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it's complicated July 17, 2018
The Struggle of Setting Digital Boundaries in an Open Relationship
By Shelby Lorman
Photo: J.V. Aranda
Welcome to It's Complicated, stories on the sometimes frustrating, sometimes confusing, always engrossing subject of modern relationships. (Want to share yours? Email pitches to itscomplicated@nymag.com.)
A month or so after my boyfriend and I made our relationship open, he sent me a strange Instagram message.
It was an innocuous video — swap in virtually any "funny web thing you'll forget about in two seconds," and you'll get the idea — but it was sent to me and another girl whose name I didn't recognize.
I clicked on her profile picture and engaged in what is, for many of us, the now-habitual exercise of piecing together disparate digital morsels. She was impossibly beautiful, and, according to her bio, an activist and model; she took a lot of selfies squatting in front of mirrors, her head cocked just so. (How do some people look so good while squatting?) I clicked on another picture of her at random — this time lounging in her bedroom, looking dewy — and saw a comment from my boyfriend: "Where are you?"
It seemed like this was a girl he might be seeing. I took a screenshot and sent it to my boyfriend, curious, but not yet accusatory — because what exactly would I be accusing him of? We were open. We were allowed to see other people. Neither of us wanted those people involved in our primary relationship, though, so I wasn't entirely sure why he'd looped both of us in to the same message thread. At any rate, I was fairly certain this wasn't some ill-thought-out introduction to a hot girl for us to "share."
Sure enough, when we talked about it, it turned out he'd meant to send the video to us individually. The comment he left on her photo was a joke, one made while she was in the bathroom on their second date. And for the time being, that's how we left it.
My boyfriend is still mortified by this moment even now, a year later, but I return to it because it's such a clear example of our biggest, most glaring blind spot. Social media extends through our screens and into our intimate partnerships — and yet I found myself lacking the language to talk critically about how these everyday internet exchanges impacted our relationship offline.
Which, clearly, they did. Offline, we talked candidly about problems that creep into all kinds of relationships: with jealousy, trust, communication, honesty. We made rules and boundaries for how to navigate these realities, especially in a relationship that included other people. But we didn't talk about how these things ran rampant on the internet.
I look back on how we handled the opening up of our relationship and find, as a millennial is wont to do, a helpful a comparison in Harry Potter. There's a moment in The Order of the Phoenix when Cho Chang, mourning Cedric's death, tells Harry she wishes Cedric had just "known this stuff," been better versed in Defense Against the Dark Arts, so that he could have stood a chance against Voldemort. To which Harry says Cedric "was really, really good!" He knew everything he needed to know to survive. Voldemort was just more powerful.
I suppose in this metaphor, social media is Voldemort. We didn't do our version of an open relationship perfectly, at all. It was messy and, in the end, not the right model for us. (We're now monogamous.) But we were really, really good at talking about and practicing the type of communication we wanted. We trained as hard as we could, but in the face of something so amorphous, sinister, and sprawling, we inevitably found ourselves struggling. We were not, alas, the chosen ones.
Here's some important personal context: for the first year of our relationship, my boyfriend and I were — simultaneously — getting more attention on Instagram. We encouraged each other to share our art with the world and soon amassed hundreds, then thousands, of followers.
In my corner of the internet, a community was growing around my comics, which are dedicated to unpacking the nuance of relationships, dating, and toxic masculinity, and seeing so many people react to them felt like catharsis. But seeing people talk to him on social media felt like the opposite: I found myself playing a perpetual game of "fan or friend?" about people who commented on his photos, then wondering which was more threatening.
Sorting out what was flirtation versus "audience engagement" became a pastime. People would comment "I'm obsessed with you" on videos he posted of himself, and sleuthing revealed they all seemed able to pull off short bangs. And probably looked great squatting. Once, on a night that we'd decided to spend apart while keeping texting to a minimum, he posted a Boomerang of a candle flickering to his Instagram story. I didn't know where he was, or with who, but then again, I had agreed to that. Still, I spent that night creating imaginary narratives for myself of what was going on, sinking deeper into digitally induced paranoia.
And there were more of them, moments like these that I couldn't prepare for. I began bracing myself every time I picked up my phone to encounter something that gave me that sinking, sick feeling in my stomach, the too-familiar itch of not-rightness that happens when you discover information you are conceivably allowed to know, but not supposed to.
We flailed in the general direction of solutions, like limiting texting or being mindful about keeping things in DMs over comments. And sometimes, when I could feel the paranoia kicking in, I would just ask my boyfriend what certain people meant to him. Like the time he commented "you are pretty" on one of Cara Delevingne's photos, an act he thought was funny and I could only interpret as some indication of (a clearly impossible) offline connection. But to ask about every single digital exchange wasn't exactly sustainable.
Of course, social media is weird regardless of what type of relationship you're in. But incidents like the accidental group chat between my boyfriend, the model, and me, as they accumulated in the year we spent in an open relationship, clarified something essential for me: We're so inundated in the amount of access we have to everyone, all the time, that it's easy to dismiss how this impacts us, especially romantically. It was this constant (if fragmented) access to my boyfriend that made me feel like a voyeur, peering down into my own relationship.
I saw a tweet recently (I forget from who) that remarked on the bygone era of saying "be right back" online. BRB is gone, because we're always here. If you're looking, there are traces of our exchanges everywhere. Even Venmo. But that unending, direct line into someone else's technological sphere isn't communication. It's a glorified version of trading "what's up" back and forth forever.
We found solace, perhaps expectedly, offline. We settled on phone calls when we needed to communicate, which gave us depth and–more importantly–intentionality. Even when we went back to being monogamous, the phone calls gave us the time to talk about the things that matter. Like if writing about the squatting hot girl in an article on the internet was okay, and whether I too could pull off that same pose if I stretched and tried some yoga someday.
To be clear, we were never experts in setting digital boundaries. In fact, we were pretty bad at it. But we made space for serious conversations about how we, as partners, were in a separate, strange relationship with social media – as are most people, regardless of follower count. As a unit, we gave credence to how even the smallest exchanges can feel not-right, and naming that—voicing it—was freeing.
Setting Digital Boundaries in an Open Relationship


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Home > Choix de la rédaction > Montana reissued by Gareth Pugh
Montana reissued by Gareth Pugh
- 13 février 2019 21 février 2019
11 great looks from Claude Montana reissued by Gareth Pugh.
Montana reissued by Gareth Pugh.
Source MG Graffin
Vote : 5 (100%) 9 vote[s]
Young designers are inspired and obsessed with the work of Claude Montana. more or less at a distance, from the French fashion designer, from his 1980s women, to strangled leather trousers and over-shoulder jackets. Only, Claude Montana gave up his mark in 1997. Among the fans of the first hour, Gareth Pugh. The English designer was given carte blanche to reissue 11 emblematic models created between 1979 and 1994. A project initiated by the vintage gems expert Gill Linton, founder of Byronesque, and put on sale on the Farfetch e-shop.
Strong shoulders and power proportions – Claude Montana did it first and best. This short film, made in collaboration with NOWNESS, celebrates his legacy and features industry figures, from Yasmin Le Bon to Joe Gafney and Marc Jacobs, that worked with or were influenced by the radical 1980s designer. And now, Byronesque has just reissued a limited collection of signature Montana designs, to be sold exclusively on Farfetch.
Claude Montana did it first and best. As one of the most radical designers of the 1980s, he shaped the defining silhouette of that era and influenced the style of an entire generation.
And now, provocative arbiter of vintage fashion Byronesque has reissued a very limited collection of signature Montana designs, with celebrated British fashion designer Gareth Pugh as creative consultant, to be sold exclusively on Farfetch. '
The 1980s really set the tone for design substance, integrity and craftsmanship,' says Gill Linton, co-founder of Byronesque. 'It's so important to preserve those high standards of design and creativity.
It's why people are buying more contemporary vintage: they're looking for unique, well-made clothes with more meaning than the mainstream. Montana is one of the last remaining brands of that calibre.'
This is the first time these designs have been seen in fashion for almost 20 years. Plus, each reissue in the 11-piece capsule has been selected to showcase elements of Claude Montana's signature aesthetic, featuring styles from 1979 to 1994. This is fashion history, brought back for now.
About Claude Montana :
Claude Montana is a French fashion designer. His company, The House of Montana, founded in 1979, went bankrupt in 1997.
Born in Paris in 1949 to a Catalan father and a German mother, Montana began his career by designing papier-mâché jewelry covered with rhinestones. Later, he discovered leather and the complex techniques associated with it, eventually becoming a leading force in leather. His first fashion show took place in 1976. He was an avid colorist and favored blue, red, metallic, and neutral tones, in luxurious materials such as cashmere, leather and silk. He started his own company The House of Montana in 1979, and quickly became a darling of 1980s high fashion along with Thierry Mugler, who also favored aggressive shapes and strong colours.
In 1981, Montana designed his first collection for men, called Montana Hommes, in which he focused on the color and material of each garment rather than trivial details. From 1990 to 1992 he designed haute couture collections for the House of Lanvin, for which he received two consecutive Golden Thimble awards. Despite critical acclaim, Montana's bold designs were financially disastrous for the house, created at a total estimated loss of $50 million, and he was ultimately replaced by Dominique Morlotti. In 1999, he designed an affordable line of clothing for women, Montana BLU. It was inspired by his favorite themes but modified to fit the style of sportswear and citywear.
Montana's fashion shows excelled in styling as well as in presentation. Because of their vibrations, modelling for Montana became prestigious and invitations to his shows the hottest tickets in town. With fashion's return to harder lines in 2007 Montana has become an inspiration for many designers. Alexander McQueen praised and honored Montana many times in his collections. Both designers shared a love for construction and high quality.
SYZ ART JEWELS – Gstaad – Switzerland feb 13-15 – 2019
Fondation Louis Vuitton - La Collection Courtauld

redpajama_set_name: RedPajamaCommonCrawl


text:
require File.join(File.dirname(__FILE__), '..', '..', '..', 'spec_helper')

include YARD::Parser::Ruby::Legacy
include YARD::Parser::Ruby::Legacy::RubyToken

describe YARD::Parser::Ruby::Legacy::TokenList do
  describe  "#initialize / #push" do
    it "should accept a tokenlist (via constructor or push)" do
      lambda { TokenList.new(TokenList.new) }.should_not raise_error(ArgumentError)
      TokenList.new.push(TokenList.new("x = 2")).size.should == 6
    end

    it "accept a token (via constructor or push)" do
      lambda { TokenList.new(Token.new(0, 0)) }.should_not raise_error(ArgumentError)
      TokenList.new.push(Token.new(0, 0), Token.new(1, 1)).size.should == 2
    end

    it "should accept a string and parse it as code (via constructor or push)" do
      lambda { TokenList.new("x = 2") }.should_not raise_error(ArgumentError)
      x = TokenList.new
      x.push("x", "=", "2")
      x.size.should == 6
      x.to_s.should == "x\n=\n2\n"
    end

    it "should not accept any other input" do
      lambda { TokenList.new(:notcode) }.should raise_error(ArgumentError)
    end

    it "should not interpolate string data" do
      x = TokenList.new('x = "hello #{world}"')
      x.size.should == 6
      x[4].class.should == TkDSTRING
      x.to_s.should == 'x = "hello #{world}"' + "\n"
    end
  end

  describe '#to_s' do
    before do
      @t = TokenList.new
      @t << TkDEF.new(1, 1, "def")
      @t << TkSPACE.new(1, 1)
      @t << TkIDENTIFIER.new(1, 1, "x")
      @t << TkStatementEnd.new(1, 1)
      @t << TkSEMICOLON.new(1, 1) << TkSPACE.new(1, 1)
      @t << TkBlockContents.new(1, 1)
      @t << TkSPACE.new(1, 1) << TkEND.new(1, 1, "end")
      @t[0].set_text "def"
      @t[1].set_text " "
      @t[2].set_text "x"
      @t[4].set_text ";"
      @t[5].set_text " "
      @t[7].set_text " "
      @t[8].set_text "end"
    end

    it "should only show the statement portion of the tokens by default" do
      @t.to_s.should == "def x"
    end

    it "should show ... for the block token if all of the tokens are shown" do
      @t.to_s(true).should == "def x; ... end"
    end

    it "should ignore ... if show_block = false" do
      @t.to_s(true, false).should == "def x;  end"
    end
  end
end

redpajama_set_name: RedPajamaGithub


Maidan activists early on Friday released Interior Troops servicemen who were captured on February 20, the press service of the Ukrainian Interior Ministry has reported.
The soldiers are currently in an Interior Troops unit, where they are receiving the necessary assistance.
According to the press service, they are in a satisfactory condition.
As reported, during the confrontation on February 20 Maidan activists captured several dozen servicemen. They were mostly conscripts aged 19-20. Early on Friday night they were released, accompanied by MPs.


text:
package ru.vyarus.dropwizard.guice.test.jupiter.param;

import java.lang.annotation.ElementType;
import java.lang.annotation.Retention;
import java.lang.annotation.RetentionPolicy;
import java.lang.annotation.Target;

/**
 * Marker annotation for junit 5 test parameter injection. Required when service not explicitly declared in guice
 * and so can't be recognized directly by type. The annotated parameter will be requested as guice JIT binding:
 * {@code injector.getInstance(ParamType)}.
 *

 * Annotation name reference guice "Just in time" binding type.
 *

 * Could be used with {@link ru.vyarus.dropwizard.guice.test.jupiter.TestDropwizardApp} or
 * {@link ru.vyarus.dropwizard.guice.test.jupiter.TestGuiceyApp} extensions.
 *
 * @author Vyacheslav Rusakov
 * @since 01.05.2020
 */
@Retention(RetentionPolicy.RUNTIME)
@Target(ElementType.PARAMETER)
public @interface Jit {
}


Getting paid is important in all businesses! For freelance translators running their own businesses, it is paramount, and while 99% of business transactions flow smoothly, what should one do with those tricky situations? How can you deal with non-payers? Or those that delay and delay?
In this episode, I deal with some of those issues. I hope to be able to help when you have done a great translation job and the client is being difficult by outlining some "debt-recuperation" strategies.
I hope you enjoy this one – and I hope that if and when you do encounter this situation – that my advice proves useful!
PLEASE let me know your opinion on this topic, and tell me about your experiences.


text:
Q: Where is GetTickCount declared in Firemonkey? I am using multi device in Delphi and I am building an android app. I need to use GetTickCount that was declared in Windows .
Does it exist somewhere in firemonkey or is there an alternative ?

A: use TThread.GetTickCount it's cross platform

A: GetTickCount is a Windows function and so does not exist on other platforms. For your cross platform needs you should use TStopWatch from System.Diagnostics.

redpajama_set_name: RedPajamaStackExchange


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Maine Youth
Read "Maine Youth: Your Questions Answered!"
Is an employer required to respect the chosen name of a minor (and for that matter, allow a uniform or name tag or bathroom access in accord with gender identity)? If the employer doesn't honor chosen name and uses legal name, is that a violation of law?
GLAD believes the answer is yes, and that an employer has to respect the chosen name of an employee of any age, including on a nametag, and allow an employee to wear the uniform consistent with their gender identity. This does not mean that an employer won't take a different point of view. This issue has not been litigated in Maine. GLAD also believes that an employer has to allow an employee to use the bathroom or other facilities consistent with their gender identity. Again though, this does not mean an employer won't take a different point of view, and it may take advocacy to resolve.
In Massachusetts, a recent decision of the Massachusetts Commission Against Discrimination recognized that an employer's continued misuse of an employee's name and pronouns violated the gender identity and constituted unlawful harassment.
The Maine anti-discrimination law (Maine Human Rights Act, Title 5 Maine Revised Statutes Sections 4551-4634) provides protection against discrimination based on actual or perceived "sexual orientation," which is defined to "include heterosexuality, bisexuality, homosexuality, and gender identity and expression." 5 Maine Revised Statutes Section 4553. The law applies to local and state governmental employers and private employers with any number of employees. The law also applies to employed minors, since there is nothing in the definition of employer or employee to suggest that an employed minor is not an employee.
It is unlawful for an employer to discriminate against an employee or potential employee on the basis of sexual orientation, including gender identity and expression, in hiring, recruitment, discharge (firing), promotion, compensation, and any other terms or conditions directly or indirectly related to employment. GLAD believes that if an employer requires a name tag or uniform, then those are conditions of employment. Likewise, access to facilities in the course of the job is also a condition of employment.
The Maine Human Rights Commission (HRC) also has issued regulations clarifying the scope of anti-discrimination protections for employees (Chapter 3: Employment Regulations of the Maine Human Rights Commission, 94-348). These regulations require employers, employment agencies, and labor organizations to make "reasonable accommodations" for employees in rules, policies, practices or service that apply directly or indirectly to gender identity or gender expression.
As noted, name tags, uniforms, and access to facilities are conditions of employment. In addition, the duty to reasonably accommodate employees in rules, policies, practices, or services that apply directly or indirectly to gender identity or expression includes a duty to reasonably accommodate employee's wearing the name tag and uniform and using the facilities consistent with their gender identity.
Note that there is an exception to the duty of accommodation, however, if the business can show that the accommodations would impose an "undue hardship" on the conduct of the business. The burden of proving undue hardship falls on the business, not the employee. GLAD believes that using an employee's chosen name, including on a nametag, and allowing an employee to wear the uniform and use the facilities consistent with their gender identity are reasonable accommodations that do not impose undue hardship on a business.
GLAD believes employers must allow employees to use the facilities consistent with their gender identity for an additional reason as well: the Maine Law Court already decided a comparable situation in schools, ruling that transgender students must be allowed to use the bathroom consistent with their gender identity. See Doe v. Reg'l Sch. Unit 26, 2014 ME 11 (2014), https://www.glad.org/wp-content/uploads/2016/10/doe-v-clenchy-decision-1-30-14.pdf. There is no difference between the antidiscrimination laws in employment and public accommodations where both prohibit different treatment based on gender identity. In fact, GLAD brought a lawsuit against Denny's for denying a transgender woman access to the women's restroom. (https://www.glad.org/cases/freeman-v-dennys/). As a result of the lawsuit, Denny's changed its policy to welcome customers to use the restroom consistent with their gender identity. Stated another way, where the law requires respect for a person's gender identity in schools and employment, that rule applies whether the employee is a youth or adult.
TIP: Some people are confused about where things stand for transgender people and restroom facilities because of the U.S. Supreme Court's April 2017 dismissal of Gavin Grimm's case. Grimm's case involved his high school's decision to bar him from using the boys bathroom and his challenge to that. He won his case at the federal appeals court because of a Guidance document from the U.S. Departments of Justice and Education, which explained why sex discrimination laws apply. When President Trump's administration rescinded that Guidance, the Court sent the case back to the Appeals Court for review. Remember: Maine nondiscrimination law provides protections in Maine. While we work to expand protections under federal law, you can still turn to Maine law for addressing discrimination.
What do I do about facilities on the job if I am a transgender or queer youth? Where do I go to the bathroom? What changing rooms and locker rooms do I use? And what if my employer refuses?
GLAD believes that an employer must allow an employee to use the facilities (including bathrooms, changing rooms, and locker rooms) consistent with their gender identity. As explained above, GLAD believes this because:
Maine's anti-discrimination law protects employees from discrimination based on actual or perceived sexual orientation, which includes gender identity and expression. Maine Human Rights Act, Title 5 Maine Revised Statutes Section 45514634.
The Maine Human Rights Commission employment regulations require employers to make reasonable accommodations for employees that apply directly or indirectly to gender identity or gender expression, as long as there isn't an undue burden on the business. Chapter 3: Employment Regulations of the Maine Human Rights Commission, 94-348. GLAD believes that allowing employees to use the facilities consistent with their gender identity is a reasonable accommodation that does not impose an undue burden.
In Doe v. Reg'l Sch. Unit 26, the Maine High Court found that schools must allow students to use the bathroom consistent with their gender identity. The Denny's case GLAD litigated was resolved quickly in favor of bathroom access when Denny's realized it was violating the law.
This should ensure access to any sexsegregated facility – including showers, changing rooms, or restrooms – consistent with a person's gender identity.
If your employer refuses, you can file a complaint of discrimination with the Maine Human Rights Commission by phone, mail, or online at:
State House Station #51
www.state.me.us/mhrc/index.shtml
For more information on pursuing a complaint, refer to GLAD's website at: https://www.glad.org/wp-content/uploads/2017/01/me-lgbt-overview.pdf beginning on page 10 or call GLAD Answers.
Does the law only cover people whose gender identity is "male" or "female" or does it also include those who identify as "non-binary?"
Regulations issued by the Maine Human Rights Commission (HRC) define the terms "gender identity" and "gender expression" as follows:
"Gender identity means an individual's genderrelated identity, whether or not that identity is different from that traditionally associated with that individual's assigned sex at birth, including, but not limited to, a gender identity that is transgender or androgynous."
This definition of gender identity is not limited to "male" and "female," and appears broad enough to encompass those not on the gender binary, including but not limited those who are "genderqueer" or "androgynous."
The regulations define gender expression as:
"the manner in which an individual's gender identity is expressed, including, but not limited to, through dress, appearance, manner, speech, or lifestyle, whether or not that expression is different from that traditionally associated with that individual's assigned sex at birth."
Gender expression is simply the outward manifestation of gender identity, and need not be "male" or "female."
In an Advisory Opinion clarifying regulations (Maine Human Rights Commission, Advisory Opinion – Employee Bathroom Access, Sept. 10, 2013), the HRC stated that gender expression is protected only when it accords with a person's gender identity. Or, a gender expression that does not accord with a person's gender identity is not protected. What the HRC is getting at here is that a person whose gender identity is male cannot expect anti-discrimination protections to apply if he dresses as a woman or attempts to access sexsegregated facilities set aside for women. It does not limit gender identity or gender expression to male and female only.
In that Advisory Opinion, the HRC also said it is not necessary that a person have genderreassignment surgery or other medical intervention to be covered by the protections on gender identity and expression. As they put it; "what is important is a person's internal sense of being male or female."
How can an individual navigate job applications when their name and official identity are different from their chosen name and affirmed gender? Do people have to hide their identity?
As explained above, the Maine antidiscrimination law protects potential employees (people applying for jobs) from being discriminated against based on their sexual orientation (which is defined to include gender identity and gender expression) during hiring (the job application process). The HRC employment regulations also protect people from discrimination based on their gender identity and gender expression. For these reasons, GLAD does not believe people should have to hide their identity, including if their chosen name and affirmed gender are different than their legal name and gender. However, this does not mean a potential employer won't take a different point of view. In addition, it is unfortunately very hard to prove discrimination during hiring.
TIP: Anyone applying for a position of employment should be careful not to lie or misrepresent information on an application that can be used by the employer to justify not hiring them even if the real reason may be bias.
If you believe you have been discriminated against during hiring, you can file a complaint with the Maine HRC and/or call GLAD Answers. If you suspect or have reason to believe you may have suffered discrimination in the hiring process of a job, you can also call GLAD Answers so we can keep track of the specific employer.
Employer questions during a job interview may reveal discriminatory animus in the hiring process. It may help to know that the Maine antidiscrimination law also forbids employers, employment agencies, or labor organization from eliciting (asking about directly or indirectly, trying to find out about) or recording (writing down) information about a person's sexual orientation (which is defined to include gender identity and gender expression). In other words, a potential employer can't ask you about your sexual orientation, gender identity, or gender expression.
GLAD has resources to help if you are interested in changing your legal documentation to reflect your chosen name and affirmed gender. See https://www.glad.org/wp-content/uploads/2017/01/trans-legal-issues.pdf beginning on page 42 or call GLAD Answers.


The Latest / How Much Does Treatment Cost?
There's no question about it: addiction treatment is a significant financial investment, and services aren't cheap. That doesn't mean, however, that it has to be exorbitant or needlessly excessive. At NTS, we take pride in a treatment cost that eliminates unnecessary expenses while focusing on what a client truly needs. Especially when compared to the costs that can result from untreated addiction, as well as the impact it can have that can't be measured in dollars, the investment in treatment is a sound one.
Our treatment fees vary based on a wide variety of factors, including length of stay, level of care, and the individual client's needs. For detailed information based on your specific needs, give us a call – we'll be happy to help answer any questions.
See here for more information that can help you understand the potential costs involved in treatment, including treatment fees, expenses for personal care, and other costs.
Is Someone In Your Family Addicted to Cocaine?


text:
It's Difficult to Hang Up on Long-Term Cell Phone Deal
KIM HART The Washington Post
Fed up with dropped calls and a string of defective cell phones, Corey Taylor said he became irate when he learned he'd have to pay $175 to get out of his long-term contract with Verizon Wireless. So he resorted to a rather extreme measure. He faked his own death.
After reading on a blog that wireless companies would cancel the contracts of deceased customers, "I thought, 'What have I got to lose, besides a cell phone I despise?'"Taylor said. The Chicago consultant fashioned a fake death certificate and had a friend fax it to Verizon Wireless. He thought he was in the clear - until the company caught on.
"In the end, I forked over the money," Taylor said. "But I bet I sent a definite message about how much people hate being strapped to a cell phone that doesn't work."
Most cell phone owners find themselves committed to two-year service contracts with wireless companies, facing hefty fees for an early escape. But as customer satisfaction with these firms continues to slide, consumers are taking more drastic actions to shed their contracts.
Such desperate attempts are "compelling evidence that the wireless carriers have failed to address the desires of the market," said Phil Doriot, a partner with consulting firm CFI Group of Ann Arbor, Mich., which has studied customer satisfaction for major cellular service providers. "No other industry could get away with being so inflexible."
Cellular companies charge up to $250 to release customers from a contract, a stipulation protested by an increasing number of cell phone users. Consumers filed more complaints about cell phones than any other industry for the past three years, according to the Council of Better Business Bureaus. Contract issues consistently rank among the top three gripes, along with billing and service problems.
The number of contract-related complaints received by the Federal Communications Commission more than doubled from 2003 to 2005. And thousands of customers were expected to pay to cancel their cell phone contracts with other service providers this summer after the iPhone was released exclusively with AT&T service, according to mobile communications research firmM:Metrics of Seattle.
Sandy Loehman, 27, of Winchester, Va., said she managed to talk her way out of her Verizon Wireless contract, avoiding the $150 fee by reading the fine print on her bill. In April, she noticed the price for receiving a text message from an international carrier had increased 5 cents. Most wireless companies will cancel a contract for free if a billing change negatively affects a customer.
"I argued with five customer-service reps and used a lot of big words," Loehman said. After she got hold of a supervisor, she threatened to complain to the FCC, the Better Business Bureau and the state's attorney's office.
"Eventually, I think they just didn't want to deal with me anymore," she said.
Most carriers offer deep discounts on expensive cell phones to attract customers. Cancellation fees, they say, help offset those costs.
Some carriers have softened their policies. Verizon Wireless now prorates its cancellation fees so customers pay less if they are near the end of their contract. Sprint Nextel lets customers change their service plans up to six months after they sign their contract. All the major carriers say they waive cancellation fees for military personnel going abroad and for customers moving to poor coverage areas, but they ask for proof of the move.
AT&T will take extenuating circumstances, such as losing a job, into account when dealing with customers, said spokeswoman Alexa Kaufman.
"We try to figure out what it is they're not happy with," she said. "Maybe the bill's too high and we can offer options to lower it."
Such efforts have not done much to boost customer satisfaction, however. A recent report by the American Consumer Satisfaction Index showed that, despite modest improvements, the wireless industry still ranks far below fast-food restaurants and airlines.
Poor customer service is the No. 1 reason customers switch to another carrier, according to a CFI Group report released this month.
Doriot, an author of the CFI report, said frustration over contract terms is especially harmful for carriers now that competition for new customers is so fierce.
"When cell phone companies charge consumers fat penalties to leave, they're throwing sand in the gears of competition, which means consumers pay higher prices for shoddy service," said Chris Murray of Consumers Union, which has been lobbying against cancellation fees.
Consumer lawsuits in several states, including California and Florida, have challenged the fees as unfair and illegal because they punish customers for moving to another service provider.
Wireless carriers have asked the FCC to treat the fees not as penalties but as rates companies can charge for service. Several members of Congress have expressed concern over the fees, and some have said they plan to introduce legislation this fall that would give states more authority to regulate the fees.
"It's amazing how many people really resent being locked into a contract," said Craig Wurtenberg, co-founder of CellTradeUSA.com, a Web site that matches people wanting to get rid of the remaining time on their contract with people looking for shorter cell phone commitments.
Wireless companies release customers from their contracts if they transfer the remaining time to someone else.


text:
Women's soccer rallies in second half, downs FIU
Sydney Shelton, Reporter|September 23, 2018
Rick Farlow
Junior forward Marah Abu-tayeh gestures for a pass from sophomore forward Canaan Booton in Marshall's home-opener against UT-Martin. Abu-tayeh's is currently tied with her sister, Farah Abu-tayeh, for a team-leading 5 goals.
Marshall women's soccer scored three second half goals to pull off a 3-2 comeback win over FIU Sunday at Hoops Family Field.
With the win, Marshall moved to a record of 4-4-2 (2-1-0 C-USA), while FIU moved to 0-11-0 (0-3-0 C-USA). Herd head coach Kevin Long said his team's persistence through rainy conditions factored into its second C-USA win of the season.
"(The match) wasn't pretty, which matched the elements today," Long said. "We had some good chances but we looked a little out of sync. But I thought they showed great resolve and persistence."
FIU took a 1-0 lead when freshman forward Kaydeen Jack scored in the 18th minute on an assist by freshman midfielder Kedie Johnson. The goal was Jack's third this season. FIU then extended its lead to 2-0 in the 45th minute off a header by redshirt sophomore forward Ashley Adams. Adams' goal, assisted by sophomore defender Sierra Moss, was her fourth of the season.
Marshall, however, began to turn things around in the 51st minute. The Herd cut FIU's lead in half when junior forward Farah Abu-Tayeh scored on a cross from inside 18-yards to the middle of the box. She was assisted by her sister, junior forward Marah Abu-Tayeh.
Marshall's senior defender Ashley Seltzer then tied the game 2-2 via penalty kick in the 81st minute. Long said he saw a change in Marshall's play and attitude following the goal.
"They allowed themselves to play more freely," Long said. "All the belief was actually showing and I think you could see it in the swagger that was in the play and the opportunities that we continued to have after that."
Two minutes after Seltzer's equalizer, Farah Abu-Tayeh scored the go-ahead goal and Marshall took a 3-2 lead in the 84th minute. The Herd held FIU scoreless for the remainder of the game.
Long said he expected and enjoyed the competitive nature of C-USA as the Herd prepares for an in-conference road trip.
"Next week is one of our tougher two games on the road," Long said. "Charlotte and ODU both play great soccer and there isn't a second that we can take our foot off the gas."
The Herd's next match is Friday at 7 p.m. in Norfolk, Virginia against ODU.
Sydney Shelton can be contacted at [email protected]
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Q: jquery css class problem There are 2 classes for the same  tag. class .bt1 set as default in html code.
I need this p tag to change its class on click and save it, and when I click on this p tag I need it to be 'bt1i' class and 'bt1i' onclick function start working. Can someone help me to understand why it do not work and where is the error.  As I understand when I change the class in jquery code, it do not save for next call of jquery.
jQuery(document).ready(function(){

  $(".slide1").animate({marginRight:"-446px"}, 500 );
  $(".commonslide").animate({width:"206px", opacity:0}, 400 );
  $(".mainarea").animate({marginRight:"206px"}, 500);

 $(".bt1").click(function(){
     $(this).toggleClass("bt1i");
  $(".mainarea").animate({marginRight:"652px"}, 400);
  $(".sidebar").animate({marginRight:"0px"}, 400 );
        $(".slide1").animate({marginRight:"0px"}, 400 );
  $(".commonside").animate({width:"652px", opacity:1}, 400 );
 });

 $(".bt1i").click(function(){
  $(".slide1").animate({marginRight:"-446px"}, 500 );
  $(".commonside").animate({width:"206px", opacity:1}, 400 );
  $(".mainarea").animate({marginRight:"206px"}, 500);
     $(this).toggleClass("bt1");
 });

});

A: You need to change the .bt1i handler to work via .live(), like this:
$(".bt1").live('click', function(){
//and...
$(".bt1i").live('click', function(){

When you do $(".bt1i").click(...) it's looking for elements with a class of bt1i at that time and binding a click handler to them...the elements you're toggling the class on didn't have the class then.  With .live() it'll listen or elements with that class, no matter when they were added...the selector is evaluated at the time the event occurs.
As a side note if you want this to behave as expected, you need to toggle off the previous class as well, just add both to each .toggleClass() call, like this:
$(this).toggleClass("bt1 bt1i");

This will effectively swap the class on the element.

A: Nick's answer is correct. Here is just another solution:
$(".bt1").click(function () {
    if ($(this).hasClass("bt1i")) {
        // add behavior for the bt1i class here
    }
    $(this).toggleClass("bt1i");
}

The reason you are having the problem is because jQuery's .click() function binds the handler only to the items that currently have the bt1i class. Since the class will not be added until later, the handler doesn't get bound to anything.


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Q: Maven cannot resolve dependencies for my project For the past couple days, I have been stuck on this problem to no avail. I have a couple dependencies described in my pom.xml. But Eclipse screams an error at me saying "Could no resolve dependencies for project"
I have the details below.
pom.xml
<project xmlns="http://maven.apache.org/POM/4.0.0" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://maven.apache.org/POM/4.0.0 http://maven.apache.org/xsd/maven-4.0.0.xsd">
<modelVersion>4.0.0</modelVersion>
<groupId>edi</groupId>
<artifactId>edi</artifactId>
<version>0.0.1-SNAPSHOT</version>
  <dependencies>
        <dependency>
            <groupId>com.oracle</groupId>
            <artifactId>ojdbc6</artifactId>
            <version>11.2.0</version>
        </dependency>
        <dependency>
            <groupId>commons-lang</groupId>
            <artifactId>commons-lang</artifactId>
            <version>2.6</version>
       </dependency>
       <dependency>
            <groupId>commons-logging</groupId>
            <artifactId>commons-logging</artifactId>
            <version>1.2</version>
        </dependency>
        <dependency>
            <groupId>struts-menu</groupId>
            <artifactId>struts-menu</artifactId>
            <version>2.4.3</version>
        </dependency>
   </dependencies>
<build>
    <sourceDirectory>WEB-INF/src</sourceDirectory>
    <resources>
      <resource>
         <directory>WEB-INF/src</directory>
         <excludes>
           <exclude>**/*.java</exclude>
         </excludes>
      </resource>
    </resources>
    <pluginManagement>
        <plugins>
            <plugin>
                <groupId>org.apache.maven.plugins</groupId>
                <artifactId>maven-war-plugin</artifactId>
                <version>2.4</version>
                <configuration>
                    <source>1.6</source>
                    <target>1.6</target>
                    <webXml>WEB-INF/web.xml</webXml>
                </configuration>
            </plugin>
        </plugins>
    </pluginManagement>
</build>
 <packaging>war</packaging>
</project>

Maven log:
[INFO] Scanning for projects...
[INFO]
[INFO] ----------------------------------------------------------------------   --
[INFO] Building edi 0.0.1-SNAPSHOT
[INFO] ---------------------------------------------------------------------- --
Downloading: http://repo1.maven.org/maven2/com/oracle/ojdbc6/11.2.0/ojdbc6-  11.2.0.pom
[INFO] ------------------------------------------------------------------------
[INFO] BUILD FAILURE
[INFO] ----------------------------------------------------------------------  --
[INFO] Total time: 22.486s
[INFO] Finished at: Tue Jun 30 10:41:56 EDT 2015
[INFO] Final Memory: 3M/118M
[INFO] ------------------------------------------------------------------------
[ERROR] Failed to execute goal on project edi: Could not resolve dependencies   for project edi:edi:war:0.0.1-SNAPSHOT: Failed to collect dependencies for    [com.oracle:ojdbc6:jar:11.2.0 (compile), commons-lang:commons-lang:jar:2.6   (compile), commons-logging:commons-logging:jar:1.2 (compile), struts-menu:struts-  menu:jar:2.4.3 (compile)]: Failed to read artifact descriptor for com.oracle:ojdbc6:jar:11.2.0: Could not transfer artifact   com.oracle:ojdbc6:pom:11.2.0 from/to central (http://repo1.maven.org/maven2): Error transferring file: Connection timed out: connect -> [Help 1]
[ERROR]
[ERROR] To see the full stack trace of the errors, re-run Maven with the -e switch.
[ERROR] Re-run Maven using the -X switch to enable full debug logging.
[ERROR]
[ERROR] For more information about the errors and possible solutions, please read the following articles:
[ERROR] [Help 1] http://cwiki.apache.org/confluence/display/MAVEN/DependencyResolutionException

Any help on this will be appreciated. Thanks.


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myomiRs and Cancer Cachexia
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Mini Review ARTICLE
Front. Nutr., 09 January 2018 | https://doi.org/10.3389/fnut.2017.00069
Role of Exosomal MicroRNAs and myomiRs in the Development of Cancer Cachexia-Associated Muscle Wasting
Rodolfo Marinho1, Paulo S. M. Alcântara2, José P. Ottoch2 and Marilia Seelaender1,2*
1Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
2Department of Clinical Surgery, University of São Paulo, São Paulo, Brazil
Cachexia is a complex metabolic syndrome that promotes great weight loss, with marked muscle mass wasting. In the last years, many efforts have been directed to improve the understanding of the mechanisms involved in the disease. This syndrome is present in up to 80% of cancer patients and, despite its clinical relevance, is underdiagnosed. The orchestration of the molecular and biochemical disruptions observed in cachexia is paralleled by inflammation and the communication among the different body compartments, including the tumor and the skeletal muscle, is still not completely described. One of the mechanisms that may be involved in the transduction of the inflammatory signals and the activation of catabolic status in muscle is the participation of exosomes containing microRNAs (miRNAs) and muscle-specific miRNAs (myomiRs). Exosomes are nanovesicles, measuring from 30 to 100 µm, and able to carry miRNAs in the circulation, promoting cell–cell and tissue–tissue communication in an autocrine, paracrine, and endocrine manner. miRNAs transported in exosomes are preserved from degradation, while these nanoparticles deliver the cargo to specific cell targets, making communication more efficient. Several miRNAs are known to modulate inflammatory pathways, to induce metastasis, to mediate cancer aggressiveness and even to participate in the regulation of protein synthesis and degradation pathways in the skeletal muscle. The aim of this mini-review is to describe the present knowledge about the role of exosomal miRNAs and myomiRs in the induction of muscle mass wasting in cancer cachexia state and to explain which transcription factors, proteins, and pathways are regulated by these molecules.
In the last decade, many efforts were directed to improve understanding of the mechanisms involved in the complex metabolic syndrome of cachexia. This disease is related with marked decrease of body weight and diminished muscle mass, in the presence or absence of fat loss (1, 2). The syndrome is associated with cancer or other chronic inflammatory diseases, affecting quality of life (3–5) and decreasing survival (6, 7). Cancer cachexia affects approximately half of all cancer patients (8); whereas in the more advanced stages of the disease, this estimate may reach 80% (9, 10). In addition, cachexia is considered the immediate cause of death of 20–50% of all cancer patients (5, 6).
Cachectic cancer patients suffer several challenges dealing with the alterations and limitations imposed by both cachexia and chemotherapeutic treatment, which induce fast and pronounced weight loss. Furthermore, cachexia reduces the efficacy and increases the toxicity of chemotherapy (2, 11). Low muscle mass is a predictor for mortality and reflects poor prognosis (2). The cachectic patient may lose up to 75% of his/her skeletal muscle mass (6). Weight loss in cachectic patient is attributable to systemic inflammation, rather than insufficient caloric intake (12).
Despite its clinical relevance, cancer cachexia is underdiagnosed and seldom treated (1, 4). This is probably a reflex of its complexity and of the interaction of factors causing the plethora of symptoms that have been described in the cachectic patient (1, 4, 13). The most prevalent alterations, beyond body mass wasting, are anorexia, fatigue, and impairment of hypothalamic circuits regulating appetite; as well as endocrine disorders and "metabolic chaos," characterized by marked deregulation of lipid, protein, and carbohydrate metabolism (4, 14).
Despite the complexity of the pathophysiology of cancer cachexia, it has been widely accepted that most alterations are associated with the presence of systemic inflammation. Tan and Fearon (15) proposed five main clusters of symptoms in which inflammation acts as a protagonist in cancer-associated cachexia: (1) systemic inflammation; (2) control of energy balance; (3) function and metabolism of muscles; (4) function and metabolism of the adipose tissue; and (5) modulation of appetite.
The most relevant pro-inflammatory cytokines contributing to the development of cancer cachexia and related with the metabolic alterations leading to muscle mass and adipose tissue wasting are interleukin-1, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interferon gamma (5, 7, 16, 17). Peripheral tissues are largely affected by cachexia, even before the detection of anorexia in the patient (18). Hence, loss of muscle mass and fat begins to occur before the patient exhibits a decrease in food intake (18, 19). Increased circulation of the abovementioned cytokines activates lipolysis in the adipose tissue and induces a reduction of protein synthesis, all the while upregulating proteolysis in the muscle (8).
There have been many attempts to describe the mechanisms involved in the onset of inflammation in cancer cachexia; however, such mechanisms are still not fully understood. We have previously shown that the white adipose tissue (WAT) contributes in a robust manner for the increase of circulating inflammatory factors (20–22). More recently, it has been shown (23–26) that WAT actively secretes exosomes containing microRNA (miRNA), which may regulate the inflammatory process in tissues and immune cells. In addition, exosomes from the adipose tissue are able to stimulate and regulate the growth, development, and the aggressiveness of tumors (23, 24).
Many studies demonstrate that tumors are likewise able to secrete exosomes containing miRNAs, which play a role in the activation of the inflammatory process in cancer (27–29). These tumor-derived exosomes interact with mesenchymal stem cells (MSCs) and increase the synthesis and release of pro-inflammatory cytokines, favoring tumor cell survival (27). In addition, exosomes released by the tumor induce the progression of the tumor itself, by modifying tumor microenvironment, and promoting metastasis (27–31).
The miRNAs are a family of small, non-coding RNA molecules, composed of 19–24 nucleotides, that regulate gene expression through the degradation of messenger RNA (mRNA) or by inhibiting protein translation (8, 32). The miRNAs were first described in the 1990s, but only in 2002 their involvement in the development of cancer was reported (12). Since the first cancer-related data were obtained, many studies have addressed miRNA participation in important steps of malignant disease, such as in tumor proliferation, apoptosis, migration, and invasion (33–35). In addition, paracrine and/or endocrine actions of miRNA are related with the propagation of systemic inflammation, in the development of metastasis, and in the activation of pathways that promote muscle loss (8).
miRNAs are synthesized from DNA gene transcription by RNA polymerase II, forming primary miRNA (pri-miRNA) transcripts. Subsequently, these pri-miRNAs undergo a process of maturation, when they are cleaved by the Drosha–DGCR8 RNase enzyme complex, generating a double-stranded pre-miRNA (36–38). Drosha is localized in the nucleus and contains two tandem RNase-III domains. After cleavage by Dorsha, the pre-miRNA exhibits an imperfect stem-loop structure with ~70-nucleotides (38). This pre-miRNA is transported from the nucleus to the cytoplasm by exportin5 (XPO5), a Ran-GTP-dependent transporter. In the cytoplasm, miRNAs undergo another maturation step in which the double strand is cleaved by the action of the Dicer enzyme. Dicer cleaves theses hairpin precursors, generating the mature miRNA strand and its complementary strand (miRNA′), these two strands range about 21–25 nucleotides. In sequence, the mature miRNA is bound by Argonaute proteins (Ago) and incorporated into an miRISC effector complex (miRNA induced silencing complex), while the other miRNA strand may be degraded, or still, form another miRISC complex. Alternatively, it may be exported into exosomes to act in a paracrine or endocrine way (37–41).
Changes in the expression profile of miRNAs may indicate the presence and/or the progression of diseases that affect the muscle (7, 37, 42). Alterations such as the upregulation or downregulation of miRNAs have hence been investigated, having provided clear evidence that they can regulate pathways implicated with myogenesis, and skeletal muscle hypertrophy and atrophy (7, 37, 42–44). One of the miRNAs whose concentration is increased, as identified in cancer patients, is miR-21. Several studies have shown an increase of miR-21 in the serum of patients with the most varied types of cancer, such as colorectal cancer (45–47), gastric cancer (48, 49), prostate cancer (50), and hepatocellular carcinoma (51, 52).
Muscle mass loss during cachexia is related with an increase in protein degradation and metabolic changes in the muscle, in response to the presence of the tumor in the organism (42). Soares et al. (43) observed different profiles of alterations in miRNA expression with in vitro and in vivo approaches in four different animal models of skeletal muscle wasting: starvation, denervation, diabetes, and cancer cachexia. The authors identified that, following the denervation protocol, miR-206 and miR-21 are upregulated and promote muscle atrophy. These two miRNAs are capable of binding to the transcription factor YY1, as well as the translational initiation factor eIF4E3, and regulate muscle mass wasting, thus interfering in myogenesis (43).
In addition, other pathways involving miRNAs and the regulation of myogenesis, hypertrophy, or atrophy have been described both in vitro and in vivo. Koutalianos et al. (53) showed that overexpression of MyoD, a myogenic transcription factor, induces the expression of miR-206. In addition, the increase of miR-206 downregulates Twist-1, decreasing the activity of Twist-1, and allowing increased differentiation of muscle cells. The authors reported that muscle cells from patients with myotonic dystrophy type 1 exhibited inhibition of MyoD protein expression and an increase of Twist-1 expression, following a reduction in miR-206 levels. The co-transfection of MyoD and miR-206 regulated the protein content of Twist-1, allowing the differentiation of muscle cells to occur (53).
Moreover, Kukreti et al. (54) showed that dexamethasone or myostatin induces atrophy of skeletal muscle through miR-1 expression modulation. The authors demonstrated that miR-1 can bind to and reduce heat shock protein 70 (HSP70) action, thus participating in the induction of atrophy. Decreased levels of HSP70 are associated with the downregulation of Akt phosphorylation (p-Akt), since HSP70 binds to and protects the integrity of p-Akt. The decrease in p-Akt promotes a reduction of Foxo3 phosphorylation, allowing for enhanced nuclear activity of Foxo3, and promoting upregulation of muscle finger protein (MuRF1) and atrogin-1; both of which induce the atrophy program in the skeletal muscle (54).
Remarkably, Narasimhan et al. (7), when analyzing rectus abdominis biopsies from cancer and cachectic cancer patients, employing next-generation sequencing, discovered eight miRNAs that are upregulated in cancer-associated cachexia and associated with muscle metabolism, myogenesis, and inflammation. The upregulated miRNAs are as follows: hsa-let-7d-3p; hsa-miR-345-5p; hsa-miR-423-5p; hsa-miR-532-5p; hsa-miR-1296-5p; hsa-miR-3184-3p; hsa-miR-423-3p; and hsa-miR-199a-3p (7).
The authors (7) described that: (1) let-7d-3p is related with transferrin receptor, promoting downregulation of this pathway, affecting muscle cell proliferation and myogenic differentiation; (2) miR-345-5p has NOV and COL1A1 genes as targets, downregulating these and upregulating CYR61. NOV and CYR61 are involved in insulin-like growth factor 1, Akt and mTOR pathways, reducing the capacity to protein synthesis; (3) miR-423-5p and miR-3184-3p downregulate two genes, SQLE and FADS2. These genes are related with lipid biosynthesis; miR-423-5p also regulates leptin and other genes associated with energy balance; in addition, miR-423-5p downregulates DLK1, which is involved with muscle hypertrophy; while (4) miR-423-3p promotes a reduction of calcium signaling, affecting CAMK2A gene; (5) miR-3184-3p is involved with Wnt/β-catenin signaling, impairing myogenic differentiation. In addition, miR-3184-3p regulates BMPR1B and GREM1, and this way, transforming growth factor β and BMP signaling are affected; (6) miR-532-5p interferes with SULF1, RPS6KA6, and NPY1R genes. SULF1 is related with BMP signaling, influencing somite development; NPY1R is involved with appetite regulation, and RPSKA6 participates in ciliary neurotrophic factor (CNTF) actions; (7) miR-1296-5p regulates HTR2A and RPS6KA6 genes. HTR2A participates in serotonin signaling (serotonin is involving in myogenesis), while RPS6KA6 is involved with CNTF signaling; and (8) miR-199a-3p affects the EIF4EBP1 gene. This gene regulates the mTOR pathway, interfering in protein synthesis (7).
Taken together, these recently published findings demonstrate the role of myomiRs in the modulation of atrophic pathways, providing insight on the possible relevant role of these molecules in cancer cachexia. Figure 1 summarizes the mechanisms by which myomiRs modulate atrophy and muscle mass wasting.
Figure 1. myomiRs and muscle mass wasting and atrophy pathways. MyoD is able to activate miR-206, promoting an inhibiting effect on Twist-1 protein, diminishing muscle cell differentiation (53). miR-206 and miR-21 regulate the action of YY1 and eIF4E3, promoting muscle mass wasting (43). Myostatin increases miR-1 expression, promoting a reduction in heat shock protein 70 (HSP70) action, decreasing Akt phosphorylation, and its regulation of Foxo3. When Foxo3 is not phosphorylated, the expression of several proteins that induce atrophy, including Atrogin-1 and MuRF1, are enhanced (54). The let-7d-3p downregulates transferrin receptor (TFRC), affecting muscle cell proliferation and myogenic differentiation (7). miR-3184-3p inhibits Wnt/β-catenin pathway, impairing myogenic differentiation (7). mir-345-5p downregulates genes and proteins involved in IGF1 pathway, decreasing anabolic signaling. miR-1296-5p regulates HTR2A gene, reducing the participation of serotonin in the induction of myogenesis (7). miR-199a-3p affects the EIF4EBP1 gene, reducing mTOR pathway activity, interfering in protein synthesis (7). miR-423-3p promotes reduction of calcium signaling, affecting CAMK2A gene (7). miR-423-5p downregulates DLK1, what is involved with muscle hypertrophy; thus, reducing this capacity (7).
Exosomes are small membrane-derived particles, ranging from about 30 to 100 µm (42). The biogenesis of exosomes is linked to the synthesis of miRNAs (8, 55). Due to high stability and specificity for delivering the cargo to the target cells, exosomes are involved in tissue-tissue communication in an autocrine, paracrine, and endocrine way (55, 56). These particles have been shown to represent an efficient way to transport other molecules, such as proteins, some types of RNAs (intact mRNA; mRNA fragments; long non-coding RNA; miRNA; ribosomal RNA; fragments of tRNA), and cytokines, reducing degradation due to transport in bloodstream (28, 55, 57).
The initiation and maintenance of cachexia-related inflammation may present a major contribution of miRNAs (7, 8, 12, 32). These actions are associated with the presence of miRNA-enriched circulating exosomes (8, 42). He et al. (32) demonstrated a mechanism underlying the participation of exosomal miRNAs in muscle mass wasting. The authors reported that lung and pancreatic cancer cells secrete exosomes containing miR-21. These are transported in the bloodstream and induce apoptosis of muscle cells. This phenomenon happens because miR-21 is able to bind and activate toll-like receptor 7 (TLR-7) in rat cells and toll-like receptor 8 (TLR-8) in human myoblasts, thereby promoting apoptosis, through the activation of the c-Jun N-terminal kinase pathway (JNK) (32).
In another study, Hudson and colleagues (58) demonstrated that miR-182 present in isolated exosomes could attenuate the role of Foxo3 in inducing atrophy in the skeletal muscle. Foxo3 is a transcript factor that promotes the increase of atrophy-related genes such as atrogin-1, autophagy-related protein 12 (ATG12), and microtubule-associated protein light chain 3. The authors demonstrated that treatment of C2C12 myotubes with dexamethasone promotes a reduction of the expression of miR-182 and an increase in autophagy, via enhanced activity of Foxo3. The same atrophy program was observed in the gastrocnemius muscle of diabetic (induced by streptozotocin) rats, with diminished expression of miR-182, and enhanced Foxo3 mRNA (58).
Recently, an elegant study performed by Zhang et al. (11) demonstrated that cancer cells release exosomes and that HSP70 and HSP90 proteins in the membrane of exosomes induce muscle mass wasting in cancer cachexia models. Extracellular HSP70 and HSP90 function as danger-associated molecular patterns (11). These two proteins can interact with TLR-4 and promote its activation, and thus, activate p38β MAPK-C/EBPβ catabolic signaling pathway in the muscle (11). Figure 2A illustrates the mechanisms by which exosomal miRNAs and proteins induce muscle mass wasting in cancer cachexia.
Figure 2. (A) Exosomal microRNAs (miRNAs), proteins, and muscle mass wasting. miR-21 interacts with and activates toll-like receptor 7 (TLR-7). TLR-7, through the c-Jun N-terminal kinase pathway (JNK) pathway, induces apoptosis of muscle cells, leading to atrophy (32). Heat shock protein 70 (HSP70) and HSP90 that compose the membrane of exosomes can bind to TLR-4, activating this receptor on muscle cells and induce the muscle mass wasting (11). Exosomal miR-182 is able to block transcript factor Foxo3's action, inhibiting its action, reducing the expression of several atrophy genes, as light chain 3 (LC3), Atrogin-1, and ATG12 (58). (B) Exosomal miRNAs, proteins, and systemic inflammation. miR-21 and miR-29 are able to interact and activate TLR-7/8–MyD88–nuclear factor kappa B (NFκB) pathway, inducing an increased expression and release of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-8, and MCP-1 (59, 60). This pro-inflammatory state enhances protein degradation and inhibits protein synthesis. HSP70 and HSP90 present in exosomes membranes can bind to, and activate TLR-2 and TLR-4. When activated, these receptors promote the activation of the NFκB pathway, inducing a pro-inflammatory status (11).
In parallel to the involvement of miRNAs in the regulation of muscle wasting and atrophy pathways, recent studies have shown that exosomes contain miRNAs and are also able to promote and perpetuate systemic inflammation present in cachectic cancer state (8, 59–62). Fabbri and colleagues demonstrated that miRNAs 21 and 29 are able to associate and activate TLR-7 and TLR-8, triggering an inflammatory signal. When activated, toll-like receptors promote the recruitment of MyD88 and the formation of the complex IRAK1, IRAK4, and TRAF6, which then activates nuclear factor kappa B (NFκB). In the nucleus, NFκB induces pro-inflammatory cytokines expression, including TNF-α and IL-6 (59, 60).
Furthermore, Li et al. (61) reported that when MSCs were incubated with exosomes derived from lung tumor cell lineage A549, the presence of those vesicles induces a pro-inflammatory phenotype in MSCs. These cells enhance the synthesis and secretion of IL-6, IL-8, and MCP-1. The authors further demonstrated that HSP70 present in the membrane of exosomes is able to bind to TLR-2 and then activate the NFκB pathway, leading to increased expression and secretion of the inflammatory cytokines IL-6, IL-8, and MCP-1 (61).
In addition, Zhang et al. (11) showed that HSP70 and HSP90 proteins, existing in exosomes membrane, interact and activate TLR-2 and TLR-4 on immune cells, triggering innate immune response. The activation of these receptors promotes an increase in the synthesis and release of pro-inflammatory cytokines (TNF-α and IL-6), collaborating to the development of systemic inflammation existing in cancer cachexia (11). Figure 2B illustrates the role of exosomal miRNAs and proteins in the perpetuation of systemic inflammation.
Collectively, these findings demonstrate an important involvement of exosomal miRNAs and proteins for the activation and perpetuation of systemic inflammation in cancer and in the induction of cancer-associated cachexia. One such systemic inflammation scenario exerts a negative influence on muscle metabolism, regulating signaling pathways involved in the synthesis and breakdown of proteins in muscle, collaborating with the development of muscle mass wasting in cancer cachexia (8, 11, 17, 59, 60, 63).
Despite the great potential in the study about exosomes, miRNAs and exosomal miRNAs, further studies are needed to enhance understanding of details in regard to some processes: steps of exosome biogenesis are not yet fully known; the mechanisms underlying sorting of each miRNA into exosome particles are likewise, not totally elucidated. In addition, it remains to be established what pathways are regulated by each miRNA; what and which functions do the proteins present in the exosomes membrane exert (28). Moreover, the development of more precise and refined methods for exosome isolation are needed, as well as improvements in protein detection techniques, allowing improved characterization of each exosome and particular functions in the pathophysiology of cachexia (55, 56, 64).
The study of exosomal miRNAs and myomiRs is a promising field of research for improving the understanding of cancer cachexia mechanisms. Both, exosomal miRNAs and myomiRs participate directly and/or indirectly in muscle mass wasting, accentuating protein degradation pathways and inhibiting myogenesis. Of particular interest, are exosomal-transported miRNAs as they seem to be markedly involved in the development and perpetuation of inflammatory status in cancer cachexia.
The role of exosomes in cancer cachexia is thus of great interest, as these nanovesicles have the capacity to facilitate communication among several tissues in a paracrine and endocrine manner, by carrying proteins and miRNAs. As cachexia is a syndrome with systemic effects in which tissue cross talk is prominent, these particles pose as likely candidates to intermediate the changes, and therefore, improved characterization and knowledge about the biogenesis and functions of exosomes and exosomal miRNAs, may promote the use of these extracellular vesicles as follows: (1) biomarkers, in the quest for faster and more accurate diagnosis, or for monitoring the evolution of the disease and (2) in the development of more specific antitumor drugs, which could diminish the release of inflammatory factors and/or factors associated with muscle mass wasting in cachexia.
All the authors contributed equally to this work. All the authors have read and approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This study was supported by Foundation for Research Support of São Paulo—FAPESP (Grant 2012/50079-0; 2016/19639-0).
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Keywords: exosomes, microRNAs, cachexia, cancer cachexia, inflammation, muscle wasting
Citation: Marinho R, Alcântara PSM, Ottoch JP and Seelaender M (2018) Role of Exosomal MicroRNAs and myomiRs in the Development of Cancer Cachexia-Associated Muscle Wasting. Front. Nutr. 4:69. doi: 10.3389/fnut.2017.00069
Received: 27 September 2017; Accepted: 18 December 2017;
Marc Poirot, Institut National de la Santé et de la Recherche Médicale, France
Sharon Ross, National Cancer Institute (NIH), United States
Luigi Iuliano, Sapienza Università di Roma, Italy
Copyright: © 2018 Marinho, Alcântara, Ottoch and Seelaender. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Marilia Seelaender, seelaend@icb.usp.br
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