provides in-depth user information. Notably, content can be leveraged to determine a customers user affinity towards a certain product or products. These insights can be utilized to serve up custom suggested content and purchases for clients throughout their customer journey.
In order to build a reciprocal relationship with customers, personalized marketing is critical. As a matter of fact, it plays a major role increasing customer awareness, loyalty and endorsement.
Not only that, email personalization is the basis for all kinetic email marketing. In fact, kinetic emails take personalization a step further by creating an interactive, choose your own adventure type style for clients.
Dynamic Emails
The key ingredient of dynamic emails is the content. It especially plays a vital role in retail campaign management because it provides in-depth user information. Notably, content can be leveraged to determine a customers user affinity towards a certain product or products. These insights can be utilized to serve up custom suggested content and purchases for clients throughout their customer journey.
The combination of dynamic and kinetic elements in your email marketing is guaranteed to boost engagement.
Who could resist a fully interactive email filled with a selection of products to explore, tailored to your personal preferences?
Targeting Recipients
In Short...
Kinetic emails are winning over marketing teams and setting email marketing on fire for 2020. As marketers, it is our job to identify and deliver experiences that our customers are looking for. Looking ahead to 2020, it is clear that kinetic emails deliver exactly what customers are looking for. An interactive, engaging experience with our brands. In other words, an interaction that allows them to take control, exploring product offerings without the pressure of making a commitment.
Today's customers want to make informed decisions on their own terms. Kinetic email allows them to do that in a simple and efficient way. If you haven't begun to integrate kinetic element into your email marketing strategy you really should. The benefits to your customer engagement strategy will be numerous.
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Choose from our service lines and submit the form, then we'll get in touch to explore how Theorem can help grow your digital revenue.
Become Your Customer's Concierge Using Contextual Marketing
By definition, contextual marketing is an online marketing model that delivers personalized, relevant content to each of your customers. Typically based on identifiers and preferences. In other words, location, local weather, past purchases, recent browsing behavior, time of opening the email, etc. It's no surprise that these personalized, timely and relevant emails create meaningful brand interactions with your customers.
In order to implement a contextual marketing strategy, it is important to be collecting and leveraging as much customer data as possible
Utilizing data is the only way you can accurately anticipate the future needs and desires of your client base.
If you are not implementing a strong data collection strategy, I highly recommend it.
In Fact
Generally speaking, brands that strategically utilize customer data insights to deploy structured contextual marketing see up to a 10% increase in engagement. You know what that can mean for your ROI and bottom line.
But What Is a Good Contextual Marketing Strategy Really?
Ok so the definition of contextual marketing is pretty straight forward. That being said, what does a real world example of this strategy really look like?
Let's say you are in the market for a new car. For the last three weeks, you have searched the web endlessly. Checking out a variety of makes and models. Namely something that will be just right for your family road trips, sporting events, carpools etc.
You spend your early morning hours researching. You know before the day becomes filled with work deadlines and after school activities, researching. Explicitly scrolling through different SUVs and crossover vehicles while sipping your morning coffee.
Just for fun, you also just so happen to live in New England, where the winters can be long and the road conditions treacherous.
What Does that Mean Exactly?
In this case, you would receive an email around 5 am showcasing their top selling line of family friendly vehicles. All of which, will be top safety rated AWD vehicles with excellent performance on snowy and icy roads. Of course, if they want to really capture your attention they will include an offer. A special incentive, an exclusive invitation to test drive at your local dealership.
And what does this mean for the marketing team at that ever so popular all terrain automobile company?
In short, they just served you up exactly what you wanted, precisely when you needed it.
Which, has a really good chance of winning your business. Win for them! And, gets you behind the wheel of the vehicle of your dreams. Win for you!
Who is Contextual Marketing Good For?
The reason why contextual email marketing is such a trending topic everywhere, is because it is applicable, and successful, anywhere. Since it leverages customer data and insights, contextual marketing strategies can be tailored to any brand in any industry.
What that means for marketing teams, is that they can create tailored emails for their customers that are guaranteed to increase their engagement rates and ROI.
Not Only That...
Contextual marketing is great for customers as well. Implementing these types of personalized marketing strategies means customers receive emails that are actually relevant to them.
And we all know customers are more likely to respond to emails that have information that pertains to them. Especially regarding something they have been actively researching. So why not take advantage of that in a way that benefits your customers as well?
In addition, contextualized marketing can provide relevant information that a customer may have been looking for. It is these bits of information, micro-moments, that can greatly influence a purchasing decision. Ultimately giving the customer what they want and need at precisely the right time.
How Do I Implement Contextual Marketing Correctly?
First Things First
The most crucial part of creating a contextual strategy is having a data strategy. Meaning you need to have a data collection, aggregation and visualization strategy in place. One that will allow you to compile, measure and leverage customer data accurately.
In other words, the first step to creating an amazing contextualize marketing strategy is creating a well rounded data strategy.
Below are some important tips to get you started on the road to contextual success:
Tip # 1: Provide Personalized Data-Driven Content
Tip # 2: Find Ways to Broaden Customer Engagement
The goal of every marketer is to create ways in which the customer can engage with their content. Specifically when that content is relevant to their anticipated need.
Developing new engagement strategies and points for customers provides more opportunities to collect data. Specifically more detailed information pertaining to customers interest, want and needs. Not only that, it creates an opportunity to showcase the brand and products. Ultimately the main purpose of which is nurturing a deeper connection between customer and brand.
For example, the SUV shopper may be asked about their auto budget via a brief survey.
Tip # 4: Target Audience Based on Specific Demography
A precise customer profile must be created based on customer behavior and insights. Specifically utilizing relevant data points like geographic locations, particular needs and interests.
Essentially, data driven customer profiles facilitate tailored messaging unique to the wants and needs of customers.
Remember a well planned data acquisition and visualization strategy will make this process fairly simple.
Tip # 5: Boost Confidence in Your Brand
It is important to limit the number of marketing efforts you deploy to customers. Too many messages can be intrusive and off-putting And ALWAYS provide an opt-in / opt-out on all of your marketing efforts.
This provides customer a sense of control in terms of their interactions with you. You are trusting them to be loyal and they are trusting to you give provide them what they need in the way they need it.
Tip # 6: Ensure Instant Customer Gratification
As we have discussed before, the need for instant gratification is more prevalent than ever before. This is especially true in terms of customer interest and research. Tracking your potential customer's page views and interactions on your site will allow you to predict and send information to customers at the moment they need it most.
Be sure to serve up the appropriate content within a relevant time frame.
This can be achieved by leveraging data to estimate what and when a customer will need information you can provide.
In other words, provide compelling messaging to the shopper that solves a problem with it arises. There is no better way to make a lasting impression and pleasantly surprises them!
Tip # 7: Make Use Of Available Robust Capabilities
Creating an multifaceted interactive email interface will capture and retain the customers attention.
If you want to really go wild dive into the world of kinetic email marketing. Go Ahead! Take your contextual emails to the next level. I promise you won't be sorry.
In a Nutshell
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5 Customer Engagement Challenges & How to Fix Them
So what does the current climate of customer engagement look like?
"95% of customers are looking for some degree of proactive communication from the companies with which they do business"*
Tight Turn Arounds and Low Bandwidth
A critical component of creating and executing an effective customer engagement strategy is having both the time and resources to bring it to fruition. Believe it or not, this is one of the most common challenges for companies of all sizes.
No matter how large or small, most brands do not have the time or internal reserves to execute a customer engagement plan. Let alone strategize, create, launch and monitor said plan.
As a result, many struggle to connect with their customers. Those that make an attempt, without a plan or resources, often fall short. Deploying poorly timed, sub-par messaging that misses the mark. The best way to overcome this hurdle is to increase your bandwidth and time.
But how?
The best brands know that they cannot possible do it all. Which is why they often seek out a partner, with credibility in the industry, who can pick up the slack. Alignment with a partner who can create and implement efficient and effective customer engagement is often the bet strategy.
Lack of Niche Skills and Certifications
The marketing landscape is in a state of constant evolution. While many brands have amazing in-house marketing teams, not all have in house customer engagement experts. And here's the thing, there is nothing wrong with that!
The industry is flooded with so many niche specialties, that there is no way one marketing person or team can have mastery of every skill.
The best thing you can do when something is not really in your wheelhouse, ask for help.
Chances are there is an expert or a team of experts, who can take on your challenges and over come them for you, just an email away.
Top brands know that they are better off outsourcing to partners who specialize in specific niche marketing, like customer engagement planning and execution. Because trying to build an in-house team can be costly ad time consuming. Often the overall cost to outsource is less than adding specialized teams. Not only that, but the quality and ROI for the campaign will be higher.
Disconnected Data Systems
With so many different platforms at our disposal accommodating our vast array of needs, the world is abuzz with talks of integrations and automation. There are a few reasons why many are struggling with integrating their systems and streamlining their processes.
Two of which include utilizing outdated systems as well as, using too many systems/softwares that require outside help for integraion. In both instances, there can be major disconnects. Inevitably leading to increased error rates and decreased success rate.
For example, if you are utilizing a customized CRM system. Specifically one that doesn't integrate into an email marketing platform, your customer engagement emails can not be automated.
This completely eliminates the possibility to utilized personalization of your emails. It also increases the likely hood of emails going out in error. Not to mention missing out on vital customer contact opportunities.
How can you tackle this issue as quickly and efficiently as possible?
In an ideal world you would update all of your platforms to user friendly systems that seamlessly integrate together. Sadly, it is never that simple. To ensure seamless connection between your marketing and customer base, your best bet is bringing in a third party expert to create an integrated system structure that suits your customer engagement needs.
Inability to Support Global Market
Thanks to the interconnected global community that is the internet, brands often have customers all over the world. This is wonderful for expansion and growth. But only if you have the ability to support a global market.
Either way, there is a simple way to curtail a lack of global marketing strategy, before it negatively impacts your organization.
Do your research and collaborate with a partner who is well versed in global marketing and customer engagement strategies. This alignment will ensure management of your global market. Not only that, it will allow your team to educate themselves on your specific global customer base and how best to market to them.
Diminished Brand Loyalty
Brand Loyalty is am important piece of every businesses success. After all, a loyalty increase of 7% can boost lifetime profits per customer by as much as 85%, and a loyalty increase of 3% can correlate to a 10% cost reduction.* The tricky aspect of establishing brand loyalty is meeting the high demands of the modern customer base.
Having a great product and amazing customer service is no longer enough to generate brand loyalty.
There are ever growing numbers of millennials and Gen Z entering the current consumer market. It is important to adapting your customer engagement strategies to suite their wants and needs. As a result, you can expect fierce brand loyalty. This means combining offers and a strong social media strategy and presence with rewards and websites that are easy to use.
Sounds simple, right? It's actually much more complicated than it looks on the surface. There are many well established brands that didn't pivot their customer engagement strategies to suite the younger generations. All of whom experienced diminished brand loyalty. Some to the point of no return.
If you take a look at the biggest brands in the world today, all of them have maintained a well planned and executed customer engagement strategy
Many of which created fierce brand loyalty among the most difficult to please audiences in history. But how did they do it? The truth is, many outsourced there client engagement planning and execution to an experience and well versed marketing partner(s).
But how did they do it?
The truth is, many outsourced there client engagement planning and execution to an experience and well versed marketing partner(s).
They collaborated with the best in the marketing industry because they understood the depth of the undertaking. They knew the impact this engagement plan would have on their companies overall success.
The Bottom Line
Customer engagement can present many challenges to variety of brands, large and small. The dynamic current of the global market and constantly connected client base can be difficult to navigate.
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Digital challenge? We've got a solution. Contact us today and let's get started.
Choose from our service lines and submit the form, then we'll get in touch to explore how Theorem can help grow your digital revenue.


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71 S Scribewood Circle, The Woodlands, TX, 77382
Rare 6 bed home on an oversized lot, Zoned to Tough K-6 in Sterling Ridge! Brand new roof, A/C 2019, wood flooring, designer carpet, crown molding, neutral paint, elegant lighting & fans. Bathed in natural light, energy efficient w/ Nest system, East facing back yard, mature trees, pergola & room for a pool. High ceilings upon entering give an open feel, study with French doors and formal dining room. The family room has a fireplace and is open to the kitchen w/ SS appliances and granite tops. The 1st floor master retreat has a XL closets, double sinks separate tub and shower. The huge game room was converted to a bedroom, though it could easily be used for either purpose. A great floorplan for extended family with 5 bedrooms up and 2 full baths, plus a study nook/loft. The attached oversized 3 car garage is equipped a dedicated line for Tesla/or similar, electric car charging & has epoxy floor coating. Walk to Tough, the 9th Grade Campus of TWHS, The YMCA or the public library.
71 S Scribewood Circle


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The Federal Election Commission, in the midst of what is shaping up to be the most expensive presidential campaign in history, cannot begin new investigations or file lawsuits because four spots on the six-member board are vacant.
The FEC also cannot certify matching funds for presidential candidates seeking public campaign money until the vacancies are filled.
The unfilled positions stem from a political stalemate over President Bush's nomination of Hans A. von Spakovsky to the commission. Mr. von Spakovsky, a former Georgia elections official and a lawyer in the Justice Department, served on the board last year as a recess appointment.
But Democratic Sens. Barack Obama of Illinois and Russ Feingold of Wisconsin have put holds on the appointment, prompting Senate Minority Leader Mitch McConnell to insist that Mr. von Spakovsky's vote be part of a slate with three other pending FEC nominations.
The deadlock has held up all four nominations and left the bipartisan board with two members, which is short of a quorum needed to conduct major business.
FEC officials said the matter hasn't stopped the commission from conducting its daily business. The commission's auditors, lawyers and investigators continue to review and process campaign-disclosure reports.
The board is scheduled to meet Jan. 24 to discuss advisory opinions and administrative matters.
Mr. Obama, who is seeking his party's presidential nomination, has raised concerns about what he called Mr. von Spakovsky's "active role" in a Georgia state law requiring voters to provide certain forms of official identification at the polls. He also questioned Mr. von Spakovsky's tenure as a lawyer with the Justice Department's Civil Rights Division.
But Mr. McConnell, Kentucky Republican, has defended Mr. von Spakovsky's record and said the FEC always has had three nominees each for Democrats and for Republicans.
"I think that's the right way to structure an agency like that, that could have a huge and adverse partisan impact on one party or the other," he said last month.
"The Democrats have their nominations, and we've picked ours," he said. "What we have here … the Democrats trying to veto one of our nominees. That isn't going to happen. They're all four going to go together, or none of them will be approved."
Presidential candidates who have been certified for seeking public funding could have to wait until the deadlock is resolved.
Former Sen. John Edwards of North Carolina, who also is seeking the Democratic nomination, has sought matching funds from the FEC. Sen. John McCain of Arizona, the front-runner among Republicans seeking the party's presidential nomination, also has filed paperwork for matching funds.
"We have the necessary resources to wage an aggressive campaign with the resources we currently have on hand," said Edwards campaign spokesman Eric Schultz. "We fully expect the FEC to meet their obligations under the public-financing system."
Copyright © 2020 The Washington Times, LLC.


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The Depot is temporarily closed due to COVID-19 precautions
The Depot offers business repair services for Macs and iPads. As an Apple Authorized Service Provider, we can not only fix issues, but upgrade things like hard drives and RAM for your corporate Macs.
Questions about what we do? Give us a call at 612-465-0700.


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Kareena Kapoor opened up about her life which gives a major impact on her personal and professional life in a recent interview with Anupama Chopra. The actor revealed that while she saw 2008's Tashan which was a flop but made her life super hit. But in Imtiaz Ali's 2007 romantic-comedy Jab We Met, which was a huge hit on silver screen made her life powerful. The turning point of her career.
Kareena said that it was Shahid Kapoor who convinced her to do Jab We Met.
"It was Shahid who actually said that I should hear the script of the film. He was like, 'It's amazing. The girl's part is amazing and you should do it.' He also got this entire project in a way, together and both of us ended up doing this film. After that, destiny had its own plan, and life took its course. And a lot happened during the making of this film, and we all went our separate ways and this beauty of a movie came out of it," she said.
While in Tashan which was starer with an actor like Anil Kapoor, Akshay Kumar, and Saif Ali Khan, flopped at the box office, but this film bought all positivities in Kareena's life and brought the great impact on Kareena's personal life since that's where she met her now-husband Saif.
Read More: Sonam Kapoor redefines romance with a passionate kiss under Eiffel Tower | See
"'Jab We Met' changed my career and 'Tashan' changed my life. Because I did meet the man of my dreams and I did marry him. And 'Jab We Met' took its own course and Shahid and I went our separate ways and this gem came out of it. I feel it was all really karmically connected. This was god's plan, because what else could it be?" she told Anupama.
She also revealed, I can't walk in the street of London and people still call me there "Poo", and now I am walking with my son, I don't want my son to be like OMG! why they are calling you Poo.


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A remote argon/hydrogen plasma is used to deposit amorphous hydrogenated silicon. The plasma is generated in a DC thermal arc (typical operating conditions 0.5 bar, 5 kW) and expands into a low pressure chamber (20 Pa) thus creating a plasma jet with a typical flow velocity of 103 m/s. Pure silane is injected into the jet immediately after the nozzle, in a typical flow mixture of Ar:H2:SiH4=55:10:6 scc/s. The electron temperature in the jet is low (typ. 0.3 eV) : silane radicals are thought to be produced mainly by hydrogen abstraction, but also by a sequence of dissociative charge exchange and consecutive dissociative recombination. In-situ ellipsometry yields refractive indices of 3.6–4.2 at 632.8 nm and growth rates of 10–20 nm/s. FTIR analysis yields a hydrogen content of 9–25 at.% and refractive indices of 2.7–3.3 in the infrared. The SiH density decreases with increasing hydrogen content, whereas the SiH2 density increases. Above 11 at.%, the majority of hydrogen is bonded in the SiH2 configuration. The optical bandgap remains constant at approximately 1.72 eV. The photoconductivity is of the order 101–6 (Ωcm) 1–6 and the photoresponse 106.
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Offices for sale in Cornwall
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Business park for sale
Approx 13,500sqft (1,250sqm) producing an attractive annual income. Opportunity for further letting or Owner occupation . Planning Permission for Re Development inc. Retail, Commercial & ... read more
Office for sale
A centrally located development opportunity offering scope for conversion to a variety of uses (subject to planning).The property is located in the historic Cathedral quarter of Truro city ... read more
Office for sale
10 Strangways Terrace, Truro, Cornwall TR1
Four storey property comprising professional offices on ground, first and second floors. A residential flat on the lower ground floor has been sold off on a 999 year lease. There is rear ... read more
Office for sale
67 Morrab Road, Penzance, Cornwall TR18
The property is 3 storey, in a corner position and has a retail/ A2 frontage. Forming part of the property is a small retail unit which is included and connected to No 67. Nearby is St John's ... read more
Office for sale
The White House, 24 Basset Road, Camborne, Cornwall TR14
Guide Price £300,000 Freehold. Former Council Offices. Grade II Listed. Nia 7063 sq ft (656 sq m). Rear car parking for approx 20 vehicles. Accessible position near A30. Alternative uses / ... read more
Office for sale
Former Post Office, High Cross Street, St Austell, Cornwall PL25
This former Post Office sorting house is arranged over ground floor, first floor and basement and comprises a mix of ancillary offices and w/c facilities. Externally there is parking area. ... read more
Office for sale
97-99 Fore Street, Saltash, Cornwall PL12
A superbly located freehold opportunity initially two separate buildings previously occupied by a solicitor's practice. Currently configured as office space the building lends itself to a ... read more
Office for sale
Saltash is an historic Cornish town, famous for the twin road and rail bridges over the Rover Tamar. The town is situated around 5 miles west of the City Centre of Plymouth with direct access ... read more
Office for sale
70-70A, Fore Street, Bodmin, Cornwall PL31
Income producing freehold building with vacant ground floor offices/retail (stp) with first floor residential flat let on AST. Leasehold may be available of ground floor space.Bodmin is one ... read more
Office for sale
New Premises At, Trevenson Road, Heartlands, Pool, Redruth, ...
The commercial unit is in a high profile development in the heart of cpr, suitable for a wide variety of potential uses. Location The unit is located on the junction of Trevenson Rd and ... read more
Office for sale
Freehold office/retail property for sale prominent corner double fronted building 1st and 2nd floor office suites ground floor retail shop The Property - This Freehold property comprises a ... read more
Office for sale
Westgate Street, Launceston PL15
Personally inspected by Tony Foster of Webbers Commercial who will be pleased to discuss this property with you in detail. However please note "Due to the present restrictions on movement put ... read more
Office for sale
15-17 High Cross Street, St. Austell, Cornwall PL25
Guide Price = £110,000+ **For Sale By Online Auction . To inspect the legal documents for this property go to our website to download the legal pack** A Vacant Mid Terraced Building Arranged ... read more
Office for sale
Current storage unit could be retail subject to informing local council This double fronted property has been used for years as a store, but it may be possible to re instate to a shop, with ... read more
Office for sale
The Old Stables, Liskey Hill, Perranporth TR6
Modern appointed loft style office accommodation with central heating and ground floor shower/wc facilities and outside parking in rural setting on the upper outskirts of the coastal town of ... read more
Office for sale
Glasteinan House, Tabernacle Street, Truro, Cornwall TR1
A detached commercial property available for the first time in over 30 years. There is a retail counter to the front of the ground floor and workshops to the rear. To the first floor is ... read more
* Sizes listed are approximate. Please contact the agent to confirm actual size.


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We keep working. Even with serious supply and travel restrictions in Spain, we are trying to supply our customers spread throughout the world with everything they may need from us. We hope from you a little understanding. Good health to all of you and remember STAY AT HOME.
Archivo de la categoría: BONZER 5
Plywood keels & Bonzer fins
Thanks to commited customers like Olatu, I can honestly assure my business Neira Custom Shop delivers products to everywhere. After 7 years since my company was created, my fins have been purchased in Europe, Australia, Hawaii, Norht and South América on and on. Saying that, check the new order shipped to Olatu…..specials fins for such boards.
Volan singles order
And here they are, for our friends @chusmasurf, couples of volan dolphin style, bonzer black center fins and custom twin fin set. 100% handmade, handfoiled , and made in europe. Check my web for the widest variety of fins you'll find at the world wide web.
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If you are a follower of this blog, that means you are a classic handmade styles stuff lover , you'll be impressed by this Bonzer 5 surfboard in wich every single thing you see in the pictures are created by my hands. Just take a minute to stare this beauty… comments are welcome!!
On the way
New 6'4 bonzer5 on the way. Hallofeen inspired set, twin cedar stringers with high density foam inserts. Something you hardly ever see at any surf shop. Stay tune to my blog to see this beauty finished.
Halloween dolphin fins, on fire and on the webpage as well. Check my e-shop to see the new batch of multicolored brand new creations.
60's inspired fins
A new batch of multicolored fins, 60's inspired, are ready to go on my web page. Remember, with every fin purchased you get the inox screw for free. Three different styles, low rider, pivot and bonzer for such a variety of boards. Enjoy the ride!!


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کد مقاله
عنوان مقاله
An Analytic Study of Mulla Sadra's Final View on Divine Knowledge of Immaterial Things
کلمات کلیدی :
divine knowledge ،
material ،
immaterial ،
Mulla Sadra ،
شماره :
96 Summer 2019
مشاهده شده :
فایل های مقاله :
Mulla Sadra has adopted different standpoints regarding the acceptance of material forms as a level of divine knowledge in his various works. He has sometimes explicitly agreed with this idea, sometimes remained neutral, and sometimes denied it. This paper is intended to shed some light on Mulla Sadra's final view in this regard based on his different standpoints in his works. In doing so, the author has investigated his various descriptions of God's knowledge of material things and his justifications and arguments for each of them. One of the justifications for such a variety of ideas is rooted in his shift from the divine Ishraqi knowledge to transcendent knowledge, while another one sees the root of this diversity in separating the receptacles of perpetual duration and time from each other. Here, the author demonstrates that both of the justifications are defective and argues that the only acceptable explanation for Mulla Sadra's final view of the knowledge of material things is the relative nature of the division of beings into material and immaterial ones. This solution conforms to the two fundamental approaches which Mulla Sadra has adopted regarding the necessity of gradation in existence and its perfections as well as the same-as-relation identity of possible things.
© 1394-1397 - طراحی و توسعه توسط سامانه یکپارچه مدیریت نشریات ایران سمینا


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It could also be that you are new to the world of western boots and are about to buy your first pair. When cowboy boots fit well, they should be. Try on both boots - your feet may be two different sizes. on a shoe), the proper location of the ball of your foot in the boot will ensure a good fit throughout. Have you always wanted to buy a pair of handmade cowboy boots? Are you a little afraid of buying them online? Are you worried they won't fit.
how should cowboy boots fit on the calf
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watch 02:27
The Loop (Games)
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Light it up!
- —In-game Description
Liteshow is an Uncommon Outfit that can be bought in the Item Shop for 800 V-Bucks. His female counterpart is Nitelite.
- This Outfit was last seen in the Item Shop on November 11th, 2019.
- Liteshow is a part of the Neon Glow set which includes the Nitelite Outfit, the Glowstick Harvesting Tool, the Glow Rider Glider, and the Neon Glow Loading Screen.
- No matter how bright it or the time of day, this Outfit always glows.
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**At the end of the Solutions Personal Contract Plan (PCP) agreement there are three options: i) pay the optional final payment and own the vehicle; ii) return the vehicle: subject to excess mileage and fair wear and tear, charges may apply; or iii) replace: part exchange the vehicle With Solutions Personal Contract Plan. 18s+. Subject to status & availability. T&Cs apply. Ordered by 31/03/2020 from participating Retailers. Indemnities may be required. Exclusions may apply. Not available in conjunction with any other offer and may be withdrawn at any time. Accurate at 01/20. Freepost SEAT Financial Services. ***Payable at the end of your agreement ^Excess mileage excludes VAT at the current rate.
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Biomed News
on Autophagy and mTOR
Issue of 2020‒02‒23
seventeen papers selected by
Viktor Korolchuk
Newcastle University
AMPK activation does not enhance autophagy in neurons in contrast to MTORC1 inhibition: different impact on β-amyloid clearance.
Macroautophagy is repressed during mitosis - seeing is believing.
Autophagy in Parkinson's disease.
Ultrastructural insights into pathogen clearance by autophagy.
The HOPS Complex Subunit VPS39 controls ciliogenesis through autophagy.
LC3C mediates selective autophagy of the MET RTK, inhibiting cancer cell invasion.
Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.
Beating the ER: novel insights into FAM134B function and regulation.
mTORC1-dependent protein synthesis and autophagy uncouple in the regulation of Apolipoprotein A-I expression.
Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression.
Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis.
Autophagic degradation of HAS2 in endothelial cells: A novel mechanism to regulate angiogenesis.
'High vault-age': non-coding RNA control of autophagy.
Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency.
Dimethyloxaloylglycine induces pexophagy in a HIF-2α dependent manner involving autophagy receptor p62.
Microautophagy regulates proteasome homeostasis.
Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block.
Autophagy. 2020 Feb 20. 1-16
AMPK activation does not enhance autophagy in neurons in contrast to MTORC1 inhibition: different impact on β-amyloid clearance.
Benito-Cuesta I
Ordóñez-Gutiérrez L
Wandosell F
The physiological AKT-MTORC1 and AMPK signaling pathways are considered key nodes in the regulation of anabolism-catabolism, and particularly of macroautophagy/autophagy. Indeed, it is reported that these are altered processes in neurodegenerative proteinopathies such as Alzheimer disease (AD), mainly characterized by deposits of β-amyloid (Aβ) and hyperphosphorylated MAPT. These accumulations disrupt the optimal neuronal proteostasis, and hence, the recovery/enhancement of autophagy has been proposed as a therapeutic approach against these proteinopathies. The purpose of the present study was to characterize the modulation of autophagy by MTORC1 and AMPK signaling pathways in the highly specialized neurons, as well as their repercussions on Aβ production. Using a double transgenic mice model of AD, we demonstrated that MTORC1 inhibition, either in vivo or ex vivo (primary neuronal cultures), was able to reduce amyloid secretion through moderate autophagy induction in neurons. The pharmacological prevention of autophagy in neurons augmented the Aβ secretion and reversed the effect of rapamycin, confirming the anti-amyloidogenic effects of autophagy in neurons. Inhibition of AMPK with compound C generated the expected decrease in autophagy induction, though surprisingly did not increase the Aβ secretion. In contrast, increased activity of AMPK with metformin, AICAR, 2DG, or by gene overexpression did not enhance autophagy but had different effects on Aβ secretion: whereas metformin and 2DG diminished the secreted Aβ levels, AICAR and PRKAA1/AMPK gene overexpression increased them. We conclude that AMPK has a significantly different role in primary neurons than in other reported cells, lacking a direct effect on autophagy-dependent amyloidosis.Abbreviations: 2DG: 2-deoxy-D-glucose; Aβ: β-amyloid; ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; AD: Alzheimer disease; AICAR: 5-aminoimidazole-4-carboxamide-1-β-riboside; AKT: AKT kinases group (AKT1 [AKT serine/threonine kinase 1], AKT2 and AKT3); AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; APP: amyloid beta precursor protein; APP/PSEN1: B6.Cg-Tg (APPSwe, PSEN1dE9) 85Dbo/J; ATG: autophagy related; ATP: adenosine triphosphate; BafA1: bafilomycin A1; CA: constitutively active; CGN: cerebellar granule neuron; CoC/compound C: dorsommorphin dihydrochloride; ELISA: enzyme-linked immunosorbent assay; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; Gmax: GlutaMAX™; IN1: PIK3C3/VPS34-IN1; KI: kinase-inactive; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3; MAPT/TAU: microtubule associated protein tau; Metf: metformin; MRT: MRT68921; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PRKAA: 5'-AMP-activated protein kinase catalytic subunit alpha; PtdIns3K: phosphatidylinositol 3-kinase; Rapa: rapamycin; RPS6KB1/S6K: ribosomal protein S6 (RPS6) kinase polypeptide 1; SCR: scramble; SQSTM1/p62: sequestosome 1; ULK1/2: unc-51 like autophagy activating kinase 1/2; WT: wild type.
2-deoxy-D-glucose; aicar; alzheimer; amyloid accumulation; bafilomycin A1; cultured cerebellar granule neuron; dorsomorphin; metformin; rapamycin; sh-SY5Y
Autophagy. 2020 Feb 20. 1-2
Macroautophagy is repressed during mitosis - seeing is believing.
Odle RI
Cook SJ
For the last two decades there has been wide ranging debate about the status of macroautophagy during mitosis. Because metazoan cells undergo an "open" mitosis in which the nuclear envelope breaks down, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. While many studies have agreed that the number of autophagosomes is greatly reduced in cells undergoing mitosis, there has been no consensus on whether this reflects decreased autophagosome synthesis or increased autophagosome degradation. Reviewing the literature we were concerned that many studies relied too heavily on autophagy assays that were simply not appropriate for a relatively brief event such as mitosis. Using highly dynamic omegasome markers we have recently shown unequivocally that autophagosome synthesis is repressed at the onset of mitosis and is restored once cell division is complete. This is accomplished by CDK1, the master regulator of mitosis, taking over the function of MTORC1, to ensure autophagy is repressed during mitosis.
ATG13 (autophagy related 13); Autophagy; CDK1 (cyclin dependent kinase 1); MTOR (mechanistic target of rapamycin kinase); MTORC1 (MTOR complex 1); RPTOR/RAPTOR (regulatory associated protein of MTOR complex 1); ULK1 (unc-51 like autophagy activating kinase 1); mitosis; omegasome
J Mol Biol. 2020 Feb 13. pii: S0022-2836(20)30103-0. [Epub ahead of print]
Autophagy in Parkinson's disease.
Hou X
Watzlawik JO
Fiesel FC
Springer W
Impaired protein homeostasis and accumulation of damaged or abnormally modified protein are common disease mechanisms in many neurodegenerative disorders including Parkinson's disease (PD). As one of the major degradation pathways, autophagy plays a pivotal role in maintaining effective turnover of proteins and damaged organelles in cells. Several decades of research efforts led to insights into the potential contribution of impaired autophagy machinery to α-synuclein accumulation and degeneration of dopaminergic neurons, two major features of PD pathology. In this review, we summarize recent pathological, genetic, and mechanistic findings that link defective autophagy with PD pathogenesis in human patients, animal and cellular models and discuss current challenges in the field.
Parkinson's disease; chaperone-mediated autophagy; macroautophagy; mitophagy; α-synuclein
Traffic. 2020 Feb 21.
Ultrastructural insights into pathogen clearance by autophagy.
Kishi-Itakura C
Ktistakis NT
Buss F
Autophagy defends cells against proliferation of bacteria such as Salmonella in the cytosol. After escape from a damaged Salmonella-containing vacuole (SCV) exposing luminal glycans that bind to Galectin-8, the host cell ubiquitination machinery deposits a dense layer of ubiquitin around the cytosolic bacteria. The nature and spatial distribution of this ubiquitin coat in relation to other autophagy-related membranes are unknown. Using Transmission Electron Microscopy we determined the exact localisation of ubiquitin, the ruptured SCV membrane and phagophores around cytosolic Salmonella. Ubiquitin was not predominantly present on the Salmonella surface, but enriched on the fragmented SCV. Cytosolic bacteria without SCVs were less efficiently targeted by phagophores. Single bacteria were contained in single phagophores but multiple bacteria could be within large autophagic vacuoles reaching 30 μm in circumference. These large phagophores followed the contour of the engulfed bacteria, they were frequently in close association with endoplasmic reticulum membranes and, within them, remnants of the SCV were seen associated with each engulfed particle. Our data suggest that the Salmonella SCV has a major role in the formation of autophagic phagophores and highlight evolutionary conserved parallel mechanisms between xenophagy and mitophagy with the fragmented SCV and the damaged outer mitochondrial membrane serving similar functions. This article is protected by copyright. All rights reserved.
Salmonella; autophagy; electron microscopy; phagophore; xenophagy
Hum Mol Genet. 2020 Feb 20. pii: ddaa029. [Epub ahead of print]
The HOPS Complex Subunit VPS39 controls ciliogenesis through autophagy.
Iaconis D
Crina C
Brillante S
Indrieri A
Morleo M
Franco B
Primary cilia are microtubule-based organelles that assemble and protrude from the surface of most mammalian cells during quiescence. The biomedical relevance of cilia is indicated by disorders ascribed to cilia dysfunction, known as ciliopathies, that display distinctive features including renal cystic disease. In this report, we demonstrate that VPS39, a component of the homotypic fusion and vacuole protein sorting (HOPS) complex, acts as a negative regulator of ciliogenesis in human renal cells, by controlling the localization of the intraflagellar transport 20 (IFT20) protein at the base of cilia through autophagy. Moreover, we show that VPS39 controls ciliogenesis through autophagy also in vivo in renal tubules of Medaka fish. These observations suggest a direct involvement of the HOPS complex in the regulation of autophagy-mediated ciliogenesis and eventually in target selection. Interestingly, we show that the impact of autophagy modulation on ciliogenesis is cell-type dependent and strictly related to environmental stimuli. This report adds a further tile to the cilia-autophagy connection and suggests that VPS39 could represent a new biological target for the recovery of the cilia-related phenotypes observed in the kidneys of patients affected by ciliopathies.
Autophagy. 2020 Feb 16. 1-3
LC3C mediates selective autophagy of the MET RTK, inhibiting cancer cell invasion.
Bell ES
Coelho PP
Park M
Macroautophagy/autophagy is an evolutionarily conserved degradative process with a central role in maintaining cellular homeostasis under conditions of stress, and recent evidence suggests this may occur in part through direct modification of cell signaling. The MET/HGF receptor tyrosine kinase (RTK) signaling axis is an important mediator of cell motility and invasion in normal cell functions and in cancer. We discovered a role for autophagy in regulating ligand-activated MET signaling and cellular responses. When autophagy is induced by starvation, the HGF-activated and internalized MET RTK is selectively recruited for autophagic degradation through complex formation with the MAP1LC3C autophagy protein. Decreased LC3C expression in cancer results in loss of autophagic degradation of MET and enhanced HGF-stimulated cell invasion implicated in metastatic progression. This emerging role for autophagy in selectively regulating signaling proteins has implications for understanding cellular adaptations to stress and the functions of autophagy at different stages of cancer progression.
Autophagy; HGF; invasion; LC3C; MET RTK; cancer; cell migration; signaling; signalophagy
Aging Cell. 2020 Feb 16. e13117
Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.
He Y
Li W
Lv D
Zhang X
Zhang X
Ortiz YT
Budamagunta V
Campisi J
Zheng G
Zhou D
The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.
MDM2; Senescence; USP7; apoptosis; p53; senolytics
EMBO J. 2020 Feb 19. e104546
Beating the ER: novel insights into FAM134B function and regulation.
De Leonibus C
Cinque L
Settembre C
To maintain cellular homeostasis, the endoplasmic reticulum (ER) necessitates a continuous removal of ER fragments via a selective, receptor-mediated, form of autophagy known as ER-phagy. In this issue of The EMBO Journal, Jiang et al (2020) shed light on how the best characterized autophagy receptor FAM134B mediates ER membrane fragmentation, the earliest event during ER-phagy. They propose a dynamic model for FAM134B protein oligomerization and ER membrane scission, which are driven by CAMK2B-mediated phosphorylation of the receptor and are altered in sensory neuropathy.
Metabolism. 2020 Feb 18. pii: S0026-0495(20)30050-0. [Epub ahead of print] 154186
mTORC1-dependent protein synthesis and autophagy uncouple in the regulation of Apolipoprotein A-I expression.
Georgila K
Gounis M
Havaki S
Gorgoulis VG
Eliopoulos AG
: Apolipoprotein A-I (ApoA-I) is involved in reverse cholesterol transport as a major component of HDL, but also conveys anti-thrombotic, anti-oxidative, anti-inflammatory and immune-regulatory properties that are pertinent to its protective roles in cardiovascular, inflammatory and malignant pathologies. Despite the pleiotropy in ApoA-I functions, the regulation of intracellular ApoA-I levels remains poorly explored.
: HepG2 hepatoma cells and primary mouse hepatocytes were used as in vitro models to study the impact of genetic and chemical inhibitors of autophagy and the proteasome on ApoA-I by immunoblot, immunofluorescence and electron microscopy. Different growth conditions were implemented in conjunction with mTORC inhibitors to model the influence of nutrient scarcity versus sufficiency on ApoA-I regulation. Hepatic ApoA-I expression was also evaluated in high fat diet-fed mice displaying blockade in autophagy.
: Under nutrient-rich conditions, basal ApoA-I levels in liver cells are sustained by the balancing act of autophagy and of mTORC1-dependent de novo protein synthesis. ApoA-I proteolysis occurs through a canonical autophagic pathway involving Beclin1 and ULK1 and the receptor protein p62/SQSTM1 that targets ApoA-I to autophagosomes. However, upon aminoacid insufficiency, suppression of ApoA-I synthesis prevails, rendering mTORC1 inactivation dispensable for autophagy-mediated ApoA-I proteolysis.
: These data underscore the major contribution of post-transcriptional mechanisms to ApoA-I levels which differentially involve mTORC1-dependent signaling to protein synthesis and autophagy, depending on nutrient availability. Given the established role of ApoA-I in HDL-mediated reverse cholesterol transport, this mode of ApoA-I regulation may reflect a hepatocellular response to the organismal requirement for maintenance of cholesterol and lipid reserves under conditions of nutrient scarcity.
ApoA-I; Autophagy; mTORC1
Dev Cell. 2020 Feb 12. pii: S1534-5807(20)30057-5. [Epub ahead of print]
Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression.
Marsh T
Kenific CM
Suresh D
Gonzalez H
Shamir ER
Mei W
Tankka A
Leidal AM
Kalavacherla S
Woo K
Werb Z
Debnath J
Although autophagy is being pursued as a therapeutic target in clinical oncology trials, its effects on metastasis, the principal cause of cancer mortality, remain unclear. Here, we utilize mammary cancer models to temporally delete essential autophagy regulators during carcinoma progression. Though genetic ablation of autophagy strongly attenuates primary mammary tumor growth, impaired autophagy promotes spontaneous metastasis and enables the outgrowth of disseminated tumor cells into overt macro-metastases. Transcriptomic analysis reveals that autophagy deficiency elicits a subpopulation of otherwise luminal tumor cells exhibiting basal differentiation traits, which is reversed upon preventing accumulation of the autophagy cargo receptor, Neighbor to BRCA1 (NBR1). Furthermore, pharmacological and genetic induction of autophagy suppresses pro-metastatic differentiation and metastatic outgrowth. Analysis of human breast cancer data reveal that autophagy gene expression inversely correlates with pro-metastatic differentiation signatures and predicts overall and distant metastasis-free survival. Overall, these findings highlight autophagy-dependent control of NBR1 as a key determinant of metastatic progression.
Keratin14; NBR1; Rubicon; TP63; autophagy; breast cancer; chloroquine; metastasis
Autophagy. 2020 Feb 19. 1-16
Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis.
Cui W
Sathyanarayan A
Lopresti M
Aghajan M
Chen C
Mashek DG
The autophagic degradation of lipid droplets (LDs), termed lipophagy, is a major mechanism that contributes to lipid turnover in numerous cell types. While numerous factors, including nutrient deprivation or overexpression of PNPLA2/ATGL (patatin-like phospholipase domain containing 2) drive lipophagy, the trafficking of fatty acids (FAs) produced from this pathway is largely unknown. Herein, we show that PNPLA2 and nutrient deprivation promoted the extracellular efflux of FAs. Inhibition of autophagy or lysosomal lipid degradation attenuated FA efflux highlighting a critical role for lipophagy in this process. Rather than direct transport of FAs across the lysosomal membrane, lipophagy-derived FA efflux requires lysosomal fusion to the plasma membrane. The lysosomal Ca2+ channel protein MCOLN1/TRPML1 (mucolipin 1) regulates lysosomal-plasma membrane fusion and its overexpression increased, while inhibition blocked FA efflux. In addition, inhibition of autophagy/lipophagy or MCOLN1, or sequestration of extracellular FAs with BSA attenuated the oxidation and re-esterification of lipophagy-derived FAs. Overall, these studies show that the well-established pathway of lysosomal fusion to the plasma membrane is the primary route for the disposal of FAs derived from lipophagy. Moreover, the efflux of FAs and their reuptake or subsequent extracellular trafficking to adjacent cells may play an important role in cell-to-cell lipid exchange and signaling.Abbreviations: ACTB: beta actin; ADRA1A: adrenergic receptor alpha, 1a; ALB: albumin; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A1; BECN1: beclin 1; BHBA: beta-hydroxybutyrate; BSA: bovine serum albumin; CDH1: e-cadherin; CQ: chloroquine; CTSB: cathepsin B; DGAT: diacylglycerol O-acyltransferase; FA: fatty acid; HFD: high-fat diet; LAMP1: lysosomal-associated membrane protein 1; LD: lipid droplet; LIPA/LAL: lysosomal acid lipase A; LLME: Leu-Leu methyl ester hydrobromide; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryo fibroblast; PBS: phosphate-buffered saline; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PLIN: perilipin; PNPLA2/ATGL patatin-like phospholipase domain containing 2; RUBCN (rubicon autophagy regulator); SM: sphingomyelin; TAG: triacylglycerol; TMEM192: transmembrane protein 192; VLDL: very low density lipoprotein.
Fatty acid; MCOLN1/TRPML1; PNPLA2/ATGL; lipid droplets; lipid metabolism; lipophagy
Matrix Biol. 2020 Feb 18. pii: S0945-053X(20)30011-1. [Epub ahead of print]
Autophagic degradation of HAS2 in endothelial cells: A novel mechanism to regulate angiogenesis.
Chen CG
Gubbiotti MA
Kapoor A
Han X
Yu Y
Linhardt RJ
Iozzo RV
Hyaluronan plays a key role in regulating inflammation and tumor angiogenesis. Of the three transmembrane hyaluronan synthases, HAS2 is the main pro-angiogenic enzyme responsible for excessive hyaluronan production. We discovered that HAS2 was degraded in vascular endothelial cells via autophagy evoked by nutrient deprivation, mTOR inhibition, or pro-autophagic proteoglycan fragments endorepellin and endostatin. Using live-cell and super-resolution confocal microscopy, we found that protracted autophagy evoked a dynamic interaction between HAS2 and ATG9A, a key transmembrane autophagic protein. This regulatory axis of HAS2 degradation occurred in various cell types and species and in vivo upon nutrient deprivation. Inhibiting in vivo autophagic flux via chloroquine showed increased levels of HAS2 in the heart and aorta. Functionally, autophagic induction via endorepellin or mTOR inhibition markedly suppressed extracellular hyaluronan production in vascular endothelial cells and inhibited ex vivo angiogenic sprouting. Thus, we propose autophagy as a novel catabolic mechanism regulating hyaluronan production in endothelial cells and demonstrate a new link between autophagy and angiogenesis that could lead to potential therapeutic modalities for angiogenesis.
ATG9A; endorepellin; extracellular matrix; hyaluronan; mTOR
Open Biol. 2020 Feb;10(2): 190307
'High vault-age': non-coding RNA control of autophagy.
Büscher M
Horos R
Hentze MW
RNA-binding proteins typically change the fate of RNA, such as stability, translation or processing. Conversely, we recently uncovered that the small non-coding vault RNA 1-1 (vtRNA1-1) directly binds to the autophagic receptor p62/SQSTM1 and changes the protein's function. We refer to this process as 'riboregulation'. Here, we discuss this newly uncovered vault RNA function against the background of three decades of vault RNA research. We highlight the vtRNA1-1-p62 interaction as an example of riboregulation of a key cellular process.
p62; riboregulation; vault RNA 1-1
Nat Commun. 2020 Feb 20. 11(1): 970
Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency.
Luciani A
Schumann A
Berquez M
Chen Z
Nieri D
Failli M
Debaix H
Festa BP
Tokonami N
Raimondi A
Cremonesi A
Carrella D
Forny P
Kölker S
Diomedi Camassei F
Diaz F
Moraes CT
Di Bernardo D
Baumgartner MR
Devuyst O
Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to deficiency of the mitochondrial methylmalonyl-coenzyme A mutase (MMUT). How MMUT deficiency triggers cell damage remains unknown, preventing the development of disease-modifying therapies. Here we combine genetic and pharmacological approaches to demonstrate that MMUT deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK1/Parkin-mediated mitophagy, causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. Using drug-disease network perturbation modelling, we predict targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived cells and alleviate phenotype changes in mmut-deficient zebrafish. These results suggest a link between primary MMUT deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and provide potential therapeutic perspectives for MMA.
Biochem Biophys Res Commun. 2020 Feb 16. pii: S0006-291X(20)30319-3. [Epub ahead of print]
Dimethyloxaloylglycine induces pexophagy in a HIF-2α dependent manner involving autophagy receptor p62.
Mu Y
Maharjan Y
Dutta RK
Kim H
Wei X
Kim JH
Kim D
Park C
Park R
Peroxisomes are metabolically active oxygen demanding organelles with a high abundance of oxidases making it vulnerable to low oxygen levels such as hypoxic conditions. However, the exact mechanism of peroxisome degradation in hypoxic condition remains elusive. In order to study the mechanism of peroxisome degradation in hypoxic condition, we use Dimethyloxaloylglycine (DMOG), a cell-permeable prolyl-4-hydroxylase inhibitor, which mimics hypoxic condition by stabilizing hypoxia-inducible factors. Here we report that DMOG degraded peroxisomes by selectively activating pexophagy in a HIF-2α dependent manner involving autophagy receptor p62. Furthermore, DMOG not only increased peroxisome turnover by pexophagy but also reduced HIF-2α dependent peroxisome proliferation at the transcriptional level. Taken together, our data suggest that hypoxic condition is a negative regulator for peroxisome abundance through increasing pexophagy and decreasing peroxisome proliferation in HIF-2α dependent manner.
Dimethyloxaloylglycine (DMOG); HIF-2α; Peroxisome biogenesis; Pexophagy; p62
Curr Genet. 2020 Feb 20.
Microautophagy regulates proteasome homeostasis.
Li J
Hochstrasser M
Proteasomes are highly abundant protein complexes that are responsible for most regulated protein degradation in cells under favorable growth conditions. When yeast cells are under nutritional stress, most proteasomes exit the nucleus and either accumulate in cytoplasmic condensates called proteasome storage granules (PSGs) or are directed to the vacuole by autophagy. Nitrogen starvation does not cause PSG formation but leads to degradation of proteasomes through the classical macroautophagy pathway. By contrast, carbon starvation or extended incubation in stationary phase results in both PSG formation and macroautophagy of proteasomes. Unexpectedly, we found that glucose limitation also causes proteasomes to be taken up directly into vacuoles by a microautophagy mechanism. Macro- and micro-autophagy occur in parallel in glucose-starved cells, and microautophagy appears biased toward aberrant or inactive proteasomes, leaving functional proteasomes to accumulate in PSGs. PSGs dissolve and proteasomes remobilize to the nucleus within minutes after glucose refeeding. We showed that AMP-activated protein kinase (AMPK) and endosomal-sorting-complex-required-for-transport (ESCRT) factors are required for proteasome microautophagy and also impact PSG dissipation and nuclear reimport of proteasomes after glucose refeeding. The insoluble protein deposit (IPOD) compartment provides an alternative means of proteasome homeostasis, including when microautophagy is impaired. Our findings reveal a surprising diversity of mechanisms for proteasome quality and quantity control during starvation. A mechanistic understanding of the AMPK-regulated ESCRT-mediated microautophagy pathway could provide new avenues for manipulating proteasome homeostasis and treating human disease.
AMPK; ESCRT; Microautophagy; Proteasome; Proteasome storage granule (PSG)
Autophagy. 2020 Feb 20. 1-20
Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block.
Sharma V
Makhdoomi M
Singh L
Kumar P
Khan N
Singh S
Verma HN
Luthra K
Sarkar S
Kumar D
Opportunistic bacterial infections amongst HIV-infected individuals contribute significantly to HIV-associated mortality. The role of HIV-mediated modulation of innate mechanisms like autophagy in promoting opportunistic infections, however, remains obscure. Here we show, HIV reactivation in or infection of macrophages inhibits autophagy and helps the survival of pathogenic Mycobacterium tuberculosis (Mtb) and nonpathogenic non-tuberculous mycobacterial strains (NTMs). The HIV-mediated impairment of xenophagy flux facilitated bacterial survival. Activation of autophagy by trehalose could induce xenophagy flux and kill intracellular Mtb or NTMs either during single or co-infections. Trehalose, we delineate, activates PIKFYVE leading to TFEB nuclear translocation in MCOLN1-dependent manner to induce autophagy. Remarkably, trehalose significantly reduced HIV-p24 levels in ex-vivo-infected PBMCs or PBMCs from treatment-naive HIV patients and also controlled mycobacterial survival within Mtb-infected animals. To conclude, we report leveraging of HIV-mediated perturbed host innate-immunity by opportunistic bacterial pathogens and show an attractive therapeutic strategy for HIV and associated co-morbidities.Abbreviations: AIDS: acquired immune deficiency syndrome; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; BafA1: bafilomycin A1; CFU: colony forming unit; CTSD: cathepsin D; CD63: CD63 molecule; EGFP: enhanced green fluorescent protein; FRET: Förster resonance energy transfer; GABARAP: gamma-aminobutyric acid receptor-associated protein; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GLUT: glucose transporter; HIV: human immunodeficiency virus; hMDMs: human monocyte derived macrophages; IL2: interleukin 2; LAMP1: lysosomal-associated membrane protein 1; LC3B-II: lipidated microtubule-associated proteins 1A/1B light chain 3B; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin; mRFP: monomeric red fluorescent protein; M6PR: mannose-6-phosphate receptor; NAC: N- acetyl- L -cysteine; NTM's: non-tuberculous mycobacteria; PBMC: Peripheral Blood Mononuclear cells; PIKFYVE: phosphoinositide kinase; FYVE-Type Zinc Finger; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; PtdIns(3,5)P2: Phosphatidylinositol 3,5-bisphosphate; ptfLC3: pEGFP-mRFP-LC3; ROS: reactive oxygen species; SQSTM1: sequestosome1; TFEB: transcription factor EB; MCOLN1/TRPML1: mucolipin 1; PIP4P1/TMEM55B: Human trans-membrane Protein 55B; UVRAG: UV Radiation Resistance Associate; VPS35: vacuolar protein sorting associated protein 35; WDR45: WD repeat domain 45; YCAM: Yellow Chameleon.
HIV-TB co-infection; mcoln1/TRPML1; non-tuberculous mycobacteria; opportunistic infection; pikfyve; trehalose; xenophagy


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The Best White House Comics
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DeLuca, who doesn't wear a hair prosthesis (or so he claims), says hair helps regulate body temperature and shield skin from ultraviolet radiation. The Hair Club for Men already has started The Hair Club for Kids, to help young cancer patients. "It's some of our most rewarding work," says Hair Club spokesman Mike Smith. "We're glad when we can make a difference."
P.S. Interesting option on the Hair Club for Men Voice Mail: "To hear about the status of your hair, press three."
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Disney Cruise Line - Stateroom 7066 Report
Review by: STLEdge
|Ship: Disney Dream
|Stateroom: 7066
|Condition: 5
|Deck: 7
|Category: 5C
|Location: Mid
|Sail Date: 10/03/13
Notes: Very convenient room to the midship elevators. No external noise of any kind. Only downside is that it faces the ocean at Castaway Cay as opposed to the beach.
|Ship: Disney Magic
|Stateroom: 7066
|Condition: 2
|Deck: 7
|Category: 5
|Location: Mid
|Sail Date: 08/17/08
Notes: Although the position is excellent there is considerable noise from deck 9 very early in the morning and also some vibration which we have not experienced before. Hope this can be rectified during dry dock.
- 04/05 - UPDATE: 38 Disney Wonder Crew Members Now Test Positive for COVID-19
- 04/05 - Disney Shares Recipe for Disney Parks Churro Bites
- 04/05 - Moving to Orlando: Local Flavor- Linda's La Cantina
- 04/04 - Jaleo Disney Springs Team Helping to Provide Meals for Nurses and Community
- 04/04 - Moving to Orlando: Four Things Disney Fans Should Know Before Moving to Orlando
- 04/04 - Saturday Snacks: Recreating the Chocolate Crinkle Cookie from Epcot's Holiday Cookie Stroll
- 04/03 - Daily Disney Video Fix! - April 3, 2020
- 04/03 - Port Canaveral Furloughs 50 Cruise and Recreation Segment Employees
- 04/03 - Inviting a Bit of Disney-inspired Beauty
- 04/03 - Will A Disney Parks Vacation Ever Be the Same After Coronavirus?


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Science Focus Podcast
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It was a good night offensively on the farm as the Chihuahuas, Missions, TinCaps, and AZL Padres all scored at least 5 runs. Out of that group, the TinCaps were the only team to lose. Hitting Prospect of the Day: Trea Turner/Nick Schulz Pitching Prospect of the Day: Rafael De Paula El Paso […]Full Article
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